Identification of host variants associated with overall survival of esophageal cancer patients receiving platinum-based therapy.

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.

Cholecystectomy during esophagectomy is safe but unnecessary.

Background: Prophylactic cholecystectomy has been proposed as a concomitant procedure during upper gastrointestinal surgery. This study evaluates the safety and the need of concurrent cholecystectomy during esophagectomy for cancer.Methods: All consecutive esophagectomies for esophageal cancer at the Center for Esophageal Diseases in Padova (Italy) between 1992 and 2011 were included. The safety of concurrent cholecystectomy was evaluated by surgical outcomes (length of stay, postoperative mortality and perioperative complications). The need for concurrent cholecystectomy was evaluated by occurrence of biliary duct stones and of cholelithiasis/cholecystitis after esophagectomy.Results: Cholecystectomy was performed during 67 out of 1087 esophagectomies (6.2%). Cirrhosis or chronic liver disease was associated with receiving cholecystectomy during esophagectomy (OR: 1.99, 95%C.I. 1.10-3.56). Patients receiving and those not receiving cholecystectomy showed similar length of stay (median 14 days, p = .87), postoperative mortality (3.0% vs. 2.5%, p = .68), intraoperative complication (4.5% vs. 7.1%, p = .62), early complications (52.2% vs. 44.6%, p = .25) and late complications (20.9% vs. 24.8%, p = .56). Cholelithiasis/cholecystitis after esophagectomy occurred in 61 (6.1%) patients, with only four requiring cholecystectomy during follow-up. The biliary stone occurrence was nil. Only pathologic stage III-IV (OR: 2.17, 95%C.I. 1.19-3.96) was associated with cholelithiasis/cholecystitis after esophagectomy.Conclusion: Routine prophylactic cholecystectomy during esophagectomy could be safe but unnecessary.

Association Between ERCC1 rs3212986 and ERCC2/XPD rs1799793 and OS in Patients With Advanced Esophageal Cancer.

Esophageal cancer (EC) is a very aggressive tumor, and no reliable prognostic markers exist especially for resectable advanced neoplasia. The principal aim of this study was to investigate the association of germline polymorphisms in nucleotide excision repair (NER) pathway genes with the overall survival (OS) of patients with advanced EC. As a second aim, we also studied the association of NER gene variants with response to cisplatin-based chemotherapy. Among the EC patients referred to our Institution between 2004 and 2012, we selected a cohort of 180 patients diagnosed with a clinical tumor stage ranging from IIB and IVA. Patients were genotyped for four NER variants, two in the ERCC1 (rs11615 and rs3212986) and two in the ERCC2/XPD (rs1799793 and rs13181) genes. Kaplan-Meier analyses and Cox proportional hazards model were used to evaluate the associations of the selected variants with OS; association with response to neoadjuvant therapy was investigated using logistic regression. Results showed that the ERCC1 rs3212986 and the ERCC2/XPD rs1799793 were significantly associated with shorter OS. On the contrary, response association analysis displayed that, while rs11615 and rs3212986 in ERCC1 were associated with response, both ERCC2/XPD variants were not. By creating survival prediction models, we showed that the rs3212986 and the rs1799793 have a better predictability of the tumor stage alone. Furthermore, they were able to improve the power of the clinical model (AUC = 0.660 vs. AUC = 0.548, p = 0.004). In conclusion, our results indicate that the ERCC1 rs3212986 and the ERCC2/XPD rs1799793 could be used as surrogate markers for a better stratification of EC patients with advanced resectable tumor.

Human papillomavirus infection is not involved in esophageal verrucous carcinoma.

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.

Cervical Esophageal Cancer Treatment Strategies: A Cohort Study Appraising the Debated Role of Surgery.

BACKGROUND: 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. METHODS: 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. RESULTS: 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). CONCLUSIONS: 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.

Time to diagnosis in esophageal cancer: a cohort study.

BACKGROUND: 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. MATERIAL AND METHODS: 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. RESULTS: 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). CONCLUSION: 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.

Esophageal Cancer Clinical Presentation: Trends in the Last 3 Decades in a Large Italian Series.

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.

Squamous Cellular Carcinoma Antigen Serum Determination as a Biomarker of Barrett Esophagus and Esophageal Cancer: A Phase III Study.

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.

Nodal skip metastasis in thoracic esophageal squamous cell carcinoma: a cohort study.

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.

Effects of laparoscopic myotomy on the esophageal motility pattern of esophageal achalasia as measured by high-resolution manometry.

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Squamous cell carcinoma antigen (SCCA) is up-regulated during Barrett's carcinogenesis and predicts esophageal adenocarcinoma resistance to neoadjuvant chemotherapy.

Squamous Cell Carcinoma Antigen (SCCA) is consistently overexpressed in many different solid tumors, and has been associated with both tumor aggressiveness and chemoresistance. No data, however, is currently available on SCCA expression during esophageal Barrett's carcinogenesis, nor on SCCA expression's role on esophageal adenocarcinoma chemoresistance. The SCCA immunohistochemical expression was assessed in a series of 100 biopsy samples covering the whole histological spectrum of Barrett's oncogenesis. Squamous native mucosa was characterized by a moderate to strong cytoplasmic and nuclear SCCA expression in suprabasal, medium, and superficial layers. On the other hand, almost half of the considered lesions did not express SCCA; the other half featured weak to moderate SCCA expression. The relationship between SCCA protein expression and tumor response to neoadjuvant chemotherapy was assessed in 90 esophageal adenocarcinoma specimens (40 biopsy and 50 surgery specimens), stratified according to Mandard tumor regression grade. As observed in other settings, the presence of SCCA expression clustered in the group of tumors characterized by a lower responsiveness to neoadjuvant treatments. The present results suggest an involvement of SCCA in a subset of Barrett-related tumors, and prompt to consider the SCCA-protein expression as response-predictive marker of neoadjuvant therapy in esophageal adenocarcinomas.

Postoperative Gastroesophageal Reflux After Laparoscopic Heller-Dor for Achalasia: True Incidence with an Objective Evaluation.

INTRODUCTION: The most common complication after laparoscopic Heller-Dor (LHD) is gastroesophageal reflux disease (GERD). The present study aimed (a) to analyze the true incidence of postoperative reflux by objectively assessing a large group of LHD patients and (b) to see whether the presence of typical GERD symptoms correlates with the real incidence of postoperative reflux. METHODS: After LHD, patients were assessed by means of a symptom score, endoscopy, esophageal manometry, and 24-h pH monitoring. Patients were assigned to three groups: those did not accept to perform 24-h pH monitoring (group NP); those with normal postoperative pH findings (group A); and those with pathological postoperative acid exposure (group B). RESULTS: Four hundred sixty-three of the 806 LHD patients agreed to undergo follow-up 24-h pH monitoring. Normal pH findings were seen in 423 patients (group A, 91.4 %), while 40 (8.6 %) had a pathological acid exposure (group B). The median symptom scores were similar: 3.0 (IQR 0-8) in group A and 6.0 (IQR 0-10) in group B (p = 0.29). At endoscopy, the percentage of esophagitis was also similar (11 % in group A, 19 % in group B; p = 0.28). CONCLUSIONS: This study demonstrated that, after LHD was performed by experienced surgeons, the true incidence of postoperative GERD is very low. The incidence of this possible complication should be assessed by pH monitoring because endoscopic findings and symptoms may be misleading.

Esophageal Cancer Surgery for Patients with Concomitant Liver Cirrhosis: A Single-Center Matched-Cohort Study.

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: Liver cirrhosis is not an absolute contraindication to esophagectomy. The MELD score can be applicable for esophagectomy risk assessment for cirrhotic patients.

Mucosal Perforation During Laparoscopic Heller Myotomy Has No Influence on Final Treatment Outcome.

BACKGROUND: 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. METHODS: 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. RESULTS: 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). CONCLUSIONS: 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.

Endoscopic Tumor Length Should Be Reincluded in the Esophageal Cancer Staging System: Analyses of 662 Consecutive Patients.

Esophageal cancer represents the 6th cause of cancer mortality in the World. New treatments led to outcome improvements, but patient selection and prognostic stratification is a critical aspect to gain maximum benefit from therapies. Today, patients are stratified into 9 prognostic groups, according to a staging system developed by the American Joint Committee on Cancer. Recently, trying to better select patients with curing possibilities several authors are reconsidering tumor length as a valuable prognostic parameter. Specifically, endoscopic tumor length can be easily measured with an esophageal endoscopy and, if its utility in esophageal cancer staging is demonstrated, it may represent a simple method to identify high risk patients and an easy-to-obtain variable in prognostic stratification. In this study we retrospectively analyzed 662 patients treated for esophageal cancer, stratified according to cancer histology and current staging system, to assess the possible role of endoscopic tumor length. We found a significant correlation between endoscopic tumor length, current staging parameters and 5-year survival, proving that endoscopic tumor length may be used as a simple risk stratification tool. Our results suggest a possible indication for preoperative therapy in early stage squamocellular carcinoma patients without lymph nodes involvement, who are currently treated with surgery alone.

A germline predictive signature of response to platinum chemotherapy in esophageal cancer.

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.

Genetic features of metachronous esophageal cancer developed in Hodgkin's lymphoma or breast cancer long-term survivors: an exploratory study.

BACKGROUND: Development of novel therapeutic drugs and regimens for cancer treatment has led to improvements in patient long-term survival. This success has, however, been accompanied by the increased occurrence of second primary cancers. Indeed, patients who received regional radiotherapy for Hodgkin's Lymphoma (HL) or breast cancer may develop, many years later, a solid metachronous tumor in the irradiated field. Despite extensive epidemiological studies, little information is available on the genetic changes involved in the pathogenesis of these solid therapy-related neoplasms. METHODS: Using microsatellite markers located in 7 chromosomal regions frequently deleted in sporadic esophageal cancer, we investigated loss of heterozygosity (LOH) and microsatellite instability (MSI) in 46 paired (normal and tumor) samples. Twenty samples were of esophageal carcinoma developed in HL or breast cancer long-term survivors: 14 squamous cell carcinomas (ESCC) and 6 adenocarcinomas (EADC), while 26 samples, used as control, were of sporadic esophageal cancer (15 ESCC and 11 EADC). RESULTS: We found that, though the overall LOH frequency at the studied chromosomal regions was similar among metachronous and sporadic tumors, the latter exhibited a statistically different higher LOH frequency at 17q21.31 (p = 0.018). By stratifying for tumor histotype we observed that LOH at 3p24.1, 5q11.2 and 9p21.3 were more frequent in ESCC than in EADC suggesting a different role of the genetic determinants located nearby these regions in the development of the two esophageal cancer histotypes. CONCLUSIONS: Altogether, our results strengthen the genetic diversity among ESCC and EADC whether they occurred spontaneously or after therapeutic treatments. The presence of histotype-specific alterations in esophageal carcinoma arisen in HL or breast cancer long-term survivors suggests that their transformation process, though the putative different etiological origin, may retrace sporadic ESCC and EADC carcinogenesis.

Esophageal carcinosarcoma: management and prognosis at a single Italian series.

BACKGROUND: Esophageal carcinosarcoma (ESC) is a rare malignant lesion of the esophagus with controversial characteristics and prognostic factors. PATIENTS AND METHODS: Seventeen consecutive patients with esophageal carcinosarcoma were referred to the Center for Esophageal Diseases located in Padua from January 1, 1980 to December 31, 2011. Clinical characteristics, pathological features, treatment and outcome were retrospectively analyzed in a prospectively collected database. RESULTS: Five patients received palliative treatment and one refused surgery; they died of unresected tumor or progression of disease within 0.6-43.5 months after diagnosis. Eleven patients underwent surgical treatment with complete tumor resection; recurrence rate was 80%, leading to death within 2 years after surgery. Only two resected patients are currently alive and free of disease over 20 years after surgery. CONCLUSION: Our results did not support the better prognosis concept of esophageal carcinosarcoma and suggested the importance of radical esophagectomy with adequate lymph node dissection.

ERCC1 C8092A (rs3212986) polymorphism as a predictive marker in esophageal cancer patients treated with cisplatin/5-FU-based neoadjuvant therapy.

OBJECTIVE: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.