miR-100-3p inhibits cell proliferation and induces apoptosis in human gastric cancer through targeting to BMPR2.

BACKGROUND: miR-100 has been reported to closely associate with gastric cancer (GC) initiation and progression. However, the underlying mechanism of miR-100-3p in GC is still largely unclear. In this study, we intend to study how miR-100-3p regulates GC malignancy. METHODS: The expression levels of miR-100-3p in vitro (GES-1 and GC cell lines) and in vivo (cancerous and normal gastric tissues) were examined by quantitative real-time PCR (qRT-PCR). MTT and PE/Annexin V analyses were responsible for measurement of the effects of miR-100-3p on GC cell proliferation and apoptosis. Transwell assay with or without matrigel was used to examine the capacity of migration and invasion in GC cells. The interaction of miR-100-3p with bone morphogenetic protein receptor 2 (BMPR2) was confirmed through transcriptomics analysis and luciferase reporter assay. qRT-PCR and Western blot analyses were applied to determine the expression of ERK/AKT and Bax/Bcl2/Caspase3, which were responsible for the dysfunction of miR-100-3p. RESULTS: miR-100-3p was down-regulated in GC cell lines and cancerous tissues, and was negatively correlated with BMPR2. Loss of miR-100-3p promoted tumor growth and BMPR2 expression. Consistently, the effects of miR-100-3p inhibition on GC cells were partially neutralized by knockdown of BMPR2. Over-expression of miR-100-3p simultaneously inhibited tumor growth and down-regulated BMPR2 expression. Consistently, over-expression of BMPR2 partially neutralized the effects of miR-100-3p over-expression. Further study demonstrated that BMPR2 mediated the effects downstream of miR-100-3p, which might indirectly regulate ERK/AKT and Bax/Bcl2/Caspase3 signaling pathways. CONCLUSION: miR-100-3p acted as a tumor-suppressor miRNA that down-regulated BMPR2, which consequently inhibited the ERK/AKT signaling and activated Bax/Bcl2/Caspase3 signaling. This finding provided novel insights into GC and could contribute to identify a new diagnostic and therapeutic target.

Quantum dots-based tissue and in vivo imaging in breast cancer researches: current status and future perspectives.

As the most common malignant tumor for females, breast cancer (BC) is a highly heterogeneous disease regarding biological behaviors. Precisely targeted imaging on BC masses and biomarkers is critical to BC detection, treatment, monitoring, and prognostic evaluation. As an important imaging technique, quantum dots (QDs)-based imaging has emerged as a promising tool in BC researches owe to its outstanding optical properties. However, few reviews have been specifically devoted to discussing applications of QDs-based imaging in BC researches. This review summarized recent promising works in QDs-based tissue and in vivo imaging for BC studies. Physicochemical and optical properties of QDs and its potential applications were briefly described first. Then QDs-based imaging studies in BC were systematically reviewed, including tissue imaging for studying biomarkers interactions, and evaluating prognostic biomarkers, in vivo imaging for mapping axillary lymphatic system, showing BC xenograft tumor, and detecting BC metastases. At last, the future perspectives with special emphasis on the potential clinical applications have also been discussed. Potential applications of QDs-based imaging on clinical BC in the future are mainly focused on tissue study, especially in BC molecular pathology due to its optimal optical properties and quantitative information capabilities on multiple biomarkers.

High expression of transform growth factor beta 1 in gastric cancer confers worse outcome: results of a cohort study on 184 patients.

BACKGROUND/AIMS: Transform growth factors beta (TGFbeta) plays different roles at different stages of tumor development. TGFbeta1 is one isoform of TGFbeta, with complex secretion mechanism and bidirectional functions. This study was to investigate TGFbeta1 expression and its clinical significance in different clinicopathological subgroups of gastric cancer (GC) patients. METHODOLOGY: Tumor and peritumoral tissues from 184 GC patients were constructed into three tumor tissue microarrays. The expression of TGFbeta1 was analyzed by immunohistochemistry methods. RESULTS: TGFbeta1 was mainly expressed in the cytoplasm and membrane of GC cells. Low TGFbeta1 expression was observed in 82 (44.6%) tumor and 28 (68.3%) peritumoral tissues, and high expression was observed in 102 (55.4%) tumor and 13 (31.7%) peritumoral tissues. TGFbeta1 expression was significantly higher in tumor than peritumoral tissues (chi2 = 7.554, P = 0.006). The high expression of TGFbeta1 was related to worse overall survival (OS) (P = 0.040). TGFbeta1 expression was higher in the old and intestinal type GC than in the young (P = 0.017) and in diffuse type GC (P = 0.015), respectively. Patients with high TGFbeta1 expression had a worse survival in young people, female, diffuse type GC, poor differentiation, and lymph nodes metastasis. Multivariate Cox proportional hazards analysis showed that age, pathological grading, serosal invasion and TGFbeta1 expression were independent risk factors. CONCLUSIONS: High TGFbeta1 expression may indicate poor prognosis of GC patients and warrant more active treatment against TGFbeta1.

Long term follow up and retrospective study on 533 gastric cancer cases.

BACKGROUND: Gastric cancer (GC) is the third leading cause of cancer death in China and the outcome of GC patients is poor. The aim of the research is to study the prognostic factors of gastric cancer patients who had curative intent or palliative resection, completed clinical database and follow-up. METHODS: This retrospective study analyzed 533 GC patients from three tertiary referral teaching hospitals from January 2004 to December 2010 who had curative intent or palliative resection, complete clinical database and follow-up information. The GC-specific overall survival (OS) status was determined by the Kaplan-Meier method, and univariate analysis was conducted to identify possible factors for survival. Multivariate analysis using the Cox proportional hazard model and a forward regression procedure was conducted to define independent prognostic factors. RESULTS: By the last follow-up, the median follow-up time of 533 GC patients was 38.6 mo (range 6.9-100.9 mo), and the median GC-specific OS was 25.3 mo (95% CI: 23.1-27.4 mo). The estimated 1-, 2-, 3- and 5-year GC-specific OS rates were 78.4%, 61.4%, 53.3% and 48.4%, respectively. Univariate analysis identified the following prognostic factors: hospital, age, gender, cancer site, surgery type, resection type, other organ resection, HIPEC, LN status, tumor invasion, distant metastases, TNM stage, postoperative SAE, systemic chemotherapy and IP chemotherapy. In multivariate analysis, seven factors were identified as independent prognostic factors for long term survival, including resection type, HIPEC, LN status, tumor invasion, distant metastases, postoperative SAE and systemic chemotherapy. CONCLUSIONS: Resection type, HIPEC, postoperative SAE and systemic chemotherapy are four independent prognostic factors that could be intervened for GC patients for improving survival.

Combined features based on MT1-MMP expression, CD11b + immunocytes density and LNR predict clinical outcomes of gastric cancer.

BACKGROUND: Given the complexity of tumor microenvironment, no single marker from cancer cells could adequately predict the clinical outcomes of gastric cancer (GC). The objective of this study was to evaluate the prognostic role of combined features including conventional pathology, proteinase and immune data in GC. METHODS: In addition to pathological studies, immunohistochemistry was used to assess membrane-type 1 matrix metalloproteinase (MT1-MMP) expression and CD11b + immunocytes density in three independent GC tissue microarrays containing 184 GC tissues. Separate and combined features were evaluated for their impact on overall survival (OS). RESULTS: We found that traditional factors including tumor size, histological grade, lymph node status, serosa invasion and TNM stage were associated with OS (P < 0.05 for all). Moreover, statistically significant differences in OS were found among lymph node ratio (LNR) subgroups (P < 0.001), MT1-MMP subgroups (P = 0.015), and CD11b + immunocytes density subgroups (P = 0.031). Most importantly, combined feature (MT1-MMP positive, low CD11b + immunocytes density and high LNR) was found by multivariate analysis to be an independent prognostic factors for OS after excluding other confounding factors (HR = 3.818 [95%CI: 2.223-6.557], P < 0.001). In addition, this combined feature had better performance in predicting clinical outcomes after surgery long before recurrence had occurred (Area under the curve: 0.689 [95%CI: 0.609-0.768], P < 0.001). CONCLUSIONS: These findings indicate that better information on GC prognosis could be obtained from combined clinico-pathological factors, tumor cells and the tumor microenvironment.

Evaluation of the staging systems for gastric cancer.

BACKGROUND: Some staging systems for gastric cancer (GC) have been developed as alternatives to the 6th and 7th TNM staging systems, including the Hybrid, tumor-ratio-metastasis (TRM), and Kiel staging systems. This study evaluated the overall performance of these systems for GC. METHODS: A total of 540 GC patients undergoing surgical resection were staged using these five systems. Homogeneity, discrimination power, predictive accuracy, and complexity of these systems were compared. RESULTS: Multivariate analyses showed that all of 7th pT, pN, and pM classifications were independent factors for GC prognosis (P < 0.001 for all). Compared with the other four systems, 7th TNM system had improved stage groups homogeneity (7 of 8 stage groups homogeneous), enhanced discrimination power (4 of 5, 5 of 7, 4 of 7, 3 of 7, and 1 of 4 adjacent stage groups were differentiated by the 6th, 7th TNM, Hybrid, TRM, and Kiel systems, respectively), and better prediction value for GC patients' outcome (AUC = 0.801, P < 0.001). In addition, the 7th TNM system did not increase the staging complexity (9 groups and 21 subgroups). CONCLUSIONS: The 7th TNM staging system represents advancement in GC staging system for better prediction of clinical outcomes.

Coevolution of the tumor microenvironment revealed by quantum dot-based multiplexed imaging of hepatocellular carcinoma.

AIM: This study aimed to provide new insights into the mechanisms of hepatocellular carcinoma (HCC) invasion by simultaneously imaging tumor cells and major components of the tumor microenvironment. MATERIALS & METHODS: Formalin-fixed paraffin-embedded human HCC tissues were studied by conventional immunohistochemistry and quantum dot-based multiplexed imaging to reveal type IV collagen, LOX and tumor angiogenesis. RESULTS: Type IV collagen degradation and repatterning in the extracellular matrix (ECM) was a continuous process, making the ECM harder, although more fragile and less resistant to cancer invasion. The distribution of LOX among cancer nests was heterogeneous, with higher expression in small cancer nests and lower expression in large cancer nests. LOX expression in cancer cells was associated with rigid stroma and tumor angiogenesis. Tumor angiogenesis occurred with type IV collagen presence. At the cancer invasion front, the ECM was hydrolyzed, with the prominent linear reorientation of type IV collagen surrounding cancer nests adjacent to neovessels. CONCLUSION: The visualization of the temporal-spatial relationship between type IV collagen, LOX and tumor angiogenesis revealed the coevolution process of HCC cells and their microenvironment, emphasizing an active role of the ECM during cancer invasion.

In vitro invasive pattern of hepatocellular carcinoma cell line HCCLM9 based on three-dimensional cell culture and quantum dots molecular imaging.

This study aimed to establish a new in vitro three-dimensional (3D) cell culture and use quantum dots (QDs) molecular imaging to examine the invasive behaviors of hepatocellular carcinoma (HCC) cells. Each well of the 24-well cell culture plate was cover-slipped. Matrigel diluted with serum-free DMEM was added and HCCLM9 cells were cultured on the Matrigel. The cell morphological and cell growth characteristics were observed by inverted microscopy and laser confocal microscopy at different culture time. Cell invasive features were monitored by QDs-based real-time molecular imaging techniques. The results showed that on this 3D cell culture platform, HCCLM9 cells exhibited typical multi-step invasive behaviors, including reversion of cell senescence, active focal proliferation and dominant clones invasion. During the process, cells under 3D cell culture showed biological behaviors of spatio-temporal characteristics. Cells first merged on the surface of matrix, then gradually infiltrated and migrated into deep part of matrix, presenting polygonal morphology with stretched protrusions, forming tubular, annular and even network structure, which suggested that HCC cells have the morphological basis for vasculogenic mimicry. In addition, small cell clones with their edges well-circumscribed in early stage, progressed into a large irregular clone with ill-defined edge, while the other cells developed invadopodia. And QDs probing showed MT1-MMP was strongly expressed in the invadopodia. These findings indicate that a novel 3D cell culture platform has been successfully established, which can mimic the in vivo tumor microenvironment, and when combined with QDs-based molecular imaging, it can help to better investigate the invasive behaviors of HCC cells.

Laparoscopy-assisted gastrectomy for advanced gastric cancer patients with situs inversus totalis: Two case reports and review of literature.

BACKGROUND: Situs inversus totalis (SIT) is a rare condition in which the positions of abdominal and thoracic organs present a "mirror image" of the normal ones in the median sagittal plane. Although minimally invasive surgery has evolved to achieve laparoscopic gastrectomy for gastric cancer (GC) patients with SIT, it is difficult to perform lymphadenectomy (LND) in such a transposed anatomical condition. Herein, we report the cases of two patients with SIT who successfully underwent laparoscopy-assisted gastrectomy (LAG) with D2 LND. CASE SUMMARY: Case 1: A 65-year-old man was admitted for intermittent abdominal pain and distension, occasional belching, and acid reflux for 4 mo. He was diagnosed with GC (cT3N1-2M0) with SIT. Before surgery, he had undergone four cycles of neoadjuvant chemotherapy and immunotherapy. Then, the patient was evaluated as having a partial response, and laparoscopy-assisted distal gastrectomy with D2 LND and Billroth II reconstruction were performed. The operation was performed successfully within 240 min with an estimated blood loss of 50 mL and no severe complications. The patient was discharged on postoperative day (POD) 9. Case 2: A 55-year-old man was admitted for upper abdominal distension with pain and discomfort after eating for 3 mo. He was diagnosed with GC (cT3N1M0) with SIT. He had a history of hypertension for more than 10 years; however, his blood pressure was well-controlled via regular medication. We performed laparoscopy-assisted total gastrectomy with D2 LND and Roux-en-Y reconstruction. The operation was performed successfully within 168 min with an estimated blood loss of 50 mL and no severe complications. The patient was discharged on POD 10. CONCLUSION: LAG with D2 LND could be considered an accessible, safe, and curative procedure for advanced GC patients with SIT.

Efficacy of Warfarin Therapy Guided by Pharmacogenetics: A Real-world Investigation Among Han Taiwanese.

PURPOSE: The anticoagulation activity of warfarin in populations with CYP2C9, VKORC1, and CYP4F2 variants differs between individuals and is correlated with poor international normalized ratio (INR) control. Pharmacogenetics-guided warfarin dosing has been successfully developed for patients with genetic variations in recent years. However, few real-world data have been used to investigate the INR and warfarin dosage and the time to target INR. This study examined the largest collection of genetic and clinical real-world data related to warfarin to provide further evidence supporting the benefits of pharmacogenetics in clinical outcomes. METHODS: We retrieved a total of 69,610 INR-warfarin records after the index date from 2,613 patients in the China Medical University Hospital database between January 2003 and December 2019. Each INR reading was obtained from the latest laboratory data after the hospital visit date. Patients with a history of malignant neoplasms or pregnancy before the index date were excluded, as were patients without data on INR measurements after the fifth day of prescription, genetic information, or gender variables. The primary outcomes were the INR and warfarin dosage during days 7, 14, 28, 56, and 84 after prescription. The secondary outcome was the time required to reach the INR ranges of 1.5 to 3.0 and >4.0. FINDINGS: A total of 59,643 INR-warfarin records from 2188 patients were retrieved. The average INR was higher for homozygous carriers of the minor allele at CYP2C9 and VKORC1 during the first 7 days (1.83 [1.03] [CYP2C9*1] and 2.46 [1.44] [CYP2C9*3], P < 0.001; 1.39 [0.36] [rs9923231 G/G], 1.55 [0.79] [rs9923231 G/A], and 1.96 [1.13] [rs9923231 A/A], P < 0.001) than for the wild-type allele. These patients with variants required lower warfarin doses than those with the wild-type allele during the first 28 days. CYP4F2 variant patients seemed to require higher doses of warfarin than those in the wild-type group; however, no significant difference in the average INR was observed (1.95 [1.14] [homozygous V433 carriers], 1.78 [0.98] [heterozygous V433M carriers], and 1.66 [0.91] [homozygous M433 carriers], P = 0.016). IMPLICATIONS: Our study indicates that genetic variants in the Han population may enhance warfarin responsiveness, which holds clinical relevance. An increased warfarin dosage was not linked to a shorter time to therapeutic INR between CYP4F2 variant patients and those with a wild-type allele. Assessing CYP2C9 and VKORC1 genetic polymorphisms before initiating warfarin treatment in real-world practice is essential for potentially vulnerable patients and is likely to optimize therapeutic dosing.

Cathepsin B cleavable novel prodrug Ac-Phe-Lys-PABC-ADM enhances efficacy at reduced toxicity in treating gastric cancer peritoneal carcinomatosis: an experimental study.

BACKGROUND: Doxorubicin (Adriamycin) is effective in gastric cancer treatment, but with severe dose-dependent toxicities. A novel prodrug of doxorubicin (Ac-Phe-Lys-PABC-ADM) is designed to deliver free doxorubicin relying on cathepsin B and reduce side effects. The authors examined the antitumor effect and toxicities of Ac-Phe-Lys-PABC-ADM against gastric cancer peritoneal carcinomatosis. METHODS: SGC-7901 gastric cancer cell line was used for the study. The in vitro study investigated the effects of doxorubicin and Ac-Phe-Lys-PABC-ADM on cell growth dynamics and cell cycle. The in vivo study investigated the efficacy and toxicity of Ac-Phe-Lys-PABC-ADM on a nude mice model of peritoneal carcinomatosis, with doxorubicin as positive control. RESULTS: In the in vitro study, Ac-Phe-Lys-PABC-ADM had a lower dose-dependent inhibitory effect on SGC-7901 cells. In the in vivo study of control, doxorubicin, and Ac-Phe-Lys-PABC-ADM groups, the median experimental peritoneal carcinomatosis indexes were 6, 1.5, and 1, respectively (P = .004); the body weights were 24.32 ± 1.40 g, 18.40 ± 2.97 g, and 23.61 ± 0.80 g, respectively (P = .000). Biochemical studies showed that Ac-Phe-Lys-PABC-ADM had significantly lower toxicities on the bone marrow, liver, kidney, and particularly heart. Histopathological studies of the control, doxorubicin, and Ac-Phe-Lys-PABC-ADM groups found significant myocardium toxicities in 3, 7, and 4 animals, respectively. CONCLUSIONS: Ac-Phe-Lys-PABC-ADM could be an effective molecular targeting drug to treat gastric cancer peritoneal carcinomatosis with enhanced efficacy and reduced toxicity.

Quantum dots-based double-color imaging of HER2 positive breast cancer invasion.

It has been well recognized that human epidermal growth factor receptor 2 (HER2) level in breast cancer (BC) is closely related to the malignant biologic behaviors of the tumor, including invasion and metastasis. Yet, there has been a lack of directly observable evidence to support such notion. Here we report a quantum dots (QDs)-based double-color imaging technique to simultaneously show the HER2 level on BC cells and the type IV collagen in the tumor matrix. In benign breast tumor, the type IV collagen was intact. With the increasing of HER2 expression level, there has been a progressive decrease in type IV collagen around the cancer nest. At HER2 (3+) expression level, there has virtually been a total destruction of type IV collagen. Moreover, HER2 (3+) BC cells also show direct invasion into the blood vessels. This novel imaging method provides direct observable evidence to support the theory that the HER2 expression level is directly related to BC invasion.

Preoperative serum carbohydrate antigen 242 is a useful predictive and prognostic marker in colorectal cancer.

BACKGROUND/AIMS: Tumor markers (TM) play an important role in the management of colorectal cancer (CRC). This study evaluates the predictive and prognostic value of preoperative serum carbohydrate antigen 242 (CA242) in CRC. METHODOLOGY: Preoperative serum CA242 level was detected by C12 protein-chip diagnostic system in 185 CRC patients, and the predictive value of CA242 in stage, lymph node metastasis and tumor invasion depth was assessed. The prognostic value of CA242 for 5-year overall survival (OS) was analyzed. RESULTS: CA242 positive rate elevated with stage advancing, lymph node metastasis and tumor invasion depth, the differences between stage III+IV and stage I+II, between positive lymph node and negative lymph node, between T3+T4 and T1+T2, reached statistical significance (all p<0.05). Receiver operating characteristic analysis demonstrated that the area under the curve of CA242 in stage, lymph node metastasis and tumor invasion depth were 0.677, 0.631 and 0.744, respectively. Patients with higher CA242 had worse 5-year OS compared to those with normal CA242 (p=0.0002). Multivariate analysis showed stage (p=0.000) and preoperative serum CA242 (p=0.026) as independent prognostic factors for 5-year OS of CRC patients. CONCLUSIONS: The preoperative serum CA242 can predict stage, lymph node metastasis and tumor invasion depth, and can be used as an independent prognostic factor for OS of CRC.

Levels of Phthalates, Bisphenol-A, Nonylphenol, and Microplastics in Fish in the Estuaries of Northern Taiwan and the Impact on Human Health.

Due to the sparsity in knowledge, we investigated the presence of various estrogenic endocrine-disrupting chemicals (EEDCs), including phthalates (PAEs), bisphenol-A (BPA), and nonylphenol (NP), as well as microplastics (MPs) in samples of the most widely consumed fish collected from different estuaries in northern Taiwan. We then proceeded to determine the likely contribution that this exposure has on the potential for health impacts in humans following consumption of the fish. Six hundred fish caught from five river estuaries (producing 130 pooled samples) were analyzed to determine how different factors (such as the river, benthic, pelagic, and migratory species) influence EEDCs' contamination and the possible impacts on human health following typical consumption patterns. The predominant EEDCs was diethyl phthalates (DEP), bis (2-ethylhexyl) phthalates (DEHP), and di-iso-nonylphthalate (DINP) in fish, present at 52.9 ± 77.3, 45.3 ± 79.8, and 42.5 ± 79.3 ng/g dry weight (d.w.), respectively. Residual levels of NP, BPA, and MPs in the fish were 17.4 ± 29.1 and 1.50 ± 2.20 ng/g d.w. and 0.185 ± 0.338 mg/g d.w., respectively. EEDCs and MPs levels varied widely among the five river estuaries sampled due, in part, to differences in habitat types and the associated diversity of fish species sampled. For DEP, the Lao-Jie River and pelagic environments produced the most severely contaminated fish species, respectively. DEP residues were also associated with the burden of MPs in the fish. Based on our analysis, we predict no substantial direct human health risk by EEDCs based on typical consumption rates of estuarine fish by the Taiwanese people. However, other sources of EEDC exposure cannot be ignored.

Co-evolution of cancer microenvironment reveals distinctive patterns of gastric cancer invasion: laboratory evidence and clinical significance.

BACKGROUND: Cancer invasion results from constant interactions between cancer cells and their microenvironment. Major components of the cancer microenvironment are stromal cells, infiltrating inflammatory cells, collagens, matrix metalloproteinases (MMP) and newly formed blood vessels. This study was to determine the roles of MMP-9, MMP-2, type IV collagen, infiltrating macrophages and tumor microvessels in gastric cancer (GC) invasion and their clinico-pathological significance. METHODS: Paraffin-embedded tissue sections from 37 GC patients were studied by Streptavidin-Peroxidase (SP) immunohistochemical technique to determine the levels of MMP-2, MMP-9, type IV collagen, macrophages infiltration and microvessel density (MVD). Different invasion patterns were delineated and their correlation with major clinico-pathological information was explored. RESULTS: MMP2 expression was higher in malignant gland compared to normal gland, especially nearby the basement membrane (BM). High densities of macrophages at the interface of cancer nests and stroma were found where BM integrity was destroyed. MMP2 expression was significantly increased in cases with recurrence and distant metastasis (P = 0.047 and 0.048, respectively). Infiltrating macrophages were correlated with serosa invasion (P = 0.011) and TNM stage (P = 0.001). MVD was higher in type IV collagen negative group compared to type IV collagen positive group (P = 0.026). MVD was related to infiltrating macrophages density (P = 0.040). Patients with negative MMP9 expression had better overall survival (OS) compared to those with positive MMP9 expression (Median OS 44.0 vs 13.5 mo, P = 0.036). Median OS was significantly longer in type IV collagen positive group than negative group (Median OS 25.5 vs 10.0 mo, P = 0.044). The cumulative OS rate was higher in low macrophages density group than in high macrophages density group (median OS 40.5 vs 13.0 mo, P = 0.056). Median OS was significantly longer in low MVD group than high MVD group (median OS 39.0 vs 8.5 mo, P = 0.001). The difference of disease-free survival (DFS) between low MVD group and high MVD group was not statistically significant (P = 0.260). Four typical patterns of cancer invasion were identified based on histological study of the cancer tissue, including Washing pattern, Ameba-like pattern, Spindle pattern and Linear pattern. CONCLUSIONS: Proteolytic enzymes MMP9, MMP2 and macrophages in stroma contribute to GC progression by facilitating the angiogenesis. Cancer invasion patterns may help predict GC metastasis.

Postoperative recurrence in gastric cancer: analysis of 59 cases.

BACKGROUND/AIMS: Gastric cancer (GC) is the leading cause of death in China. Although surgery based comprehensive treatment is the best approach to improve survival, postoperative recurrence is a major problem. This study was aimed to find out the relationship of cancer recurrence with major clinico-pathological factors, with special attention focused on time of recurrence. METHODOLOGY: Data of 59 recurrences after surgery among 286 GC patients were systemically collected and analyzed. Time of recurrence, the relationship between clinical stages and time of recurrence, and between number of adjuvant chemotherapy cycles and time of recurrence were evaluated. RESULTS: 76.3% (45/59) recurrence happened within 1 year after surgery. Median time to recurrence was 7 months. Most recurrences were locoregional recurrence (57.6%). The differences in time of recurrence among stage I, stage II, stage III and stage IV were statistically not significant (p > 0.05, Kruskal-Wallis Test). There were significant differences among different adjuvant chemotherapy cycles for time to recurrence (p = 0.014, Kruskal-Wallis Test). CONCLUSION: Close monitoring and active followup of patients with GC should be conducted over the first 2 years after operation. Adjuvant chemotherapy could prolong recurrence-free survival.

[Increased coronin-1C expression is related to hepatocellular carcinoma invasion and metastasis].

OBJECTIVE: To search for hepatocellular carcinoma (HCC) invasion related biomarkers using the cell membrane proteomics approaches, and to validate the markers using experimental and clinical specimens. METHODS: The HCCLM9 and MHCC97L cells with a similar genetic background and remarkably different metastasis behaviors were used for comparative membrane proteome profiling using sodium dodecyl sulfate polyacrylamide gel electrophoresis and electrospray ionization mass spectrometry technologies. Candidate protein makers were further validated by western blot on cells, immunohistochemistry (IHC) on animal tumor tissues, and tissue micro-array on clinical specimens. RESULTS: The membrane proteins of MHCC97L and HCCLM9 cells were compared by sodium dodecyl sulfate polyacrylamide gel electrophoresis analyses. 14 proteins were identified by ESI-MS/MS among the differential bands. Coronin-1C was overexpressed in HCCLM9 (7.31+/-0.73) versus MHCC97L (2.84+/-0.99) validated by western blot. Elevated coronin-1C expression was observed in liver cancer tissues of HCCLM9 nude mice. IHC study in 115 human HCC specimens demonstrated that patients with higher coronin-1C expression had more advanced stage. CONCLUSION: The study suggests that coronin-1C could be a potential molecule to predict HCC invasive behavior.

Carcinoembryonic antigen level is related to tumor invasion into the serosa of the stomach: study on 166 cases and suggestion for new therapy.

BACKGROUND/AIMS: The present study aim is to study the significance of serum tumor markers in predicting tumor progression and clinical outcomes in gastric cancer (GC). METHODOLOGY: Preoperative serum tumor markers were determined in 166 GC patients, who were followed after curative gastrectomy. The associations between tumor marker status and tumor invasion depth, clinical stage, lymph node metastasis, and survival were analyzed. RESULTS: Carcinoembryonic antigen (CEA) was significantly correlated with serosal invasion of the stomach and clinical stage, and carbohydrate antigen 19-9 (CA19-9) related to the clinical stage (p < 0.05). Patients with more markers positive had a shorter survival, 19.0, 11.0 and 3.0 months median survival time for one, two and three markers positive, respectively (p < 0.01). CA19-9, CEA and cancer antigen 125 (CA125) were more sensitive and specific in predicting worse prognosis than diagnosis. Multivariate analysis showed that CA19-9 and clinical stage were independent prognostic factors (p < 0.05). The degree of the CA19-9 elevation had a modest negative correlation with survival (r = -0.466, p = 0.008). CONCLUSIONS: Increased preoperative CEA level signifies tumor invasion into the serosa of the stomach, which may call for new therapies. CA19-9 is an independent negative prognostic factor.

Evaluating the prognostic significance of tumor-infiltrating lymphocytes in solid tumor: practice of a standardized method from the International Immuno-Oncology Biomarkers Working Group.

PURPOSE: Tumor-infiltrating lymphocytes (TILs) become increasingly relevant to tumor progression. This study aims to evaluate (a) methods of TILs assessment and (b) their prognostic significance in gastric cancer (GC). METHODS: The percentage of stromal TILs (psTIL) was reported semi-quantitatively by H&E evaluation. Herein, we screened two independent cohorts of breast cancer (n=240) and GC (n=481) for psTIL characterization. Correlations between psTIL and clinic-pathological features, as well as overall survival (OS) were further explored. Additionally, the prediction role of psTIL in GC was evaluated by receiver operating characteristic curve (ROC) analysis. RESULTS: TILs could be demonstrably distinguished from other stromal areas and surrounding tumor nests according to the assessment method. More importantly, it is reproducible, easily to determine, and quickly performed. In GC, a two-grade scale for psTIL was appropriate to be divided into low and high subgroups by using the median value of 10% as the threshold. High psTIL was correlated with no serosa invasion, earlier TNM stage and better survival state (P<0.05 for all), and identified as a favorable prognostic factor both by univariate (HR: 0.734, P=0.047) and multivariate analyses (HR: 0.722, P=0.030). A beneficial OS of high psTIL was found in a linear manner with increasing TILs infiltrates associated with improved survival by Kaplan-Meier survival curve (P=0.030) and ROC analysis (AUC: 0.432, P=0.012). CONCLUSION: TILs provide a reproducible method for assessment that can potentially be used to guide management. The parameter psTIL could be served as an independent, favorable prognostic factor of GC.

The prognosis role of AJCC/UICC 8th edition staging system in gastric cancer, a retrospective analysis.

OBJECTIVE: The present study was designed to investigate whether AJCC/UICC 8th edition staging system precisely differentiated patients with different prognosis of gastric cancer (GC). METHODS: There were 540 GC cases included in this study. Stratification was done according to the 7th and 8th AJCC/UICC tumor-node-metastasis (TNM) staging systems. Detailed comparison was conducted between two editions in terms of the sub-classification of pN3 stage, redefinitions of stage III, homogeneity, discrimination power, predictive accuracy, and complexity. RESULTS: Compared to the 7th edition, the 8th TNM staging system performed better by incorporating pN3a and pN3b into the final stage of GC (P<0.001), had better stage grouping homogeneity (P<0.001), prognostic value (area under the curve, AUC-value was 0.809), and comparable discrimination power. CONCLUSIONS: AJCC 8th TNM staging system showed improved efficiency in GC prognosis.