Intestinal Histological Type Research Articles

Clinicopathologic features and prognosis of HER2- positive gastric cancer

Abstract Background The role of human epidermal growth factor receptor 2 (HER2) overexpression has been well established in breast cancer, with corresponding targeted therapies. In contrast, the clinicopathological features and prognosis of HER2 overexpression in gastric cancer remain inconclusive. Methods In this study, 334 patients with gastric cancer who received surgical resection between May 2017 and June 2021 were enrolled at a single medical center in Taiwan. HER2 status was determined by immunohistochemistry (IHC) staining or fluorescence in situ hybridization (FISH). The clinicopathological features and survival curves of the HER2-positive and HER2-negative gastric cancer patients were analyzed. Results The HER2-positive ratio was 7.2%. HER2-positive gastric cancer was associated with more differentiated tumors (P=0.016), more Lauren’s intestinal type (P=0.010) and a higher portion of Ming’s expanding type (P=0.033) in the univariate analysis, but only Lauren’s intestinal type was an independent factor in the logistic regression model (P=0.015). The overall survival and disease-free survival between the HER2-positive and HER2-negative groups were not significantly different. Patients with HER2-positive gastric cancer were more likely to have distant lymphatic recurrence than those with HER2-negative gastric cancer (P=0.026). Conclusions HER2-positive gastric cancer is associated with intestinal histological type and distant lymphatic recurrence, but HER2 is not an independent prognostic factor.

Contribution of PGAP3 co-amplified and co-overexpressed with ERBB2 at 17q12 involved poor prognosis in gastric cancer.

The locus at 17q12 erb-b2 receptor tyrosine kinase 2 (ERBB2) has been heavily amplificated and overexpressed in gastric cancer (GC), but it remains to be elucidated about the clinical significance of the co-amplification and co-overexpression of PGAP3 gene located around ERBB2 in GC. The profile of PGAP3 and ERBB2 in four GC cell lines and tissue microarrays containing 418 primary GC tissues was assessed to investigate the co-overexpression and clinical significance of the co-amplified genes, and to evaluate the impact of the co-amplified genes on the malignancy of GC. Co-amplification of PGAP3 and ERBB2 accompanied with co-overexpression was observed in a haploid chromosome 17 of NCI-N87 cells with double minutes (DMs). PGAP3 and ERBB2 were overexpressed and positively correlated in 418 GC patients. Co-overexpression of the PGAP3 and ERBB2 was correlated with T stage, TNM stage, tumour size, intestinal histological type and poor survival proportion in 141 GC patients. In vitro, knockdown of the endogenous PGAP3 or ERBB2 decreased cell proliferation and invasion, increased G1 phase accumulation and induced apoptosis in NCI-N87 cells. Furthermore, combined silencing of PGAP3 and ERBB2 showed an additive effect on resisting proliferation of NCI-N87 cells compared with targeting ERBB2 or PGAP3 alone. Taken together, the co-overexpression of PGAP3 and ERBB2 may be crucial due to its significant correlation with clinicopathological factors of GC. Haploid gain of PGAP3 co-amplified with ERBB2 is sufficient to facilitate the malignancy and progression of GC cells in a synergistic way.

Incidence, clinicopathological features, and clinical outcomes of low HER2 expressed, inoperable, advanced, or recurrent gastric/gastroesophageal junction adenocarcinoma

According to the DESTINY-Breast04 trial, treating patients with breast cancer and low human epidermal growth factor receptor 2 expressions (HER2-low) varies from that of those with no HER2 expression. However, it is interesting to know if HER2-low indicates for anti-HER2 therapy in the gastric or gastroesophageal junction (G/GEJ) adenocarcinoma. Hence we conducted this study to assess the incidence, clinicopathological features, and treatment outcomes of patients with HER2-low G/GEJ adenocarcinoma. This was a single-center, retrospective observational study. Patients with previously untreated G/GEJ adenocarcinoma were classified based on their HER2 status using immunohistochemistry (IHC) with or without in situ hybridization (ISH) as follows: HER2 negative (IHC 0), HER2-low (IHC 1+ or 2+/ISH-), and HER2-positive (IHC2+/ISH+ or 3+). In total, 734 patients with G/GEJ adenocarcinoma were divided into three groups (HER2-negative, n= 410; HER2-low, n= 154, and HER2-positive, n= 170). The intestinal-type histology, peritoneal metastasis, and higher serum carcinoembryonic antigen (CEA) levels differed significantly among patients with negative, low, and positive HER2 statuses: intestinal-type histology (21.0%, 44.2%, and 59.8%, respectively), peritoneal metastasis (56.3%, 44.8%, and 21.8%, respectively), and higher serum CEA level (32.2%, 41.6%, and 56.5%, respectively). Improved survival was observed in the HER2-positive group than in the HER2-negative G/GEJ adenocarcinoma group [hazard ratio (HR)= 0.73, 95% confidence interval (CI) 0.59-0.89; P= 0.002]. However, the prognoses of the HER2-low and HER2-negative groups were similar (HR= 1.01, 95% CI 0.82-1.23; P= 0.843). Patients with HER2-low G/GEJ adenocarcinoma exhibited intermediate and distinct characteristics than those in the HER2-negative group. Similarly, the HER2-low group's prognosis was worse than that of the HER2-positive group. Therefore developing novel therapeutic strategies targeting HER2-low G/GEJ adenocarcinoma is required.

Clinicopathological Significance and Prognostic Role of Her2neu Protein Expression in Patients with Carcinoma Stomach: A Prospective Study from Northern India

Background and Aims Gastric cancer is the third most common cause of cancer-related mortality worldwide after lungs and colorectum. Although controversial, Her2neu overexpression by immunohistochemistry is usually associated with poor prognosis in patients with carcinoma stomach. We conducted a prospective study to evaluate the prognostic role of Her2neu and its correlation with clinical, pathologic type, and stage of the disease. Methods A prospective study was performed on paraffin blocks of 111 gastric cancer specimens (88 patients were biopsy specimens and 23 were gastrectomy specimens). The paraffin blocks were processed for Her2neu receptor immunohistochemical staining and fluorescence in situ hybridization, and scoring was done. Results Her2neu overexpression was detected in 30 out of 111 (27%) patients. The mean age was 57.68 ± 12.82 years, with males constituting two-thirds of total patients. Tobacco addiction was found in 44% of the patients and smoking in 33% of the patients. Her2neu expression was similar in Lauren's intestinal and diffuse histologic type; however, proximal gastric tumors overexpressed Her2neu as compared with distal tumors. Her2neu 2+ or 3 + (odds ratio: 2.52, 95% CI: 1.61–3.95, p = 0.001) was the only independent predictor of survival in gastric cancer patients. Kaplan–Meir survival analysis showed that the survival of gastric cancer patients with Her2neu overexpression (Her2neu 2+ or 3 + ) was significantly lower than that of those with Her2neu nonexpression (p = 0.001). Conclusion Her2neu positivity was a significant predictor of mortality in patients with carcinoma stomach, and Her2neu overexpression was associated with a lower overall survival rate compared with Her2neu nonexpression.

Landscape of KRAS, BRAF, and PIK3CA Mutations and Clinical Features of EBV-Associated and Microsatellite Unstable Gastric Cancer

Personalization of gastric cancer (GC) treatment is an urgent problem because of the clinical heterogeneity and aggressive course of the disease. Four GC subtypes were isolated based on molecular characteristics by The Cancer Genome Atlas researchers in 2014: Epstein-Barr virus positive (EBV^(+)), microsatellite unstable (MSI), chromosomally unstable (CIN), and genomically stable (GS). There is no unified method to detect the CIN and GS subtypes today, while MSI and EBV status assessments are used routinely and are of great clinical importance. A total of 159 GC samples were tested for MSI, EBV DNA, and somatic mutations in codons 12-13 (exon 2), 61 (exon 3), and 146 (exon 4) of the KRAS gene; codons 597-601 (exon 15) of the BRAF gene; and codons 542-546 (exon 9), 1047-1049 (exon 20) of the PIK3CA gene. EBV^(+) GC was detected in 8.2% of samples; and MSI, in 13.2%. MSI and EBV+ were found to be mutually exclusive. The mean ages at GC manifestation were 54.8 and 62.1 years in patients with EBV^(+) and MSI GCs, respectively. EBV^(+) GC affected men in 92.3% of cases, 76.2% of the patients were older than 50 years of age. Diffuse and intestinal adenocarcinomas were diagnosed in 6 (46.2%) and 5 (38.5%) EBV^(+) cases, respectively. MSI GC equally affected men (n = 10, 47.6%) and women (n = 11, 52.4%). The intestinal histological type was the most prevalent (71.4%); the lesser curvature was affected in 28.6% of the cases. The E545K variant of PIK3CA was observed in one EBV^(+) GC case. A combination of clinically significant variants of KRAS and PIK3CA was found in all MSI cases. The BRAF V600E mutation, which is specific to MSI colorectal cancer, was not detected. The EBV^(+) subtype was associated with better prognosis. The five-year survival rates were 100.0 and 54.7% for MSI and EBV^(+) GCs, respectively.

Prolonged Survival in Peritoneal Metastatic Appendiceal Carcinoma Patients Treated With Combined Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy

IntroductionPrimary treatment for peritoneal dissemination of appendiceal cancer is the combination of cytoreductive surgery and hyperthermic intraperitoneal chemotherapy. The endpoints were overall survival and evaluation of prognostic factors. MethodsClinicopathological and treatment-related factors were obtained from a prospective database. A total of 84 patients, 55 (65%) primary and 29 (35%) recurrent malignant appendiceal carcinomas with synchronous and metachronous peritoneal metastases, underwent multimodal treatment between 2011 and 2021. The endpoints of the study were overall survival and evaluation of prognostic factors. ResultsThe median follow-up was 4.8 y; the mean age was 54.5 y (range 25-77), with a sex distribution of 69% female and 31% male. The mean peritoneal cancer index was 11.3. The proportion of mucinous, intestinal-type, signet ring cell, and goblet cell carcinoma was 56%, 23%, 11%, and 10%, respectively. The 5-y survival rate of the whole cohort was 56.7%. In primary and recurrent diseases, the overall median survival was 8.4 and 4.9 y. Significantly improved survival was detected after complete cytoreduction resection (hazard ratio [HR] for CCR-2 versus CCR-0: 9.388, 95% confidence interval [CI] 3.026-29.124, P = 0.001) and initial local operation with undelayed admission to the center (HR 0.262, 95% CI 0.089-0.773; P = 0.015). The five independent factors in Kaplan–Meier analysis and univariable Cox regression analysis associated with significant adverse survival were cancer antigen (CA) 19-9 over 37 IU/mL, signet ring cell and intestinal-type histology, positive nodal status, grading, and peritoneal cancer index >20. Neoadjuvant chemotherapy administration did not impact survival (HR 1.220, 95% CI 0.612-2.432, P = 0.571). ConclusionsWith multimodal treatment, prolonged survival is attainable in stage IV primary and recurrent appendiceal carcinoma with peritoneal dissemination. Direct referral to specialized centers after confirmation of peritoneal metastasis is recommended because prompt definitive treatment may significantly improve survival.

Defining and Targeting Esophagogastric Cancer Genomic Subsets With Patient-Derived Xenografts.

Comprehensive genomic profiling has defined key oncogenic drivers and distinct molecular subtypes in esophagogastric cancer; however, the number of clinically actionable alterations remains limited. To establish preclinical models for testing genomically driven therapeutic strategies, we generated and characterized a large collection of esophagogastric cancer patient-derived xenografts (PDXs). We established a biobank of 98 esophagogastric cancer PDX models derived from primary tumors and metastases. Clinicopathologic features of each PDX and the corresponding patient sample were annotated, including stage at diagnosis, treatment history, histology, and biomarker profile. To identify oncogenic DNA alterations, we analyzed and compared targeted sequencing performed on PDX and parent tumor pairs. We conducted xenotrials in genomically defined models with oncogenic drivers. From April 2010 to June 2019, we implanted 276 patient tumors, of which 98 successfully engrafted (35.5%). This collection is enriched for PDXs derived from patients with human epidermal growth factor receptor 2-positive esophagogastric adenocarcinoma (62 models, 63%), the majority of which were refractory to standard therapies including trastuzumab. Factors positively correlating with engraftment included advanced stage, metastatic origin, intestinal-type histology, and human epidermal growth factor receptor 2-positivity. Mutations in TP53 and alterations in receptor tyrosine kinases (ERBB2 and EGFR), RAS/PI3K pathway genes, cell-cycle mediators (CDKN2A and CCNE1), and CDH1 were the predominant oncogenic drivers, recapitulating clinical tumor sequencing. We observed antitumor activity with rational combination strategies in models established from treatment-refractory disease. The Memorial Sloan Kettering Cancer Center PDX collection recapitulates the heterogeneity of esophagogastric cancer and is a powerful resource to investigate mechanisms driving tumor progression, identify predictive biomarkers, and develop therapeutic strategies for molecularly defined subsets of esophagogastric cancer.

Gastric Cancer in Older Patients: A Retrospective Study and Literature Review.

BackgroundWith increasing life expectancy, the incidence of gastric cancer (GC) in older adults is increasing. This study analyzed differences in GC characteristics according to age and sex among patients who underwent surgical treatment for GC.MethodsA total of 2,983 patients diagnosed with gastric adenocarcinoma who underwent surgical treatment at Seoul National University Bundang Hospital between 2003 and 2017 were classified into three groups: I (<65 years, n=1,680), II (60–74 years, n=919), and III (≥75 years, n=384). We compared the baseline clinical characteristics, pathological characteristics of the tumor, overall and GC-specific survival rates, and associated risk factors between the groups.ResultsCancer of the distal third of the stomach (p<0.001), with intestinal-type histology (p<0.001), and with p53 overexpression (p=0.004) were more common in groups II and III than in group I, and the proportion of intestinal-type GC increased with age. The cancer type, lymph node metastasis, and cancer stage did not differ significantly. In terms of overall survival, survival decreased with increasing age (p<0.001), but this difference decreased significantly for GC-specific survival. Cox multivariate analyses revealed age, histologic type (diffuse or mixed type), and advanced cancer stage (p=0.002, 0.001, and <0.001, respectively) as risk factors for GC-related mortality.ConclusionAge itself was found to be one of the most important prognostic factors for overall and disease-specific survival in elderly GC patients, along with cancer stage.

Brain metastasis in gastroesophageal adenocarcinoma: Outcomes and molecular features.

347 Background: Brain metastases (BrM) rarely occur in patients with metastatic gastroesophageal adenocarcinoma (GEA) and represent a unique therapeutic challenge. We describe the unique clinical, molecular, and genomic factors associated with mGEA cancer and BrM development in order to help guide future clinical management. Methods: Patients (pts) with GEA seen at Memorial Sloan Kettering Cancer Center (MSKCC) from 2008-2019 and who had consented for genomic tumor profiling with MSK-IMPACT, a capture-based next-generation sequencing platform that detects mutations, copy-number variations, and select fusions, were retrospectively identified. Clinical and pathologic characteristics were reviewed. BrM were identified via International Classification of Diseases (ICD) billing codes and electronic medical record problem lists, and then manually validated. Survival was calculated from the time of BrM diagnosis until date of death or last follow up and estimated using the Kaplan-Meier method. Results: Fifty pts with GEA metastatic to the brain were identified. Most pts were male (86%) and white (80%), with primary tumor of the esophagus/gastroesophageal junction (82%) and intestinal-type Lauren histology (90%). Twenty-three pts (46%) were HER2 positive (defined as IHC 2+/FISH+ or IHC 3+). Frequencies of PTEN (16%) and EGFR (22%) alterations in primary or metastatic sites were enriched in pts with BM compared to that seen across the MSKCC retrospective cohort and the GEA Cancer Genome Atlas (TCGA) cohort. The majority (68%) of pts had stage IV disease at initial diagnosis, and 4 pts were found to have BrM within 1 month (mo) of stage IV diagnosis, while 27 pts developed BrM during therapy. Median time to BrM diagnosis was 18.3 mos (IQR 11.5-28.9) and 15.1 mos from stage IV diagnosis (IQR 4.8-25.5). Median survival was 7.6 mos from BrM diagnosis and 15.6 (95% CI 10.0-NR, n = 19), 7.6 (95% CI 2.5-NR, n = 13), and 4.3 (95% CI 3.5-12.3, n = 18) mos for pts with 1, 2-3, or 4+ BrM, respectively. Conclusions: GEA pts with BrM had increased frequency of HER2 positivity, as well as PTEN and EGFR alterations, compared to GEA pts overall historically. Further correlation between BrM development, molecular characteristics, and survival in a larger cohort will be presented.

Prognostic Value of the Immunohistochemical Expression of RAD51 and BRCA2 in Gastric Adenocarcinoma.

Current scientific literature lacks data on the prognostic value of the expression of RAD51 and BRCA2 in gastric adenocarcinoma. Therefore, we aimed to evaluate those and other homologous recombination-related proteins (ATM, ATR, BRCA1, CHK2, γH2AX, p53) in gastric cancer, assessing their correlation with clinical prognosis. Paraffin-embedded samples were obtained from surgical specimens collected in total or subtotal gastrectomy procedures. Between 2008 and 2017, 121 patients with advanced gastric adenocarcinoma underwent surgical resection and were included in this study. Negativity for nuclear RAD51 correlated with vascular invasion, lymph node metastasis, larger tumor size, and lower overall survival and disease-free survival in univariate analysis. However, nuclear RAD51-negative cases presented better response rates to adjuvant therapy than the positive ones. Nuclear ATR negativity correlated with larger tumor size and a higher histological grade. Positivity for ATM was associated with more prolonged disease-free survival. Positivity for nuclear BRCA2 correlated with lower overall survival and diffuse histological type, whereas its high expression was associated with vascular invasion. Nevertheless, tumors positive for nuclear BRCA2 were more frequently low grade in the intestinal histological type. Our findings indicate that RAD51 and BRCA2 are valuable immunohistochemical prognostic markers in gastric adenocarcinoma.

The Incidence and Risk Factors for Metachronous Gastric Cancer in the Remnant Stomach after Gastric Cancer Surgery.

Background/AimsLess invasive surgical treatment is performed in East Asia to preserve postoperative digestive function and reduce complications such as postgastrectomy syndromes, but there is an issue of metachronous gastric cancer (GC) in the remaining stomach. This study aimed to analyze the incidence of metachronous GC and its risk factors in patients who had undergone partial gastrectomy.MethodsA total of 3,045 GC patients who had undergone curative gastric partial resection at Seoul National University Bundang Hospital were enrolled and analyzed retrospectively for risk factors, including age, sex, smoking, alcohol, Helicobacter pylori status, family history of GC, histological type, and surgical method.ResultsMetachronous GC in the remaining stomach occurred in 35 of the 3,045 patients (1.1%) 23 in the distal gastrectomy group (18 with Billroth-I anastomosis, five with Billroth-II anastomosis), seven in the proximal gastrectomy (PG) group, and five in the pylorus-preserving gastrectomy (PPG) group. Univariate and multivariate Cox regression analyses showed that age ≥60 years (p=0.005) and surgical method used (PG or PPG, p<0.001) were related risk factors for metachronous GC, while male sex and intestinal type histology were potential risk factors.ConclusionsMetachronous GC was shown to be related to older age and the surgical method used (PG or PPG). Regular and careful follow-up with endoscopy should be performed in the case of gastric partial resection, especially in patients with male sex and intestinal type histology as well as those aged ≥60 years undergoing the PG or PPG surgical method.

Are Borrmann's Types of Advanced Gastric Cancer Distinct Clinicopathological and Molecular Entities? A Western Study.

Simple SummaryBorrmann classification is widely used for advanced gastric cancer (GC). Most studies on the clinicopathological impact of this classification have been performed in Asian countries, and almost all authors analyzed only type IV tumors. We assessed the clinicopathological, molecular features and the prognostic value of Borrmann types in all patients with advanced GC resected in a Western institution (n = 260). We observed a significant relationship between Borrmann types and several clinicopathological and molecular features, including age at diagnosis, systemic symptoms, tumor size, Laurén subtype, presence of signet-ring cells, infiltrative pattern, high grade, necrosis, size of the largest lymph node metastasis, HERCEPTEST positivity, microsatellite instability and molecular subtypes. No association was found between Borrmann classification and prognosis. According to our results, Borrmann types may represent distinct clinicopathological and biological entities. Further studies should be performed to confirm the role of Borrmann classification in the stratification of patients with advanced GC.Most studies on the clinicopathological impact of Borrmann classification for gastric cancer (GC) have been performed in Asian patients with type IV tumors, and immunohistochemical features of Borrmann types have scarcely been analyzed. We assessed the clinicopathological, molecular features and prognostic value of Borrmann types in all patients with advanced GC resected in a Western institution (n = 260). We observed a significant relationship between Borrmann types and age, systemic symptoms, tumor size, Laurén subtype, presence of signet-ring cells, infiltrative growth, high grade, tumor necrosis, HERCEPTEST positivity, microsatellite instability (MSI) and molecular subtypes. Polypoid GC showed systemic symptoms, intestinal-type histology, low grade, expansive growth and HERCEPTEST positivity. Fungating GC occurred in symptomatic older patients. It presented intestinal-type histology, infiltrative growth and necrosis. Ulcerated GC showed smaller size, intestinal-type histology, high grade and infiltrative growth. Most polypoid and ulcerated tumors were stable-p53-not overexpressed or microsatellite unstable. Flat lesions were high-grade diffuse tumors with no MSI, and occurred in younger and less symptomatic patients. No association was found between Borrmann classification and prognosis. According to our results, Borrmann types may represent distinct clinicopathological and biological entities. Further research should be conducted to confirm the role of Borrmann classification in the stratification of patients with advanced GC.

Sex difference in the incidence of cardia and non-cardia gastric cancer in the United States, 1992\u20132014

BackgroundGastric cancer is more common in men than in women, but underlying reasons have not been completely understood. This study aimed to assess patterns of the sex difference in the incidence of gastric cancer in the United States.MethodsUsing data from 13 cancer registries in the Surveillance, Epidemiology, and End Results Program, we analyzed the age-specific sex difference in the incidence of gastric cancer by ethnicity, anatomic site and histological type in the United States during 1992–2014. We assessed the temporal trends in the sex differences in the incidence of gastric cancer during the study period.ResultsThe male-to-female incidence ratio of cardia cancer increased with age until peaking at ages 55–69 years and decreased thereafter, while the ratio for non-cardia gastric cancer increased with age before ages < 60 years and remained stable onwards. The age-specific patterns in the sex difference of gastric cancer incidence varied between intestinal and diffuse histological types. The sex difference in the incidence of cardia cancer remained relatively stable except for that the absolute difference between the sexes in whites decreased on average by 0.8% per year from 1992 to 2014. The absolute incidence difference between the sexes in non-cardia gastric cancer decreased over time in whites, blacks, and Asian and Pacific islanders by approximately 4% per year. The male-to-female incidence ratio of non-cardia gastric cancer decreased over time in whites and blacks, but remained relatively stable in Asian and Pacific islanders.ConclusionsBoth extrinsic and intrinsic factors may have contributed to the sex difference in gastric cancer. Sex hormones may play a role in the development of cardia cancer and intestinal type of gastric cancer.

Hypergastrinemia is associated with an increased risk of gastric adenocarcinoma with proximal location: A prospective population-based nested case-control study.

The incidence of proximal gastric adenocarcinoma is increasing among younger adults. Rodent models have shown that hypergastrinemia causes carcinogenesis in the proximal stomach. The aim of our study was therefore to assess if hypergastrinemia was associated with an increased risk of developing gastric adenocarcinoma also in humans. A prospective population‐based nested case‐control study within the Nord‐Trøndelag Health Study (HUNT) cohort, Norway, was used to assess this association. Serum was collected from 78 962 participants in 1995 to 1997 and 2006 to 2008. In the cohort, 181 incident gastric adenocarcinoma cases were identified from the Norwegian Cancer and Patient Registries through 2015 and matched with 359 controls. The risk of gastric adenocarcinoma was compared between participants with prediagnostic hypergastrinemia (>60 pmol/L) and normal serum gastrin (≤60 pmol/L). Logistic regression provided odds ratios (ORs) with 95% confidence intervals (CIs), adjusted for body mass index, tobacco smoking and comorbidity. Hypergastrinemia was associated with increased risk of gastric adenocarcinoma overall (OR 2.2, 95% CI 1.4‐3.4) and in particular for gastric adenocarcinoma with proximal location (OR 6.1, 95% CI 2.7‐13.8), but not with gastric adenocarcinoma with distal location (OR 1.7, 95% CI 0.9‐3.4). Moreover, hypergastrinemia was associated with an increased risk of gastric adenocarcinoma of intestinal histological type (OR 3.8, 95% CI 1.8‐7.9), but not for diffuse histological type (OR 1.6, 95% CI 0.7‐3.7). In conclusion, hypergastrinemia was associated with an increased risk of proximal and intestinal type gastric adenocarcinoma.

The Impact of Severe Infectious Complications on Long-term Prognosis for Gastric Cancer.

The aim of this study was to evaluate the impact of postoperative infectious complications on long-term outcomes after curative resection of gastric cancer. Patients who underwent curative gastrectomy with lymphadenectomy for gastric cancer at Yokohama City University and Kanagawa Cancer Center from January 2000 to August 2015 were retrospectively selected from medical records. Clinicopathological factors between patients with and without infectious complications were compared. Prognostic factors of long-term survival were analyzed by univariate and multivariate Cox proportional hazards analyses. A total of 2,254 patients were eligible for inclusion in the present study. Fifty-eight patients had postoperative infectious complications (IC group); 2,196 had no postoperative infectious complications (NC group). In the IC group, the median age (p=0.031), body mass index (p=0.004), American Society of Anesthesiologists physical status (p=0.006) and percentage of male patients (p<0.001) were higher in comparison to the NC group. The operation time was longer (p<0.001) and the incidence of intestinal-type histology was higher (p=0.017) in the IC group. The 5-year overall survival rates of the IC and NC groups were 59.8% and 83.2%, respectively (p<0.001). Univariate and multivariate analyses demonstrated that postoperative infectious complications were a significant risk factor for poorer overall survival (hazard ratio=2.38; 95% confidence interval=1.47-3.85, p<0.001). Perioperative management is necessary to reduce the incidence of postoperative infectious complications and improve the survival of patients after curative resection of gastric cancer.

Intestinal-type histology is associated with better prognosis in patients undergoing liver resection for gastric/esophagogastric-junction liver metastasis.

The indication for resection of gastric/esophagogastric-junction liver metastasis (GELM) has yet to be established. This study aimed to investigate prognostic factors in patients undergoing GELM resection. From 2001 to 2015, 31 consecutive patients underwent resection for GELM; and factors for poor prognosis were evaluated. Of the 31 patients, 23 (74.2%) developed multiple liver metastases. The histology of gastric cancer was intestinal-type adenocarcinoma in 21 patients (67.7%). Median overall survival (OS) was 3.2 years. The 1-, 3-, and 5-year OS rates were 92.8%, 56.2%, and 42.2%, respectively. The 1-, 3-, and 5-year recurrence-free survival (RFS) rates were 58.5%, 31.3%, and 31.3%, respectively. Multivariate analysis indicated that intestinal-type adenocarcinoma was associated with a significantly lower risk of OS (hazard ratio [HR], 0.26; p =0.022) and RFS (HR, 0.25; p = 0.008). In multiple logistic regression analysis, intestinal-type adenocarcinoma (odds ratio, 0.14; p = 0.012) reduced incidence of extra-hepatic recurrence after GELM resection. In conclusion, GELM resection in patients with intestinal-type histology is preferable because intestinal-type adenocarcinoma is associated with better prognosis and a lower incidence of extra-hepatic recurrence than diffuse/other-type adenocarcinoma.

Evaluation of toll-like receptors as prognostic biomarkers in gastric cancer: high tissue TLR5 predicts a better outcome

Toll-like receptors (TLRs), key proteins in innate immunity, appear to contribute to the inflammatory environment in carcinogenesis. Thus, we aimed to evaluate the tissue expressions of TLR1, TLR2, TLR4, TLR5, TLR7, and TLR9 as potential prognostic biomarkers in gastric cancer. We applied immunohistochemistry to study tissue samples from 313 patients operated on for gastric adenocarcinoma between 2000 and 2009 at the Department of Surgery, Helsinki University Hospital, Finland. A high expression of each TLR studied associated with the high expression of each other and with the intestinal-type histology (p < 0.001 for all). Five-year disease-specific survival among patients with a high TLR5 was 53.4% (95% confidence interval [CI] 43.4–63.4), whereas among patients with a low TLR5 it was 37.6% (95% CI 30.0–45.2; p = 0.014). A high TLR5 expression functioned as a marker of a better prognosis, particularly among those with a stage II disease (hazard ratio [HR] 0.33; 0.13–0.83; p = 0.019) or an intestinal-type cancer (HR 0.58; 95% CI 0.34–0.98; p = 0.043). In this study we show, for the first time, that a high TLR5 tissue expression may identify gastric cancer patients with a better prognosis, particularly among those with a stage II disease or an intestinal-type cancer.

Molecular and pathological features in patients with gastric cancer in Argentina. Association between Epstein Barr Virus, MSI, PD-L1 expression and T-cells infiltration

Introduction: The incidence of gastric cancer (CG) in Argentina is about 3900 cases and 3200 deaths per year. In the recent molecular classification stand out among others, those tumors associated with Epstein Barr virus (EBV) infection and microsatellite instability (MSI). Both are associated with an increase in the lymphoid infiltrate and this tumor microenvironment has been related to an increase in the expression of PD-L1. The clinical relevance of these features remains unclear. The objective of this study is to evaluate the expression of EBV and MSI, to analyze the expression of PD-L1 together with the presence of CD3 and CD8 lymphocytes in the tumor microenvironment and to describe their relationship with clinical-pathological characteristics. Methods: We evaluated a cohort of 47 patients with gastric adenocarcinoma, without neoadjuvant treatment, who underwent curative surgery. Immunohistochemistry (IHC) for MLH1, PMS2, MSH2, MSH6, PD-L1, CD3 and CD8; MSI assay with BAT25, BAT26, NR21, NR24, and MONO27 markers, and qualitative detection of EBV were performed. Results: Qualitative PCR for EVB was positive in 21% (n = 10) of cases. MSI was identified in 8% (N = 4) cases. The status of MSI and EBV positive GC were mutually exclusive. Correlation between MSI and MMR deficiency by IHC was 100% (MLH1 and PMS2 loss in all cases). CG EBV positive and CG MSI were more frequent in male patients, older than 50 years and distal gastric localization. The intestinal histological type was the most frequent in CG MSI, whereas represented 50% in CG EBV cases. 50% of the GC EBV and 75% of the CG MSI showed a high density of tumor-infiltrating lymphocytes (TILs). PDL1 was positive in tumor cells and in infiltrating immune cells in 28% (n = 13) cases (6/10 CG-EVB positive, 2/4 CG-MSI and 5/33 CG-EVB negative / MSS). GCs EBV positive and CG MSI that expressed PD-L1 had a high density of CD3 T-lymphocytes in both intratumoral region and invasion margin but low for CD8 T lymphocytes. Conclusion: In our gastric patients, PD-L1 expression was associated with distinct molecular and histopathological features including a high density of CD3 T lymphocytes, MSI status, and EBV. These data could be relevant to identify potential candidate patients for immunotherapies.

Perioperative (P) UGT1A1 genotype guided irinotecan (iri) dosing ‘gFOLFIRINOX’ for gastroesophageal adenocarcinoma (GEA).

4050 Background: Complete resection (R0) and pathologic response grade (PRG) correlate with long-term GEA outcome. FOLFIRINOX demonstrated efficacy in advanced GEA; gFOLFIRINOX improved tolerability. We evaluated R0, PRG and tolerability in this pilot P study. Methods: Gastric body (GB) + esophagogastric (EGJ) GEA patients (pts) with ≥T3Nx or TxN+ were enrolled &amp; treated with 4 pre + 4 postoperative biweekly cycles of gFOLFIRINOX (5-FU 2400mg/m2 over 46 hrs; oxaliplatin 85mg/m2; iri: 180mg/m2 for UGT1A1 genotype 6/6, 135mg/m2 for 6/7, 90mg/m2 for 7/7) (+ trastuzumab (T) 6mg/kg then 4mg/kg for HER2+) with prophylactic peg-filgastrim. 1°endpoint R0 resection required 36 pts to assess for a 90% R0 rate (intention to treat (ITT)) with 90% power + 0.05 alpha; ≥30/36 R0 considered positive. Co-1°endpoint was PRG (Becker); 36 pts provided 85% power with 0.05 alpha for a complete (pCR G1a) rate of 16%. 2°endpoints were safety/toxicity, PET response, &amp; R0/PRG by tumor site, histologic subtype, HER2 status, &amp; UGT1A1 genotype. We report efficacy and toxicity data from the neoadjuvant (Neo) portion of the study; postop data &amp; survival outcomes will be presented at the meeting. Results: 4 sites enrolled 36 ITT pts between 2/2014-8/2018; 75% male, median age 66 (range 27-85). All pts completed all 4 cycles of Neo therapy: 10% had any dose reduction of iri (16%/0%/25% by genotype 6/6, 6/7, 7/7); any G3+ toxicity occurred in 35% of pts (32% 6/6, 29% 6/7, 75% 7/7). G3+ toxicity in ≥5% of pts: diarrhea (17.5%; 6/6 21%, 6/7 11%, 7/7 25%), anemia (5%), vomiting (5%). Efficacy is shown in the Table. Of pts going to surgery, both R1 resections were GB linitus. PRG1(a+b) was achieved in 36% of ITT pts, 46% of intestinal type histology. Conclusions: Neo gFOLFIRINOX was tolerable with surrogate efficacy comparable to FLOT. Clinical trial information: NCT02366819. [Table: see text]

Prediction of survival benefit when deciding between chemotherapy and best supportive therapy in elderly patients with advanced gastric cancer: A retrospective cohort study.

It remains unclear whether elderly patients (EPs) with advanced gastric cancer (AGC) benefit from chemotherapy. The aim of the present study was to examine the prognostic factors for EPs with AGC in order to generate a prognosis-predicting scoring system. This single-center retrospective study examined consecutive patients with AGC between April 2012 and July 2017. Risk factors for survival in EPs aged ≥75 years were identified using a Cox proportional hazards model, and a prognostic scoring system was generated and retrospectively evaluated to determine its usefulness for predicting patient prognosis. A total of 61 patients were enrolled as EPs (mean age, 81 years) and compared with 80 non-EPs (mean age, 66 years). The median survival time (MST) was significantly longer for non-EPs compared with that for EPs (3.8 vs. 10.1 months, respectively; P=0.0447). Among the EPs, 29 (48%) received chemotherapy and 32 received best supportive care (BSC). A total of 68 non-EPs (85%) received chemotherapy and 12 non-EPs received BSC. Among EPs with AGC, age-adjusted multivariate analysis revealed that performance status (PS), neutrophil/lymphocyte ratio (NLR)<4, intestinal-type histology and chemotherapy were significant prognostic factors. To predict EPs too frail for chemotherapy prior to treatment, one point was assigned for a PS of 1, diffuse-type histology and NLR≥4, whereas 2 points were assigned for PS≥2, and the point totals for each patient were calculated. A cut-off point of 2 had the best P-value by the log-rank test and was used to divide the patients into low-risk (LoR: Score 0–1) and high-risk (HiR: Score 2–4) groups. The MST of the LoR and HiR groups was 23.6 and 3.6 months, respectively (P<0.001). As regards treatment strategies and risk groups, the LoR chemotherapy group had the best prognosis (P=0.0010), and LoR EPs who were administered chemotherapy had a longer MST (30.3 months) compared with EPs who received BSC (8.7 months). In conclusion, scoring systems using PS, histology and NLR may be useful when considering chemotherapy in EPs with AGC.