Gastric cancer

Gastric cancer is a multi-step process and multi-factorial disease. However, Helicobacter pylori plays the most important role in gastric carcinogenesis because most gastric cancers including both intestinal type and diffuse type arise from mucosa infected by H. pylori. The relationship between H. pylori infection and gastric cancer has been proved in epidemiological studies, animal experiments with Mongolian gerbils, and clinical prospective studies. Significant preventive effect of H. pylori eradication was reported in Japanese randomized study for secondary gastric cancer after endoscopic resection of primary gastric cancer and meta-analysis of randomized studies. The Japanese Society for Helicobacter Research has published a guideline recommending that H. pylori infection should be treated by eradication therapy to suppress the incidence of gastric cancer. The development of endoscopic technology has advanced the diagnosis and treatment of gastric cancer. In the diagnosis of gastric cancer, image enhancement endoscopy including magnifying observation with narrow-band imaging system and microscopic magnifying observation opens the possibility of optical biopsy. Endoscopic resection for early stage of gastric cancer has been established as proper treatment of early gastric cancer. Recently endoscopic submucosal dissection had made en bloc resection possible for mucosal cancers >2 cm in diameter. Because of endoscopic submucosal dissection, endoscopic resection is indicated in a greater number of cases. Although the use of endoscopic treatment for gastric cancer has been increasing steadily, long-term outcome data is necessary.

Background. Current information of the prognosis of mixed-type gastric cancer (GC) is poor. A few studies have shown that mixed GC differs from other types in the Lauren classification by more frequent of the lymph nodes metastasis and an aggressive behavior. Aim. To study the prognosis of mixed GC versus other Lauren GC types and evaluate the prognostic value of the predominant component in mixed carcinoma. Materials and methods. 315 patients with GC were reviewed by using a semi-quantitative assessment of the proportion of the diffuse and intestinal components of the tumor after surgical treatment by evaluation of the specimens slides to clarify the type of GC according to the Lauren classification, as well as the proportion of each component in the mixed GC. 166 patients (52.7%) with GC had the intestinal type, 72 (22.8%) had the diffuse type, 60 (19.0%) had the mixed type, and 17 (5.4%) had an unclassified type. Results. Mixed-type GC exhibited more aggressive behavior than intestinal and diffuse types of GC. It was characterized by deeper invasion of the gastric wall and more extensive lymphogenic metastasis. Early cancer (pT1b) was diagnosed in only 1 (1.7%) case, while in intestinal and diffuse types, it was detected in 18.6% and 29.2% of patients (p0.01), respectively. Invasion into the serous membrane of the stomach was reported in 56.7% of cases versus 45.1% (p=0.1270) and 27.7% (p=0.0008), respectively. Mixed GC metastasized to regional lymph nodes metastasis more frequently than intestinal or diffuse cancer (80% vs. 59.0% and 29.2%, respectively; p0.004). The average number of lymphogenic metastases was significantly higher than in intestinal and diffuse GC types (6.73±7.51 vs 3.58±5.04 and 2.15±4.39, respectively; p0.001). More frequently lymph node involvement in patients with mixed GC was observed with a similar depth of tumor invasion in the compared groups. In the study population, the 5-year overall survival (OS) in patients with mixed-type GC was significantly lower than in patients with intestinal and diffuse-type GC: 26.4% vs. 58.7% (p=0.00000) and 51.1% (p0.03). Stage-by-stage analysis showed significant differences in OS between mixed and intestinal GC in the largest group of patients with stage III disease and found no significant differences between mixed and diffuse GC at any stage. If the diffuse component was prevailed in patients with mixed-type GC, the 5-year OS rate was 37.9%; if the intestinal component prevailed, there were no survivors 5 years after surgery, and the 3-year OS rate was 12.8% (Log rank test; p=0.022). The frequency of metastatic lesions of regional lymph nodes in subgroup 1 was lower than in subgroup 2 (74.4% vs. 94.1%; p=0.0856). Conclusion. Mixed GC is diagnosed in later stages compared to other types of GC according to the Lauren classification, which translates into lower OS rates. This histological type shows a higher rate of lymphatic metastases, even with the same depth of tumor invasion. In a step-by-step analysis, OS in patients with mixed GC was significantly worse than that in the intestinal type, and was comparable to the results of treatment of diffuse GC. The predominant component assessment in mixed carcinoma may prove to be an additional prognostic factor.

Introduction: Gastric cancer is the second most common GI cancers and third leading cause of cancer-related deaths worldwide. In Ghana, gastric cancer contributes significantly to cancer morbidity and mortality. The recent development on the benefit of targeted therapy in the management of gastric cancer using HER-2 monoclonal antibody in combination with chemotherapy has greatly improved the overall survival of patients. This study therefore aims at determining the frequency of Her-2 over-expression in gastric carcinomas in Kumasi, Ghana and comparing with other prognostic factors. Methodology: Demographic data and histological diagnosis were retrieved from the surgical day book of the Department of Pathology, Komfo Anokye Teaching Hospital, Kumasi. The slides were retrieved and reviewed to confirm diagnosis, grading and classification of gastric cancer. Immunohistochemistry was done with anti-HER-2 antibody to confirm HER-2 over-expression. The data was analysed with SPSS version 17. Results: Of the 99 cases of gastric cancer seen over the 8 year period, there were 57 males and 42 females, adenocarcinoma (91), GIST (5) and Non Hodgskin Lymphoma (3). The age range of the study population was 8-90 years with modal age group in the 6th decade. There were more biopsies (63) than resections (36). Of the adenocarcinomas, 45 were poorly differentiated, 38 moderately differentiated and 8 well differentiated. Diffuse type is most common with 47 cases followed by intestinal 41cases and mixed type 3 cases. Three of the 4 patients under the age of 30 years had lymphoma. HER-2 over-expression was seen in 14 out of the 47 tested and all were intestinal type. Conclusion: HER -2 over-expression was seen a small cohort of our patients with gastric cancer especially those with intestinal type. Citation Format: Babatunde M. Duduyemi, Mary Y. Afihene, Emmanuel A. Asiamah. Human epidermal growth receptor-2 immunohistochemistry in gastric cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 753. doi:10.1158/1538-7445.AM2017-753

Expanding the Lauren Classification: A New Gastric Cancer Subtype?

The investigation of prognostic factor for gastric cancer is still desirable because of dismal prognosis in gastric cancer. Lauren's classification is currently a useful histological classification. There are few large series evaluating the prognostic significance of Lauren's classification in gastric cancer. From January 1987 to December 2013, a total of 3071 patients received gastrectomy for gastric cancer. According Lauren's classification, 1423(46.3%) patients were intestinal type, 1000 patients (32.6%) were diffuse type, and 648 patients (21.1%) were mixed type. The clinicopathological characteristics and prognosis in Lauren's classification were analyzed in these patients. Our results showed that patients with intestinal type gastric cancer (57.7%) had a better 5-year overall survival than diffuse type (45.6%) and mixed type (43.4%, P < 0.001). The clinicopathological characteristics showed that gastric cancer patients with intestinal type were older (P < 0.001), male predominant (P < 0.001), smaller tumor size (P < 0.001), distal stomach predominant (P < 0.001), relative well differentiated (P < 0.001), less advanced Borrmann type (P < 0.001), less scirrhous type stromal reaction(P < 0.001), less infiltrating type of Ming's histology type(P < 0.001), less tumor invasion depth and less lymphovascular invasion (P < 0.001). Multivariate analysis with overall survival as an endpoint showed that age (P = 0.005), Borrmann classification (P < 0.001), pathological T category (P = 0.023), pathological N category (P < 0.001) and Lauren's classification (P = 0.003) were significant correlated in gastric cancer. Lauren's classification is an independent prognostic factor in gastric cancer patient undergoing gastrectomy. Lauren's classification can serve as a prognostic marker for gastric cancer patient receiving gastrectomy. The clinicopathological appearance and prognosis of mixed type gastric cancer is similar to diffuse type gastric cancer.

There exist differences in the epidemiological characteristics, clinicopathological features, tumor biological characteristics, treatment patterns, and drug selections between gastric cancer patients from the Eastern and Western countries. The Chinese Society of Clinical Oncology (CSCO) has organized a panel of senior experts specializing in all sub‐specialties of gastric cancer to compile a clinical guideline for the diagnosis and treatment of gastric cancer since 2016 and renews it annually. Taking into account regional differences, giving full consideration to the accessibility of diagnosis and treatment resources, these experts have conducted expert consensus judgment on relevant evidence and made various grades of recommendations for the clinical diagnosis and treatment of gastric cancer to reflect the value of cancer treatment and meeting health economic indexes in China. The 2021 CSCO Clinical Practice Guidelines for Gastric Cancer covers the diagnosis, treatment, follow‐up, and screening of gastric cancer. Based on the 2020 version of the CSCO Chinese Gastric Cancer guidelines, this updated guideline integrates the results of major clinical studies from China and overseas for the past year, focused on the inclusion of research data from the Chinese population for more personalized and clinically relevant recommendations. For the comprehensive treatment of non‐metastatic gastric cancer, attentions were paid to neoadjuvant treatment. The value of perioperative chemotherapy is gradually becoming clearer and its recommendation level has been updated. For the comprehensive treatment of metastatic gastric cancer, recommendations for immunotherapy were included, and immune checkpoint inhibitors from third‐line to the first‐line of treatment for different patient groups with detailed notes are provided.

To summarize the resectable rate of advanced gastric cancer characterized by abdominal lymph node metastases with the arteriovenous neoadjuvant FLEOX chemotherapy plus appropriate nutritional support. Arteriovenous neoadjuvant FLEOX chemotherapy was administered to 50 patients of gastric cancer with advanced abdominal lymph node metastases. Of the 50 patients, 42 had never received any previous therapy and preoperative CT scanning revealed unresectable tumors because of advanced lymph node (station No.3, 7, 9, 12) or distant lymph node (No.14,16) metastases. The other 8 were characterized with relapse of severe lymph node metastases or with unresectable lymph node metastases demonstrated by exploratory laparotomy. Arteriovenous neoadjuvant FLEOX chemotherapy was conducted as follows: from day 1 to day 5, 5-FU 370 mg/m(2) and leukovorin 30 mg/kg intravenously, at day 6 and day 20, CDDP 70 mg/m(2) and epotoside 70 mg/m(2) intraarterially. This FLEOX regimen was repeated every five weeks for two or three courses. Out of the 50 patients,12 malnutritional cases received parenteral and/or enteral nutritional support according to the nutritional condition. Arteriovenous neoadjuvant FLEOX chemotherapy was then administered after the improvement of nutritional state. Their nutritional support methods were adapted to their chemotherapy as well. All the patients' general conditions and symptoms were improved significantly. For the 50 cases, the imageological and histological response rate (CR+PR) was 84.0%, and curative resection rate was 78.0%. Thus, 39 patients underwent subtotal or total gastrectomy, even combined organ resection, with D(2)+alpha or D(3) lymphadenectomy. Despite neoadjuvant chemotherapy, all malnutritional cases had significant weight gain after nutritional support, and other nutritional indexes,such as serum albumin, also resumed to normal. Arteriovenous neoadjuvant FLEOX chemotherapy proves favorable therapeutic effect for gastric cancer with advanced abdominal lymph node metastases, and downstages inoperable metastatic lymph nodes for radical operation. This combined modality regimen and nutritional support may play an important role in the treatment of advanced gastric cancer.

There are two major stage classification systems for gastric cancer: the tumor-node-metastasis (TNM) staging by the International Union against Cancer (UICC)/the American Joint Committee on Cancer(AJCC) and the Japanese Classification of Gastric Carcinoma by the Japanese Gastric Cancer Association(JGCA). The evolution of these two systems showed the advancement of gastric cancer treatment. The independence of TNM and JGCA staging system is not conducive to global communication and cooperation. The integration of 2010 Japan's 14th edition of the General Rules for Gastric Cancer Study and the 7th edition of UICC/AJCC TNM staging formed an internationally unified clinical staging system. TNM staging determined by the N factor according to the number of lymph node metastasis more accurately stratified the survival curves of different stages. On January 1, 2018, the 8th edition of the TNM staging system for gastric cancer was officially implemented. The 8th edition of TNM staging provided a new definition of the staging criteria for esophagogastric junction cancer. On the basis of a single staging system, clinical TNM staging(cTNM) and neoadjuvant treatment staging (ypTNM) were added. N3a and N3b were seperately staged, and adjustments were made to the histological grading. A comprehensive treatment plan was determined by accurate clinical staging in the model of multidisciplinary diagnosis and treatment for gastric cancer. Comprehensive application of endoscopic ultrasonography (EUS), multi-slice spiral CT(MDCT), positron computed tomography combined with CT(PET-CT), and staging laparoscopy can improve the accuracy of preoperative staging of gastric cancer. The emergence of ypTNM staging is a highlight of the 8th edition of the staging, but due to insufficient case data for cTNM and ypTNM staging, the staging criteria are relatively broad, and more data validation, refinement and revision are required in the future. The 8th edition system is superior to the 7th edition system in terms of homogeneity, discriminatory ability, and monotonicity of gradients for Chinese patients with gastric cancer. The new version of the staging can guide clinicians to develop treatment plans more rationally, evaluate the treatment more scientifically, and assess the prognosis more accurately. New lymph node staging methods such as metastatic rate(rN), log odds of positive lymph nodes (LODDS), and a new staging system based on the anatomical range of lymph node metastasis can also better predict the prognosis of patients. At present, molecular type of gastric cancer has little significance for prognosis guidance, and may be rewritten or supplemented with TNM staging of gastric cancer in the future. This article discusses the history, current status and research progress of gastric cancer staging.

To investigate the current status of diagnosis and treatment of early gastric cancer in China, based on the nationwide survey by China Gastrointestinal Cancer Surgery Union. The union sent questionnaires on basic diagnosis and treatment data of gastric and colorectal cancer to all the centers of the union. Different centers collected and summarized their data by year and sent back the questionnaires to the e-mail of theunion(gi_union@foxmail.com) for summary. From 2014 to 2016, the union collected 285 questionnaires from 85 centers all over China. In these 3 years, a total of 88 340 cases of gastric cancer were summarized and there were 17 187 cases of early gastric cancer (part of the data was not available in some centers). The proportion of early gastric cancer varied from 19.5%(5711/29290) in 2014 to 19.0%(6081/32050) in 2015 and 20.0%(5395/27000) in 2016. Significant difference was found among them (χ2=9.553, P=0.008). Significant differences existed not only in the proportion of early gastric cancer between the south (20.9%, 7618/ 36518) and the north (18.5%, 9569/51822) of China (χ2=78.468, P=0.000), but also between the general (20.4%, 11991/58672) and the specialized (17.5%, 5196/29668) hospitals(χ2=107.473, P=0.000). Ultrasonic endoscope was used as routine practice in 10(17.5%, 10/57) general hospitals and 9(56.2%,9/16) specialized hospitals, and significant difference was found between them (χ2=9.721, P=0.002). A total of 4555 early gastric cancer patients received endoscopic therapy. The proportion of patients receiving endoscopic therapy was significantly different between the hospitals in the first-tier cities (36.0%, 2243/6233) and the other cities (21.1%, 2312/10954) (χ2=451.526, P=0.000), and between the hospitals with more than 800 gastric cancer patients per year (28.9%, 3434/11884) and those with less than 800 gastric cancer patients (21.1%, 1121/5303)(χ2=113.270, P=0.000). 37.1%(5270/14186) of early gastric cancer patients received laparoscopic surgery. The proportion of patients receiving laparoscopic surgery was 39.4%(3807/9651) in general hospitals and 32.3%(1463/4535) in specialized hospitals, whose difference was significant (χ2=68.244, P=0.000). The proportion of patients receiving laparoscopic surgery was 29.3%(1269/4328) in the first-tier cities and 40.6%(4001/9858) in the other cities, whose difference was significant as well(χ2=163.480, P=0.000). The proportion of patients receiving laparoscopic surgery was significantly different between the hospitals with more than 800 gastric cancer patients per year(34.5%, 3425/9929) and those with less than 800 gastric cancer patients (43.3%, 1845/4257) (χ2=100.057, P=0.000), and between the hospitals in the south (42.4%, 2552/6016) and those in the north (33.3%, 2718/8170) of China (χ2=124.296, P=0.000). 48.5%(6975) of early gastric cancer patients staged pT1a and 51.5%(7402) staged pT1b. Lymph node metastasis was found in 12.7%(1825/14377) of early gastric cancer. The lymph node metastasis rate of pT1a and pT1b was 5.7%(399/6975) and 19.3%(1426/7402), respectively. The lymph node metastasis rate of early gastric cancer varied from 12.7%(510/4017) in 2014 to 12.2%(668/5494) in 2015 and 13.3%(647/4866) in 2016. The data report of China Gastrointestinal Cancer Surgery Union partly reflects the epidemiologic characteristics, current status of diagnosis and treatment of early gastric in China.

Gastric cancer is one of the most frequently diagnosed cancers worldwide, with a relative 5 year survival of 27.7 %. The clinical outcome for advanced gastric cancer remains poor, with 5-year relative survival of only 3.9 %. Many risk factors have been identified in relation to gastric cancer, including Helicobacter pylori, Epstein-Barr virus infection, family history of gastric cancer, and the presence of pathologic changes such as atrophic gastritis, intestinal metaplasia, and high-grade dysplasia. At this time, the current standard of care in the first-line treatment of advanced or metastatic gastric cancer includes a platinum plus fluoropyrimidine backbone, while the primary treatment of early stage disease is resection with consideration for neoadjuvant, perioperative, or adjuvant chemotherapy. While early-stage gastric cancers may be successfully treated with surgical and medical therapy, metastatic gastric cancer continues to have a limited overall survival despite treatment. Herein we discuss the pathogenesis, screening, diagnosis, and treatment of gastric cancer, including future directions such as targeted therapies.

Gaining Ground in the Genetics of Gastric Cancer

Gastric adenocarcinoma is a major cause of morbidity and mortality in the world with median overall survival being less than a year [1-4]. Advanced gastric adenocarcinoma is associated with a dismal prognosis, and increasing survival time, even by a few months, can be significant in this patient population [3,5,6]. Recently there was a major breakthrough in the treatment of gastric cancer, which arose by studying a therapy currently used for treatment of another solid tumor, HER2 positive breast carcinoma. Trastuzumab, a monoclonal antibody that targets the extracellular domain of the HER2 receptor, has become standard first-line treatment in this classification of breast carcinomas [7-10]. A recent clinical trial (ToGA) using trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of HER2positive advanced gastric or gastro-esophageal junction cancer showed an increase in overall survival in advanced (inoperable locally advanced, recurrent, or metastatic) gastric cancer treated with chemotherapy plus trastuzumab versus chemotherapy alone [1]. This was the first time a biological therapeutic was proven to increase survival in gastric cancer. Critical to the ToGA trial was determining which patients would be eligible for randomization i.e. which patients had tumors that over-expressed HER2. Therefore, not only was trastuzumab shown to prolong survival in patients with advanced gastric cancer, but a protocol was proposed for HER2 testing in gastric cancer in a corollary study [11]. HER2 interpretation in gastric cancer is similar to, but slightly different than interpretation in breast cancer. Hofmann put forth an initial proposal, which was subsequently validated with minor clarifications added by Ruschoff [11,12]. The modifications in gastric cancer HER2 interpretation are related to heterogeneity (percentage of cells positive and different criteria in biopsies versus resections) and physiology (pattern of staining basolateral/lateral versus complete circumferential staining). The ToGA study established trastuzumab as a viable treatment option in advanced gastric cancer and led to approval by the Food and Drug Administration (FDA) and the European Union for its use in combination with chemotherapy in that setting [13,14]. The most recent National Comprehensive Cancer Network (NCCN) Guidelines recommend trastuzumab with chemotherapy for patients with advanced or metastatic cancer, if the tumor is HER2 positive as confirmed by immunohistochemistry (IHC 3+) or fluorescence in situ hybridization (FISH score ≥ 2 for IHC 2+ tumors).

Background. Gastric cancer is the fourth most common cancer and the second leading cause of cancer-related death worldwide. Despite many advances in the diagnosis and treatment of gastric cancer, the overall five-year survival rate does not exceed 25–30 %, and distant metastases and loco-regional recurrence develop in more than 50 % of patients. Disease recurrence is not only associated with the presence of tumor micro-metastases at the time of surgery, but also with dissemination of tumor cells during mobilization of the stomach or lymph node dissection. Even after performing radical surgery, the prognosis remains extremely unfavorable. No standardized methods of treatment for isolated loco-regional recurrence have been developed yet. Cases of successful treatment of distant metastases and regional recurrence are sporadic. Case report. We present the case of a 75-year-old patient with histologically proven well-differentiated tubular adenocarcinoma of the stomach. The patient underwent neoadjuvant chemoradiation therapy (total radiotherapy dose was 45 Gy, modified Capox regimen) followed by gastrectomy and D2lymph node dissection. The control examination revealed an isolated regional recurrence of gastric cancer. It was decided to perform surgical treatment for isolated regional gastric cancer recurrence. Conclusion. There is no standardized approach to the treatment of regional recurrence of gastric cancer. Surgical treatment in such cases is a method of choice, especially for patients who previously received neoadjuvant chemoradiotherapy. According to the worldwide literature, the median survival of such patients does not exceed a few months. The key point that determines the effectiveness of neoadjuvant therapy is the achievement of complete or partial pathological response to therapy, thus demonstrating improved survival compared to surgery alone. Therefore, it is extremely important to search for immunohistochemical and molecular genetic markers for predicting tumor response to neoadjuvant therapy in order to administer it for only potential responders.

Gastric cancer is one of the most common and highest mortality rate cancers in the world. Exosomes are vesicles secreted by cells carrying different types of molecules, such as protein and RNA. Numerous studies have confirmed that exosomes are involved in various stages of the occurrence and development of gastric cancer and play an important role. With the gradual development, exosomes have been widely employed in the diagnosis and treatment of gastric cancer. In this review, we have provided a basic overview of exosome, and discussed the role of exosome in the occurrence, proliferation, invasion, metastasis, and drug resistance in gastric cancer. In addition, we have emphasized the bright development prospect of exosome in the diagnosis and treatment of gastric cancer. The data on the discovery, diagnosis, treatment, and prognosis of gastric cancer are not particularly optimistic, but the discovery of exosome, applied in diagnosis and treatment, provides a new and effective way to improve the survival rate of patients with gastric cancer.

IntroductionOne of the changes implemented following the publication of the Improving Outcome Guidances (IOG) is the centralisation of cancer services to ensure delivery of an effective management plan to all...