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Aim: Clinical features of esophageal cancer (EC) patients have poor prognostic power. Thus, it is paramount to discover biomarkers that can allow a more accurate survival prediction. Methods: To detect genetic variants associated with survival, DNA from 120 patients treated with cisplatin-based neoadjuvant therapy were genotyped using drug metabolism enzymes and transporters array. Results: We identified two variants: the rs2038067 in PPARD (p = 0.0004) and the rs683369 (F160L) in SLC22A1 (p = 0.001). Their prognostic power was greater than that of clinical stage alone (p = 0.017) and comparable to that of response to neoadjuvant therapy (p = 0.71). Interestingly, the prognostic accuracy of response models increased significantly when genetic variables were included (p = 0.003). Conclusion: Our data, though preliminary, strengthen the potential utility of germline variants for a better-tailored management of EC patients.

Cirrhosis is a risk factor with nonhepatic surgery, but only three series regarding esophagectomy are reported. The Model for End-Stage Liver Disease (MELD) score has shown benefit in risk evaluation, but there is no experience regarding esophagectomy. This study aimed to compare the outcomes of surgery for esophageal cancer between cirrhotic and noncirrhotic patients and to evaluate whether the MELD score has a prognostic value for risk stratification. From the authors’ esophageal cancer database, they selected all the patients with concomitant cirrhosis who underwent surgery with curative intent and a matched cohort of patients without cirrhosis. The preoperative data included demographics, medical history, blood work, American Society of Anesthesiologists (ASA) score, Child-Turcotte-Pugh (CTP) score, and MELD score. The operative data included type of surgery, radicality, operative time, and blood loss. The postoperative data included hemoderivatives, 90-day morbidity and mortality rates, lab works, and hospital length of stay. The cirrhotic patients were further divided and analyzed according to a MELD score cutoff of 9. Of 3445 esophageal cancer patients, 73 cirrhotic patients underwent surgery. Their 90-day morbidity and mortality rates were higher than those for 146 noncirrhotic patients. The cirrhotic patients also had more respiratory events (p = 0.013) and infections (p = 0.005). The anastomotic complications among the cirrhotic patients were significantly more severe (p = 0.046). No difference in 5-year survival rates was registered. Stratification according to the MELD score showed that patients with a MELD score higher than 9 had a significantly worse postoperative course (5-year survival: p = 0.004). The patients with a MELD score of 9 or lower showed an outcome similar to that of the noncirrhotic patients. Liver cirrhosis is not an absolute contraindication to esophagectomy. The MELD score can be applicable for esophagectomy risk assessment for cirrhotic patients.

Verrucous carcinoma of the esophagus (VCE) is a rare variant of squamous cell cancer, with a puzzling clinical, etiological, and molecular profile. The etiological involvement of human papillomavirus (HPV) in the cancer's natural history is controversial. This study considers 9 cases of VCE, focusing on patients' clinical history before surgery, histologic phenotype, immunophenotype (epidermal growth factor receptor [EGFR], E-cadherin, cyclin D1, p16, and p53 expression), HPV infection, and TP53 gene mutational status (exons 5-8). Using 3 different molecular test methods, not one of these cases of VCE featured HPV infection. The only case with synchronous nodal metastasis was characterized by a TP53 missense point mutation in association with high EGFR and low E-cadherin expression levels. In conclusion, HPV infection is probably not involved with VCE, while TP53 gene mutation, EGFR overexpression, and E-cadherin loss might fuel the tumor's proliferation and lend it a metastatic potential.

Background: Prophylactic cholecystectomy has been proposed as a concomitant procedure during upper gastrointestinal surgery. This study evaluates the safety and the need of concurrent chole...

The association between shorter time to diagnosis and favorable outcome is still unproven in esophageal cancer. This study aims to evaluate the effect of time to diagnosis on patient prognosis. Retrospective cohort study of all 3613 symptomatic patients referred for esophageal cancer to our center from 1980 to 2011. Time to diagnosis was calculated as the number of days from first symptom onset to the diagnosis of esophageal cancer. The main outcome measures were: resectability and severe malnutrition at diagnosis; postoperative morbidity, mortality and survival. Longer time to diagnosis was significantly associated with severe malnutrition at diagnosis (odds ratio (OR): 1.003, 95% confidence interval (C.I.).: 1.001–1.006) but not with resectability (OR: 0.997, 95% C.I.: 0.994–1.001). Longer time to diagnosis was not associated with postoperative morbidity (OR: 1.000, 95% C.I.: 0.998–1.003), postoperative mortality (OR: 1.002, 95% C.I.: 0.998–1.006), five-year overall survival (hazard ratio (HR): 0.999, 95% C.I.: 0.997–1.001) or five-year disease free survival (HR: 0.999, 95% C.I.: 0.998–1.001). Longer time to diagnosis did not affect resectability, postoperative morbidity or survival. Further campaigns to raise awareness of cancer among population and primary health care providers may have limited effect on clinical outcome.

"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.. . " 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. © 2011 Cancer Research UK All rights reserved.

Few studies have examined optimal treatment specifically for cervical esophageal carcinoma. This study evaluated the outcome of three common treatment strategies with a focus on the debated role of surgery. All patients with cervical esophageal cancer treated at a single center were identified and their outcomes analyzed in terms of morbidity, mortality, and recurrence according to the treatment they received, i.e. surgery alone, definitive platinum-based chemoradiation (CRT), or CRT followed by surgery. The study population included 148 patients with cervical esophageal cancer from a prospective database of 3445 patients. Primary surgery was the treatment of choice for 56 (37.83%) patients, definitive CRT was the treatment of choice for 52 (35.13%) patients, and CRT followed by surgery was the treatment of choice for 40 (27.02%) patients. CRT-treated patients obtained 36.96% complete clinical response, with overall morbidity and mortality rates of 36.95 and 2.17%, respectively. Surgical complete resection was achieved in 71.88% of surgically treated cases, with morbidity and mortality rates of 52.17 and 6.25%, respectively. No significant survival difference existed among the three treatments, but patients who underwent surgery alone had a significantly lower stage of disease (p = 0.031). Compared with patients with complete response after CRT, surgery did not confer any significant survival benefit, and overall 5-year survival was lower than definitive CRT alone. In contrast, surgery improved survival significantly in patients with non-complete response after definitive CRT (p = 0.023). Definitive platinum-based CRT should be the treatment of choice for cervical esophageal cancer. Surgery has a role for patients with non-complete response as it adds significant survival benefit, with acceptable morbidity and mortality.

Background Nodal skip metastasis is a prognostic factor in some sites of malignancies, but its role in esophageal cancer is still unclear. The present study aimed to investigate occurrence and effect of nodal skip metastases in thoracic esophageal squamous cell carcinoma. Methods All 578 patients undergoing esophagectomy for thoracic esophageal squamous cell carcinoma at the Center for Esophageal Diseases located in Padova between January 1992 and December 2010 were retrospectively evaluated. Selection criteria were R0 resection, pathological M0 stage and pathological lymph node involvement. Patients receiving neoadjuvant therapy were excluded. Results The selection identified 88 patients with lymph node involvement confirmed by pathological evaluation. Sixteen patients (18.2%) had nodal skip metastasis. Adjusting for the number of lymph node metastases, patient with nodal skip metastasis had similar 5-year overall survival (14% vs. 13%, p = 0.93) and 5-year disease free survival (14% vs. 9%, p = 0.48) compared to patients with both peritumoral and distant lymph node metastases. The risk difference of nodal skip metastasis was: −24.1% (95% C.I. -43.1% to −5.2%) in patients with more than one lymph node metastasis compared to those with one lymph node metastasis; −2.3% (95% C.I. -29.8% to 25.2%) in middle thoracic esophagus and −23.0% (95% C.I. -47.8% to 1.8%) in lower thoracic esophagus compared to upper thoracic esophagus; 18.1% (95% C.I. 3.2% to 33.0%) in clinical N0 stage vs. clinical N+ stage. Conclusions Nodal skip metastasis is a common pattern of metastatic lymph involvement in thoracic esophageal squamous cell carcinoma. However, neither overall survival nor disease free survival are associated with nodal skip metastasis occurrence.

Goal To evaluate the potential role of the determination of the immunocomplexed form of squamous cell carcinoma antigen [SCCA-immunoglobulin (Ig)M] for the screening of Barrett esophagus (BE) and esophageal adenocarcinoma (EAC). Background The cost-effectiveness of surveillance in BE is still debated and the use of biomarkers in screening and surveillance still not recommended. No information is available regarding SCCA-IgM determination in BE. Study SCCA-IgM levels were determined (enzyme-linked immunosorbent assay) in 231 patients prospectively recruited, 71 with BE, 53 with EAC, and 107 controls, including 42 blood donors and 65 patients with gastroesophageal reflux. SCCA-IgM cutoffs between BE/EAC and controls and for BE "at risk" versus short nondysplastic BE were calculated by receiver operating characteristic curves. Immunostaining for SCCA-IgM was obtained in a subgroup of patients. Results Median SCCA-IgM values were significantly higher in BE and EAC than in controls (P=0.0001). Patients with SCCA-IgM levels above the cutoff had a 33 times higher relative risk of harboring BE or EAC (P=0.0001). Patients "at risk," with long or dysplastic BE had SCCA-IgM levels significantly higher than those with short nondysplastic BE (P=0.035) and patients with SCCA-IgM above the cutoff had a 8 times higher relative risk of having BE "at risk." SCCA was expressed in Barrett mucosa but not in cardiac metaplasia. Conclusions Serum SCCA-IgM determination allows the identification of patients at risk for BE/EAC and the stratification of BE patients in subgroups with different cancer risk. Because of the still limited number of controls, large, prospective studies are required to confirm this evidence.

Objective The aim of this study was to investigate trends in patients' characteristics and comorbidities in esophageal cancer (EC) patients. Background Identifying changing pattern is essential to understand and predict further changes and to plan surgical procedures and resource allocation. Methods Trends in patients' characteristics and comorbidities were evaluated in 4440 EC patients at the Center for Esophageal Diseases in Padova, Italy, during 1980 to 2011. Joinpoint regression analysis was performed to evaluate trends and to estimate annual percentage changes (APCs). Results During the study period, there has been a statistically significant increment of the rate of esophageal adenocarcinoma (APC 3.70). The rates of elderly and of asymptomatic patients increased over time (APCs 0.98 and 6.24), whereas the rates of malnutrition, alcoholic drinking, and gastric ulcer decreased (APCs -1.50, -1.72, and -5.20). Reflux rate increased until 1997 and decreased thereafter (APCs 6.96 and -4.48), whereas the rate of Barrett esophagus increased until 1992 (APC 35.84) and then leveled. The rates of patients with previous neoplasms increased over time (APCs 3.22 and 4.86). There have been significant changes in systemic comorbidities, with an increase of hypertension and cardiac disease (APCs 7.56 and 1.86) and a decrease of advanced liver disease and pulmonary disease (APCs -2.67 and -1.74). Conclusion The current EC patient has more often an esophageal adenocarcinoma and is more frequently elderly, asymptomatic, a survivor of previous neoplasms, and a patient with hypertension and cardiac disease than 30 years ago. On the contrary, malnutrition, alcoholic drinking, gastric ulcer, pulmonary disease, and advanced liver disease decreased.

The aims of the study were (a) to examine the final outcome in patients experiencing accidental mucosal perforation during laparoscopic Heller myotomy with Dor fundoplication (LHD) and (b) to evaluate whether perforation episodes might influence the way in which surgeons subsequently approached the LHD procedure. We studied all consecutive patients that underwent LHD between 1992 and 2015. Patients were divided into two main groups: those who experienced an intraoperative mucosal perforation (group P) and those whose LHD was uneventful (group NP). Two additional groups were compared: group A, which consisted of patients operated by a given surgeon immediately before a perforation episode occurred, and group B, which included those operated immediately afterwards. Eight hundred seventy-five patients underwent LHD; a mucosal perforation was detected in 25 patients (2.9 %), which was found unrelated to patients’ symptom’s score and age, radiological stage, manometric pattern, or the surgeon’s experience. The median postoperative symptom score was similar for the two groups as the failure rate: 92 failures in group NP (10.8 %) and 4 in group P (16 %) (p = 0.34); moreover, symptoms recurred in 2 patients of group A (10 %) and 3 patients of group B (15 %) (p = 0.9). Accidental perforation during LHD is infrequent and impossible to predict on the grounds of preoperative therapy or the surgeon’s personal experience. Despite a longer surgical procedure and hospital stay, the outcome of LHD is much the same as for patients undergoing uneventful myotomy. A recent mucosal perforation does not influence the surgeon’s subsequent performance.

Esophageal achalasia can be classified on the grounds of three distinct manometric patterns that correlate well with final outcome after laparoscopic Heller-Dor myotomy (LHM). No analytical data are available, however, on the postoperative picture and its possible correlation with final outcome. The aims of this study were: (a) to investigate whether manometric patterns change after LHM for achalasia; (b) to ascertain whether postoperative patterns and/or changes can predict final outcome; and (c) to test the hypothesis that the three known patterns represent different stages in the evolution of the disease. During the study period, we prospectively enlisted 206 consecutive achalasia patients who were assessed using high-resolution manometry (HRM) before undergoing LHM. Symptoms were scored using a detailed questionnaire. Barium swallow, endoscopy and HRM were performed, before and again 6 months after surgery. Preoperative HRM revealed the three known patterns with statistically different esophageal diameters (pattern I having the largest), and patients with pattern I had the highest symptom scores. The surgical treatment failed in 10 cases (4.9%). The only predictor of final outcome was the preoperative manometric pattern (p = 0.01). All patients with pattern I preoperatively had the same pattern afterward, whereas nearly 50% of patients with pattern III before LHM had patterns I or II after surgery. There were no cases showing the opposite trend. Neither a change of manometric pattern after surgery nor a patient’s postoperative pattern was a predictor of final outcome, whereas preoperative pattern confirmed its prognostic significance. The three manometric patterns distinguishable in achalasia may represent different stages in the disease’s evolution, pattern III and pattern I coinciding with the early and final stages of the disease, respectively.

Objective: Oesophageal carcinoma is a well-known late complication of caustic ingestion, occurring in up to 7% of cases. We report a large series of patients with oesophageal scar cancer (SC), investigating the association between fibrosis and survival. Methods: A total of 25 patients with a history of oesophageal SC (1979—2005) were retrospectively studied. The amount of intra- and peri-tumoral fibrotic tissue was measured with Azan—Mallory staining. A control group of patients with non-SC was used for comparison. Results: Twenty-five patients (16 males:9 females, median age 59 years), presented with SC. The histotype was squamous cell carcinoma (SCC) in 20 (80%) patients, adenocarcinoma (AC) in three (12%) and verrucous carcinoma in two (8%). Oesophageal resection was performed in 17 of 25 (68%) patients; in eight (32%), only a palliative treatment (endoscopic/surgical) was possible. Mortality and morbidity rates were 4% and 40%, respectively. One-, 3- and 5-year overall actuarial survivalratesforSCpatientswere72%,56%and52%,respectively.Theamountoffibrotictissuearound/withinthetumourwassignificantly higher in SC patients (34.5% vs5.9% non-SC,p = 0.01);these patients hadalso a higher prevalenceof tumours limitedto the muscularwall (pT1—T2)(76% vs 28% non-SC, p < 0.0001) and less lymph node metastases in T1—T2 cases (8% vs 34% non-SC, p = 0.07). The 5-year survival was significantly better in SC patients: 71% versus 24% for resected cancers (p < 0.0001), and 52% versus 15% for all observed patients (p = 0.0001). Conclusions: The presence offibrotictissue around/within the tumour is associated with a better prognosis in SC. Fibrosis might offer a protection against both local spread and nodal dissemination. # 2010 European Association for Cardio-Thoracic Surgery. Published by Elsevier B.V. All rights reserved.

Achalasia is a rare esophageal motility disorder, incurable but amenable to palliative treatments to relieve dysphagia. Given the rarity of the disease, there is a paucity of data from population-based studies on incidence and outcome of the two treatments most commonly used in clinical practice, i.e., endoscopic pneumatic dilation (PD) and surgical myotomy (SM).A retrospective longitudinal study was conducted on the Veneto region, in north-eastern Italy. All patients with achalasia as their primary diagnosis between 2001 and 2005 were identified and their demographics and treatment details obtained.The overall incidence of achalasia was 1.59 cases/100,000/year. Achalasia patients were mainly seen at University Hospitals. Fifty-five percent of the patients received treatment, 23.3% SM and 31.8% PD. The cumulative risk of any subsequent intervention for achalasia was 20% in treated patients (29.7% in patients treated primarily with PD and 4% in patients treated with SM first).The epidemiology of achalasia in the Veneto Region is in line with the situation reported elsewhere and did not change between 2001 and 2005. Achalasia patients are mostly seen at University Hospitals. We observed a greater risk of subsequent intervention for patients previously treated with PD compared with SM.

Laparoscopic myotomy is the currently preferred treatment for achalasia. Our objectives were to assess the long-term outcome of this operation and preoperative factors influencing said outcome.Demographic and clinical characteristics and data on long-term outcome were prospectively collected on patients undergoing laparoscopic myotomy for achalasia at our institution from 1992 to 2007. Treatment failure was defined as a postoperative symptom score higher than the 10th percentile of the preoperative score (9). Logistic regression analysis was used to identify independent preoperative factors associated with successful myotomy.Four hundred seven consecutive patients (220 men, 187 women) underwent the laparoscopic Heller-Dor procedure during the study period; 89 (22%) of them had previously had endoscopic treatment(s). The mortality rate was 0; the conversion and morbidity rates were 1.5% and 1.9%, respectively. The operation failed in 10% of patients (39/407) and the 5-year actuarial probability of being asymptomatic was 87%. Most failures (25/39, 64%) occurred within 12 months of the operation and can be considered as technical failures (incomplete myotomy). Pneumatic dilation overcome the dysphagia in 75% of patients whose surgery was unsuccessful. Considering both the primary surgery and this ancillary treatment, the operation was effective in 97% of achalasia patients. The frequency of sigmoid esophagus, lower esophageal sphincter (LES) resting pressures, and chest pain scores differed statistically between patients with and without recurrences. At multivariate analysis, high preoperative LES pressures (30 mm Hg) was an independent predictor of a good response. The presence of chest pain and of sigmoid esophagus independently predicted the failure of the procedure.Laparoscopic myotomy can durably relieve dysphagia symptoms. High preoperative LES pressures represent the strongest predictor of a positive outcome, probably reflecting a less severely damaged esophageal muscle.

OBJECTIVE:: The aim of this study was to determine whether the risk of systemic disease after esophagectomy can be predicted by the number of involved lymph nodes. SUMMARY BACKGROUND DATA:: Primary esophagectomy is curative in some but not all patients with esophageal cancer. Identification of patients at high risk for systemic disease would allow selective use of additional systemic therapy. This study is a multinational, retrospective review of patients treated with resection alone to assess the impact of the number of involved lymph nodes on the probability of systemic disease. METHODS:: The study population included 1053 patients with esophageal cancer (700 adenocarcinoma, 353 squamous carcinoma) who underwent R0 esophagectomy with >/=15 lymph nodes resected at 9 international centers: Asia (1), Europe (5), and United States (3). To ensure a minimum potential follow-up of 5 years, only patients who had esophagectomy before October 2002 were included. Patients treated with neoadjuvant or adjuvant therapy were excluded. The impact of the number of involved lymph nodes on the risk of systemic disease recurrence was assessed using univariate and multivariate analyses. RESULTS:: Systemic disease occurred in 40%. The number of involved lymph nodes ranged from 0 to 26 with 55% of patients having at least 1 involved lymph node. The frequency of systemic disease after esophagectomy was 16% for those without nodal involvement and progressively increased to 93% in patients with 8 or more involved lymph nodes. CONCLUSIONS:: This study shows that the number of involved lymph nodes can be used to predict the likelihood of systemic disease in patients with esophageal cancer. The probability of systemic disease exceeds 50% when 3 or more nodes are involved and approaches 100% when the number of involved nodes is 8 or more. Additional therapy is warranted in these patients with a high probability of systemic disease

The use of cytoreductive therapy followed by surgery is preferred by many centers dealing with locally advanced esophageal cancer. However, the potential for increase in mortality and morbidity rates has raised concerns on the use of chemoradiation therapy, especially in elderly patients. The aim of this study was to assess the effects of induction therapy on postoperative mortality and morbidity in elderly patients undergoing esophagectomy for locally advanced esophageal cancer at a single institution.Postoperative mortality and morbidity of patientsor = 70 years old undergoing esophagectomy after neoadjuvant therapy, between January 1992 and October 2005 for cancer of the esophagus or esophagogastric junction, were compared with findings in younger patients also receiving preoperative cytoreductive treatments.818 patients underwent esophagectomy during the study period. The study population included 238 patients70 years and 31or = 70 years old undergoing esophageal resection after neoadjuvant treatment. Despite a significant difference in comorbidities (pulmonary, cardiological and vascular), postoperative mortality and morbidity were similar irrespective of age.Elderly patients receiving neoadjuvant therapies for cancer of the esophagus or esophagogastric junction do not have a significantly increased prevalence of mortality and major postoperative complications, although cardiovascular complications are more likely to occur. Advanced age should no longer be considered a contraindication to preoperative chemoradiation therapy preceding esophageal resection in carefully selected fit patients.

Breast metastases of mucosal/submucosal layers of the esophagus are extremely rare: esophageal involvement is usually part of a mediastinal carcinosis.We report the largest series to date of 25 cases of metastatic esophageal involvement from breast cancer, discussing both diagnostic techniques and treatment options.Twenty-five female patients with a history of breast cancer referred for secondary esophageal involvement (1980-2006) were studied.All patients presented with worsening dysphagia. Twenty-four had undergone surgery for breast cancer a median of 10 years earlier: 1 had received chemoradiotherapy, and 17 had adjuvant radiotherapy/telecobalt therapy following breast surgery. Endoscopic biopsy/cytology were negative for cancer in 17 of 19 patients; in 9 patients, the diagnosis was made with thoracoscopy/laparoscopy. Immunohistochemical staining was done in 10 patients (ER and/or PrR positive). Fifteen patients presented with distant metastatic involvement. Therapy was directed toward dysphagia relief, mostly with endoscopic dilations/prostheses. Complications (4 perforations) occurred only in those 15 patients who had endoscopic dilations/prostheses. Fifteen patients had cytoreductive therapy. Nine of 25 patients are still alive. The median overall survival was 7 months; 1-, 3-, and 5-year survival rates were 44%, 16%, and 8%, respectively.A "breast-esophagus" syndrome can be defined: it is often diagnosed only after excluding other diseases or after relief of dysphagia with adequate therapy. The presence of distant metastases helps the diagnosis of esophageal involvement from mediastinal carcinosis, while diagnosis is a problem in case of mediastinal/pleural disease only: in this case, exploratory thoracoscopy is mandatory for a final diagnosis. Given the high related risk of perforation from endoscopic procedures (dilations/prostheses), the treatments of choice are currently hormone therapy or chemotherapy/radiotherapy.

Most papers report excellent results of laparoscopic fundoplication but with relatively short follow-up. Only few studies have a follow-up longer than 5 years. We prospectively collected data of 399 consecutive patients with gastroesophageal reflux disease (GERD) or large paraesophageal/mixed hiatal hernia who underwent laparoscopic fundoplication between January 1992 and June 2005. Preoperative workup included symptoms questionnaire, videoesophagogram, upper endoscopy, manometry, and pH-metry. Postoperative clinical/functional studies were performed at 1, 6, 12 months, and thereafter every other year. Patients were divided into four groups: GERD with nonerosive esophagitis, erosive esophagitis, Barrett's esophagus, and large paraesophageal/mixed hiatal hernia. Surgical failures were considered as follows: (1) recurrence of GERD symptoms or abnormal 24-h pH monitoring; (2) recurrence of endoscopic esophagitis; (3) recurrence of hiatal hernia/slipped fundoplication on endoscopy/barium swallow; (4) postoperative onset of dysphagia; (5) postoperative onset of gas bloating. One hundred and forty-five patients (87 M:58 F) were operated between January 1992 and June 1999: 80 nonerosive esophagitis, 29 erosive esophagitis, 17 Barrett's esophagus, and 19 large paraesophageal/mixed hiatal hernias. At a median follow-up of 97 months, the success rate was 74% for surgery only and 86% for primary surgery and 'complementary' treatments (21 patients: 13 redo surgery and eight endoscopic dilations). Dysphagia and recurrence of reflux were the most frequent causes of failure for nonerosive esophagitis patients; recurrence of hernia was prevalent among patients with large paraesophageal/mixed hiatal hernia. Gas bloating (causing failure) was reported by nonerosive esophagitis patients only. At last follow-up, 115 patients were off 'proton-pump inhibitors'; 30 were still on medications (eight for causes unrelated to GERD). Conclusion confirms that laparoscopic fundoplication provides effective, long-term treatment of gastroesophageal reflux disease. Hernia recurrence and dysphagia are its weak points.

Prognosis and treatment of esophagus and cardia cancer (ECC) depend on the precision with which the disease is staged according to the American Joint Committee of Cancer (AJCC) criteria. Imaging modalities normally used in clinical staging are esophagography, esophagoscopy, endoscopic ultrasound (EUS), computed tomography (CT) and positron emission tomography- CT fusion (CT-PET). The combination of these methods is crucial in determining not only the right diagnosis but also the stage and follow-up after multimodal treatment. The purpose of our investigation was to define the role of each imaging modality in determining the most appropriate treatment options in patients with ECC. Fifty-six patients with ECC diagnosed by X-ray of the upper digestive tract, endoscopy and biopsy were staged using EUS, chest and abdomen CT scan, and CT-PET. Thirty-four patients in stage II and 18 patients in stage III underwent surgery after neoadjuvant chemotherapy; four patients in stage IV were treated with the positioning of an endoprosthesis after chemoradiotherapy. In the 52 patients who had surgery, follow-up included digestive tract X-ray, endoscopy and CT of the chest and abdomen every 6–8 months for the first 3 years. CT-PET was only performed in patients with a clinical suspicion of recurrence and/or CT findings suspicious of persistent disease (12 cases). In all 56 patients, endoscopy, EUS, CT and CT-PET in combination were crucial in determining the site of disease, locoregional extent and depth of esophageal wall penetration (T), and any involvement of the mediastinal lymph nodes (N1), extrathoracic lymph nodes (M1) or hepatic metastases. In the locoregional staging of ECC before chemotherapy, we were able to differentiate T2–T3 from T4 in 40 patients; T4 disease was found in 12 potentially resectable cases. We were able to distinguish N0 from N1 in 12 patients. In four cases, the presence of small lymph node and/or liver metastases prompted positioning of an endoprosthesis. The specificity of CT in detecting small lymph nodes in the mediastinum was less than 50% while for CT-PET, it was more than 80%; EUS revealed sensitivity higher than 90% but a low specificity in seven cases. Only CT-PET revealed metastatic subdiaphragmatic lymph nodes (diameter

Background: The treatment of esophageal achalasia is still controversial: current therapies are palliative and aim to relieve dysphagia by disrupting or relaxing the lower esophageal sphincter muscle fibers with botulinum toxin. The aim of this study was to compare the clinical and economic results of two such treatments: laparoscopic myotomy and botulinum toxin injection. Methods: A total of 37 patients with esophageal achalasia were randomly assigned to receive laparoscopic myotomy (20) or two Botox injections 1 month apart (17). All patients were treated at the same hospital and were part of a larger multicenter study. Symptom score, lower esophageal sphincter pressure, and esophageal diameter at barium swallow were compared. The economic analysis was performed considering only the direct costs (cost per treatment and cost effectiveness, i.e., cost per patient healed). Results: Mortality and morbidity were nil in both groups. The actuarial probability of being asymptomatic at 2 years was 90% for surgery and 34% for Botox (p < 0.05). The initial cost was lower for Botox (€1,245) than for surgery (€3,555), but when cost effectiveness at 2 years was considered, this difference nearly disappeared: Botox €3,364, surgery €3,950. Conclusion: Botox is still the least costly treatment, but the minimal difference in the longer term does not justify its use, given that surgery is a risk-free, definitive treatment.

An open prospective study was carried out in 82 consecutive patients undergoing resective surgery for esophageal cancer from January 1995 to July 1996. Antimicrobial prophylaxis was done using a single dose of ceftriaxone (2 g i.v.) given at the induction of anesthesia in combination with metronidazole (0.5 g i.v.). Two further doses of metronidazole were administered 8 and 16 hours postoperatively. Fourteen patients (17%) experienced postoperative infections. This study, even though open and non-comparative, confirms that ceftriaxone given as a single-dose plus metronidazole provides adequate prophylaxis and significant cost-savings in comparison with multiple-dose prophylactic regimens in patients undergoing major surgery for esophageal cancer. Furthermore, the single-dose regimen reduces the workload for the nursing staff, the risk of side effects, and the possibility of selecting resistant strains.

Background The aims of this study were to evaluate the prevalence of invasive cancer in patients with high-grade dysplasia in Barrett's oesophagus and to verify whether a second endoscopy with multiple biopsies could improve the accuracy of preoperative diagnosis. In addition, the mortality, morbidity and survival rates in patients with high-grade dysplasia having oesophageal resection were recorded. Methods Fifteen patients were observed from 1982 to 1998; the first seven patients were offered primary oesophageal resection after diagnosis. The other eight patients underwent a second endoscopy with a median of 12 biopsies examined. All later underwent oesophageal resection. Results Invasive adenocarcinoma was found in five patients, with a minimal difference between the first and second periods (two of seven versus three of eight). There were no perioperative deaths. Early morbidity was observed in eight patients and late morbidity in four. The actuarial survival rate was 79 per cent at 5 years. The Karnofsky status was unchanged from preoperative values in 13 of 15 patients after a median follow-up of 46 months. Conclusion These patients with high-grade dysplasia had a 33 per cent probability of harbouring invasive oesophageal carcinoma but even a second endoscopy failed to identify patients with invasive tumour. Oesophagectomy was performed with no deaths and remains a rational treatment in patients fit for surgery.

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. (J Thorac Cardiovasc Surg 2000;119:453-7)

OBJECTIVE: The objective of this prospective, nonrandomized study was to evaluate the immediate and long-term results of first-line chemotherapy and possible surgery in locally advanced, presumably T4 squamous cell esophageal cancer. SUMMARY BACKGROUND DATA: Locally advanced esophageal cancer is rarely operable and has a dismal prognosis. For this reason, neoadjuvant cytoreductive treatments are more and more frequently used with the aim of downstaging the tumor, increasing the resection rate, and possibly improving survival. Methods: From January 1983 to December 1991, 163 consecutive patients with a presumedly T4 squamous cell carcinoma of the thoracic esophagus (group A) received on average 2.5 cycles (range, 1-6) of first-line chemotherapy with cisplatin (100 mg/m2 on day 1) and 5-fluorouracil (1000 mg/m2 per day, in continuous infusion from day 1 through day 5). Chemotherapy was followed by surgery when adequate downstaging of the tumor was obtained. RESULTS: Chemotherapy toxicity was WHO grade 0 to 2 in 80% of cases, but 3 toxic deaths (1.9%) occurred. Restaging suggested a downstaging of the tumor in 101 of 163 patients (62%), but only 85 patients (52%) underwent resection surgery; it was complete or R0 in 52 (32%) and incomplete or R1-2 in 33. Overall postoperative mortality was 11.7% (10 of 85), morbidity 41% (35 of 85). Complete pathologic response was documented in 6 patients, and significant downstaging to pStage I, IIA, or IIB occurred in 25 more patients. The overall 5-year survival was 11 % (median, 11 months). After resection surgery, the 5-year survival was 20% (median, 16 months); none of the nonresponders survived 4 years after palliative treatments without resection (median survival, 5 months). The 5-year survival rate of the 52 patients undergoing an R0 resection was 29% (median, 23 months). Stratifying patients according to the R, pT, pN, and pStage classifications, the survival curves were comparable to the corresponding data obtained in the 587 group B patients with "potentially resectable" esophageal cancer who underwent surgery alone during the same period. Furthermore, the results were improved in comparison with 136 previous or subsequent patients with a locally advanced tumor who did not undergo neoadjuvant treatments (group C). In these patients, the R0 resection rate was 7%, and the overall 5-year survival was 3% (median, 5 months). CONCLUSION: Although nonrandomized, these results suggest that in locally advanced esophageal carcinoma, first-line chemotherapy increases the resection rate and improves the overall long-term survival. In responding patients who undergo R0 resection surgery, the prognosis depends on the final pathologic stage and not on the initial pretreatment stage.

Aims: An inverse correlation between bcl-2 and p53 expression has been reported in several types of epithelial tumour. The role of bcl-2 and p53 in the development of oesophageal squamous carcinoma has yet to be established. The expression of bcl-2 and p53 proteins has been evaluated in the multistage oesophageal tumorigenesis, which progresses from normal mucosa to dysplasia (squamous intraepithelial lesion, SIL), to invasive early and advanced oesophageal squamous cancer. Methods and results: Sixty-four cases of squamous oesophageal cancer, coexisting with SIL in 18 cases, were immunohistochemically analysed for any overexpression of bcl-2 and p53 proteins. Any association of bcl-2 and p53 protein expression with patient survival was also analysed. We observed bcl-2 expression that decreased significantly during the progression of oesophageal carcinogenesis. A decreasing frequency in the expression of bcl-2 in advanced oesophageal squamous cancer coincided with frequent p53 overexpression. bcl-2 expression was correlated with patient survival by univariate analysis. The association disappeared after adjusting for tumour stage. p53 overexpression showed no association with patient survival by either univariate or multivariate analysis. Conclusions: The down-regulation of bcl-2 and up-regulation of p53 in advanced oesophageal squamous cancer suggest that bcl-2 and p53 proteins may interact in the progression of oesophageal squamous cancer.

At present, no consensus exists on the beneficial effect of preoperative cisplatin/5-fluorouracil (5-FU)-based chemotherapy versus primary surgery in the management of patients with esophageal cancer. The aim of this study was to evaluate the impact of some relevant genetic polymorphisms, within drug-related and DNA repair genes, on the clinical outcome of esophageal cancer patients subjected to cisplatin/5-FU-based neoadjuvant treatment.DNA from 143 esophageal cancer patients, 63 receiving neoadjuvant therapy and 80 receiving primary surgery, was analyzed for the following polymorphisms: the GSTM1 null, GSTT1 null, and GSTP1 Ile105Val (rs16953) in glutathione S-transferase (GST) family, 2 in thymidylate synthase (TS) gene, and the ERCC1 Asn118Asn (rs11615), ERCC1 C8092A (rs3212986), XPD/ERCC2 Asp312Asn (rs1799793), and XPD/ERCC2 Lys751Gln (rs13181) of the nucleotide excision repair pathway.We found that the ERCC1 rs3212986, although not associated with therapeutic response, is an independent predictive marker of better outcome in a cisplatin/5-FU-based neoadjuvant setting (hazard ratio: 0.38, 95% confidence interval: 0.2-0.73, P=0.008). In contrast, no association with clinical outcome was observed for this polymorphism in the primary surgery group.Our study indicates the ERCC1 rs3212986 as a predictive marker in the cisplatin/5-FU-based neoadjuvant setting, and also suggests its use as a marker to select the appropriate therapeutic approach in esophageal cancer patients.

Neoadjuvant chemoradiotherapy (CT-RT) before oesophagectomy is standard management for squamous cell carcinoma(SCC) of the thoracic oesophagus. The aim of this study was to compare the outcome of patients who had clinical complete response(CR) with neoadjuvant CT-RT + oesophagectomy with the survival of patients who had clinical CR and were not operated on.Seventy-seven consecutive patients with SCC of the thoracic oesophagus with CR with neoadjuvant CT-RT presenting at the Regional Center of Esophageal Diseases from 1992 to 2008 were included in this retrospective study on a prospectively collected database. Thirty-nine patients underwent oesophagectomy (CT-RT + oesophagectomy), while 38(CT-RT) were not operated on because they were considered unfit for surgery or refused the operation. Patients’ outcome and survival were compared.In the CT-RT + oesophagectomy group, clinical CR was confirmed after histological examination of the surgical specimen in 27/39 (69.2 %) patients. Five-year overall survival rates were 50.0 % in the CT-RT + oesophagectomy group and 57.0 % in the CT-RT group (p=0.99); 5-year disease-free survival rates were 55.5%in the CT-RT + oesophagectomy group and 34.6%in the CTRT group (p=0.15). Even after adjusting for propensity score, age, ASA and clinical stage, the treatment regimen did not show a statistically significant effect on overall survival (adjusted p=0.65) nor on disease-free survival (adjusted p=0.15).In our group of patients with clinical CR after neoadjuvant CT-RT for SCC of the thoracic oesophagus, waiting for recurrence and then using salvage surgery did not negatively impact their survival compared to patients treated with surgery. More accurate restaging protocols are warranted to improve decision making after CR with neoadjuvant CT-RT.

SUMMARY There is evidence that both cellular and humoral components of the immune response are required for viral clearance to occur in chronic hepatitis B. Recent studies demonstrated that CD30 molecule, a member of the tumour necrosis factor superfamily of membrane cytokine receptors, is expressed on, and released as a soluble molecule (sCD30) by activated T cells producing T helper 2 (Th2) cytokines, which modulate antibody responses. To better characterize the immunoregulatory mechanisms in chronic hepatitis B virus (HBV) infection, sCD30 values were evaluated by an ELISA in 90 hepatitis B surface (HBsAg)-positive patients with chronic hepatitis, selected on the basis of active viral replication and biochemical activity. At presentation abnormal levels (>20 U/ml) of sCD30 were detected in 57 (63%) out of 90 patients with chronic hepatitis B, and median value was significantly higher in this group of patients compared with that of healthy HBsAg carriers (26.7 versus 10.5 U/ml, P

Platinum-based neoadjuvant therapy is the standard treatment for esophageal cancer (EC). At present, no reliable response markers exist, and patient therapeutic outcome is variable and very often unpredictable. The aim of this study was to understand the contribution of host constitutive DNA polymorphisms in discriminating between responder and nonresponder patients. DNA collected from 120 EC patients treated with platinum-based neoadjuvant chemotherapy was analyzed using drug metabolism enzymes and transporters (DMET) array platform that interrogates polymorphisms in 225 genes of drug metabolism and disposition. Four gene variants of DNA repair machinery, 2 in ERCC1 (rs11615; rs3212986), and 2 in XPD (rs1799793; rs13181) were also studied. Association analysis was performed with pTest software and corrected by permutation test. Predictive models of response were created using the receiver-operating characteristics curve approach and adjusted by the bootstrap procedure. Sixteen single nucleotide polymorphisms (SNPs) of the DMET array resulted significantly associated with either good or poor response; no association was found for the 4 variants mapping in DNA repair genes. The predictive power of 5 DMET SNPs mapping in ABCC2 , ABCC3 , CYP2A6 , PPARG , and SLC7A8 genes was greater than that of clinical factors alone (area under the curve [AUC] = 0.74 vs 0.62). Interestingly, their combination with the clinical variables significantly increased the predictivity of the model (AUC = 0.78 vs 0.62, P = 0.0016). In conclusion, we identified a genetic signature of response to platinum-based neoadjuvant chemotherapy in EC patients. Our results also disclose the potential benefit of combining genetic and clinical variables for personalized EC management.

Esophageal adenocarcinoma is often associated with obesity, and a 5 Kg m(-2) increase in body mass index (BMI) has, in fact, been found to be strongly associated with the risk of this type of cancer (RR, 1.52; p 0.0001). Esophagectomy with lymphoadenectomy is the mainstay of therapy for these patients. The aim of this study was to assess and compare the surgical and oncological outcomes as well as the survival rates of underweight, normal weight, overweight, and obese patients following esophagectomy for esophageal cancer.Data relative to 1,127 patients with esophageal adenocarcinoma presenting at a specialized tertiary hospital (the Center of Esophageal Diseases for the Veneto Region) between 2000 and 2008 were prospectively collected. The 278 subjects whose BMI values before disease onset were available and underwent esophagectomy were enrolled in the study. Sixty-one of the 278 patients were classified as obese (BMI30), 121 were classified as overweight (BMI, 25-29.9), 81 were classified as normal weight (BMI24.9), and 15 ones as underweight (BMI20). The outcome and survival of the four groups were compared. Frequency and survival analyses were carried out.The rate of R0 esophagectomy and the incidence of toxicity during neoadjuvant chemotherapy were similar in the four groups. Respiratory complications after R0 esophagectomy seemed to be more frequent in the underweight and normal-weight patients group (p 0.01). Moreover, underweight patients had a significantly higher rate of septic, cardiovascular, and metabolic postoperative complications. The 121 overweight patients had a better overall survival rate compared to normal weight and obese patients (p = 0.05). This difference was not significant if patients were stratified in stages I or II or stages III or IV.Overweight patients seem to respond better to esophageal cancer and esophagectomy with respect to normal-weight ones. This data seem to suggest that in spite of several unfavorable features, a moderate increase of weight may be helpful to survive after esophagectomy for cancer.

Barrett's esophagus (BE) is the most serious complication of GERD. In BE patients, this observational study compares the effects of antireflux surgery versus antisecretory medical therapy.Overall, 89 BE patients (long BE = 45; short BE = 44) were considered: 45 patients underwent antireflux surgery and 44 underwent medical therapy. At both initial and follow-up endoscopy, symptoms were assessed using a detailed questionnaire; BE phenotypic changes [intestinal metaplasia (IM) presence/type, Cdx2 expression] were assessed by histology (HE), histochemistry (HID), and immunohistochemistry. Surgical failures were defined as follows: (1) abnormal 24-h pH monitoring results after surgery, (2) endoscopically evident recurrent esophagitis, and (3) recurrent hiatal hernia or slipped fundoplication on endoscopy or barium swallow.Reversion of IM was observed in 12/44 SSBE and 0/45 LSBE patients (p 0.01). Reversion was more frequently observed after effective antireflux surgery than after medical treatment (p = 0.04). In patients with no further evidence of IM after therapy, Cdx2 expression was also absent (p = 0.02). The extent of IM was reduced, and the IM phenotype improved in SSBE patients after surgery.Patients with short BE (but not those with long BE) may benefit from surgically reducing the esophagus' exposure to GE reflux; among these patients, successful surgery carries a higher IM reversion rate than medical treatment.

Hepatitis C virus is the most frequent cause of chronic non-A, non-B hepatitis, and the antibodies to structural and nonstructural proteins encoded by viral genome have been suggested to be markers of ongoing HCV infection. We studied the behavior of these antibodies during interferon therapy in 18 patients with chronic hepatitis C and also during a follow-up period of at least four years. A significant decrease of anti-HCV titer was found only in patients who had shown positive response to therapy and all of them were anti-HCV negative at the end of follow-up. Analysis by recombinant immunoblotting assay showed that only anti-c100 were affected by interferon therapy, whereas anti-c22 and anti-c33 were not modified. Using polymerase chain reaction to detect small amounts of HCV genome in serum, we could confirm that the behavior of HCV-RNA during and after interferon therapy is similar to that of anti-HCV and the loss of anti-c100 seems to be closely related to HCV-RNA disappearance from serum. Our patients with chronic hepatitis C were found to be of type 1b and 2, according to the recent score of Simmonds, and the clearance of serum HCV-RNA during treatment and its sustained negative status are closely related to genotype 2 and to long-term positive response to interferon.

Between 1992 and 1997 we conducted a case-control study of oesophageal cancer in 3 areas of northern Italy. Cases were 304 patients (29 women), ages 39-77 years (median age 60 years), with a first incident squamous-cell carcinoma (SCC) of the oesophagus, Controls were 743 patients (150 women), ages 35-77 years (median age 60 years), admitted for acute illnesses, unrelated to tobacco and alcohol, to major hospitals of the areas under surveillance. We derived estimates of daily dietary intake of 6 macronutrients, cholesterol, and 20 micronutrients or minerals from a validated food-frequency questionnaire, including 78 food groups and recipes and 15 questions on individual eating patterns. After allowance for age, gender, area of residence, education, body mass index, physical activity, smoking habit, alcohol consumption and energy intake, most micronutrients were inversely associated with oesophageal SCC risk. Highly significant associations emerged for monounsaturated fatty acids [odds ratio (OR) in highest vs. lowest intake quintile = 0.5]; carotene (OR = 0.3); lutein + zeaxanthin (OR = 0.4); vitamin C (OR = 0.4); and niacin (OR = 0,5). Only retinol appeared to be positively related to risk (OR = 1.9), The effect of the above nutrients, expressed as ORs, appeared to be similar in non-smokers and smokers, and non/light drinkers and heavy drinkers. (C) 2000 Wiley-Liss, Inc. RI Parpinel, Maria/B-1605-2012

Differences in human epithelial growth factor receptor 2 dysregulation in primary solid tumors and metastases may (at least partially) explain human epithelial growth factor receptor 2-targeted therapeutic inconsistencies. Human epithelial growth factor receptor 2 status was tested in a series of 47 radically treated consecutive esophagogastric junction adenocarcinomas (male/female, 38/9; mean age, 67.9 years) in both primary cancers and paired synchronous nodal metastases. None of the patients received neoadjuvant therapy. For each case, 2 nonadjacent tissue samples from primary esophagogastric junction adenocarcinoma and 2 different metastatic nodes were considered (188 tissue samples in all). Human epithelial growth factor receptor 2 status was assessed by immunohistochemistry (PATHWAY-HER2/neu [4B5]; Ventana Medical Systems, Milan, Italy) and dual chromogenic in situ hybridization (duoCISH; DAKO, Glostrup, Denmark). Immunohistochemistry staining scores were nil in 22 tumors (47%), 1 (21%) in 10, 2 (13%) in 6, and 3 (19%) in 9. Human epithelial growth factor receptor 2 gene amplification (25.5%) was associated with more differentiated phenotype (Fisher exact test, P = .039) and advanced tumor stage (Fisher exact test, P = .015). Significant agreement was observed between human epithelial growth factor receptor 2 protein expression (immunohistochemistry) and human epithelial growth factor receptor 2 gene's amplification (chromogenic in situ hybridization) (κ = 0.84, P < .001). Both immunohistochemistry and chromogenic in situ hybridization documented an excellent intratumor agreement in human epithelial growth factor receptor 2 status (κ = 0.75, P < .001; κ = 0.88, P < .001, respectively). Human epithelial growth factor receptor 2 status was comparable in primary versus metastatic nodal cancers by both immunohistochemistry and chromogenic in situ hybridization (Cohen Φ, both P < .001). In esophagogastric junction adenocarcinomas, human epithelial growth factor receptor 2 status (as assessed by immunohistochemistry and/or chromogenic in situ hybridization) is virtually unaffected by intratumor variability; it is consistent with findings in nodal metastases, and it reliably identifies patients with esophagogastric junction adenocarcinoma eligible for anti-human epithelial growth factor receptor 2 therapy.

We report multiplex ligation-dependent probe amplification analysis (MLPA) of DNA copy number alterations in 59 esophageal cancer samples, stratified by histotype. Results showed that squamous cell carcinoma (SCC) samples present clustered abnormalities with several genes altered at high frequency. Instead, esophageal adenocarcinoma (ADC) samples are characterized by a more widespread genomic instability, and in these patients total DNA copy number alterations resulted to be an independent prognostic factor. The detection of characteristic molecular changes represents a step towards a better understanding of the molecular basis of esophageal tumorigenesis, and might offer the potential for the discovery of tumor-specific biomarkers.

Neoadjuvant chemoradiotherapy (CT-RT) before esophagectomy seems to affect the number of nodal metastasis and to alter the distribution of those that remain. The aim of this study was to define how neoadjuvant chemoradiotherapy changes nodal metastasis patterns in locally advanced esophageal cancer. A total of 402 consecutive patients with cancer of the esophagus or esophagogastric junction (181 adenocarcinoma [AC] and 221 squamous cell carcinoma [SCC]) (evaluated at clinical stage T1N1, T2N1, T3N0, or T3N1 and pathological stage M0) presenting in our Department between 1992 and 2007 and who underwent complete resection (R0) were included in this retrospective study on a prospectively collected database. All dissected lymph nodes were retrieved and microscopically analyzed. Nodal metastasis patterns in patients who underwent chemotherapy (CT) or chemoradiotherapy (CT-RT) neoadjuvant therapy were compared with those in patients who underwent surgery alone. Almost 30% of the adenocarcinoma patients and approximately 40% of the SCC patients showed effective tumor downstaging after neoadjuvant therapy. There were fewer paracardial node metastases (P = .002) in the AC patients who underwent CT-RT neoadjuvant therapy. There were, likewise, significantly fewer paraesophageal, paracardial, and subcarinal node metastases in the SCC patients in whom the perigastric nodes became the second-most frequent site of metastasis. Not only was frequency of lymph node metastases decreased after neoadjuvant therapy, but nodal localization and pattern were also significantly modified.

Screening for genes down-regulated in esophageal cancers (Oncomine database) pinpointed programmed cell death 4 (PDCD4) as one of the most consistently involved. PDCD4 is a new putative tumor suppressor gene implicated in cell transformation, tumorigenesis, and invasiveness. Based on such a biological rationale, the aim of the present study was to evaluate the prognostic value of PDCD4 in esophageal cancers. The immunohistochemical expression of PDCD4 protein was assessed in 111 consecutive esophageal cancers (63 adenocarcinomas and 48 squamous cell carcinomas) and paired non-cancerous samples. PDCD4 immunostaining was significantly lower in cancer samples than in non-cancerous mucosa (p

Hepatic splenosis is a nodular implant of normal spleen tissue in the liver. This innocent liver nodule is frequently misinterpreted as a malignancy. Almost all hepatic splenoses have been associated with a clinical history of splenic trauma or prior surgery. This report describes two cases of hepatic splenosis. In both patients, the nodular lesions were initially thought to be liver malignancies and they were ultimately assessed by histology. The clinico-pathological findings of all published cases of liver splenosis underwent critical review. Although they are rare, hepatic spleen nodules should always be included in the diagnostic spectrum of nodular liver lesions because of their impact on treatment decisions.

Aim of this study was to evaluate whether delayed surgery after neoadjuvant chemoradiotherapy (CRT) affects postoperative outcomes in patients with locally advanced squamous cell carcinoma (SCC) of the thoracic esophagus.Esophagectomy is usually recommended within 4 to 6 weeks after completion of neoadjuvant CRT. However, the optimal timing of surgery is not clearly defined.A total of 129 consecutive patients with locally advanced esophageal cancer, treated between 1998 and 2007, were retrospectively analyzed using prospectively collected data. Patients were divided into 3 groups on the basis of timing to surgery: group 1, ≤30 days (n = 17); group 2, 31 to 60 days (n = 83); and group 3, 61 to 90 days (n = 29). Subsequently, only 2-numerically more consistent-groups were studied, using the median value of timing intervals as a cutoff level: group A, ≤46 days (n = 66); and group B,46 days (n = 63).Groups were comparable in terms of patient and tumor characteristics, type of neoadjuvant regimen, toxicity, postoperative morbidity and mortality rates, tumor downstaging, and pathologic complete responses. The overall 5-year actuarial survival rate was 0% in group 1, 43.1% in group 2, and 35.9% in group 3 (P = 0.13). After R0 resection (n = 106), the 5-year actuarial survival rate was 0%, 51%, and 47.3%, respectively (P = 0.18). Tumor recurrence after R0 resection seemed to be inversely related, even if not significantly (P = 0.17), to the time interval between chemoradiation and surgery: 50% in group 1, 40.6% in group 2, and 21.7% in group 3. When considering only 2 groups, the overall 5-year survival was 33.1% in group A and 42.7% in group B (P = 0.64); after R0 resection, the 5-year survival was 37.8% and 56.3%, respectively (P = 0.18). The rate of tumor recurrence was significantly lower in group B (25%) than in group A (48.3%) (P = 0.02).Delayed surgery after neoadjuvant chemoradiation does not compromise the outcomes of patients with locally advanced SCC of the esophagus. Delaying surgery up to 90 days offers relevant advantages in the clinical management of the patients, can reduce tumor recurrences, and may improve prognosis after complete R0 resection surgery.

To investigate trends in results of esophagectomies to treat esophageal cancer at a single high-volume institution during the past 25 years.Retrospective cohort study in a university tertiary referral center.Patients with cancer of the thoracic esophagus or esophagogastric junction seen from 1980 through 2004 were included (N = 3493). Three time periods were defined: 1980-1987, 1988-1995, and 1996-2004.Clinical presentation, tumor characteristics, and morbidity, mortality, and survival rates among patients with esophageal cancer undergoing esophagectomy.The ratio of squamous cell carcinoma to adenocarcinoma decreased from 3.3 to 1.7 (P.001) during the study period, in parallel with an increase in the number of patients with tumors in the lower esophagus/esophagogastric junction. An increasing proportion of patients who underwent resection received neoadjuvant treatment (chemotherapy/chemoradiotherapy), and 1978 patients underwent esophagectomy. The R0 resection rate increased from 74.5% to 90.1% (P.001). In addition, an increasing proportion of patients had early-stage tumor in the resected specimen. In-hospital postoperative mortality decreased from 8.2% to 2.6% (P.001), and the 5-year survival rate significantly improved from 18.8% to 42.3% (P.001) for all patients who underwent resection. Pathological tumor stage, completeness of the resection, time period, sex, tumor histological type, and tumor location influenced the prognosis of patients with esophageal cancer undergoing esophagectomy.A change in location and histological type of esophageal cancer has occurred during the past 25 years. Earlier diagnosis, a multidisciplinary approach, and refinements in surgical technique and perioperative care have led to a significant reduction in postoperative mortality rate and improved long-term survival among patients with cancer of the thoracic esophagus or esophagogastric junction.

Despite recent advances in surgical and multidisciplinary treatment, prognosis for patients with esophageal adenocarcinoma remains poor, and the low prognostic significance of pTNM staging suggests that additional parameters are needed. To identify genomic abnormalities characteristic of esophageal adenocarcinoma, a panel of 33 samples obtained at surgery from previously untreated patients were analyzed by muliplex ligation-dependent probe amplification technique. We detected frequent gains of 6p, 8q, 13q, 17q, 20q, and losses of 4q, 5q, 15q, and 18q. When DNA copy number changes were correlated to clinicopathological features of patients no association was found between the number of chromosomal aberrations and gender, age, tumor grade or pTNM staging. However, interestingly, a significant correlation between patient survival and total number of chromosomal aberrations was found when esophageal adenocarcinoma cases were stratified according to the median of survival (20 months) (P=0.002) or the median of aberrations (12 aberrations) (P=0.014). Evaluation of the distribution of gains and losses at the level of single chromosomes indicated that gains on chromosomes 5, 6, 8, 11, 20 and losses on chromosomes 1, 3, 5, 11, and 18 were significantly different in the two survival groups. Furthermore, when single gene imbalances were analyzed in further details, we found that besides alterations that involve genes shared by both survival groups, a few genes (KIAA0170, EMS1, ABCC4, F3, and MIF) were altered only in samples from patients with poor survival. Thus, we established a good correlation between the total number of chromosomal alterations and survival, suggesting that the estimation of total imbalances might represent an additional indicator of disease outcome. In addition, the finding of alterations specific for the more aggressive esophageal adenocarcinoma subset might represent promising biomarkers to increase the accuracy of clinical outcome prediction.

Zenker's diverticula (ZD) can be treated by transoral diverticulostomy or open surgery (upper esophageal sphincter myotomy and diverticulectomy or diverticulopexy). The aim of this study was to compare the effectiveness of a minimally invasive (group A) versus a traditional open surgical approach (group B) in the treatment of ZD.Between 1993 and September 2007, 128 ZD patients underwent transoral diverticulostomy (n = 51) or cricopharyngeal myotomy and diverticulectomy or diverticulopexy (n = 77). All patients were evaluated for symptoms using a detailed questionnaire. Manometry recorded upper esophageal sphincter (UES) pressure, relaxations, and intrabolus pharyngeal pressure. The size of the pouch was measured on the barium swallow. The choice of treatment was based on the size of the diverticulum and the patients' preference. Long-term follow-up data were available for 121/128 (94.5%) patients with a median follow-up of 40 months (interquartile range, 17-83).Mortality was nil. Three patients in group A (5.8%) and ten in group B (13%) had postoperative complications (p = n.s.). Hospital stays were markedly shorter for patients after diverticulostomy (p0.01). Postoperative manometry showed a reduction in UES pressure, improved UES relaxation, and lower intrabolus pressure in both groups (p0.05). Four patients in the open surgery group (5.2%) complained of severe dysphagia after surgery (three of them required endoscopic dilations). In the transoral diverticulostomy group, 11 patients (21.5%) required additional septal reduction (n = 8) or a surgical myotomy (n = 3) for persistent symptoms (p0.01); nine of these 11 patients had a ZDor = 3 cm in size. After primary and complementary treatments, symptoms disappeared or improved significantly at long-term follow-up in 93.5% of patients in group A and 96% of those in group B.Diverticulostomy is safe, quick, and effective for most patients with medium-sized ZD, but open surgery offers better long-term results as a primary treatment and should be recommended for younger, healthy patients, especially those with small diverticula. Small ZD may represent a formal contraindication to the transoral approach because an excessively short septum prevents a complete division of the sphincter fibers.

OBJECTIVE: Surveillance, Epidemiology and End Results (SEER) data indicate that number of lymph nodes removed impacts survival in gastric cancer. Our aim was to study this relationship in esophageal cancer. METHODS: The study population included 2303 esophageal cancer patients (1381 adenocarcinoma, 922 squamous) from 9 international centers that had R0 esophagectomy prior to 2002 and were followed at regular intervals for 5 years or until death. Patients treated with neoadjuvant or adjuvant therapy were excluded. RESULTS: Operations consisted of esophagectomy with (1700) and without (603) thoracotomy. Median number of nodes removed was 17 (IQR10-29). There were 508 patients with stage I, 853 stage II, and 942 stage III. Five-year survival was 40%. Cox regression analysis showed that the number of lymph nodes removed was an independent predictor of survival (P < 0.0001). The optimal threshold predicted by Cox regression for this survival benefit was removal of a minimum of 23 nodes. Other independent predictors of survival were the number of involved nodes, depth of invasion, presence of nodal metastasis, and cell type. CONCLUSIONS: The number of lymph nodes removed is an independent predictor of survival after esophagectomy for cancer. To maximize this survival benefit a minimum of 23 regional lymph nodes must be removed

Diaphragmatic herniation is the protrusion of abdominal structures into the chest through a defect in the diaphragm. It is a rare complication following oesophagectomy. Preoperative diagnosis is important in order to establish both the nature and extent of the diaphragmatic defect. The treatment of choice is surgery. In a series of 574 intrathoracic oesophagogastroplasties performed at our Institution from 1990 to 2004, the prevalence of diaphragmatic herniation was 0.35%. We report two cases of major diaphragmatic herniation after oesophagectomy for cancer performed using a laparotomic-thoracotomic (case 1) and a laparoscopicthoracotomic approach (case 2). The case 1 patient was asymptomatic: hernia repair involved hiatoplasty and mesh positioning. The case 2 patient presented with vomiting and abdominal pain: she underwent emergency laparoscopic surgery and direct closure of the diaphragmatic tear. At 12 months' follow-up, both patients were symptom-free. A barium swallow confirmed that the previously herniated abdominal viscera had returned to the abdomen. Diaphragmatic herniation following oesophagectomy is a rare complication which may be asymptomatic or present as bowel obstruction. Several aetiopathogenetic factors may be responsible for diaphragmatic hernias: enlargement of the diaphragmatic hiatus, a combination of negative pressure in the chest and positive pressure in the abdomen, and small number of adhesions in the case of patients operated on with minimally invasive surgery. Surgical repair is the treatment of choice and is mandatory as emergency treatment in the case of symptomatic hernias.

Pseudoachalasia is a rare clinical entity which has clinical, radiographic and manometric features often indistinguishable from achalasia. A small primary adenocarcinoma arising at the gastroesophageal junction or a tumor of the distal esophagus are the most frequent causes. Rarely, processes other than esophagogastric cancers may lead to the development of pseudoachalasia. We present three cases of pseudoachalasia in which the primary cause of the disease was not an esophagogastric cancer. The causes were a pancreatic carcinoma, a breast cancer and an histiocytosis X. Aspects of these three patients' diagnostic and therapeutic course are discussed in detail.

Adenocarcinoma of the proximal esophagus is a rare clinical entity, with only 28 cases described in the literature. We report our experience with 9 patients and a review of the literature on this topic. Between 1980 and 2004, 1010 patients with esophageal or gastroesophageal junction adenocarcinoma (from a total of 4655 cancers, 3510 squamous and 1145 adeno) presenting at our department were retrospectively evaluated. Nine patients (0.9%) had adenocarcinoma located in the proximal esophagus. Four patients (Group A) were considered unfit for surgery due to severe comorbidities and/or advanced stage disease. Three of them received endoscopic yttrium-aluminum-garnet (YAG)-laser therapy; 1 patient had feeding gastrostomy. Their median survival was 6 months (range, 3–9 months). The other 5 patients (Group B) were given a first-line cytoreductive treatment: 4 had complete response, and 1 patient did not complete chemotherapy due to toxicity and underwent surgery for residual disease. The median survival for these 5 patients receiving cytoreductive therapy was 36 months (range, 24–132 months). For the 4 patients with complete clinical response to cytoreductive treatment, the median survival was 54 months (range, 24–132 months). First-line chemoradiotherapy is an effective treatment for adenocarcinoma of the proximal esophagus. Salvage surgery may be reserved for patients with incomplete response or recurrent disease.

Objective The aging of the population and a longer life expectancy have led to an increased number of elderly patients with esophageal cancer being referred for surgical treatment. The aim of this study was to assess the effects of age on the outcome of surgery for esophageal cancer at a single institution. Methods Perioperative outcome and long-term survival of patients at least 70 years old undergoing esophagectomy between 1992 and 2005 for cancer of the esophagus or esophagogastric junction were compared with findings in younger patients. Patients who underwent an abdominal procedure only were excluded from the analysis. Results The analysis considered 580 patients younger than 70 years and 159 at least 70 years old. Clinical presentation in the two groups was similar, as were postoperative morbidity and mortality, despite significant differences in perioperative risk factors. Irrespective of age, overall survival was 34% at 5 years for all patients and 37% for patients with R0 resection. Conclusions Increased experience and refinements in perioperative care explain the better results of esophagectomy in elderly patients in recent years. Short- and long-term outcomes after esophagectomy for carcinoma in patients older than 70 years are comparable with those of their younger counterparts. Advanced age per se thus should not be considered a contraindication to esophageal resection.

The aim of the study was to evaluate the feasibility and efficacy of treatment with oxaliplatin, 5-fluorouracil and leucovorin concomitant with radiation therapy in locally advanced oesophageal cancer. Fifty-eight patients with previously untreated, histologically proven oesophageal cancer were enrolled. Downstaged patients underwent either surgery or received brachytherapy. We report the results obtained in the first 54 patients. The median age was 58 years. The diagnosis was squamous cell carcinoma/adenocarcinoma/poorly differentiated: 45/8/1; clinical stage: T3N1M0 38 (70%), T4 10 (19%), M1a 6 (11%). Thirty-nine patients (72%) received the planned 8 weeks of chemotherapy and 45 completed the entire course of scheduled radiotherapy. Four (7%) toxic deaths were recorded, 2 more patients died prematurely from massive oesophageal bleeding and 1 from progression of disease. We recorded 8 (15%) complete responses and 24 (44%) partial responses. Resection was complete (R0) in 24 (80% of resected patients, 44% of treated patients). A complete pathological response was documented in 6 patients (11% of those treated). Postoperative complications were recorded in 8 (25%) patients, with 2 (6.2%) deaths. RO resection was accomplished in 44% of patients. Toxicity was moderate, but postoperative mortality was not negligible. Survival data are awaited before a phase III comparison with cisplatin-containing chemo-radiotherapy may be considered.

We quantified the expression of survivin, both as mRNA in real-time PCR and protein in immunohistochemistry, in tumor samples of 112 patients with esophageal cancer (56 squamous cell carcinomas and 56 adenocarcinomas). Overall survival of squamous cell carcinoma patients with high survivin mRNA levels was significantly less than that of patients with low survivin mRNA levels (p = 0.0033). Distribution pattern of survivin (nuclear vs. cytoplasmic or mixed) was not correlated to survival, while the extent of immunostaining was significantly correlated to survivin mRNA values (p = 0.016) and had prognostic relevance in univariate analysis (p = 0.0012). Cox's proportional-hazard regression model showed that tumor survivin expression in esophageal squamous cell carcinoma was the most important prognostic factor, independent of tumor stage and other histopathological factors, both as mRNA relative value (p = 0.0259) and protein immunostaining (p = 0.0147). In esophageal adenocarcinoma, survivin expression and pattern of distribution had no prognostic relevance. Thus, quantifying survivin expression provides a prognostic marker only for esophageal squamous tumors.