Intestinal-type Tumors Research Articles

Influence of TS (rs34743033) and RUNX1 (rs2014300) gene polymorphisms on survival outcomes of fluorouracil-based chemotherapy in Chinese advanced gastric cancer patients

BackgroundThis study aimed to explore the clinical correlation of single-nucleotide polymorphisms of thymidylate synthase (TS) and runt-related transcription factor 1 (RUNX1) in patients with postoperative stage II and III gastric cancer (GC).Patients and methodsSamples were obtained from 661 patients with postoperative stage II and III GC. TS (rs34743033) and RUNX1 (rs2014300) were genotyped in 261 patients who received postoperative basic platinum and fluorouracil chemotherapy regimens and 400 patients who did not accept chemotherapy.ResultsTS (rs34743033) variant genotypes significantly prolonged the median overall survival (OS) time compared to the patients who only received adjuvant chemotherapy (HR 1.604, 95% CI 1.068–2.410, p=0.021). Moreover, 3R/3R variant genotypes were demonstrated to have a positive effect on the OS of patients who received chemotherapy based on cisplatin (HR 1.754, 95% CI 1.041–2.954, p=0.031) compared to oxaliplatin. A stratification analysis indicated that 2R/3R and 2R/2R variant genotypes were associated with inferior survival in GC patients with intestinal-type tumors, tumor less than 5 cm in size, and poorly differentiated tumors (p<0.05). However, RUNX1 (rs2014300) AA genotypes markedly increased the risk of death in GC patients compared with the GG/GA genotypes (p=0.007), but no significant difference was observed between chemotherapy based on platinum. The stratification analysis showed that the GA/AA genotype was significantly associated with inferior survival in well to moderately differentiated tumors (HR 2.001, 95% CI 1.082–3.703, p=0.023).ConclusionThese preliminary results indicated that the two polymorphisms had a significant effect on postoperative adjuvant chemotherapy. TS (rs34743033) and RUNX1 (rs2014300) may be used as biomarkers to predict prognosis and select chemotherapy regimens in GC patients.

Surgical treatment outcomes of patients with T1-T2 gastric cancer: does the age matter when excellent treatment results are expected?

BackgroundThe proportion of early gastric cancer stages is increasing, as is the incidence of gastric cancer among the elderly population. Therefore, this study was designed to analyze surgical treatment outcomes of T1-T2 gastric cancer in elderly patients.MethodsA total of 457 patients with T1-T2 gastric cancer who underwent gastrectomy between 2005 and 2015 were enrolled in this retrospective study. Patients were classified into two groups according to age (< 70 years versus ≥ 70 years). Clinicopathological features, surgical treatment results, and clinical outcomes were compared between the groups.ResultsHigher ASA score (ASA 3/4), differentiated cancer, and intestinal-type tumors were more common in elderly patients. Postoperative complication rates were similar between the two groups; however, postoperative mortality rates were significantly higher in the elderly group. Higher ASA score was independently associated with postoperative complications in the elderly group. Furthermore, severe postoperative complications were found as an independent factor associated with higher 90-day mortality rate. Elderly patients had a significantly poorer 5-year overall survival rate. Two surgery-related factors—total gastrectomy and complicated postoperative course—were revealed as independent prognostic factors for poor overall survival in the elderly group.ConclusionsDespite higher postoperative mortality rate and poorer overall survival results, elderly patients with gastric cancer should be considered for radical surgery. ASA score may be useful for predicting surgical treatment outcomes in elderly patients undergoing surgery for GC and hence assists clinicians in planning treatment strategies for each individual patient.

Functional loss of p53 cooperates with the in vivo microenvironment to promote malignant progression of gastric cancers

p53 mutations are frequently detected in malignant gastric cancers. However, the molecular mechanisms by which loss of p53 function promotes gastric cancer are not clear. We utilized Gan mice (K19-Wnt1/C2mE), which have functional p53 and develop intestinal-type gastric tumors, to investigate the role of p53 in gastric cancer progression by knocking out p53. We found that gastric epithelial cells acquire tumorigenicity in the subcutis of C57BL/6 mice as a result of Wnt activation, COX-2 activation and p53 deficiency. With repeated allograft transfers, these gastric epithelial cells gradually acquired the properties of malignant gastric cancer. Loss of p53 conferred cell stemness and induced epithelial to mesenchymal transition (EMT) in gastric epithelial cells, and these properties were further enhanced by the in vivo microenvironment, ultimately leading to gastric cancer formation and metastasis. We also found that the in vivo microenvironment enhanced activation of the COX-2 pathway, which further contributed to cancer progression. With this system, we have succeeded in recapitulating the development of malignant gastric cancer from gastric epithelial cells in a normal immune environment.

Clinical impact of tumour-infiltrating B-cells in periampullary adenocarcinoma in relation to adjuvant chemotherapy.

330 Background: The prognostic significance of tumour-infiltrating lymphocytes of the B lineage in solid cancers has only recently begun to receive attention. Herein, we explored the relationship between B cell and plasma cell density and survival in patients with periampullary adenocarcinoma, including pancreatic cancer, with particular reference to morphological type. Methods: Immunohistochemistry was applied to quantify the abundance of B cells (CD20+), and plasma cells (CD138+) in tissue microarrays with tumours from a retrospective consecutive cohort of 175 patients who had undergone pancreaticoduodenectomy for periampullary adenocarcinoma. Cox regression was applied to calculate univariable and multivariable hazard ratios (HR) for recurrence and death within five years up until March 2017. Multivariable HRs were adjusted for established clinical parameters. Results: High CD20+ cell density was an independent prognostic factor for a prolonged overall survival in both intestinal-type (HR 0.32; 95% CI 0.12-0.86) and pancreatobiliary-type (HR 0.38; 95% CI 0.23-0.66) tumours. CD138+ was an independent prognostic factor in pancreatobiliary-type tumours (HR 0.51; 95% CI 0.32-0.82) only. A significant positive interaction was seen between adjuvant chemotherapy and CD20+ cells in relation to OS for PB-type tumours (pinteraction= 0.027). Conclusions: These results demonstrate that dense infiltration into the tumour by cells of the B lymphocyte lineage confers an improved prognosis in periampullary adenocarcinoma including pancreatic cancer. The impact of B cells in the local anti-tumour response is gradually being unravelled, and their potential influence on adjuvant chemotherapy response in the more aggressive pancreatobiliary-type tumours may be clinically relevant and merits further study.

Clinicopathological factors associated with HER2-positive gastric cancer: A meta-analysis.

Background:The treatment of patients with advanced gastric cancer remains a most challenging task in the clinical practice. Recently, targeted therapies have significantly impacted the treatment strategy for many common malignancies. The use of trastuzumab, a monoclonal antibody against human epidermal growth factor receptor 2 (HER2; also known as ERBB2), plus chemotherapy proved to improve median overall survival in patients with advanced gastric cancer, compared with chemotherapy alone in Trastuzumab for Gastric Cancer (ToGA) trial. However, the prognostic value of HER2 status in gastric cancer remains controversial. Therefore, the aim of this study was to investigate the clinical pathology significance of HER2 overexpression in resectable gastric cancer for selecting the right patients with gastric cancer who may benefit from trastuzumab treatment.Methods:Publications reported the clinicopathological factors associated with HER2 status in gastric cancer from 2012 to 2017 were collected. The literature databases, such as “Cochrane Library”, “Sciencedirect”, “Springer”, “PubMed”, “Embase”, were extensively searched to retrieve the clinical studies of HER2 expression in gastric cancer. The major outcomes measures were odds ratios (ORs) and their 95% CIs. Statistical analysis was carried out by Revman software 5.3. The Newcastle–Ottawa scale was used to assess the quality of evidence.Result:Fifteen studies met our inclusion criteria. This study demonstrated that the pooled OR for HER2 positivity was associated with being male (OR: 1.42; 95% CI: 1.23–1.64), well/moderately differentiated tumor (OR: 2.76; 95% CI: 1.72–4.45), and for intestinal-type tumor (OR: 0.31; 95% CI: 0.25–0.38). However, it had no correlation with depth of tumor (P = .07), venous invasion (P = .82), and lymphovascular invasion (P = .24).Conclusion:HER2-positive expression was associated with male gender, intestinal type, and well/moderate cell differentiation. We recommend that those gastric cancer patients who may benefit from trastuzumab treatment should be subjected to targeted therapies. However, detecting HER2 status may contribute to the target therapy for gastric carcinoma using trastuzumab. This would be strengthened by further studies incorporating comorbidity data, and outcomes from centralized programs.

Gastric cancer: immunohistochemical classification of molecular subtypes and their association with clinicopathological characteristics

Gastric cancer is traditionally divided into intestinal and diffuse histological subtypes, but recent molecular analyses have led to novel classification proposals based on genomic alterations. While the intestinal- and diffuse-type tumours are distinguishable from each other at the molecular level, intestinal-type tumours have more diverse molecular profile. The technology required for comprehensive molecular analysis is expensive and not applicable for routine clinical diagnostics. In this study, we have used immunohistochemistry and in situ hybridisation in molecular classification of gastric adenocarcinomas with an emphasis on the intestinal subtype. A tissue microarray consisting of 244 gastric adenocarcinomas was constructed, and the tumours were divided into four subgroups based on the presence of Epstein-Barr virus, TP53 aberrations and microsatellite instability. The intestinal- and diffuse-type tumours were separately examined. The distribution of EGFR and HER2 gene amplifications was studied in the intestinal-type tumours. Epstein-Barr virus positive intestinal-type tumours were more common in male patients (p = 0.035) and most often found in the gastric corpus (p = 0.011). The majority of the intestinal-type tumours with TP53 aberrations were proximally located (p = 0.010). All tumours with microsatellite instability showed intestinal-type histology (p = 0.017) and were associated with increased overall survival both in the univariate (p = 0.040) and multivariate analysis (p = 0.015). In conclusion, this study shows that gastric adenocarcinomas can be classified into biologically and clinically different subgroups by using a simple method also applicable for clinical diagnostics.

Immunohistochemical study of MUC5AC, MUC1, MUC2, Cdx-2 in hyperplastic polyps and intestinal-type gastric adenocarcinoma

Aim – to study the features of MUC1, MUC2, MUC5AC, Cdx-2 immunohistochemical expression in hyperplastic polyps and intestinal-type gastric adenocarcinoma, and their relationships with the proliferation and apoptosis markers expression levels, EGFR and HER-2/neu growth receptors. Materials and м ethods. Pathomorphological and immunohistochemical studies of hyperplastic polyps from 30 patients (the age ranged from 52 to 73 years) and intestinal-type gastric adenocarcinoma from 30 patients (the age ranged from 49 to 86 years) were carried out. Results. It has been established that the gastric hyperplastic polyps are characterized by the high MUC5AC expression level, the moderate MUC1expression level, as well as the low MUC2 and Cdx-2 expression levels. The tumor cells of the intestinal-type gastric adenocarcinoma express gastric mucins less often, and are characterized by the moderate expression levels of the examined markers. In doing so, the carcinoma is characterized by the inverse correlations between gastric and intestinal mucins expression levels, and also by the correlations between the mucins markers expression levels and the histological grade of the tumor. It has been found, that the decrease in the MUC1 expression level by the tumor cells is associated with the increase in their proliferative level, while the decrease in the MUC1 and MUC5AC expression levels – with the decrease in their apoptosis level and also with the increase in the ErbB family growth receptors expression levels by the tumor cells. In addition, the increase in MUC2 expression level is associated with the decrease in apoptosis level, while the increase in the MUC2 and Cdx-2 expression levels – with the increase in EGFR expression level. Conclusions. There are close relationships between MUC1, MUC2, MUC5AC, Cdx-2 immunohistochemical expression levels and the levels of proliferative and apoptotic activity of intestinal-type gastric adenocarcinoma tumor cells, and also their expression of ErbB growth receptors.

The clinicopathological features and risk factors of recurrence in patients with mucinous borderline ovarian tumors

Objective: To investigate the clinicopathological features and risk factors in patients with mucinous borderline ovarian tumors (MBOT). Methods: From 1999 to 2006, 66 MBOT patients in our hospital with more than ten-year follow-up were enrolled retrospectively. They were re-classified according to the literature. The clinicopathological features of different subgroups, including age, preoperative serum tumor markers, surgical methods, pathological features, surgical pathology staging, as well as the risk factors of recurrence and survival were analyzed. Results: Median age was 39 years in 66 patients. Before the surgery, 33.3% (20/60) patients had elevated CA125 and 51.7% (30/58) had elevated CA199. The accurate rate for fast frozen pathology of resected specimen was 73.4%. 21 patients underwent conservative surgery and 45 patients underwent extensive surgery. 57 patients underwent comprehensive operation and 43 cases (75.4%) resulted in stage Ⅰ. 48 of the 66 patients (72.7%) had intestinal-type tumors (IMBT) and 18 patients (27.3%) had endocervical-like tumors (EMBT). The median follow-up was 150 months. Eight recurrences (12.1%) were identified. The mean time between surgery to the initial recurrence was 26.4 months (13 to 50 months). Recurrence rate of IMBT was higher than that of EMBT (14.6% versus 5.6%) with no significance (P>0.05). All patients with pseudomyxoma had disease recurrence. Recurrence rate of stage Ⅲ patients was significantly higher than that of stage Ⅰ patients (33.3% versus 9.3%, P<0.05). During the follow-up period, tumor-related death occurred in 2 cases with a 10-year survival rate of 95.4%. Kaplan-Meier method and Log Rank analysis showed that clinical staging and peritonealmyxoma were adverse prognostic factors (P<0.05). Although the recurrence rate of patients undergoing conservative surgery was higher than that of patients with extensive surgery (23.8% versus 6.7%, P=0.047), the overall survival was almost the same between these two groups (P>0.05). Conclusions: MBOT patients have relatively good prognosis. IMBT are more common than EMBT subtypes, but recurrence rate and patient survival were almost the same between these two groups. Patients with pseudomyxoma was more likely to have disease recurrence. Patients who underwent conservative surgery resulted in higher recurrence rate but did not affect the overall survival of patient. Pseudomyxoma and clinical staging were adverse prognostic factors in MBOT patients.

Staging with Unilateral Salpingo-Oophorectomy and Expert Pathological Review Result in No Recurrences in a Series of 81 Intestinal-Type Mucinous Borderline Ovarian Tumors

Objective: Recent studies suggest that mucinous borderline ovarian tumors (MBOTs) belong to a high-risk group that is more likely to develop an invasive recurrence. The objective is to determine these risk factors. Methods: A monocentric retrospective review of all consecutive patients with intestinal-type MBOT diagnosed between 1993 and 2013. All tumors were evaluated by one pathologist without knowledge of clinical outcome. Extensive surgical staging and pathological tumor sampling (1 block/cm diameter in tumors <10 cm and 2 blocks/cm diameter in tumors >10 cm) were performed in all cases. Results: A total of 81 patients were included. Patients with micro-invasion were also included. None of the patients recurred. No bilateral tumors, nor tumors with International Federation of Gynecology and Obstetrics stage II or higher, were diagnosed. Median follow-up was 87 months. Conclusions: In our series of pure intestinal-type MBOT, including micro-invasion, no recurrences were observed. Given the heterogeneity of these tumors staging with at least unilateral salpingo-oophorectomy, extensive pathological sampling, and expert pathological review are of paramount importance to be able to diagnose a pure intestinal-type MBOT and excluding gastrointestinal mucinous tumors and more important, excluding an invasive focus, defining a mucinous ovarian carcinoma. When these conditions are fulfilled, the prognosis of pure intestinal-type MBOT is excellent.

Abstract 2953: Tumor-associated macrophages infiltration highly associated with PD-L1 expression in gastric cancer

Abstract Objectives: programmed death ligand 1 (PD-L1) is key protein for tumor to acquire the evacuation form T cell immune response and PD-L1 inhibitors are useful for an immune checkpoint blockade therapy. Tumor-associated macrophages (TAM) facilitate not only tumor cell progression, but also immunosuppression, which prevent tumor cell attack by T cell. Therefore, TAM is considered to be associated with PD-L1 expression, however it remain unclear in gastric cancer (GC). Methods: We performed immunohistochemical staining of PD-L1, CD68 (pan-macrophage) and CD163 (M2 macrophage) in 217 GC sample tissue microarray. The area of CD68 and CD163 positive cells were evaluated by using by the Cytoplasmic V2.0 algorithm on the Aperio ImageScope software. Results: 31 samples (14.3%) were positive for PD-L1 expression. The mean of rate for CD68 and CD163 positive area were 6.8±0.38% and 6.2±0.30%, respectively. CD163 positive macrophage infiltration is significantly more in diffuse type tumor than in intestinal type tumor (diffuse (n=111): 6.9%, intestinal (n=91): 5.3%, p=0.0056), but CD68 positive macrophage infiltration is similar in both type (p=0.38). Interestingly, PD-L1 expression tumor have significantly more CD68 and CD163 positive macrophage infiltration (CD68: PD-L1 negative 6.3%, positive 10.4%, p=0.0002, CD163: PD-L1 negative 5.7%, positive 9.2%, p&amp;lt;0.0001). PD-L1 expression and CD68 and CD163 positive area had no relationship between any clinicopathological features. Conclusions: Macrophages infiltration in GC is highly associated with PD-L1 expression of tumor cells. M2 macrophage infiltration is significantly associated with diffused type of GAC. This result suggests that TAM infiltration is associated with the immunosuppression through upregulating PD-L1 expression in GC cells. Thus, macrophages infiltration can serve as a potential therapeutic target. . Citation Format: Kazuto Harada, Jeannelyn S Estrella, Arlene M Correa, Lang Ma, Xiaoquan Dong, Yan Xu, Wayne L Hofstette, Kazuki Sudo, Hisashi Onodera, Koyu Suzuki, Akihiro Suzuki, Randy L Johnson, Zhenning Zhenning, Shumei Song, Jaffer A Ajani, Hisashi Onodera. Tumor-associated macrophages infiltration highly associated with PD-L1 expression 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 2953. doi:10.1158/1538-7445.AM2017-2953

Expression of coproporphyrinogen oxidase is associated with detection of upper gastrointestinal carcinomas by 5-aminolevulinic acid-mediated photodynamic diagnosis

Background5-Aminolevulinic acid is a precursor of photosensitizing protoporphyrin IX and has been applied for photodynamic diagnosis of brain and bladder tumors with few side effects. Although most upper gastrointestinal tumors can be detected during photodynamic diagnosis, some tumors containing signet-ring cells cannot be visualized. Here, we aimed to assess whether proteins involved in the absorbance, activation, and turnover of protoporphyrin IX altered the fluorescence signal in gastric cancer. MethodsAminolevulinic acid-mediated photodynamic diagnosis was performed in 23 lesions from 20 patients using an endoscope equipped with a blue laser light that caused red fluorescence emission of photosensitizing protoporphyrin IX. Red fluorescence signal and intensity was assessed during photodynamic diagnosis procedures. Lesions were resected by endoscopic and/or laparoscopic surgery, and specimens were immunostained and assessed for the expression of ATP-binding cassette sub-family G member 2, oligopeptide transporter-1, and coproporphyrinogen oxidase. ResultsPhotodynamic diagnosis was negative in four cases (17.4%). Three cases of photodynamic diagnosis-negative lesions were signet-ring cell carcinomas, and only one case was differentiated adenocarcinoma (intestinal type). Twenty intestinal type, photodynamic diagnosis-positive lesions showed high expression of coproporphyrinogen oxidase, whereas signet-ring cell carcinomas were all negative. Oligopeptide transporter-1 immunoreactivity was significantly higher in tumors of intestinal type. ATP-binding cassette sub-family G member 2 expression tended to be higher in luminal surface tumors than in intestinal type tumors. ConclusionAminolevulinic acid-mediated photodynamic diagnosis provided good detection of upper gastrointestinal tumors of intestinal type but not diffuse type tumors, such as signet-ring cell carcinomas, possibly owing to coproporphyrinogen oxidase expression.

Coexpressed modular gene expression reveals inverse correlation between immune responsive transcription and aggressiveness in gastric tumours.

The existing large number of gene expression profiles of tumour samples offers a great advantage for the integrative functional genomic exploration of molecular dysregulation in cancers. The clusters of genes (modules) derived from a gastric cancer (GC) coexpression network were explored to understand their clinical and functional significance. Among the modules derived from the GC mRNA expression network, six modules were relatively highly expressed in diffuse type gastric tumours. Elevated expression of genes related to extracellular matrix (ECM), angiogenesis, collagen and intracellular cytoskeletal components and immune response were identified in these modules. ECM-related modules exhibited an inverse correlation with modules representing the expression of immune response genes. A reduced expression of immune response genes was identified as the key factor associated with the aggressive features of diffuse gastric tumours, which is indicative of tumour progression involving the escape from immune surveillance in diffuse tumours. A part of the identified aggressive factors was common between intestinal and diffuse type tumours. The coexpressed modules and their expression patterns delineate the fine transition involved in cancer progression in the later stages of tumours. The identified modules could serve as surrogate gene-sets, indicating the molecular staging of GC aggressiveness with underlying biological interaction.

Clinicopathological characteristics of duodenal epithelial neoplasms: Focus on tumors with a gastric mucin phenotype (pyloric gland-type tumors).

ObjectiveEpithelial tumors less commonly occur in the duodenum than in the stomach or large intestine. The clinicopathological characteristics of duodenal epithelial tumors remain a matter of debate. We therefore studied resected specimens to investigate the clinicopathological characteristics of duodenal epithelial tumors.Materials and methodsAmong duodenal epithelial tumors resected endoscopically or surgically in our hospital, we studied the clinicopathological characteristics of 110 adenomas or intramucosal carcinomas. The grade of atypia of all tumors was classified into 3 groups according to the World Health Organization (WHO) 2010 classification. The tumors were immunohistochemically evaluated to determine the frequency of differentiation toward fundic glands.ResultsAs for patient characteristics, there were 76 men (75.2%) and 25 women (24.8%), with a median age of 65 years (range, 34 to 84). The tumors most commonly arose in the first to second part of the duodenum. Many lesions were flat, and the median tumor diameter was 8.0 mm. The lesions were classified into 2 types according to mucin phenotype: intestinal-type tumors (98 lesions, 89.1%) and gastric-type tumors (12 lesions, 10.9%). Intestinal-type tumors were subdivided into 2 groups: tubular-type tumors (91 lesions, 82.7%) and tubulovillous-type tumors (7 lesions, 6.4%). Gastric-type tumors were classified into 2 types: foveolar type (3 lesions, 2.7%) and pyloric gland-type (PG) tumors (9 lesions, 8.2%). The grade of atypia was significantly higher in gastric-type tumors (p<0.01). PG tumors were gastric-type tumors characterized by pyloric glands and findings suggesting differentiation toward fundic glands.ConclusionsAbout 10% of the duodenal tumors had a gastric-type mucin phenotype. Gastric-type tumors showed high-grade atypia. In particular, PG tumors showed similarities to PG tumors of the stomach, such as differentiation toward fundic glands.

The histopathologic type predicts survival of patients with ampullary carcinoma after resection: A meta-analysis

ObjectivesThe results of studies on the prognostic value of histopathologic differentiation of the intestinal and pancreatobiliary types of ampullary carcinoma after resection are conflicting. A meta-analysis was undertaken to investigate this issue. MethodsA systematic literature search was performed to identify articles published from January 2000 to August 2016. Data were pooled for meta-analysis using Review Manager 5.3. ResultsTwenty three retrospective studies involving a total of 2234 patients were identified for inclusion, of whom 1021 (45.7%) had intestinal type tumors and 899 (40.2%) had pancreaticobiliary type tumors. Patients with the pancreaticobiliary type had high rates of poor tumor differentiation (P < 0.001), lymph node metastasis (P < 0.001), vascular invasion (P < 0.001), perineural invasion (P < 0.001), and positive resection margins (P = 0.004), as compared with those with the intestinal type. The pancreaticobiliary type predicted a worse overall survival (hazard ratio [HR] 1.84, 95% CI 1.49–2.27; P < 0.001) and disease-free survival (HR 1.93, 95% CI 1.23–3.01; P = 0.004). ConclusionThe histopathologic type has major impact on survival in patients with ampullary carcinoma after resection, and the pancreaticobiliary type reflects a more aggressive tumor biology and is associated with worse survival.

Staging laparoscopy for advanced gastric cancer: significance of preoperative clinicopathological factors.

Although the use of staging laparoscopy (SL) for detecting peritoneal metastasis (P) and determining peritoneal lavage cytology (CY) is widespread in advanced gastric cancer, an indication for SL based on preoperative clinicopathological factors is controversial. From May 2006 to September 2015, 120 patients with advanced gastric cancer with primary tumors ≥5cm and/or with bulky regional lymph nodes (bulky N) underwent SL for assessment of P/CY status. Clinicopathological factors were analyzed retrospectively to determine their influence on peritoneal spread (P1 and/or CY1). An additional analysis of 379 consecutive patients with clinically T2 or deeper gastric cancer in the same time period was carried out to confirm the SL results. Peritoneal spread was confirmed by SL in 54 cases (45%). The presence of type-4 tumors (n=38, p<0.0001) and diffuse-type tumors (n=85, p=0.04) correlated significantly with peritoneal spread. These two factors were also correlated significantly with increased peritoneal spread in a subgroup analysis among patients with tumors with bulky N (n=44). The additional analysis of 379 patients showed results consistent with the SL results. The frequency of peritoneal spread was 78% among type-4 tumors, 47% among diffuse-type tumors ≥5cm, and 38% among diffuse-type tumors with bulky N, whereas among intestinal-type tumors, it was 18% in tumors ≥5cm and 13% among tumors with bulky N. Among tumors ≥5cm or with bulky N, type-4 tumors and diffuse-type tumors had a high potential for peritoneal spread and patients with such tumors were considered more suitable candidates for SL.

Comparative immunohistochemical characteristics of Ki-67, p53, caspase-3 expression in gastric hyperplastic polyps and non-invasive intestinal-type gastric adenocarcinoma

Aim. The problem of early diagnostic of gastric cancer has a tight connection with the issue of premalignant lesions, especially gastric polyps. The aim of this research was to compare the expression levels of Ki-67, p53 and caspase-3 in epithelial cells and stromal cells of gastric hyperplastic polyps on the one hand and tumor cells and stromal cells of non-invasive intestinal-type gastric adenocarcinoma on the other hand. Materials and methods. For this purpose, pathohistological and immunohistochemical studies were used. The biopsies of 10 patients with hyperplastic polyps (the age of the patients ranged from 52 to 73 years) and surgical material of 10 patients with non-invasive (pTis, pT1) intestinal-type gastric adenocarcinoma (the age of patients ranged from 45 to 83 years) were analyzed. Results. It was established that epithelial cells of gastric hyperplastic polyps are characterized by low expression level of Ki-67, p53 and caspase-3, just as stromal cells of hyperplastic polyps are characterized by low expression level of Ki-67 and the medium expression level of caspase-3. Moreover, it has been established that tumor cells of non-invasive intestinal-type gastric adenocarcinoma are characterized by medium expression level of Ki-67, caspase-3 and also low expression level of p53, just as stromal cells of non-invasive adenocarcinoma are characterized by low expression level of Ki-67 and low expression level of caspase-3. The differences between the expression levels of Ki-67, p53 and caspase-3, that were established for hyperplastic polyps on the one hand and non-invasive adenocarcinoma on the other hand, are statistically significant (p<0,05). Conclusion. These data demonstrate, that proliferative activity of non-invasive intestinal-type gastric adenocarcinoma tumor cells is higher than proliferative activity of gastric hyperplastic polyps epithelial cells. Moreover, non-invasive intestinal-type gastric adenocarcinoma differs by higher activity of p53 accumulation, higher level of tumor cells apoptosis and lower level of stromal cells apoptosis.

Differentiation and prognostic markers in ampullary cancer: Role of p53, MDM2, CDX2, mucins and cytokeratins

IntroductionSubclassification of ampullary adenocarcinomas into intestinal and pancreatobiliary type has prognostic and therapeutic implications. Immunohistochemical staining against specific biomarkers has been proven to be a useful adjunct in determining the exact histotype. Furthermore the immunohistochemical profile is suggestive of the molecular pathogenic mechanisms through which the tumor evolved. The aim of this study was to correlate p53, MDM2, CK7, CK20, MUC1, MUC2 and CDX2 expression in ampullary adenocarcinomas with the type of differentiation and patients’ survival. Material and methodsForty-seven radically resected ampullary adenocarcinomas were included in this study. Thirty-eight of them were eligible for survival analysis. Patients’ data were retrospectively collected. All tumors were classified as intestinal or pancreatobiliary type, according to histologic criteria, and immunohistochemically stained against the aforementioned markers. ResultsThere were 18 intestinal and 29 pancreatobiliary type ampullary adenocarcinomas. A trend was found between intestinal type tumors and large tumor size. CK20, MUC2 and CDX2 expression was more prevalent in intestinal type tumors, while MUC1 was more frequently expressed in pancreatobiliary type tumors. Neither p53 nor MDM2 differential expression between the two histotypes reached statistical significance. Multivariate analysis indicated CK20 and MUC1 as independent predictors of the histotype. Mean and median survival was 90.3 and 55 months respectively. Overall 5-year survival rate was 48%. Survival analysis indicated TNM stage as the only independent prognostic factor. Although significant difference in survival rates among the two histotypes was implied based on survival plots, this difference could not gain statistical significance. ConclusionImmunoreactivity against CK20 and MUC1 in ampullary carcinomas is a useful adjunct to histologic examination in determining histotype. None of the immunohistochemical markers studied has prognostic significance. Future studies focused on other signaling pathways should seek further evidence of distinct tumorigenic mechanisms between histotypes of ampullary adenocarcinoma.

Differential Expression of β-Catenin, EGFR, CK7, CK20, MUC1, MUC2, and CDX2 in Intestinal and Pancreatobiliary-Type Ampullary Carcinomas.

The purpose of this study was to associate immunohistochemical expression of β-catenin, EGFR, CK7, CK20, MUC1, MUC2, and CDX2 in ampullary adenocarcinomas with the type of differentiation and prognosis. Forty-seven patients with ampullary adenocarcinoma who underwent pancreatoduodenectomy with curative intent from 1997 to 2014 were included in this study. Nine patients with perioperative death were included in the association analysis but excluded from survival analysis. All tumors were classified as intestinal or pancreatobiliary type, according to histologic criteria, and immunohistochemically stained against the aforementioned markers. Eighteen carcinomas were classified as intestinal type and 29 carcinomas as pancreatobiliary type. Univariate analysis revealed that CK20 and CDX2 expression correlates with intestinal type, whereas MUC1 positivity indicates pancreatobiliary type. A marginally significant trend was shown for intestinal-type tumors toward larger size and more frequent MUC2 expression. Using multivariate analysis CK20 ( P = .003) and MUC1 ( P = .004) were identified as independent predictors of the intestinal and pancreatobiliary types, respectively. Mean and median survival was 90.3 and 55 months, respectively. Overall 5-year survival rate was 48%. On univariate survival analysis, overall survival was adversely influenced by the number of infiltrated lymph nodes, elevated Ca19-9 serum levels, jaundice, poor differentiation, T4 stage, N1 stage, TNM stage III, and CDX2 immunonegativity. Multivariate analysis identified TNM stage as the only independent prognostic factor in ampullary adenocarcinoma ( P = .048). Immunoreactivity against CK20 and MUC1 in ampullary carcinomas is a useful adjunct to histologic examination in determining histotype. None of the immunohistochemical markers studied had prognostic significance.

Evaluation of a trastuzumab-containing treatment regimen for patients with unresectable advanced or recurrent gastric cancer.

The present study aimed to evaluate the efficacy and safety of trastuzumab plus chemotherapy for patients with unresectable advanced or recurrent gastric cancer. A retrospective analysis of 213 patients with unresectable advanced or recurrent gastric cancer who received systemic chemotherapy, including 15 patients who were also administered trastuzumab, at Kochi Medical School between 2007 and 2013 was performed. The overall survival was compared between patients who received trastuzumab plus chemotherapy and patients who received chemotherapy alone, and the safety and efficacy of the trastuzumab-containing regimen was evaluated. Human epidermal growth factor receptor (HER)2 status was examined in 86 patients, of whom 15 (17.4%) exhibited strong positive HER2 expression. The rate of strong positive HER2 expression was significantly higher for intestinal type tumors compared with diffuse type tumors [23.6 (13/55) vs. 6.5% (2/31); P=0.044]. The median overall survival of the patients treated with trastuzumab was significantly longer compared with that for patients who were not treated with trastuzumab (22.9 vs. 11.6 months; P=0.014). The objective response rate and disease control rate for trastuzumab plus chemotherapy were 46.7 and 86.7%, respectively. Frequently encountered grade 3-4 toxicities included neutropenia (26.7%; 4/15), anemia (13.3%; 2/15) and fatigue (13.3%; 2/15). Trastuzumab plus chemotherapy is effective for patients with HER2-positive advanced or recurrent gastric cancer, and the frequencies of hematological and non-hematological toxicities experienced by patients in the present study indicated that it can be safely administered clinically.

Expression and Prognostic Significance of Human Epidermal Growth Factor Receptors 1, 2 and 3 in Periampullary Adenocarcinoma.

Periampullary adenocarcinoma, including pancreatic cancer, is a heterogeneous group of tumours with dismal prognosis, for which there is an urgent need to identify novel treatment strategies. The human epithelial growth factor receptors EGFR, HER2 and HER3 have been studied in several tumour types, and HER-targeting drugs have a beneficial effect on survival in selected types of cancer. However, these effects have not been evident in pancreatic cancer, and remain unexplored in other types of periampullary cancer. The prognostic impact of HER-expression in these cancers also remains unclear. The aim of this study was therefore to examine the expression and prognostic value of EGFR, HER2 and HER3 in periampullary cancer, with particular reference to histological subtype. To this end, protein expression of EGFR, HER2 and HER3, and HER2 gene amplification was assessed by immunohistochemistry and silver in situ hybridization, respectively, on tissue microarrays with tumours from 175 periampullary adenocarcinomas, with follow-up data on recurrence-free survival (RFS) and overall survival (OS) for up to 5 years. EGFR expression was similar in pancreatobiliary (PB) and intestinal (I) type tumours, but high HER2 and HER3 expression was significantly more common in I-type tumours. In PB-type cases receiving adjuvant gemcitabine, but not in untreated cases, high EGFR expression was significantly associated with a shorter OS and RFS, with a significant treatment interaction in relation to OS (pinteraction = 0.042). In I-type cases, high EGFR expression was associated with a shorter OS and RFS in univariable, but not in multivariable, analysis. High HER3 expression was associated with a prolonged RFS in univariable, but not in multivariable, analysis. Neither HER2 protein expression nor gene amplification was prognostic. The finding of a potential interaction between the expression of EGFR and response to adjuvant chemotherapy in PB-type tumours needs validation, and merits further study.