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The presence of lymphovascular invasion (LVI) in early esophageal adenocarcinoma (EAC) is associated with more aggressive disease. Molecular markers associated with LVI are still largely unknown. Using a combination of transcriptomic analysis and validation experiments, we sought to describe markers for LVI and survival. We performed NanoString expression profiling using RNA from 60 EAC specimens collected from surgery-only cases between 2000 and 2012. Differentially expressed genes (DEGs) were correlated with pathologic characteristics (T and N status and presence of LVI). Kaplan-Meier and Cox regression analyses were used to correlate gene expression with overall survival. Expression of alanyl aminopeptidase, membrane (ANPEP)/CD13 was validated by immunohistochemistry (IHC) in EAC tissue microarray and in EAC cell lines. We identified >20 up-regulated DEGs in tumor samples containing LVI. Multivariable analysis showed depth of invasion and ANPEP /CD13 expression were independently associated with overall survival, whereas nodal status was not. IHC analysis demonstrated overexpression of the ANPEP/CD13 protein in dysplastic Barrett esophagus and EAC tumors. Kaplan-Meier analysis showed that patients with higher RNA expression and strongly positive ANPEP /CD13 membrane IHC-Histoscore staining have shorter survival (P =.002). Down-regulation of ANPEP /CD13 expression by short hairpin RNA vector reduces colony formation, migration, and invasion of FLO-1 EAC cells. Overexpression of CD13 in SKGT4 EAC cells increases colony formation, motility, and invasion in vitro. Elevated expression of ANPEP /CD13 indicates shorter survival of EAC patients and a more invasive phenotype of cancer cells in vitro. Validation in a larger sample group is required to better understand the clinical significance of ANPEP /CD13 and other candidate genes. [ABSTRACT FROM AUTHOR]

Whereas current guidelines recommend staging laparoscopy for most patients with potentially resectable gastric cancer, such a recommendation for patients with adenocarcinoma of the gastroesophageal junction (AEG) is lacking. This study sought to identify baseline clinicopathologic characteristics associated with peritoneal metastasis (PM) among patients with Siewert II AEG. Trimodality therapy–eligible patients with Siewert II AEG (2000-2015, single institution) were retrospectively identified. A composite PM outcome was defined as follows: (1) PM at staging laparoscopy; (2) PM diagnosed during neoadjuvant chemoradiation; or (3) PM ≤6 months postoperatively. Logistic regression was used to identify features associated with PM; bootstrapped analysis (Youden J) identified the distal tumor extension that best discriminated the composite outcome. Of 188 patients, a composite PM outcome was observed in 26 of 188 (13.8%); 12 of 26 had positive staging laparoscopy, 10 of 26 experienced PM during chemoradiation, and 4 of 26 had PM ≤6 months postoperatively. Tumor extension below the GEJ was greater in patients with PM (median, 4.0 cm [interquartile range, 3.0-5.0] vs 3.0 cm [interquartile range, 2.0-3.0]; P <.001). All patients with PM had cT3 to cT4 tumors. Among patients with cT3 to cT4 tumors (n = 168 of 188; 89.4%), distal tumor extent (odds ratio, 1.67/cm; 95% CI, 1.23-2.28; P =.001) was independently associated with increased odds of PM. Gastric tumor extension ≥4 cm remained independently associated with PM (OR, 5.14; 95% CI, 2.11-12.53; P <.001) after adjustment for signet ring cell status. Distal tumor extent beyond the GEJ is independently associated with increased odds of PM in patients with Siewert II AEG. Patients with extensive gastric involvement should therefore be considered for staging laparoscopy before trimodality therapy. [ABSTRACT FROM AUTHOR]

In retrospective studies the definition of salvage esophagectomy has been inconsistent and is a source of bias. We sought to describe how variability in the definition of salvage affects comparative outcomes of trimodality therapy (TMT) and bimodality therapy (BMT). Patients with locally advanced esophageal squamous cell carcinoma who completed chemoradiation therapy (CRT) from 2002 to 2017 were identified. TMT included patients who had a planned esophagectomy after CRT. BMT included patients treated with CRT only plus salvage esophagectomy, variably defined as an esophagectomy occurring (A) 3 months after CRT; (B) 3 months after CRT, excluding delayed recovery; (C) 3 months after CRT, excluding delayed workup; or (D) 6 months after CRT. Long-term survival outcomes between the TMT and BMT groups were compared for each definition of salvage esophagectomy. Time to surgery was included a priori in a multivariable model for overall survival. Of 143 patients, 90 (63%) underwent esophagectomy and 53 (37%) received CRT only. Although the total patients remained the same, the composition of the TMT and BMT groups varied by salvage definitions A through D. Various definitions resulted in different 5-year survival rates for TMT vs BMT groups: (A) 56% vs 39%, (B) 61% vs 34%, (C) 50% vs 42%, and (D) 51% vs 39%. In a Cox multivariable analysis age and proximal/middle esophageal tumors were associated with worse postoperative survival, but time to surgery was not. Slight variations in the definition of salvage esophagectomy can influence the interpretation of TMT and BMT outcomes. Future studies should consistently define treatment groups. [ABSTRACT FROM AUTHOR]

Objective: We aimed to evaluate the frequency of paratracheal lymph nodes (LN) metastases and their prognostic influence. Summary Background Data: Paratracheal LNs are considered regional nodes in the esophageal cancer classification, but their metastatic rate and influence on survival remain unclear. Methods: One thousand one hundred ninety-nine patients with resectable esophageal or gastroesophageal junction adenocarcinoma (EAC) (January 2002 and December 2016) in our Gastrointestinal Medical Oncology Database were analyzed. Paratracheal LNs were defined as1R, 1L, 2R, 2L, 4R, and 4L, according to the 8th American Joint Committee on Cancer classification. Results: Of 1199 patients, 73 (6.1%) had positive paratracheal LNs at diagnosis. The median overall survival (OS) of 73 patients with initial paratracheal LN involvement was 2.10 years (range 0.01–10.1, 5-yrs OS 24.2%). Of 1071 patients who were eligible for recurrence evaluation, 70 patients (6.5%) developed paratracheal LN metastases as the first recurrence. The median time to recurrence was 1.28 years (range 0.28–5.96 yrs) and the median OS following recurrence was only 0.95 year (range 0.03–7.88). OS in 35 patients who had only paratracheal LN recurrence was significantly longer than in patients who had other recurrences (median OS 2.26 vs 0.51 yrs, 5-yrs OS; 26.8% vs 0%, P < 0.0001). Higher T stage (T3/T4) was an independently risk factor for paratracheal LN recurrence (odds ratio 5.10, 95% confidence interval 1.46–17.89). We segregated patients in 3 groups based on the distance of tumor's proximal edge to esophagogastric junction (low; ≤2 cm, medium; 2.0–7.0 cm, and high; >7.0 cm). Paratracheal LN metastases were more frequent with the proximal tumors (low, 4.2%; medium, 12.0%; high, 30.3%; Cochran–Armitage Trend test, P < 0.001). Conclusion: Paratracheal LN metastases were associated with a shorter survival in resectable EAC patients. Alternate approaches to prolong survival of this group of patients are warranted. [ABSTRACT FROM AUTHOR]

Surgeons have shifted away from the practice of en bloc esophagectomy, particularly in the era of neoadjuvant therapies. Although some still advocate for this radical approach, contemporary data establishing its superiority are sparse. We hypothesized that a more complete, radical resection could be completed in the setting of chemoradiation without adding morbidity. Patients undergoing esophagectomy after neoadjuvant chemoradiation for esophageal adenocarcinoma from 2006-2018 were evaluated. Outcomes after right transthoracic en bloc esophagectomy were compared with standard esophagectomy to determine the impact on outcomes. A Cox proportional hazard model was evaluated, and logistic regression was performed to determine the impact of en bloc resection on postoperative morbidity. A total of 604 patients were identified, including 133 (22%) who underwent modified en bloc esophagectomy. Positive margins were most likely to occur in standard esophagectomy (35 of 471, 7%) vs en bloc (3 of 133, 2%) (P =.026). En bloc resection yielded a greater lymph node harvest (27; interquartile range, 22-36), as compared to standard esophagectomy (22; interquartile range, 17-28), P <.001. Multivariable analysis demonstrated prolonged progression-free survival with en bloc resection (hazard ratio, 0.74; P =.041), with 3-year freedom from locoregional recurrences of 78% and 90% for standard and en bloc approaches (P =.044). There were no differences in cardiopulmonary, gastrointestinal, or wound complications, as well as leak or chylothorax. Our experience demonstrates improved locoregional disease control with en bloc esophagectomy, with equivalent morbidity. Although these results may be multifactorial, including adequate clearance of both primary tumor and nodal micrometastases, this approach is safe and feasible. [ABSTRACT FROM AUTHOR]

Objective: The aim of the study was to determine the prognostic impact of co-existence of APC and PIK3CA mutations in patients undergoing preoperative chemotherapy and resection for colorectal liver metastases (CLM). Background: Co-occurring genetic events have been shown to drive carcinogenesis in multiple malignancies. Methods: We identified 396 patients with primary colorectal cancer and known somatic mutation status by next-generation sequencing who underwent hepatectomy for CLM (2005-2015). Survival after hepatectomy in patients with double mutation of APC and PIK3CA and others was analyzed. Predictors of pathologic response and survival were determined. The prognostic value of double mutation was evaluated with a separate cohort of 157 patients with CLM undergoing chemotherapy alone. Results: Forty-five patients had double mutation of APC and PIK3CA; 351 did not. Recurrence-free survival (RFS) and overall survival (OS) after hepatectomy were worse in patients with double mutation (3-year RFS, 3.1% vs 20% [P < 0.001]; 3-year OS, 44% vs 84% [P < 0.001]). Independent predictors of major pathologic response were bevacizumab use (odds ratio [OR] 2.22; P = 0.001), tumor size <3 cm (OR 1.97; P = 0.004), wild-type RAS (OR 2.00; P = 0.003), and absence of double mutation (OR 2.91; P = 0.002). Independent predictors of worse OS were primary advanced T category (hazard ratio [HR] 2.12; P = 0.021), RAS mutation (HR 1.74; P = 0.015), and double mutation (HR 3.09; P < 0.001). In the different medical cohort, patients with double mutation had worse 3-year OS of 18%, compared with 35% without double mutation (P = 0.023). Conclusions: Double mutation of APC and PIK3CA predicts inferior response to preoperative chemotherapy and poor survival in patients with CLM. [ABSTRACT FROM AUTHOR]

Adenocarcinoma of the gastroesophageal junction (AEG) poses a management challenge, as preoperative prediction of occult mediastinal nodal metastasis is difficult. We sought to identify factors predictive of mediastinal involvement among patients undergoing trimodality therapy. Patients undergoing trimodality therapy for Siewert II and III AEG at a single institution between 2000 and 2015 were identified. Mediastinal involvement was defined as pathologic nodal involvement after neoadjuvant chemoradiation (ypN+) in mediastinal stations or mediastinal recurrence 2 years or less after resection. Maximal χ2 analysis and Youden's J index were used to identify the pretreatment proximal tumor extent that best discriminated mediastinal involvement. In all, 204 patients (151 [74%] AEG II, 53 [26%] AEG III) were included, of whom 47 (23%) had clinical evidence of thoracic nodal disease. Thirty-one of the 204 patients (15%) met criteria for mediastinal involvement (24 of 31 ypN+, 10 of 31 mediastinal recurrence). Patients with mediastinal involvement had greater proximal tumor extent (median 2 cm [interquartile range, 1.0 to 3.0 cm] vs 1.4 cm [interquartile range, 0.7 to 3.0 cm], P =.030), were more frequently Siewert II lesions (27 of 31 [87.1%] vs 124 of 173 [71.7%], P =.071), and were more often observed to have clinical thoracic nodal metastasis (cN) evidence (13 of 31 [42%] vs 34 of 173 [20%], P =.007) than patients who did not. On multivariable analysis of patients with intrathoracic cN0, esophageal extent of 1.5 cm or greater was independently predictive of mediastinal involvement (odds ratio 5.46, P =.011), whereas Siewert classification was not (Siewert II odds ratio 3.48, P =.116). Pretreatment proximal tumor extent, rather than Siewert classification, is an independent predictor of mediastinal involvement among AEG II/III patients without clinical evidence of mediastinal metastasis and should be considered during treatment planning. [ABSTRACT FROM AUTHOR]

Supplemental Digital Content is available in the text Objective: To determine the impact of histology on pathologic response, survival outcomes, and recurrence patterns in patients with esophageal cancer (EC) who received neoadjuvant chemoradiotherapy (CRT). Summary of Background Data: There is a paucity of data regarding comparative outcomes after neoadjuvant CRT between esophageal squamous cell carcinoma (SCC) and adenocarcinoma. Methods: Between 2002 and 2015, 895 EC patients who underwent neoadjuvant CRT followed by esophagectomy at 3 academic institutions were retrospectively reviewed, including 207 patients with SCC (23.1%) and 688 patients with adenocarcinoma (76.9%). Pathologic response, survival, recurrence pattern, and potential prognostic factors were compared. Results: Pathologic complete response (pCR) rate was significantly higher for SCC compared with adenocarcinoma (44.9% vs 25.9%, P < 0.001). After a median follow-up of 52.9 months, 71 patients (34.3%) with SCC versus 297 patients (43.2%) with adenocarcinoma had recurrent disease (P = 0.023). For patients who achieved a pCR, no significant differences were found in recurrence pattern, sites, or survival end-points between the 2 histology groups. For non-pCR patients, the SCC group demonstrated significantly higher regional and supraclavicular recurrence rates but a lower hematogenous metastasis rate than adenocarcinoma patients, whereas the adenocarcinoma patients had a more favorable locoregional failure-free survival (P = 0.005) and worse distant metastasis-free survival (P = 0.024). No differences were found in overall survival (P = 0.772) or recurrence-free survival (P = 0.696) between groups. Conclusions: SCC was associated with a significantly higher pCR rate than adenocarcinoma. Recurrence pattern and survival outcomes were significantly different between the 2 histology subtypes in non-pCR patients. [ABSTRACT FROM AUTHOR]

Objective: To discern recurrence risk stratification and investigate its influence on postoperative surveillance in patients with esophageal adenocarcinoma (EAC) after neoadjuvant chemoradiotherapy (CRT). Background: Reports documenting recurrence risk stratification in EAC after neoadjuvant CRT are scarce. Methods: Between 1998 and 2014, 601 patients with EAC who underwent neoadjuvant CRT followed by esophagectomy were included for analysis. The pattern, site, timing, and frequency of the first recurrence and potential prognostic factors for developing recurrences were analyzed. This cohort was used as the training set to propose a recurrence risk stratification system, and the stratification was further validated in another cohort of 172 patients. Results: A total of 150 patients (25.0%) achieved pathologic complete response (pCR) after neoadjuvant CRT and the rest were defined as the non-pCR group (n = 451) in the training cohort. After a median follow-up of 63.6 months, the pCR group demonstrated a significantly lower locoregional (4.7% vs 19.1%) and distant recurrence rate (22.0% vs.44.6%) than the nonpCR group (P < 0.001). Based on independent prognostic factors, patients were stratified into 4 recurrence risk categories: pCR with clinical stage I/II, pCR with clinical stage III, non-pCR with pN0, and non-pCR with pN+, with corresponding 5-year recurrence-free survival rates of 88.7%, 65.8%, 55.3%, and 33.0%, respectively (P < 0.001). The risk stratification was reproducible in the validation cohort. Conclusions: We proposed a recurrence risk stratification system for EAC patients based on pathologic response and pretreatment clinical stage. Riskbased postoperative surveillance strategies could be developed for different risk categories. [ABSTRACT FROM AUTHOR]

Introduction Dorsophilia protein, mothers against decapentaplegic homolog 4 (SMAD4) is a key mediator in the transforming growth factor (TGF)-β signaling pathway and SMAD4 gene mutations are thought to play a critical role in colorectal cancer (CRC) progression. However, little is known about its influence on survival in patients undergoing resection for colorectal liver metastases (CLM). Methods Between 2005 and 2015, all patients with known SMAD4 mutation status who underwent resection of CLM were identified. Patients with SMAD4 mutation were compared to those with SMAD4 wild type. Next, the prognostic value of SMAD4 mutation was validated in a separate cohort of patients with synchronous stage IV CRC who underwent systemic therapy alone. Results Of 278 patients, 37 (13%) were SMAD4 mutant while 241 (87%) were wild type. Overall survival (OS) after hepatic resection was worse in SMAD4 -mutant patients compared to SMAD4 wild type (OS rate at 3 years, 62% vs. 82%; P < 0.0001). Independent predictors for worse OS were poor differentiation (hazard ratio [HR] 2.586; P = 0.007), multiple tumors (HR 1.970; P = 0.01), diameter greater than 3 cm (HR 1.752; P = 0.017), R1 margin status (HR 2.452; P = 0.014), RAS mutation (HR 2.044; P = 0.002), and SMAD4 mutation (HR 2.773; P < 0.0001). Among 237 patients in the validation cohort, SMAD4 -mutations were significantly associated with worse 3-year OS rate (22% vs. 38%; P = 0.012) and was an independent predictor for worse OS (HR, 1.647; P = 0.032). Conclusion SMAD4 mutation is independently associated with worse outcomes among patients undergoing resection of CLM. [ABSTRACT FROM AUTHOR]

Background: The aim of this study was to determine the prognostic value of embryonic origin in patients undergoing resection after chemotherapy for colon cancer liver metastases (CCLM). Methods: We identified 725 patients with primary colon cancer and known RAS mutation status who underwent hepatic resection after preoperative chemotherapy for CCLM (1990 to 2015). Survival after resection of CCLM from midgut origin (n = 238) and hindgut origin (n = 487) was analyzed. Predictors of pathologic response and survival were determined. Prognostic value of embryonic origin was validated with a separate cohort of 252 patients with primary colon cancer who underwent resection of CCLM without preoperative chemotherapy. Results: Recurrence-free survival (RFS) and overall survival (OS) after hepatic resection were worse in patients with midgut origin tumors (RFS rate at 3 years: 15% vs 27%, P < 0.001; OS rate at 3 years: 46% vs 68%, P < 0.001). Independent factors associated with minor pathologic response were midgut embryonic origin [odds ratio (OR) 1.55, P = 0.010], absence of bevacizumab (OR 1.42, P = 0.034), and mutant RAS (OR 1.41, P = 0.043). Independent factors associated with worse OS were midgut embryonic origin [hazard ratio (HR) 2.04, P < 0.001], carcinoembryonic antigen value ≥5 ng/ mL at hepatic resection (HR 1.46, P = 0.0021), synchronous CCLM (HR 1.45, P = 0.012), and mutant RAS (HR 1.43, P = 0.0040). In the validation cohort, patients with CCLM of midgut origin had a worse 3-year OS rate (55% vs 78%, P = 0.003). Conclusions: Compared with CCLM from hindgut origin, CCLM from midgut origin are associated with worse pathologic response to chemotherapy and worse survival after resection. This effect appears to be independent of RAS mutation status. [ABSTRACT FROM AUTHOR]

Background Recent genomic studies indicated that esophageal adenocarcinoma (EAC) is driven by amplification of c-MET or HER2 or both in a subset of patients. We studied the effect of MET targeting by the small molecule inhibitor foretinib in EAC cells and the interplay between MET and HER2 signaling. Methods We measured the expression levels and phosphorylation status of MET and HER2 proteins in EAC cell lines using Western blot analysis. The expression levels of MET and HER2 were manipulated by transfecting cells with specific siRNA or a plasmid expressing HER2. The small molecule inhibitors of c-MET and ERBB1/2 (foretinib and lapatinib, respectively) were tested for effect on growth, apoptosis, and downstream signaling pathways of EAC cells as single agents or in combination. The response to inhibitors was correlated to the levels of MET, HER2 expression, and amplification status. Results Foretinib inhibits phosphorylation of MET, which correlated with reduced EAC cell growth and inhibition of AKT and ERK phosphorylation. Cell growth inhibition by foretinib is most profound in the ESO51 cell line, which has MET gene amplification and overexpression. Inhibition of MET signaling by foretinib or siRNA-specific knock down of MET expression induces apoptosis in ESO51 cells. Ectopic expression of HER2 reduces foretinib-mediated growth inhibition and downstream ERK phosphorylation in ESO51-HER2 cells. The EAC OE33 cell line, with amplification and overexpression of both MET and HER2, demonstrated reduced sensitivity to foretinib or lapatinib and had a transient effect on downstream inhibition of phosphorylated AKT and ERK (p-AKT, p-ERK). The coadministration of foretinib and lapatinib effectively blocked both MET and HER2 signaling through the p-AKT and p-ERK pathways, dramatically inhibited growth, and induced apoptosis to overcome single-agent resistance in OE33 cells. Conclusions The mechanism for foretinib growth inhibition in MET-amplified EAC tumor cells is demonstrated. The interplay of dual MET/HER2 overexpression in the AKT and ERK pathways for esophageal cancer is described. Therefore, combination therapy could be a novel strategy for EAC with amplification of both MET and HER2. [ABSTRACT FROM AUTHOR]

Background RAS mutations are associated with limited overall survival after resection of colorectal liver metastases. Our aim was to determine criteria for considering hepatectomy for patients with RAS mutant colorectal liver metastases. Methods Of 1,163 patients who underwent liver resection for colorectal liver metastases during 2005–2014, all patients operated on with curative intent who had known RAS mutation status were included. Factors associated with overall survival were determined using multivariate analysis. Results A total of 524 patients met the inclusion criteria; 212 (40%) had mutated RAS. Mutations were located on codon 12 in 128 patients (60%) and codon 13 in 29 (14%). At median follow-up of 38 months, median overall survival was 72.6 months for wild-type RAS and 50.9 months for mutated RAS ( P < .001). Median overall survival for patients with codon 12 and 13 mutations was 51.9 and 50.9 months, respectively ( P = .839), significantly worse than for patients with wild-type RAS ( P = .005, and P = .038 for codon 12 and 13, respectively). For patients with RAS mutation, factors associated independently with worse overall survival were node-positive primary tumor, tumor >3 cm, and >7 cycles of preoperative chemotherapy. Major and 2-stage hepatectomy were not associated independently with overall survival. Median overall survival was 57, 41, and 21.5 months for patients with 1, 2, and 3 risk factors, respectively. There were no 4-year survivors in the highest-risk group. Conclusion Patients with multiple risk factors had poor overall survival after curative resection of RAS mutant colorectal liver metastases. For such patients, hepatectomy may be ill advised, and alternative therapies or further systemic therapy should be considered. [ABSTRACT FROM AUTHOR]

Background Endoscopic resection is increasingly utilized for treating early stage esophageal cancer, and endoscopic ultrasound (EUS) frequently guides treatment selection. Studies report greater than 80% sensitivity and 90% specificity, but our experience suggests less accuracy at the gastroesophageal (GE) junction. The objective of this study is to determine the accuracy of EUS for depth of GE junction cancer and the potential treatment implications. Methods A retrospective review of a prospective database was performed for patients from 1995 to 2014 with GE junction esophageal cancer that underwent EUS staging and resection (surgical or endoscopic) without neo-adjuvant therapy. Patient, tumor, EUS, and pathologic characteristics were examined. Results For the 181 patients that met criteria, the median age was 66 years, 17% were female, 91% white, and 98% had adenocarcinoma. Concordance between EUS (u) T and pathologic (p) T was 48%, with 23% under-staged and 29% over-staged. The EUS was accurate in the following: uT0 6% (1 of 18); uT1a 56% (23 of 41); uT1b 58% (41 of 71); uT2 10% (2 of 21); and uT3 70% (21 of 30). Inaccurate EUS depth had potential to lead to over-treatment in 38% (27 of 71) of uT1b and 76% (16 of 21) of uT2. In 50% of pT1a tumors, EUS depth was T1b or greater. Logistic regression revealed tumor length (continuous variable) to be associated with inaccurate uT ( p = 0.016). Accurately staged tumors were significantly longer than inaccurately staged tumors (2.7 vs 1.7 cm, p = 0.011). Conclusions Early to intermediate GE junction tumors are frequently over-staged. This highlights the importance of diagnostic endoscopic resection for determining accurate tumor depth and selecting correct therapy. [ABSTRACT FROM AUTHOR]

Tumor response to neoadjuvant therapy is a significant predictive indicator of recurrence-free survival. We measured tumor response using residual tumor thickness at the tumor-normal tissue interface (TNI) and evaluated its association with outcome in patients with liver metastasis of breast cancer. We included 48 patients who underwent neoadjuvant therapy followed by partial liver resection at MD Anderson Cancer Center between 1997 and 2010. The hematoxylin-eosin–stained tumor sections were evaluated for both pathologic response and the residual tumor thickness at the TNI by 3 pathologists who were blinded to the clinical information, treatment regimen, and patient outcome. The residual tumor thickness at the TNI was correlated with recurrence-free survival using Kaplan-Meier method and log-rank test. Cox proportional hazard model was used to identify predictors of recurrence-free survival. All patients were women with a median age of 43 years. The median duration of follow-up was 52.1 months. Residual tumor thickness less than or equal to 3 mm at the TNI correlated with major pathologic response and was associated with longer recurrence-free survival in both univariate and multivariate analyses. Residual tumor thickness at the TNI predicts recurrence-free survival and provides an objective outcome end point in patients who underwent neoadjuvant therapy and liver resection of metastatic breast cancer. We suggest using both the pathologic response and the residual tumor thickness at the TNI to measure tumor response to therapy to improve accuracy. [ABSTRACT FROM AUTHOR]

Background The purpose of this study was to examine the significance of signet ring cell histology to predict response to preoperative chemoradiotherapy in patients with esophageal adenocarcinoma. Methods Two groups of patients with locoregional esophageal adenocarcinoma treated with neoadjuvant chemoradiation and surgery were studied: those with signet ring cell adenocarcinoma (n = 85) and a reference group (n = 638) with usual and other types of adenocarcinoma. Surgical specimens were reviewed for degree of pathologic response and pathologic stage. Cox regression models were used to assess the effects of clinicopathologic variables on survival. Results Tumors from patients in the signet ring cell group had a lower rate of complete pathologic response (9% versus 26%, p < 0.001) and more frequent positive margins (24% versus 10%, p < 0.001) compared with tumors from the reference group. Median overall survival (22 versus 48 months, p = 0.003) and disease-free survival (16 versus 35 months, p = 0.007) were shorter in the signet ring cell group than in the reference group. Signet ring cell histology and high pathologic stage were significant predictors of decreased overall survival and disease-free survival. Survival durations for patients whose resected specimens showed downstaging after neoadjuvant chemoradiation did not significantly differ from survival durations of patients whose specimens did not show downstaging in the signet ring cell group, unlike the reference group. Conclusions Signet ring cell histology on pretreatment biopsy predicts a decreased likelihood of complete pathologic response and survival for patients with esophageal adenocarcinoma treated with preoperative chemoradiation and surgery. [ABSTRACT FROM AUTHOR]

Background: Outcomes of salvage esophagectomy after definitive chemoradiation (CRT) for squamous cell carcinoma are well defined. Previous reports of salvage esophagectomy in patients with recurrent adenocarcinoma after definitive CRT are limited by small numbers and high morbidity and mortality rates. Methods: We reviewed our experience of 65 patients with esophageal adenocarcinoma treated from 1997 to 2010 who underwent salvage esophagectomy after failed definitive CRT. We then compared this group to 65 matched patients of 521 total patients with esophageal adenocarcinoma who received preoperative CRT followed by planned esophagectomy. Propensity matching and multivariable analysis were performed. Results: Median time to surgery from completion of therapy for the salvage group was 216 days. Major postoperative events (major pulmonary event, conduit loss, leak, readmission to intensive care unit) occurred in 35% (23 of 65) of salvage patients and 31% (20 of 65) of the planned resection matched group. Anastomotic leak occurred in 18.5% (12 of 65) and 11.3 (59 of 521) of salvage and planned groups, respectively. Thirty-day mortality was 3.1% (2 of 65) after salvage resection and 4.6% (3 of 65) after planned resection. There was no difference in 3-year overall or median survival between the two groups of patients (32 months, 48% salvage, versus 40 months, 57% planned resection). Multivariable analysis did not identify salvage strategy or time from completion of therapy to resection as a predictor of major event or death. Conclusions: Postoperative morbidity, mortality, and overall survival of patients after salvage esophagectomy are comparable to matched patients after planned resection. These results suggest that patients with esophageal adenocarcinoma who fail definitive CRT and recur locoregionally should be considered for salvage esophagectomy at experienced esophageal centers. [ABSTRACT FROM AUTHOR]

Background: Confocal endomicroscopy has revolutionized endoscopy by offering subcellular images of the GI epithelium; however, the field of view is limited. Multiscale endoscopy platforms that use widefield imaging are needed to better direct the placement of high-resolution probes. Design: Feasibility study. Objective: This study evaluated the feasibility of a single agent, proflavine hemisulfate, as a contrast medium during both widefield and high-resolution imaging to characterize the morphologic changes associated with a variety of GI conditions. Setting: The University of Texas MD Anderson Cancer Center, Houston, Texas, and Mount Sinai Medical Center, New York, New York. Patients, Interventions, and Main Outcome Measurements: Resected specimens were obtained from 15 patients undergoing EMR, esophagectomy, or colectomy. Proflavine hemisulfate, a vital fluorescent dye, was applied topically. The specimens were imaged with a widefield multispectral microscope and a high-resolution microendoscope. The images were compared with histopathologic examination. Results: Widefield fluorescence imaging enhanced visualization of morphology, including the presence and spatial distribution of glands, glandular distortion, atrophy, and crowding. High-resolution imaging of widefield abnormal areas revealed that neoplastic progression corresponded to glandular heterogeneity and nuclear crowding in dysplasia, with glandular effacement in carcinoma. These widefield and high-resolution image features correlated well with the histopathologic features. Limitations: This imaging approach must be validated in vivo with a larger sample size. Conclusions: Multiscale proflavine-enhanced fluorescence imaging can delineate epithelial changes in a variety of GI conditions. Distorted glandular features seen with widefield imaging could serve as a critical bridge to high-resolution probe placement. An endoscopic platform combining the two modalities with a single vital dye may facilitate point-of-care decision making by providing real-time, in vivo diagnoses. [Copyright &y& Elsevier]

Objectives: The incidence and consequence of an isolated involved circumferential radial margin (CRM) after resection for esophageal adenocarcinoma in the setting of neoadjuvant chemoradiotherapy (CRT) has not been reported. We aimed to determine the frequency and significance of a close (<1 mm) or involved CRM in patients undergoing esophagectomy after CRT. Methods: We retrospectively analyzed the data from patients undergoing resection from 1997 to 2008 for esophageal adenocarcinoma after neoadjuvant CRT. A positive CRM was defined as microscopic tumor at or less than 1 mm of the radial margin. An R1 resection was tumor at the radial margin. Only patients with ypT3 or greater tumors were included. R2 resections were excluded. Statistical comparisons were performed using Cox regression and Kaplan-Meier analyses. Results: A total of 160 patients met the inclusion criteria, 42 (26%) had a positive CRM. The median survival did not significantly differ between the CRM-negative and -positive groups (28 vs 50 months, P = .84). A propensity score matching analysis also failed to find a significant difference in outcomes. When analyzed by tumor present at the margin (R1), R0 patients had a longer median survival compared with R1 patients (28 vs 8 months, P = .01). This difference, however, was not seen on propensity score matching. Conclusions: Resections of locally advanced esophageal adenocarcinoma with residual transmural viable tumor after CRT frequently showed involvement of the radial margin with tumor either close to or at the margin. Tumor close (<1 mm) to the radial margin did not result in a significant decrease in overall or disease-free survival or increase in local recurrence. [ABSTRACT FROM AUTHOR]

Background: After neoadjuvant chemoradiation (CXRT) for esophageal cancer, surgery has traditionally been recommended to be performed within 8 weeks. However, surgery is often delayed for various reasons. Data from other cancers suggest that delaying surgery may increase the pathologic complete response rate. However, there are theoretical concerns that waiting longer after radiation may lead to a more difficult operation and more complications. The optimal timing of esophagectomy after CXRT is unknown. Methods: From a prospective database, we analyzed 266 patients with resected esophageal cancer who were treated with neoadjuvant CXRT from 2002 to 2008. Salvage resections were excluded from this analysis. We compared patients who had surgery within 8 weeks of CXRT and those who had surgery after 8 weeks. We used multivariable analysis to determine whether increased interval between chemoradiation and surgery was independently associated with perioperative complication, pathologic response, or overall survival. Results: One hundred fifty patients were resected within 8 weeks and 116 were resected greater than 8 weeks after completing CXRT. Mean length of operation, intraoperative blood loss, anastomotic leak rate, and perioperative complication rate were similar for the two groups. Pathologic complete response rate and overall survival were also similar for the two groups (p = not significant). In multivariable analysis, timing of surgery was not an independent predictor of perioperative complication, pathologic complete response, or overall survival. Conclusions: The timing of esophagectomy after neoadjuvant CXRT is not associated with perioperative complication, pathologic response, or overall survival. It may be reasonable to delay esophagectomy beyond 8 weeks for patients who have not yet recovered from chemoradiation. [ABSTRACT FROM AUTHOR]

Summary: Pancreatic heterotopia has been described at several abdominal and intrathoracic locations, most commonly in the stomach and upper part of the small intestine. Its occurrence in the rectum is unusual, and malignant transformation in the rectum has not been reported. We report a case of ductal adenocarcinoma arising in a rectal pancreatic heterotopia in a 42-year-old woman with delayed local recurrence. The tumor was composed of well to moderately differentiated ductal adenocarcinoma infiltrating through the full thickness of the anorectal wall with extension into the vaginal septum. A focus of ectopic pancreas consisting of exocrine acini and small ducts adjacent to the tumor with some ducts showing mild to severe dysplasia reminiscent of pancreatic intraepithelial neoplasia was also observed. Although our literature search found 31 documented reports of tumors arising in the heterotopic pancreas, the present case is the first case of ductal adenocarcinoma arising in a focus of pancreatic heterotopia in the rectum. [Copyright &y& Elsevier]

Background: Controversy currently exists about the optimum preoperative treatment platform for locoregionally advanced esophageal cancer, namely, preoperative chemoradiotherapy (preoperative C/RT) or preoperative chemotherapy alone. We therefore reviewed sequential phase II/III trials performed at a single institution to assess the impact of preoperative chemotherapy versus preoperative C/RT strategies. Methods: In all, 157 esophageal cancer patients were sequentially enrolled in phase II/III trials at the University of Texas M.D. Anderson Cancer Center from March 27, 1990, to March 8, 2005. The treatment approaches included preoperative chemotherapy, n = 76 (INT 113 and ID90-01); preoperative C/RT, n = 81 (ID96-189 and DM98-349). Analysis was by intention to treat. Factors evaluated included demographics, preoperative staging, type of surgery, pathology, adjuvant therapies, and long-term outcome. Results: Adenocarcinoma predominated (85%), with cT3 (73%) and cN1 (43%). No significant difference was noted between groups in demographics or perioperative mortality. More patients with preoperative C/RT were staged with endoscopic ultrasound (52% versus 9%, p < 0.001). Preoperative C/RT demonstrated increased pathologic complete response (28% versus 4%, p < 0.001) and overall survival (3 years, 48% versus 29%, p = 0.04). Preoperative C/RT was a significant independent predictor of improved overall survival (hazard ratio 0.58, 95% confidence interval: 0.37 to 0.90, p = 0.015) and disease-free survival (hazard ratio 0.55, 95% confidence interval: 0.35 to 0.85, p = 0.007) in multivariable regression. Conclusions: In sequential phase II/III trials involving locoregionally advanced esophageal cancer patients, preoperative C/RT was associated with improved overall and disease-free survival rates (p = 0.046 and p = 0.015, respectively) and increased pathologic complete response (p < 0.001) compared with preoperative chemotherapy. [ABSTRACT FROM AUTHOR]

Background: Patients with esophageal carcinoma who appear to have a complete response at the primary tumor site after undergoing neoadjuvant chemoradiotherapy may still have residual disease in regional lymph nodes despite clinically negative restaging (ypT0N1). We hypothesized that these patients would have similar survival to patients with incomplete response to therapy. Methods: We reviewed 336 esophageal cancer patients who received neoadjuvant chemoradiotherapy followed by complete resection. We identified 20 patients who obtained complete pathologic response at the primary tumor with persistent metastatic disease to regional lymph nodes (ypT0N1). These patients were compared to 123 patients with pathologic complete response and 193 with partial response for overall survival. Results: Demographics among the three groups of patients were similar except that this cohort of patients with ypT0N1 had higher initial clinical stage (p = 0.013) and had more squamous cell carcinoma pathology (p = 0.005). Eighty-six percent of the ypT0N1 patients who had modern preoperative staging were felt to have clinical complete response. Five-year survival of ypT0N1 patients was intermediate, similar to pathologic partial response stage II patients in both the sixth and seventh editions of the American Joint Committee on Cancer staging criteria. Conclusions: Clinical staging of complete response to chemoradiotherapy may not translate to pathologic complete response. Patients with ypT0N1 disease at resection have intermediate but reasonable survival, justifying an aggressive approach to curative therapy. Future revisions of the staging system should place this group of patients with patients who have metastatic regional lymph nodes, stratified by number of nodes involved. [ABSTRACT FROM AUTHOR]

Introduction: The impact of esophageal tumor length on pT1 esophageal adenocarcinoma has not been well evaluated. Methods: Case histories of all patients (n = 133) undergoing esophageal resection from 1979 to 2007 with pT1 adenocarcinoma of the esophagus were reviewed. Univariate and multivariate analyses of esophageal tumor length and other standard prognostic factors were performed. Results: Patients with early-stage pT1 esophageal adenocarcinoma with tumors less than 3 cm demonstrate decreased long-term survival (3 years: >3 cm = 46% vs 93%; P < .001) and higher risk of lymph node involvement (lymph node positive: >3 cm = 47% vs 10%; P < .001). Multivariable analysis shows that esophageal tumor length (>3 cm) is an independent risk factor for survival in patients with pT1 early-stage esophageal cancer (hazard ratio: 4.8, 95% confidence intervals: 1.4–16.5; P < .001) even when controlled for submucosal involvement, lymph node involvement, and lymphatic/vascular invasion status. In combination with submucosal involvement, esophageal tumor length (>3 cm) identifies a high-risk population of pT1 esophageal adenocarcinoma (3 years: group 1 [0 risk factors] = 100%, group 2 [1 risk factor] = 87%, and group 3 [2 risk factors] = 33%; P < .001). Conclusions: This study demonstrates that esophageal tumor length (>3 cm) is a risk factor for long-term survival and lymph node involvement in early-stage pT1 esophageal adenocarcinoma. Esophageal tumor length (>3 cm) in combination with submucosal involvement may help to identify a high-risk group of patients with pT1 esophageal adenocarcinoma. [Copyright &y& Elsevier]

Abstract: Inclusion of histologic classification into the risk assessment of adenocarcinoma arising from Barrett''s esophagus (BE) has placed surgical pathologist in the center of clinical care and research endeavors. Recent advances in endoscopic diagnostic and therapeutic modalities demand additional proficiency in diagnosis and grading of dysplasia. The objectives of this study are as follows: (1) Discuss the definition of BE and features differentiating BE vs intestinal metaplasia involving cardia. (2) Describe the morphological approach of diagnosing and grading of dysplasia and differentiation of high-grade dysplasia from intramucosal carcinoma. (3) Role of special stains in diagnosis of BE and dysplasia. (4) Brief review the literature on histologic and endoscopic factors associated with progression of BE to adenocarcinoma. (5) Discuss the biomarkers in progression of BE to adenocarcinoma. The following conclusions from this review are important and should be applied in routine practice. Because of the controversy in defining BE, the histologic type of columnar mucosa and presence or absence of intestinal metaplasia should be specified in pathology report. The major limitations of appropriately diagnosing and grading dysplasia include technical problems related to biopsy processing and staining, presence of acute inflammation, and high interobserver variations among pathologists. The extent of high-grade dysplasia, high-grade dysplasia with certain endoscopic abnormalities, and low-grade dysplasia, when diagnosed with consensus by 2 or 3 gastrointestinal pathologists, has higher risk of progression to adenocarcinoma. All nonhistologic markers are still in the investigational phase and have not yet been validated in phase 3/4 prospective trials. [Copyright &y& Elsevier]

Background: This report describes the clinical evaluation of a novel, low-cost, high-resolution endoscopic microscope for obtaining fluorescent images of the cellular morphology of the epithelium of regions of the esophagus with Barrett''s metaplasia. This noninvasive point imaging system offers a method for obtaining real-time histologic information during endoscopy. Objective: The objective of this study was to compare images taken with the fiberoptic endoscopic microscope with standard histopathologic examination. Design: Feasibility study. Setting: The University of Texas M.D. Anderson Cancer Center Department of Gastroenterology. Patients, Interventions, and Main Outcome Measurements: The tissue samples studied in this report were obtained by endoscopic resection from patients with previous diagnoses of either high-grade dysplasia or esophageal adenocarcinoma. Results: Three distinct tissue types were observed ex vivo with the endoscopic microscope: normal squamous mucosa, Barrett''s metaplasia, and high-grade dysplasia. Squamous tissue was identified by bright nuclei surrounded by dark cytoplasm in an ordered pattern. Barrett''s metaplasia could be identified by large glandular structures with intact nuclear polarity. High-grade dysplasia was visualized as plentiful, irregular glandular structures and loss of nuclear polarity. Standard histopathologic examination of study samples confirmed the results obtained by the endoscopic microscope. Limitations: The endoscopic microscope probe had to be placed into direct contact with tissue. Conclusions: It was feasible to obtain high-resolution histopathologic information using the endoscopic microscope device. Future improvement and integration with widefield endoscopic techniques will aid in improving the sensitivity of detection of dysplasia and early cancer development in the esophagus. [Copyright &y& Elsevier]

Background: The current American Joint Committee on Cancer (AJCC) esophageal cancer staging for nodal status is difficult to interpret and is based solely on lymph node location relative to the primary tumor’s esophageal location. Recent reports suggest that the number of lymph nodes involved is also an important factor. We reviewed our esophageal experience to propose an improved nodal staging system. Methods: In all, 1,027 patients with resected esophageal cancer from 1970 to 2005 were reviewed. Lymph nodes stations were assigned according to AJCC criteria. Overall survival was assessed by Kaplan-Meier analysis. The impact of location, number of involved lymph nodes, and use of preoperative chemotherapy or radiation therapy, or both, was assessed. Results: Nonregional nodal involvement (n = 17) was associated with decreased survival compared with regional (n = 441) or celiac nodal (n = 73) involvement (3-year: 0% versus 24% and 23%; p < 0.001). The number of involved lymph nodes was strongly associated with survival (3-year: 0 nodes = 63%, 1 to 3 nodes = 31%, more than 3 nodes = 13%; p < 0.001), and multivariable Cox proportional-hazards analysis suggested that the location and number of involved lymph nodes were independent predictors of survival (p < 0.001). We propose a modified nodal staging system that designates celiac nodes as regional and includes number of involved nodes: pN0, no nodes (3 years = 63%, n = 496); pN1-regional, 1 to 3 nodes (3 years = 32%, n = 292); pN2-regional, more than 3 nodes (3 years = 14%, n = 222); pN3-nonregional node (3 years = 0%, n = 17 [p < 0.0001]). This modified nodal staging system better predicts survival than the current AJCC nodal staging system in which survival for pN1 (3 years = 24%) and pM1a (3 years = 23%) do not differ (p = 0.67). The use of induction before surgical resection did not alter the predictive effect of the new nodal staging system. Conclusions: Modification of the AJCC nodal classification system to incorporate the number of involved lymph nodes with regional and nonregional node location simplifies and better predicts long-term survival than does the current AJCC nodal system. [Copyright &y& Elsevier]

Multiple investigations have shown inferior outcomes for esophageal cancer patients with signet ring cell (SRC) histology. Traditionally, SRC adenocarcinoma has been defined by ≥50% of the tumor composed of SRC. We hypothesized that patients with SRC even <50% would show resistance to standard multimodality therapy with poorer long-term outcomes. Patients treated with trimodality therapy for adenocarcinoma from 2006 to 2018 were evaluated for SRC on pretreatment biopsy specimens. Available hematoxylin and eosin slides containing SRC tumors were re-reviewed by an esophageal pathologist to quantify the percent composition of SRC. SRC histology was identified on at least 1 pathologic specimen in 106 of 819 (13%) patients. Rates of pathologic complete response (pCR) among usual-type and SRC tumors were 25% (177/713) and 10% (11/106), respectively (P =.006). The pretreatment SRC components did not independently affect the rate of pCR (1%-10% SRC: 4% [2/46] pCR; 11%-49% SRC: 25% [7/28] pCR; 50%-100% SRC: 7% [2/30] pCR). Kaplan–Meier analysis demonstrated worse survival among patients with any degree of SRC present on pretreatment biopsy, as compared with usual-type esophageal adenocarcinoma (P <.0001). Cox multivariable analysis failed to identify a relationship between increasing SRC component and poorer survival. We present the only known evaluation of the percentage of SRC component in esophageal carcinoma. Our data support the hypothesis that esophageal adenocarcinoma with any component of SRC are more resistant to chemoradiation with poorer survival. Pathologic reporting of esophageal adenocarcinoma should include any component of SRC. Alternative therapies in patients with any SRC component may be indicated. [Display omitted] [ABSTRACT FROM AUTHOR]

Biomarkers are needed to risk stratify after chemoradiotherapy for localized esophageal cancer. These could improve identification of patients at risk for cancer progression and selection of additional therapy. We performed deep sequencing (CAncer Personalized Profiling by deep Sequencing, [CAPP-Seq]) analyses of plasma cell-free DNA collected from 45 patients before and after chemoradiotherapy for esophageal cancer, as well as DNA from leukocytes and fixed esophageal tumor biopsy samples collected during esophagogastroduodenoscopy. Patients were treated from May 2010 through October 2015; 23 patients subsequently underwent esophagectomy, and 22 did not undergo surgery. We also sequenced DNA from blood samples from 40 healthy control individuals. We analyzed 802 regions of 607 genes for single-nucleotide variants previously associated with esophageal adenocarcinoma or squamous cell carcinoma. Patients underwent imaging analyses 6–8 weeks after chemoradiotherapy and were followed for 5 years. Our primary aim was to determine whether detection of circulating tumor DNA (ctDNA) after chemoradiotherapy is associated with risk of tumor progression (growth of local, regional, or distant tumors, detected by imaging or biopsy). The median proportion of tumor-derived DNA in total cell-free DNA before treatment was 0.07%, indicating that ultrasensitive assays are needed for quantification and analysis of ctDNA from localized esophageal tumors. Detection of ctDNA after chemoradiotherapy was associated with tumor progression (hazard ratio, 18.7; P <.0001), formation of distant metastases (hazard ratio, 32.1; P <.0001), and shorter disease-specific survival times (hazard ratio, 23.1; P <.0001). A higher proportion of patients with tumor progression had new mutations detected in plasma samples collected after chemoradiotherapy than patients without progression (P =.03). Detection of ctDNA after chemoradiotherapy preceded radiographic evidence of tumor progression by an average of 2.8 months. Among patients who received chemoradiotherapy without surgery, combined ctDNA and metabolic imaging analysis predicted progression in 100% of patients with tumor progression, compared with 71% for only ctDNA detection and 57% for only metabolic imaging analysis (P <.001 for comparison of either technique to combined analysis). In an analysis of cell-free DNA in blood samples from patients who underwent chemoradiotherapy for esophageal cancer, detection of ctDNA was associated with tumor progression, metastasis, and disease-specific survival. Analysis of ctDNA might be used to identify patients at highest risk for tumor progression. [ABSTRACT FROM AUTHOR]

Objectives Endoscopic mucosal resection (EMR) is a diagnostic and potentially therapeutic option for patients with submucosal esophageal adenocarcinoma. However, there are significant concerns regarding the risk of lymph node metastasis. Our purpose was to construct a comparative effectiveness analysis comparing recurrence patterns after therapeutic EMR or esophagectomy. Methods Patients who underwent therapeutic EMR or esophagectomy from 2007 to 2015 with pathologically staged submucosal adenocarcinoma were identified from a departmental database. Cancer-related outcomes were compared among an unmatched as well as a propensity matched cohort. Risk stratification was also used to compare results among those with a low, medium, or high risk of nodal metastasis. Results Seventy-two patients met criteria for analysis, among whom 23 underwent therapeutic EMR with esophageal preservation and 49 underwent esophagectomy. Median follow-up was 43 months. Patients who underwent esophagectomy had larger, deeper tumors. Esophageal preservation was associated with an increased risk of local recurrence ( P = .01), but not distant recurrence ( P = .44). After propensity matching, there continued to be no difference in distant recurrence rate ( P = .66). In a risk-stratified analysis, low-risk patients showed no recurrences or cancer-related deaths, however, high-risk patients showed a trend toward increased distant recurrence after therapeutic EMR. Conclusions Esophageal preservation after therapeutic EMR was associated with an increased risk of local recurrence. Among low-risk patients, either strategy resulted in excellent cancer control. However, among high-risk patients, esophageal preservation showed a trend toward increased distant failure. These findings should prompt further investigation to determine optimal treatment for patients with submucosal esophageal adenocarcinoma. [ABSTRACT FROM AUTHOR]