Decellularized and matured esophageal scaffold for circumferential esophagus replacement: Proof of concept in a pig model.

Surgical resection of the esophagus requires sacrificing a long portion of it. Its replacement by the demanding gastric pull-up or colonic interposition techniques may be avoided by using short biologic scaffolds composed of decellularized matrix (DM). The aim of this study was to prepare, characterize, and assess the in vivo remodeling of DM and its clinical impact in a preclinical model. A dynamic chemical and enzymatic decellularization protocol of porcine esophagus was set up and optimized. The resulting DM was mechanically and biologically characterized by DNA quantification, histology, and histomorphometry techniques. Then, in vitro and in vivo tests were performed, such as DM recellularization with human or porcine adipose-derived stem cells, or porcine stromal vascular fraction, and maturation in rat omentum. Finally, the DM, matured or not, was implanted as a 5-cm-long esophagus substitute in an esophagectomized pig model. The developed protocol for esophageal DM fulfilled previously established criteria of decellularization and resulted in a scaffold that maintained important biologic components and an ultrastructure consistent with a basement membrane complex. In vivo implantation was compatible with life without major clinical complications. The DM's scaffold in vitro characteristics and in vivo implantation showed a pattern of constructive remodeling mimicking major native esophageal characteristics.

Significance of Microscopically Incomplete Resection Margin After Esophagectomy for Esophageal Cancer.

OBJECTIVE: The objectives of this study were to establish if R1 resection margin after esophagectomy was (i) a poor prognostic factor independent of patient and tumor characteristics, (ii) a marker of tumor aggressiveness and (iii) to look at the impact of adjuvant treatment in this subpopulation. METHODS: Data were collected from 30 European centers from 2000 to 2010. Patients with an R1 resection margin (n = 242) were compared with those with an R0 margin (n = 2573) in terms of short- and long-term outcomes. Propensity score matching and multivariable analyses were used to compensate for differences in baseline characteristics. RESULTS: Independent factors significantly associated with an R1 resection margin included an upper third esophageal tumor location, preoperative malnutrition, and pathological stage III. There were significant differences between the groups in postoperative histology, with an increase in pathological stage III and TRG 4-5 in the R1 group. Total average lymph node harvests were similar between the groups; however, there was an increase in the number of positive lymph nodes seen in the R1 group. Propensity matched analysis confirmed that R1 resection margin was significantly associated with reduced overall survival and increased overall, locoregional, and mixed tumor recurrence. Similar observations were seen in the subgroup that received neoadjuvant chemoradiation. In R1 patients adjuvant therapy improved survival and reduced distant recurrence however failed to affect locoregional recurrence. CONCLUSIONS: This large multicenter European study provides evidence to support the notion that R1 resection margin is a prognostic indication of aggressive tumor biology with a poor long-term prognosis.

Salvage Surgery After Chemoradiotherapy in the Management of Esophageal Cancer: Is It a Viable Therapeutic Option?

PURPOSE: The aim of this large multicenter study was to assess the impact of salvage esophagectomy after definitive chemoradiotherapy (SALV) on clinical outcome. PATIENTS AND METHODS: Data from consecutive adult patients undergoing resection for esophageal cancer in 30 European centers from 2000 to 2010 were collected. First, groups undergoing SALV (n = 308) and neoadjuvant chemoradiotherapy followed by planned esophagectomy (NCRS; n = 540) were compared. Second, patients who benefited from SALV for persistent (n = 234) versus recurrent disease (n = 74) were compared. Propensity score matching and multivariable analyses were used to compensate for differences in some baseline characteristics. RESULTS: SALV versus NCRS groups: In-hospital mortality was similar in both groups (8.4% v 9.3%). The only significant differences in complications were seen for anastomotic leak (17.2% v 10.7%; P = .007) and surgical site infection, which were both more frequent in the SALV group. At 3 years, groups had similar overall (43.3% v 40.1%; P = .542) and disease-free survival (39.2% v 32.8%; P = .232) after matching, along with a similar recurrence pattern. Persistent versus recurrent disease groups: There were no significant differences between groups in incidence of in-hospital mortality or major complications. At 3 years, overall (40.9% v 56.2%; P = .046) and disease-free survival (36.6% v 51.6%; P = .095) were lower in the persistent disease group. CONCLUSION: The results of this large multicenter study from the modern era suggest that SALV can offer acceptable short- and long-term outcomes in selected patients at experienced centers. Persistent cancer after definitive chemoradiotherapy seems to be more biologically aggressive, with poorer survival compared with recurrent cancer.

Impact of postoperative chemotherapy in patients with locally advanced gastroesophageal adenocarcinoma treated with perioperative chemotherapy strategy.

BACKGROUND: The aim of this study was to determine the clinical impact of postoperative chemotherapy (POC) in patients with locally advanced gastroesophageal adenocarcinoma and determine the predictors of delivery of planned POC. METHODS: All consecutive patients with locally advanced gastroesophageal adenocarcinoma treated by perioperative chemotherapy (PCT) at our center were selected. Overall survival and disease-free survival were compared in patients who did not undergo planned POC (nondelivery of nPOC group) and patients who underwent POC (POC group). RESULTS: Among 385 patients who underwent esophagectomies or gastrectomies, PCT was performed in 110 patients. Of these, 74 (67%) patients underwent POC. Predictors of overall survival included postoperative morbidity, pT3-4 stage, R1 resection, and delivery of more than 1 cycle of POC. Factors predicting POC application included postoperative morbidity, esophagectomy, and body mass index. CONCLUSIONS: Two cycles of POC were necessary to improve survival in patients with gastroesophageal adenocarcinoma.

Predictive Factors of Recurrence in Patients with Pathological Complete Response After Esophagectomy Following Neoadjuvant Chemoradiotherapy for Esophageal Cancer: A Multicenter Study.

BACKGROUND: Minimal data have previously emerged from studies regarding the factors associated with recurrence in patients with ypT0N0M0 status. The purpose of the study was to predict survival and recurrence in patients with pathological complete response (pCR) following chemoradiotherapy (CRT) and surgery for esophageal cancer (EC). METHODS: Among 2944 consecutive patients with EC operations in 30 centers between 2000 and 2010, patients treated with neoadjuvant CRT followed by surgery who achieved pCR (n = 191) were analyzed. The factors associated with survival and recurrence were analyzed using a Cox proportional hazard regression analysis. RESULTS: Among 593 patients who underwent neoadjuvant CRT followed by esophagectomy, pCR was observed in 191 patients (32.2 %). Recurrence occurred in 56 (29.3 %) patients. The median time to recurrence was 12 months. The factors associated with recurrence were postoperative complications grade 3-4 [odds ratio (OR): 2.100; 95 % confidence interval (CI) 1.008-4.366; p = 0.048) and adenocarcinoma histologic subtype (OR 2.008; 95 % CI 0.1.06-0.3.80; p = 0.032). The median overall survival was 63 months (95 % CI 39.3-87.1), and the median disease-free survival was 48 months (95 % CI 18.3-77.4). Age (>65 years) [hazard ratio (HR): 2.166; 95 % CI 1.170-4.010; p = 0.014), postoperative complications grades 3-4 [HR 2.099; 95 % CI 1.137-3.878; p = 0.018], and radiation dose (<40 Gy) (HR 0.361; 95 % CI 0.159-0.820; p = 0.015) were identified as factors associated with survival. CONCLUSIONS: An intensive follow-up may be beneficial for patients with EC who achieve pCR and who develop major postoperative complications or the adenocarcinoma histologic subtype.

Pattern of Postoperative Mortality After Esophageal Cancer Resection According to Center Volume: Results from a Large European Multicenter Study.

BACKGROUND: High center procedural volume has been shown to reduce postoperative mortality (POM); however, the cause of POM has been poorly studied previously. The aim of this study was to define the pattern of POM and major morbidity in relation to center procedural volume. METHODS: Data from 2,944 consecutive adult patients undergoing esophagectomy for esophageal cancer in 30 centers between 2000 and 2010 were retrospectively collected. Data between patients who suffered 30-day POM were compared with those who did not. Factors associated with POM were identified using binary logistic regression, with propensity matching to compare low- (LV) and high-volume (HV) centers. RESULTS: The 30-day and in-hospital POM rates were 5.0 and 7.3 %, respectively. Pulmonary complications were the most common, affecting 38.1 % of patients, followed by surgical site infection (15.5 %), cardiovascular complications (11.2 %), and anastomotic leak (10.2 %). Factors that were independently associated with 30-day POM included American Society of Anesthesiologists grade IV, LV center, anastomotic leak, pulmonary, cardiovascular and neurological complications, and R2 resection margin status. Surgical complications preceded POM in approximately 30 % of patients compared to medically-related causes in 68 %. Propensity-matched analysis demonstrated LV centers were significantly associated with increased 30-day POM, and POM secondary to anastomotic leak, and pulmonary- and cardiac-related causes. CONCLUSIONS: The results of this large, multicenter study provide further evidence to support the centralization of esophagectomy to HV centers, with a lower rate of morbidity and better infrastructure to deal with complications following major surgery preventing further mortality.

Neoadjuvant chemoradiotherapy improves histological results compared with perioperative chemotherapy in locally advanced esophageal adenocarcinoma.

BACKGROUND: Neoadjuvant treatment is considered the standard treatment for locally advanced adenocarcinoma of the esophagus. This study compared the effectiveness of neoadjuvant chemoradiotherapy (CRT) and perioperative chemotherapy (PCT) based on postoperative results and long-term survival. METHODS: All patients with locally advanced adenocarcinoma of the esophagus were treated with a single protocol of neoadjuvant CRT (cisplatin and 5-fluorouracil [5-FU] with 45 Gy of concurrent radiotherapy) or with a single protocol of PCT (docetaxel, cisplatin, 5-FU). The responses to CRT and PCT were evaluated by considering the rates of pathologic complete response (pCR) and radical resection (R0). Overall survival (OS), disease-free survival (DFS), and recurrence were evaluated according to the neoadjuvant treatment. RESULTS: A total of 116 patients underwent CRT or PCT followed by esophagectomy; 61 patients underwent PCT, and 55 patients underwent CRT. R0 was achieved in 98 patients (84.5 %) and was more frequent in the CRT group (94.6 vs. 75.4 %; p = 0.010). pCR was observed in 13 patients (11.2 %) and was more frequent in the CRT group (20 vs. 3.3 %; p = 0.011). OS was comparable between the CRT and PCT groups (41 vs. 45 months; p = 0.284). DFS was comparable between the CRT and PCT groups (21 vs. 36 months; p = 0.522). CONCLUSIONS: In this study, better histological results were observed in patients who had been treated with CRT, although similar survival rates were observed for patients treated with either CRT or PCT. Further study is necessary to select patients who will benefit most from CRT or PCT.

Major post-operative complications predict long-term survival after esophagectomy in patients with adenocarcinoma of the esophagus.

BACKGROUND: Esophagectomy provides the best opportunity for a long-term cure despite its high post-operative morbidity. We reviewed our institutional records to evaluate the impact of major post-operative complications on the long-term survival of patients following esophagectomy after neoadjuvant treatment for locally advanced adenocarcinoma. METHODS: We identified 241 patients who underwent esophagectomy as a curative procedure at our tertiary referral center. All consecutive patients with locally advanced adenocarcinoma of the esophagus who underwent neoadjuvant treatment followed by esophagectomy were analyzed. Complications were graded according to the Clavien scale. Patients were compared according to the complication grade (grades 0-1-2 vs. grades 3-4). Overall survival and disease-free survival were calculated using the Kaplan-Meier method, and survival curves were compared using log-rank tests. Factors predictive of survival were determined using multivariate analysis. RESULTS: A total of 116 patients underwent esophagectomy after neoadjuvant treatment for locally advanced adenocarcinoma of the esophagus. Fifty-four patients (46.5 %) developed post-operative complications. The post-operative mortality rate was 4.3 % (five patients). Patients with grade 3-4 complications had decreased overall survival and disease-free survival rates (p = 0.006 and 0.045). Grade 3-4 complications and positive nodes were found to be contributing factors to survival (p = 0.027 and 0.005). CONCLUSIONS: Our single-institution study found that major morbidity had a negative impact on long-term survival in patients who underwent esophagectomy after neoadjuvant treatment for locally advanced adenocarcinoma.

Impact of neoadjuvant chemoradiotherapy on postoperative outcomes after esophageal cancer resection: results of a European multicenter study.

OBJECTIVES: To assess the impact of neoadjuvant chemoradiotherapy (NCRT) on anastomotic leakage (AL) and other postoperative outcomes after esophageal cancer (EC) resection. BACKGROUND: Conflicting data have emerged from randomized studies regarding the impact of NCRT on AL. METHODS: Among 2944 consecutive patients operated on for EC between 2000 and 2010 in 30 European centers, patients treated by NCRT after surgery (n=593) were compared with those treated by primary surgery (n=1487). Multivariable analyses and propensity score matching were used to compensate for the differences in some baseline characteristics. RESULTS: Patients in the NCRT group were younger, with a higher prevalence of male sex, malnutrition, advanced tumor stage, squamous cell carcinoma, and surgery after 2005 when compared with the primary surgery group. Postoperative AL rates were 8.8% versus 10.6% (P=0.220), and 90-day postoperative mortality and morbidity rates were 9.3% versus 7.2% (P=0.110) and 33.4% versus 32.1% (P=0.564), respectively. Pulmonary complication rates did not differ between groups (24.6% vs 22.5%; P=0.291), whereas chylothorax (2.5% vs 1.2%; P=0.020), cardiovascular complications (8.6% vs 0.1%; P=0.037), and thromboembolic events (8.6% vs 6.0%; P=0.037) were higher in the NCRT group. After propensity score matching, AL rates were 8.8% versus 11.3% (P=0.228), with more chylothorax (2.5% vs 0.7%; P=0.030) and trend toward more cardiovascular and thromboembolic events in the NCRT group (P=0.069). Predictors of AL were high American Society of Anesthesiologists scores, supracarinal tumoral location, and cervical anastomosis, but not NCRT. CONCLUSIONS: Neoadjuvant chemoradiotherapy does not have an impact on the AL rate after EC resection (NCT 01927016).

Lateral incisional hernia after renal transplantation: a comparative study.

BACKGROUND: Because of the lack of published data and the relative rarity of lateral incisional hernias (LIHs), especially after renal transplantation, mesh repair of LIH remains a challenge for surgeons. The aim of the present study was to evaluate the outcomes of LIH treated by mesh repair after renal transplantation. METHODS: All consecutive patients who had undergone LIH mesh repair after renal transplantation were compared with patients who had undergone LIH mesh repair without renal transplantation. Demographic data, incisional hernia characteristics, operative data, and postoperative outcomes were prospectively recorded. Early complications and recurrence rates were evaluated. RESULTS: Altogether, 112 patients were treated for LIH with mesh repair. Among these patients, 61 (54.4 %) underwent LIH after renal transplantation. The early complications were similar for the patients with and without renal transplantation (24.5 vs. 23.5 %, respectively; p = 0.896). The recurrence rates also were similar for the patients with and without renal transplantation (9.8 vs. 9.8 %, respectively; p = 1). CONCLUSIONS: Mesh graft repair is feasible in patients with LIH after renal transplantation. Postoperative complications and recurrences were not more frequent in renal transplantation patients than in those without renal transplantation.

Esophageal tissue engineering.

Esophageal tissue engineering is still in an early state, and ideal methods have not been developed. Since the beginning of the 20th century, advances have been made in the materials that can be used to produce an esophageal substitute. Three approaches to scaffold-based tissue engineering have yielded good results. The first development concerned non-absorbable constructs based on silicone and collagen. The need to remove the silicone tube is the main disadvantage of this material. Polymeric absorbable scaffolds have been used since the 1990s. The main polymeric material used is poly (glycolic) acid combined with collagen. The problem of stenosis remains prevalent in most studies using an absorbable construct. Finally, decellularized scaffolds have been used since 2000. The promises of this new approach are unfulfilled. Indeed, stenosis occurs when the esophageal defect is circumferential regardless of the scaffold materials. Cell supplementation can decrease the rate of stenosis, but the type(s) of cells and their roles have not been defined. Finally, esophageal tissue engineering cannot provide a functional esophageal substitute, and further development is necessary prior to conducting human clinical studies.

Laparoscopic resection of hepatocellular carcinoma: a French survey in 351 patients.

OBJECTIVES: Current clinical studies report the results of laparoscopic resection of hepatocellular carcinoma (HCC) obtained in small cohorts of patients. Because France was involved in the very early development of laparoscopic surgery, the present study was conducted in order to report the results of a large, multicentre experience. METHODS: A total of 351 patients underwent laparoscopic liver resection for HCC during the period from 1998 to 2010 in nine French tertiary centres. Patient characteristics, postoperative mortality and morbidity, and longterm survival were retrospectively reviewed. RESULTS: Overall, 85% of the study patients had underlying liver disease. Types of resection included wedge resection (41%), left lateral sectionectomy (27%), segmentectomy (24%), and major hepatectomy (11%). Median operative time was 180 min. Conversion to laparotomy occurred in 13% of surgeries and intraoperative blood transfusion was necessary in 5% of patients. The overall morbidity rate was 22%. The 30-day postoperative mortality rate was 2%. Negative resection (R0) margins were achieved in 92% of patients. Rates of overall and progression-free survival at 1, 3 and 5 years were 90.3%, 70.1% and 65.9%, and 85.2%, 55.9% and 40.4%, respectively. CONCLUSIONS: This multicentre, large-cohort study confirms that laparoscopic liver resection for HCC is a safe and efficient approach to treatment and can be proposed as a first-line treatment in patients with resectable HCC.

Is the negative prognostic impact of signet ring cell histology maintained in early gastric adenocarcinoma?

BACKGROUND: Although the signet ring cell histologic subtype (SRC) is an independent predictor of poor prognosis in advanced gastric adenocarcinomas (GA), its prognostic value in early GA remains highly controversial. The aim of the study was to evaluate the prognostic impact of SRC in mucosal and submucosal GAs. METHODS: Based on a multicenter cohort of 3,010 patients operated on for GA between January 1997 and January 2010, patients with pTis or pT1 tumors were extracted and analyzed comparatively between the SRC and non-SRC groups. The primary objective was to compare the 5-year survival rate between groups. RESULTS: Among 421 patients with a pTis or pT1 tumor, 104 (25%) were SRC and 317 (75%) were non-SRC. Demographic variables were comparable between groups, except median age, which was less in the SRC group (59.6 vs 68.8 years; P < .001). Submucosal involvement was more frequent in the SRC group (94% vs 85%; P = .043), whereas lymph node involvement and number of invaded nodes were comparable between the 2 groups. When comparing SRC and non-SRC, recurrence rates (6% vs 9%; P = .223) and sites of recurrence were similar. The 5-year overall survival benefit in SRC patients (85% vs 76%, respectively; P = .035), was not evident when considering exclusively disease-specific survival or in multivariable analysis. CONCLUSION: Contrary to more advanced GA, SRC morphologic subtype is not a negative prognostic factor in early GA. Better survival identified in some reports may be related to the younger age in SRC patients.

Lymph node invasion might have more prognostic impact than R status in advanced esophageal adenocarcinoma.

BACKGROUND: Advanced esophageal adenocarcinomas are associated with 5-year survival rates ranging from 14% to 35%. Nodal status and tumor clearance are the main prognostic factors. However, their respective prognostic values have not been compared to date. METHODS: Seventy consecutive patients with stage T3 adenocarcinomas of the esophagus or gastric cardia were retrospectively assessed. Neoadjuvant therapy was indicated in all cases. Prognostic values of R0 resection and nodal status were evaluated using univariate and multivariate analyses. RESULTS: Neoadjuvant therapy was achieved in 62 patients, 41 with radiochemotherapy and 21 with perioperative chemotherapy. Transthoracic esophagectomy and transhiatal esophagectomy were performed in 54 and 15 patients, respectively. Clavien-Dindo grade III or IV complications occurred in 16 patients (23%). Two patients died in the hospital (3%). In univariate and multivariate analyses, nodal status was the main independent factor predicting overall survival; tumor clearance (R0 or R1) had less prognostic impact and was not statistically significant. Furthermore, R1 resection was a prognostic indicator for metastatic recurrence. CONCLUSIONS: These results indicate that nodal status has more prognostic impact than R status in stage T3 adenocarcinomas of the esophagus or gastric cardia. Thus, local control in R1 patients by postoperative radiotherapy is not justified.