Endoscopy for the diagnosis and treatment of gastrointestinal bleeding caused by malignancy.

BACKGROUND AND AIM: The diagnosis and treatment of gastrointestinal (GI) bleeding secondary to malignancy can be challenging. Endoscopy is the gold standard to diagnose and treat gastrointestinal bleeding but clinical characteristics and outcomes of patients with malignancy-related bleeding are not well understood. This study aims to look at clinical characteristics, endoscopic findings, safety and clinical outcomes of endoscopic interventions for GI malignancy-related bleeding. METHODS: We retrospectively reviewed outcomes of patients with confirmed GI malignancies who underwent endoscopy for GI bleeding at MD Anderson Cancer Center between 2010 and 2019. Cox hazard analysis was conducted to identify factors associated with survival. RESULTS: A total of 313 patients were included, with median age of 59 years; 74.8% were male. The stomach (30.0%) was the most common tumor location. Active bleeding was evident endoscopically in 47.3% of patients. Most patients (77.3%) did not receive endoscopic treatment. Of the patients who received endoscopic treatment, 57.7% had hemostasis. No endoscopy-related adverse events were recorded. Endoscopic treatment was associated with hemostasis (P < 0.001), but not decreased recurrent bleeding or mortality. Absence of active bleeding on endoscopy, stable hemodynamic status at presentation, lower cancer stage, and surgical intervention were associated with improved survival. CONCLUSIONS: This study indicates that endoscopy is a safe diagnostic tool in this patient population; while endoscopic treatments may help achieve hemostasis, it may not decrease the risk of recurrent bleeding or improve survival.

Navigating Nodal Metrics for Node-Positive Gastric Cancer in the United States: An NCDB-Based Study and Validation of AJCC Guidelines.

BACKGROUND: The optimal number of examined lymph nodes (ELNs) and the positive lymph node ratio (LNR) for potentially curable gastric cancer are not established. We sought to determine clinical benchmarks for these values using a large national database. METHODS: Demographic, clinicopathologic, and treatment-related data from patients treated using an R0, curative-intent gastrectomy registered in the National Cancer Database during 2004 to 2016 were evaluated. Patients with node-positive (pTxN+M0) disease were considered for analysis. RESULTS: A total of 22,018 patients met the inclusion criteria, with a median follow-up of 2.2 years. Mean age at diagnosis was 65.6 years, 66% were male, 68% were White, 33% of tumors were located near the gastroesophageal junction, and 29% of patients had undergone preoperative therapy. Most primary tumors (62%) were category pT3-4, 67% had a poor or anaplastic grade, and 19% had signet features. Clinical nodal staging was inaccurate compared with staging at final pathology. The mean [SD] number of nodes examined was 19 [11]. On multivariable analysis, the pN category, ELNs, and LNR were independently associated with survival (all P<.0001). Using receiver operating characteristic (ROC) analysis, an optimal ELN threshold of ≥30 was established for patients with pN3b disease and was applied to the entire cohort. Node positivity and LNR had minimal change beyond 30 examined nodes. Stage-specific LNR thresholds calculated by ROC analysis were 11% for pN1, 28% for pN2, 58% for pN3a, 64% for pN3b, 30% for total combined. By using an ELN threshold of ≥30, prognostically advantageous stage-specific LNR values could be determined for 96% of evaluated patients. CONCLUSIONS: Using a large national cancer registry, we determined that an ELN threshold of ≥30 allowed for prognostically advantageous LNRs to be achieved in 96% of patients. Therefore, ≥30 examined nodes should be considered a clinical benchmark for practice in the United States.

Benchmarks for nodal yield and ratio for node-positive gastric cancer.

BACKGROUND: We aimed to elucidate prognostic markers of node-positive gastric cancers with a focus on examined lymph nodes and lymph node ratio. METHODS: Patients treated with curative-intent gastrectomy at The University of Texas MD Anderson Cancer Center from 1995-2019 were evaluated. Patients with non-metastatic, node-positive gastric cancers were considered for analysis. RESULTS: Of 775 patients, 281 met the inclusion criteria. The mean age was 58 years, 61% were male, 51% were White, 65% received preoperative therapy, and 71% of tumors were located in the gastric body. The median overall survival was 3.6 years, and 1-, 5-, and 10-year overall survival rates were 91%, 41%, and 29%, respectively. pN3 category was associated with worse overall survival (hazard ratio 1.79, P = .001) and recurrence-free survival (hazard ratio 1.92, P = .004). Nodal burden was associated with aggressive biologic traits in primary tumors, including higher rates of lymphovascular and perineural invasion and lower preoperative therapy response rates. By receiver-operative characteristic analysis, threshold values of ≥30 examined lymph nodes and <30% lymph node ratio were most discriminant for overall survival. On adjusted analysis, positive margins, additional organ resection, <30 examined lymph nodes, and ≥30% lymph node ratio were associated with worse recurrence-free survival and overall survival. Among patients with high node burden (pN3), <30 examined lymph nodes remained significant on adjusted survival analysis. CONCLUSION: Greater than or equal to 30 examined lymph nodes and <30% lymph node ratio were significantly associated with longer recurrence-free survival and overall survival, independent of lymphadenectomy type. These prognostic benchmarks should be considered in the surgical management of gastric cancer in the United States.

Chemotherapy Versus Chemotherapy Plus Chemoradiation as Neoadjuvant Therapy for Resectable Gastric Adenocarcinoma: A Multi-institutional Analysis.

OBJECTIVE: We compare neoadjuvant chemotherapy (CT) to neoadjuvant chemotherapy plus chemoradiation (CRT) for patients with gastric adenocarcinoma (GA). SUMMARY OF BACKGROUND DATA: The optimal neoadjuvant therapy regimen for resectable GA is not defined. METHODS: Utilizing data from 2 high-volume cancer centers, we analyzed patients who underwent surgery for localized GA from 1/1/2000-12/31/2017. Standard CT regimens were used according to treatment period. We compared propensity matched cohorts based on age, sex, race, histology, and clinical stage. RESULTS: Four-hundred five patients (age 62 ± 12 year, 58% male, 56% White) were analyzed. 231 (57%) received CRT and 174 (43%) received CT. Groups differed based on histopathologic characteristics including preoperative stage (p = 0.013). To control for these differences, propensity matched cohorts of 113 CT and 113 CRT patients were compared. CRT had similar frequencies of microscopically negative resections to CT (93% vs 91%, p = 0.81), but higher rates of complete pathologic response (15% vs 4%, p = 0.003) and lower pathologic stage (p = 0.002). Completion of intended perioperative therapy occurred in 63% of CT and 91% of CRT patients (p < 0.001). Median DFS was 45mo (95%CI: 20-70) in the CT group and 113mo (95%CI: 75-151) in the CRT group (p = 0.018). Median OS was 53mo (95%CI: 30-77) versus 120mo (95%CI: 101-138); p = 0.015. CONCLUSIONS: In this multi-institutional comparison of neoadjuvant CT and CRT for resectable GA, CRT is associated with higher rates of completed perioperative therapy, higher rates of complete pathologic response, lower pathologic stage, and improved survival.Level of Evidence: Level III.

Determinants of Survival for Patients with Neoadjuvant-Treated Node-Negative Gastric Cancer.

BACKGROUND: This study sought to determine prognostic markers for disease recurrence and survival in a cohort of neoadjuvant-treated, node-negative gastric cancer patients (ypT0-4N0M0). METHODS: Clinicopathologic data from patients treated with neoadjuvant therapy followed by curative-intent gastrectomy at the University of Texas MD Anderson Cancer Center from 1995 to 2017 were evaluated. Patients with AJCC TNM stage ypT0-4N0M0 were considered for analysis. RESULTS: The inclusion criteria were met by 212 patients with a mean age of 58.3 years. Of these patients, 60 % were male, 53 % were Caucasian, 87 % received chemoradiation, and 13 % received chemotherapy. The findings showed a median overall survival (OS) rate of 11.3 years, a 5-year survival rate of 72 %, and a 10-year survival rate of 57 %. During a median follow-up period of 5.5 years, 38.2 % of the patients died. In the multivariable analysis, ypT4-stage and nodal yield fewer than 16 were significantly associated with reduced OS. Cancer classified as ypT4 had more aggressive biologic traits, including lymphovascular and perineural invasion, and was treated more aggressively with total gastrectomy and additional organ resection despite frequent positive margins. Depth of invasion remained significantly associated with worse outcome after the analysis controlled for nodal yield and possible stage migration. Compared with ypT0-3 tumors, ypT4 cancers were associated with significantly more recurrences (13 % vs. 45 %; p < 0.05), and the primary modes of failure for ypT4 lesions were local recurrence and peritoneal metastases (88 % of recurrences). CONCLUSIONS: Depth of primary tumor invasion and nodal yield were significantly associated with OS among the patients with ypT0-4N0M0 gastric cancer. Serosal invasion (ypT4) was associated with a high rate of peritoneal recurrence, and trials of intraperitoneal therapy targeting these patients should be considered.

Chemotherapy Versus Chemotherapy Plus Chemoradiation as Preoperative Therapy for Resectable Gastric Adenocarcinoma: A Propensity Score-Matched Analysis of a Large, Single-Institution Experience.

BACKGROUND: We compared oncologic outcomes of patients who received neoadjuvant chemotherapy (CT) with those of patients who received neoadjuvant chemotherapy plus chemoradiation (CRT) for resectable gastric adenocarcinoma. METHODS: We compared oncologic and survival outcomes of patients who received CT or CRT for gastric adenocarcinoma at our institution between July 1995 and July 2018. We analyzed propensity score-matched cohorts based on age, sex, race, tumor histologic characteristics, and clinical stage. RESULTS: We identified 440 patients (mean age 61 ± 12 years, 62% male, 55% white); 345 (78%) received CRT, and 95 (22%) received CT. The propensity score-matched cohorts included 65 patients who received CT and 65 who received CRT. The CRT group had similar frequencies of R1 resection margins to the CT group (7.7% vs. 6.2%, p = 0.75) but significantly higher frequency of pathologic complete response (27.7% vs. 1.5%, p < 0.001). The CRT group had lower pathologic stages (p = 0.002). Median disease-free survival was 50.9 months (95% confidence interval [CI]: 4.7-97.2) in the CT group and 122.1 months (95% CI: 69.0-175.1) in the CRT group (p = 0.07). Median overall survival was 70.7 months (95% CI: 23.9-117.5) in the CT group and 122.1 months (95% CI: 68.7-175.4) in the CRT group (p = 0.21). CONCLUSIONS: Compared with CT, CRT for resectable gastric adenocarcinoma is associated with higher rates of pathologic complete response and subsequent lower final pathologic stage, but survival differences are not significant. Ongoing investigation is necessary to better determine the optimal neoadjuvant therapy and identify patients who receive optimal benefit from CRT. LEVEL OF EVIDENCE: III.

Comparison of laparoscopy versus mini-laparotomy for jejunostomy placement in patients with gastric adenocarcinoma.

BACKGROUND: Optimal nutrition is challenging for patients with gastric and gastroesophageal adenocarcinoma and often requires feeding tube placement prior to preoperative therapy. Feeding jejunostomy (FJ) placement via mini-laparotomy is technically easier to perform than laparoscopic FJ. The purpose of this study was to compare outcomes in patients with gastric adenocarcinoma undergoing laparoscopic versus mini-laparotomy FJ placement. METHODS: A retrospective cohort study was performed of patients with gastric adenocarcinoma receiving laparoscopic versus mini-laparotomy FJ at a single tertiary referral center from 2000 to 2018. 30-day outcomes included complications, conversion to laparotomy, reoperation, length of stay, and readmission. RESULTS: A total of 656 patients met the inclusion criteria and were studied. The majority of patients were male (68.1%) with a mean age of 60.6 years. The difference in surgical approach remained relatively stable over time. Overall, 82 (12.5%) patients experienced complications, and three (0.5%) patients died postoperatively. While readmission and conversion to open laparotomy did not differ between groups, overall complications (10.5% vs. 20.8%, p = 0.002), Clavien-Dindo ≥ 3 complications (4.0% vs. 8.9%, p = 0.021), length of stay (4.1 vs. 5.6 days, p < 0.001), and reoperation (0.9% vs. 4.0%, p = 0.002) favored the laparoscopic over mini-laparotomy group. CONCLUSION: The current study helps clarify the risk of FJ placement in patients with gastric adenocarcinoma requiring nutritional support. Laparoscopic FJ placement has lower overall morbidity and length of stay compared to mini-laparotomy. However, caution is needed in preventing and identifying the rare causes of postoperative mortality that may be associated with laparoscopic FJ placement.

Treatment Patterns for Gastroesophageal Junction Adenocarcinoma in the United States.

Despite the increasing incidence of gastroesophageal junction adenocarcinoma (GEJA), the optimal treatment strategy for the disease remains unknown. The objective of this study was to describe treatment patterns for GEJA in the United States. The National Cancer Database was searched to identify all patients who underwent resection of the lower esophagus, abdominal esophagus, and/or gastric cardia for GEJA between 2006 and 2016. Patients were grouped by clinical disease stage: early localized (L; T1-2N0), locally advanced (LA; T3-4N0), regional (R; T1-2N+), or regionally advanced (RA; T3-4N+). The search identified 28,852 GEJA patients. The dominant age range was 60-69 years (39%). Most patients were men (85%), and most were white (92%). Most L patients (69%) underwent upfront surgery, whereas most LA, R, and RA patients received neoadjuvant therapy (NAT; 86%, 80%, and 90%, respectively). Among patients who received NAT, 85% received chemoradiotherapy. Adjuvant therapy was relatively uncommon across all groups (15-20%). In the LA, R, and RA groups, overall survival was greater in patients who received NAT compared to upfront surgery (p < 0.001). With the exception of patients with early localized node-negative disease, most GEJA patients receive neoadjuvant chemoradiotherapy despite the lack of prospective trials reporting survival benefit over chemotherapy alone.

Preoperative Therapy Regimen Influences the Incidence and Implication of Nodal Downstaging in Patients with Gastric Cancer.

PURPOSE: Nodal downstaging after preoperative therapy for gastric cancer has been shown to impart excellent prognosis, but this has not been validated in a national cohort. The role of neoadjuvant chemoradiation (NACR) in nodal downstaging remains unclear when compared with that of neoadjuvant chemotherapy alone (NAC). Furthermore, it is unknown whether the prognostic implications of nodal downstaging differ by preoperative regimen. MATERIALS AND METHODS: Using the National Cancer Database, overall survival (OS) duration was compared among natural N0 (cN0/ypN0), downstaged N0 (cN+/ypN0), and node-positive (ypN+) gastric cancer patients treated with NACR or NAC. Factors associated with nodal downstaging were examined in a propensity score-matched cohort of cN+ patients, matched 1:1 by receipt of NACR or NAC. RESULTS: Of 7,426 patients (natural N0 [n=1,858, 25.4%], downstaged N0 [n=1,813, 24.4%], node-positive [n=3,755, 50.4%]), 58.2% received NACR, and 41.9% received NAC. The median OS durations of downstaged N0 (5.1 years) and natural N0 (5.6 years) patients were similar to one another and longer than that of node-positive patients (2.1 years) (P<0.001). In the matched cohort of cN+ patients, more recent diagnosis (2010-2015 vs. 2004-2009) (odds ratio [OR], 2.57; P<0.001) and NACR (OR, 2.02; P<0.001) were independently associated with nodal downstaging. The 5-year OS rate of downstaged N0 patients was significantly lower after NACR (46.4%) than after NAC (57.7%) (P=0.003). CONCLUSIONS: Downstaged N0 patients have the same prognosis as natural N0 patients. Nodal downstaging occurred more frequently after NACR; however, the survival benefit of nodal downstaging after NACR may be less than that when such is achieved by NAC.

Relationship between initial management strategy and survival in patients with gastric outlet obstruction due to gastric cancer.

BACKGROUND: The optimal management of gastric outlet obstruction (GOO) due to gastric cancer (GC) is unclear. We examined the relationships between clinical and management variables and outcomes in patients with GC having GOO. METHODS: The GOO management and clinical course were reviewed in patients with GC and GOO. Cox regression and Kaplan-Meier analyses were used to identify variables predictive of overall survival (OS). RESULTS: The study included 59 patients. Eleven had imaging evidence of metastasis and 35 had pathologically confirmed peritoneal disease. Initial management included resection in 23 patients, feeding jejunostomy ± decompressive gastrostomy (JT/GT) in 25, surgical gastrojejunostomy in five, and endoscopic intervention in six. Seven patients with initial JT/GT underwent resection after neoadjuvant therapy. Median OS (95% confidence interval [CI]) was 21.4 (0.0-45.1) months in the upfront resection group (median follow-up, 14.7 months) and not reached in those with initial JT/GT, neoadjuvant therapy, and later resection (median follow-up, 26.5 months) (P = .18). On multivariable analysis, clinically positive nodes (hazard ratio [HR]: 3.76; 95% CI, 1.17-12.12; P = .03), metastasis on CT (HR: 3.97; 95% CI: 1.53-10.26;P = .01), and resection (HR: 0.37; 95% CI: 0.17-0.79;P = .01) independently predicted OS. CONCLUSION: In GOO due to GC, OS is similar after treatment with upfront resection compared with JT/GT, neoadjuvant therapy, and later resection. Upfront JT/GT may allow patients to tolerate chemotherapy and improve selection for gastrectomy.

Laparoscopic HIPEC for Low-Volume Peritoneal Metastasis in Gastric and Gastroesophageal Adenocarcinoma.

BACKGROUND: We seek to determine whether laparoscopic hyperthermic intraperitoneal chemoperfusion (LS-HIPEC) improves overall survival (OS) in patients with gastric and gastroesophageal adenocarcinoma and low-volume peritoneal metastasis compared with standard of care treatment. PATIENTS AND METHODS: We reviewed data from a prospectively maintained database of patients with gastric and gastroesophageal adenocarcinoma to identify patients with radiologically occult carcinomatosis or positive peritoneal cytology, no evidence of distant metastasis, and without disease progression during initial chemotherapy or observation. Univariate and multivariable analyses were performed to evaluate the impact of LS-HIPEC on OS. RESULTS: We identified 25 patients who underwent LS-HIPEC and 27 treated with a standard of care approach due to patient (33.3%) or provider (51.9%) preference or financial limitations/lack of insurance coverage (14.8%). Resection was ultimately performed in 28% of LS-HIPEC patients and no standard care patients. At a median follow-up of 18.9 months, median OS was 24.7 (IQR 20.8-34.2) months in LS-HIPEC patients and 21.3 (IQR 12.3-23.1) months in standard care patients (p = 0.08). Three-year OS in the LS-HIPEC group was 19.1%, compared with 9.6% (p = 0.08). Patients who underwent resection had a median OS of 25.3 (IQR 22.6-47.1) months compared with 21.3 months in standard care patients (p = 0.05). CONCLUSIONS: Neoadjuvant LS-HIPEC for the treatment of low-volume peritoneal disease in gastric and gastroesophageal cancer patients did not significantly improve OS compared with standard care. Multiinstitutional studies are necessary to further elucidate the benefit of LS-HIPEC for this patient population.

Preoperative Chemoradiation Versus Chemotherapy in Gastroesophageal Junction Adenocarcinoma.

BACKGROUND: The incidence of lower esophageal and gastroesophageal junction adenocarcinoma has sharply increased over the past several decades and is a serious public health problem. Preoperative therapy with either chemotherapy or chemoradiation is recommended, but the optimal regimen is unknown. We used the National Cancer Database and propensity score matching to investigate whether preoperative chemoradiation therapy offers an advantage over chemotherapy alone for patients with these tumors. METHODS: From the National Cancer Database esophageal and gastric dataset, we selected patients with either lower esophageal or gastric cardia adenocarcinomas who had undergone definitive resection after chemotherapy or chemoradiation. We used propensity score matching to balance groups based on the preoperative treatment they received. We then used conditional multivariable logistic regression and Cox proportional hazard models to examine the association between preoperative therapy regimen and pathological response, overall survival (OS), and postoperative outcomes. RESULTS: Our study included 13,783 patients; 12,129 (89.0%) had received preoperative chemoradiation. Propensity score matching created 1650 pairs. Patients receiving chemoradiation were 2.7 (95% confidence interval, 1.29-3.23) times more likely to achieve complete response in the primary tumor than were those receiving chemotherapy alone; however, chemoradiation was not associated with improved OS (hazard ratio, 1.01; 95% confidence interval, 0.91-1.12). Short-term outcomes (length of stay, mortality, and readmissions) were similar between the 2 groups. CONCLUSIONS: Preoperative chemoradiation was associated with a higher complete response rate in the primary tumor but not with improved OS in lower esophageal and gastroesophageal junction adenocarcinoma.

Staging laparoscopy and peritoneal cytology in patients with early stage gastric adenocarcinoma.

BACKGROUND: Staging laparoscopy and peritoneal cytology can detect occult metastatic disease prior to treatment of gastric cancer. The yield of peritoneal staging in patients with early stage disease is lacking. We assess the yield of peritoneal staging in early stage gastric cancer and its impact on survival. METHODS: Data were obtained from a prospective database of patients who underwent staging laparoscopy and peritoneal cytology for gastric cancer at our institution between July 1995 and July 2018. Clinical stage was determined by endoscopic ultrasound, and early stage was defined as cT1-2 and cN0. Rates of positive cytology and carcinomatosis at time of laparoscopy were obtained. Univariate analyses were used to compare groups, and Kaplan-Meier survival analyses were used to assess survival outcomes. RESULTS: Eight hundred sixty-seven patients underwent staging laparoscopy and peritoneal cytology; 56 were defined as early stage. Age was 61 ± 12 years, 66.4% were male, and 62.3% were white. Of the patients with early stage disease, 17.9% had either gross carcinomatosis (10.7%) and/or positive peritoneal cytology (10.9%). All cases of peritoneal disease were in patients with cT2 disease. There were no differences in age, gender, or race based on peritoneal disease (all p > 0.05). The presence of carcinomatosis or positive cytology significantly affected overall survival (p < 0.001), regardless of clinical T or N stage. CONCLUSIONS: Peritoneal staging identifies metastatic disease in a significant number of patients with early stage disease. Given its poor prognosis and alternate therapy options, independent staging laparoscopy and peritoneal cytology should be considered in patients with early stage gastric adenocarcinoma.

Prognostic Value of Lymph Node Yield After Neoadjuvant Chemoradiation for Gastric Cancer.

BACKGROUND: Optimal lymphadenectomy (LAD) for gastric cancer (GC) after neoadjuvant chemoradiation (NACXRT) is not defined. This study assessed the prognostic value of LAD extent after modern preoperative therapy for GC. METHODS: The study analyzed patients who underwent resection after NACXRT for GC at the authors' institution. Survival of the patients was compared between D1 and D2 resections and between lymph node (LN) yields (LNY) of fewer than 15 LNs and 15 or more LNs. The patients with early clinical nodal disease (cN0-1) were separately analyzed. Kaplan-Meier survival analyses were used to assess overall survival (OS) and disease-free survival (DFS). RESULTS: Resection of GC was performed for 345 patients after NACXRT. Of these patients, 269 (78%) received a D2 resection, and 277 (80%) had an LNY of 15 LNs or more. There were no differences in length of stay (12[10-16] days vs. 12[10-15] days, p = 0.917) or in any major complication including leak rates, intraabdominal infections, and bleeding (all p > 0.05). There was a significant difference in DFS (p = 0.050) and an OS trend (p = 0.085) based on D1 versus D2. Those who had 15 LNs removed showed a trend toward improved survival (DFS, p = 0.082; OS, p = 0.096). Among the patients with early clinical N stage disease (cN0-1), those who underwent D2 resections had better survival (DFS, p = 0.040; OS, p = 0.030). CONCLUSIONS: Patients with GC who underwent resection after NACXRT showed evidence of improved survival after an extended LAD, particularly those with early N stage disease. Perioperative morbidity did not differ based on extent of LAD. Despite the potential effects of tumor downstaging with preoperative therapy, a thorough locoregional lymphatic resection is recommended.

Linitis Plastica: a Distinct Type of Gastric Cancer.

BACKGROUND: The prognosis of patients with linitis plastica (LP) gastric cancer is reported to be poor. The purpose of our retrospective study was to characterize the clinicopathologic features and survival outcomes of patients with LP, using a univocal definition. METHODS: We defined LP as gastric cancer that involves more than 1/3 of the gastric wall macroscopically. We reviewed a prospectively maintained institutional database of gastric cancer patients and summarized and compared clinicopathologic factors of patients with and without LP who had undergone gastrectomy. Patients were matched 1:1 using propensity score matching, and their overall survival (OS) rates and durations were compared. Multivariable Cox regression analyses were conducted, using gastrectomy as a time-varying covariate. RESULTS: We identified 740 patients with radiographically non-metastatic gastric cancer, 157 (21.2%) of whom had LP. Most patients with LP had advanced-stage disease (75.8% had stage IV disease, mainly due to peritoneal involvement). Patients with LP had significantly shorter OS durations than did those without LP in the entire cohort (median OS, 14.0 vs. 33.5 months; p value < 0.001) and in the surgical cohort (median OS after gastrectomy, 21.8 vs. 91.0 months; p < 0.001), as well as in the propensity-matched surgical cohort. In the LP cohort, chemotherapy (hazard ratio [HR] = 0.594; p = 0.076), chemoradiation therapy (HR = 0.346; p = 0.001), and gastrectomy (HR = 0.425; p = 0.003) were associated with a longer OS. CONCLUSIONS: LP is a phenotype of gastric cancer that often presents at an advanced stage, with a high rate of peritoneal involvement. The survival durations of patients with LP were poor in our study, even in the surgical cohort. The use of preoperative chemotherapy, chemoradiation therapy, and gastrectomy appeared to be important in carefully selected patients with localized LP.

A novel patient-derived orthotopic xenograft model of esophageal adenocarcinoma provides a platform for translational discoveries.

Mouse models of gastroesophageal junction (GEJ) cancer strive to recapitulate the intratumoral heterogeneity and cellular crosstalk within patient tumors to improve clinical translation. GEJ cancers remain a therapeutic challenge due to the lack of a reliable mouse model for preclinical drug testing. In this study, a novel patient-derived orthotopic xenograft (PDOX) was established from GEJ cancer via transabdominal surgical implantation. Patient tumor was compared to subcutaneously implanted patient-derived tumor xenograft (PDX) and PDOX by Hematoxylin and Eosin staining, immunohistochemistry and next-generation sequencing. Treatment efficacy studies of radiotherapy were performed. We observed that mechanical abrasion of mouse GEJ prior to surgical implantation of a patient-derived tumor in situ promotes tumor engraftment (100%, n=6). Complete PDOX engraftment was observed with rapid intra- and extraluminal tumor growth, as evidenced by magnetic resonance imaging. PDOXs contain fibroblasts, tumor-associated macrophages, immune and inflammatory cells, vascular and lymphatic vessels. Stromal hallmarks of aggressive GEJ cancers are recapitulated in a GEJ PDOX mouse model. PDOXs demonstrate tumor invasion into vasculature and perineural space. Next-generation sequencing revealed loss of heterozygosity with very high allelic frequency in NOTCH3, TGFB1, EZH2 and KMT2C in the patient tumor, the subcutaneous PDX and the PDOX. Immunohistochemical analysis of Her2/neu (also known as ERBB2), p53 (also known as TP53) and p16 (also known as CDKN2A) in PDX and PDOX revealed maintenance of expression of proteins found in patient tumors, but membranous EGFR overexpression in patient tumor cells was absent in both xenografts. Targeted radiotherapy in this model suggested a decrease in size by 61% according to Response Evaluation Criteria in Solid Tumors (RECIST), indicating a partial response to radiation therapy. Our GEJ PDOX model exhibits remarkable fidelity to human disease and captures the precise tissue microenvironment present within the local GEJ architecture, providing a novel tool for translating findings from studies on human GEJ cancer. This model can be applied to study metastatic progression and to develop novel therapeutic approaches for the treatment of GEJ cancer.This article has an associated First Person interview with the first author of the paper.

Yield of peritoneal cytology in staging patients with gastric and gastroesophageal cancer.

BACKGROUND: Guidelines for gastric and gastroesophageal (GE) cancer recommend staging laparoscopy (SL) with peritoneal cytology (PC). However, the reliability of PC is unknown. The primary purpose of this study was to determine the sensitivity of PC. METHODS: We analyzed a prospectively maintained database of patients who underwent SL and PC for gastric and GE cancer. Test sensitivity of PC for detecting peritoneal disease was assessed. Survival analyses were used to examine the implication of PC. RESULTS: There were 1186 patients that underwent SL and PC; 282 (24%) were found with carcinomatosis. PC was analyzed in 214 (76%) of these patients and 77 (36%) were found to have no malignant cells. In this setting, PC had a sensitivity of 64% for confirming peritoneal disease. Those with peritoneal disease had a poorer 5-year overall survival (5.8% vs 37.7%; P < .001). Those with positive PC without carcinomatosis had a similar survival to those with gross disease with and without cytological confirmation (both P > .05). CONCLUSIONS: PC has limited sensitivity for detecting peritoneal disease. Positive PC alone carries a similar poor survival as in patients with gross carcinomatosis. Improvements in the identification of microscopic disease in peritoneal washings are needed.

Results of a Phase 1/2 Trial of Chemoradiotherapy With Simultaneous Integrated Boost of Radiotherapy Dose in Unresectable Locally Advanced Esophageal Cancer.

Importance: Effective treatment options for locally advanced esophageal cancer are limited, and rates of local recurrence after standard chemoradiotherapy remain high. Objective: To evaluate toxic effects, local control, and overall survival rates after chemoradiotherapy with a simultaneous integrated boost of radiotherapy dose to the gross tumor and nodal disease for patients with unresectable locally advanced esophageal cancer. Design, Setting, and Participants: A phase 1/2, single-arm trial was conducted in 46 patients from April 28, 2010, to April 9, 2015 (median follow-up, 52 months [range, 2-86 months]), at a tertiary academic cancer center. Outcomes of the study patients were compared with those of 97 similar patients treated at the same institution from January 10, 2010, to December 5, 2014, as part of the interim analysis. Statistical analysis was performed from December 15, 2018, to February 12, 2019. Interventions: Chemoradiotherapy with a simultaneous integrated boost of radiotherapy dose (50.4 Gy to subclinical areas at risk and 63.0 Gy to the gross tumor and involved nodes, all given in 28 fractions) with concurrent docetaxel and capecitabine or fluorouracil. Main Outcomes and Measures: Toxic effects, local (in-field) control, and overall survival rates. Results: All 46 patients (11 women and 35 men; median age, 65.5 years [range, 37.3-84.4 years]) received per-protocol therapy, as intensity-modulated photon therapy (39 [85%]) or intensity-modulated proton therapy (7 [15%]); 11 patients (24%) ultimately underwent resection. No patients experienced grade 4 or 5 toxic effects; the 10 acute grade 3 toxic events were esophagitis (4), dysphagia (3), and anorexia (3) and the 3 late grade 3 toxic events were all esophageal strictures. The actuarial local recurrence rates were 22% (95% CI, 11%-35%) at 6 months, 30% (95% CI, 18%-44%) at 1 year, and 33% (95% CI, 20%-46%) at 2 years. Overall, 15 patients (33%) experienced local failure, at a median interval of 5 months (range, 1-24 months). The median overall survival time was 21.5 months (range, 2.3-86.4 months). Exploratory comparison with a 97-patient contemporaneous institutional cohort receiving standard-dose (non-simultaneous integrated boost) chemoradiotherapy showed superior local control (hazard ratio, 0.49; 95% CI, 0.26-0.92; P = .03) and overall survival (hazard ratio, 0.66; 95% CI, 0.47-0.94; P = .02) in the group that received chemoradiotherapy with a simultaneous integrated boost. Conclusions and Relevance: These findings suggest that chemoradiotherapy with a simultaneous integrated boost of radiotherapy dose for locally advanced esophageal cancer is well tolerated, with encouraging local control, and thus warrants further study. Trial Registration: ClinicalTrials.gov identifier: NCT01102088.

Targeting CDK9 and MCL-1 by a new CDK9/p-TEFb inhibitor with and without 5-fluorouracil in esophageal adenocarcinoma.

BACKGROUND: CDK9 inhibitors are antitumorigenic against solid tumors, including esophageal adenocarcinoma (EAC). However, efficacy of a CDK9 inhibitor combined with 5-fluorouracil (5-FU) and target proteins that are targeted by these agents in EAC are unknown. METHODS: The anti-EAC efficacy of a new CDK9 inhibitor, BAY1143572, with and without 5-FU was assessed in vitro and in xenograft models in athymic nu/nu mice. Synergy between BAY1143572 and 5-FU in inhibiting cell proliferation was analyzed by calculating the combination index using CompuSyn software. Potential targets of BAY1143572 and 5-FU were identified by reverse-phase protein array. The effects of BAY1143572 and 5-FU on MCL-1 in vitro were analyzed by Western blotting, quantitative real-time polymerase chain reaction, and chromatin immunoprecipitation assay. MCL-1 protein expression in tumors from patients with locoregional EAC treated with chemoradiation and surgery was assessed by immunohistochemistry. RESULTS: BAY1143572 had dose-dependent antiproliferative and proapoptotic effects and demonstrated synergy with 5-FU against EAC in vitro. The median volumes of FLO-1 and ESO-26 xenografts treated with 5-FU plus BAY114352 were significantly smaller than those of xenografts treated with either agent alone (p < 0.05). BAY1143572 downregulated MCL-1 by inhibiting HIF-1α binding to the MCL-1 promoter. 5-FU enhanced BAY1143572-induced MCL-1 downregulation and stable MCL-1 overexpression reduced the apoptosis induced by BAY1143572 and 5-FU in vitro. High patients' tumor MCL-1 expression was correlated with shorter overall and recurrence-free survival. CONCLUSIONS: BAY1143572 and 5-FU have synergistic antitumorigenic effects against EAC. MCL-1 is a downstream target of CDK9 inhibitors and a predictor of response to neoadjuvant chemoradiation in EAC.