RESUMEN

Gastric cancer is a significant global health concern with complex molecular underpinnings influencing disease progression and patient outcomes. Various molecular drivers were reported, and these studies offered potential avenues for targeted therapies, biomarker discovery, and the development of precision medicine strategies. However, it was posed that the heterogeneity of the disease and the complexity of the molecular interactions are still challenging. By seamlessly integrating data from single-cell RNA sequencing (scRNA-seq) and bulk RNA sequencing (bulk RNA-seq), we embarked on characterizing molecular signatures and establishing a prognostic signature for this complex malignancy. We offered a holistic view of gene expression landscapes in gastric cancer, identified 226 candidate marker genes from 3 different dimensions, and unraveled key players' risk stratification and treatment decision-making. The convergence of molecular insights in gastric cancer progression occurs at multiple biological scales simultaneously. The focal point of this study lies in developing a prognostic model, and we amalgamated four molecular signatures (COL4A1, FKBP10, RNASE1, SNCG) and three clinical parameters using advanced machine-learning techniques. The model showed high predictive accuracy, with the potential to revolutionize patient care by using clinical variables. This will strengthen the reliability of the model and enable personalized therapeutic strategies based on each patient's unique molecular profile. In summary, our research sheds light on the molecular underpinnings of gastric cancer, culminating in a powerful prognostic tool for gastric cancer. With a firm foundation in biological insights and clinical implications, our study paves the way for future validations and underscores the potential of integrated molecular analysis in advancing precision oncology.

RESUMEN

Background: Colorectal cancer (CRC) is the third most prevalent malignancy globally, ranking as the second leading cause of cancer-related mortality. Emerging evidence highlights RAB10's involvement in the progression of various malignant tumors; however, its specific role in CRC remains unclear. Objective: To explore the oncogenic role of RAB10 in colorectal cancer progression by investigating its impact on NF-κB activation, aiming to identify a novel genetic biomarker for enhanced diagnosis and treatment of CRC. Methods: This study collected CRC tissue samples and utilized The Cancer Genome Atlas (TCGA) database for RAB10 expression verification through Western blot (WB). Cellular phenotype experiments were conducted on CRC cell lines, including quantitative real-time-polymerase chain reaction (qRT-PCR), CCK-8, transwell assay, and wound healing assay (HCT116 and SW480). Additionally, the impact of RAB10 on NF-κB signaling was assessed through qRT-PCR and WB. Results: RAB10 exhibited upregulation in CRC tissue samples compared to normal counterparts. Furthermore, RAB10 promoted the proliferation, migration, and invasion of HCT116 and SW480 cells. Notably, RAB10 induced NF-κB activation in CRC in vitro. Conclusion: This study revealed the oncogenic function of RAB10, explaining its role in activating NF-κB in CRC. The findings present RAB10 as a potential genetic biomarker for CRC diagnosis and treatment.

RESUMEN

BACKGROUND: Colorectal neuroendocrine carcinoma is a relatively rare tumor, for which a prognosis prediction model is lacking. Based on the data from Surveillance, Epidemiology, and End Results (SEER) database and Fujian Cancer Hospital, the study constructed and validated a prognostic nomogram to assess overall survival of patients with colorectal neuroendocrine carcinoma(CRNEC). METHODS: We extracted data of patients diagnosed with CRNEC from the SEER database. These patients were randomly divided into a training cohort(N = 1425) and an internal validation cohort(N = 612). Data of patients diagnosed with CRNEC in Fujian Cancer Hospital was collected as an external validation cohort(N = 54). A prognostic nomogram was established. The performance of the nomogram was assessed with ROC curve, C-index and calibration curve. Decision curve analysis(DCA) and ROC curve were used to compare the prediction efficacy of nomogram with the seventh edition of the TNM classification of the American Joint Commission of Cancer. RESULTS: Nine variables were identified as independent predictors. Nomogram were established by the nine variables. AUC of the nomogram in predicting 1-, 3- and 5-year OS were 0.900, 0.912 and 0.915 in training cohort, 0.900, 0.925 and 0.919 in internal validation cohort, 0.900, 0.903 and 0.928 in external validation cohort. C-index were 0.845, 0.854 and 0.837. Calibration curves overlapped well with reference lines. Compared with the AJCC TNM staging system, the nomogram performed more effectively. Patients classified into low-risk and high-risk groups by the nomogram scores and performed well in stratification. CONCLUSION: The prognostic nomogram established and validated in our study can accurately and effectively predict the prognosis of patients with CRNEC.

Asunto(s)

RESUMEN

Objectives: This study aimed to select patients with cancer-related pain to further analyze the relationship between pain severity, fatigue severity, and quality of life. Methods: A cross-sectional study was conducted. A convenience sampling method was used to select 224 patients with cancer-related pain who were undergoing chemotherapy and met the inclusion criteria in two hospitals of two provinces from May to November 2019. All participants were invited to complete a general information questionnaire, the Brief Fatigue Inventory (BFI), the Numerical Rating Scale (NRS) for pain intensity, and the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30). Results: In the 24 h before completing the scales, 85 patients (37.9%) had mild pain, 121 (54.0%) had moderate pain, and 18 (8.0%) had severe pain. In addition, 92 (41.1%) patients had mild fatigue, 72 (32.1%) had moderate fatigue, and 60 (26.8%) had severe fatigue. Most patients with mild pain only experienced mild fatigue, and their quality of life was also at a moderate level. Patients with moderate and severe pain mostly had moderate or higher levels of fatigue and a lower quality of life. There was no correlation between fatigue and quality of life in patients with mild pain (r = -0.179, P = 0.104). There was a correlation between fatigue and quality of life in patients with moderate and severe pain (r = -0.537, P < 0.01; r = -0.509, P < 0.05). Conclusions: Patients with moderate and severe pain have more fatigue symptoms and lower quality of life than those with mild pain. Nurses should pay more attention to patients with moderate and severe pain, explore the interaction mechanism between symptoms, and carry out joint symptom intervention to improve the quality of life of patients.

RESUMEN

Climate change is closely related to the distribution of plant resources. Cerasus serrulata is an important plant resource in China. The study on the influence of environmental factors on the distribution of suitable areas of C. serrulata is conducive to the protection and development of C. serrulata. In this paper, the distribution information of 238 Chinese Cerasus serrulata plants was processed by DIVA-GIS. The MaxEnt model was used to simulate the current and future distribution, and the ecological distribution and richness of Cerasus were analyzed. The results showed that the Cerasus serrulata was widely distributed in Hebei, Heilongjiang, Shandong, Jiangsu, Zhejiang, Anhui, Jiangxi, Hunan, and Guizhou provinces, mainly in the low and middle elevation areas of 10 to 1200 m. Based on this model, the precipitation of the warmest quarter, the precipitation of the driest month, and the mean temperature of the coldest were the most significant bioclimatic variables affecting the distribution of C. serrulata. In the future, climate change may lead to a slight increase of 2.31% in the area of suitable habitat for Cerasus serrulata, while the optimal habitat will decrease from 20.81 to 14.55%. Therefore, conservation measures should be taken to protect these precious resources.

Asunto(s)

RESUMEN

Climate change is very important for the distribution of plant resources, especially for crops. Angelica plants have a long history of use and significant crop resources in China, whose rhizomes are extensively used in medicine and food. In this paper, 1599 georeferenced herbarium records were analyzed using DIVA-GIS, and the ecological distribution and richness of the current and future distribution simulation were analyzed using the MaxEnt model. The results show that they are from 32 provinces in China. Among these provinces, Sichuan, Gansu, and Yunnan have the largest number of herbariums. According to the MaxEnt model simulation, it is found that the precipitation in the warmest season, annual precipitation, and the driest monthly precipitation are the foremost bioclimatic variables that control the distribution of eight selected Angelica plants (A. biserrata, A. gigas, A. laxifoliata, A. likiangensis, A. longicaudata, A. omeiensis, A. polymorpha, and A. valida). It can be seen from the potential distribution map that the suitable growth areas of A. polymorpha and A. valida have increased, while the suitable growth areas of the six species of Angelica have decreased in varying degrees, 18.24%, 20.01%, 9.91%, 53.16%, 10.06%, and 12.64% respectively. Therefore, it is necessary to protect the Angelica plants.

Asunto(s)

RESUMEN

Climate change has an extremely important impact on the geographic distribution of plants. The genus Millettia is an important plant resource in China and is widely used in medicine and ornamental industries. Due to the continuous changes of climate and the development and utilization of plant resources of the genus Millettia, it is of great significance to systematically investigate the geographic distribution of plants of the Millettia and their potential distribution under climate change. DIVA-GIS software was used to analyze 3492 plant specimens of 35 species of genus Millettia in the herbarium, and the ecological geographic distribution and richness of Millettia were analyzed, and the MaxEnt model was used to analyze the current and potential distribution in the future. The results show that the genus Millettia is distributed in 30 provinces in China, among which Yunnan and Guangdong provinces are the most distributed. Our model determines that precipitation in the driest month and annual temperature range are the most important bioclimatic variables. Future climate changes will increase the suitable habitat area of M. congestiflora by 16.75%, but other cliff beans Suitable habitats for vines will decrease significantly: M. cinereal by 47.66%, M. oosperma by 39.16%, M. pulchra by 36.04%, M. oraria by - 29.32%, M. nitida by 22.88%, M. dielsiana by 22.72%, M. sericosema by 19.53%, M. championii by 7.77%, M. pachycarpa by 7.72%, M. speciose by 2.05%, M. reticulata by 1.32%. Therefore, targeted measures should be taken to protect and develop these precious plant resources.

Asunto(s)

RESUMEN

OBJECTIVE: To evaluate the location and characterization value of contrast-enhanced ultrasound (CEUS) in the detection of sentinel lymph nodes (SLNs) in malignant melanoma. METHODS: SLNs and the lymph node network were tracked by subcutaneous injection of ultrasonic contrast agent around the tumor and preoperative localization, and qualitative analyses were performed. The SLNs were also detected by the intraoperative subcutaneous injection of carbon nanoparticles, and the findings were compared with lymph nodes located by CEUS. The accuracy of the preoperative lymph node identification was evaluated by the results of postoperative pathology, which served as the gold standard of detection. RESULTS: In 47 patients with malignant melanoma, the mean number of SLNs detected by CEUS was 1.72 ± 0.10, while that by carbon nanoparticle administration it was 1.79 ± 1.07 (P = .371 > .05). Seven cases of lymph node metastasis were detected by CEUS, with a sensitivity of 70.0%, specificity of 97.3%, positive predictive value of 87.5%, negative predictive value of 92.3%, and accuracy of 91.5%. There was high consistency between the findings of CEUS and pathology in differentiating benign and malignant lymph nodes (kappa = 0.726, χ2  = 25.243, P < .001). CONCLUSIONS: CEUS can localize and differentiate SLNs in malignant melanoma, and thus, may potentially guide clinical treatment in the future.

Asunto(s)

RESUMEN

Umbelliferae plants, which are widely used as traditional Chinese medicine because of their characteristics of relieving rheumatism, alleviating fever, circulating blood and easing pain. This experimental study was based on ear edema model caused by 12-O-tetracycline-propylphenol-13-acetic acid (TPA) in mice and compared with the Ibuprofen (Ib) group. Gas chromatography-mass spectrometry (GC-MS) was used to analyse the composition of the essential oils from the four studied Umbelliferae plants (Angelica sinensis (Oliv.) Diels, A. dahurica (Hoffm.) Benth. & Hook.f. ex Franch. & Sav., A. pubescens Maxim and Foeniculum vulgare Mill.). Biologically active components in volatile oils from the four studied Umbelliferae plants were evaluated. The expression levels of inflammatory cytokines Tumor Necrosis Factor-α (TNF-α), Cyclooxygenase-2 (COX-2), Interleukin-6 (IL-6) and RelA (p65) in mouse skin were determined by immunohistochemical method. The refractive index of the four essential oils was calculated. A total of 239 compounds were identified by GC-MS from the four studied plants, and the main constituents were osthole (44.61%, APEOs), obepin (0.59%, APEOs & 86.58%, FVEOs), undecanol (8.58%, ADEOs), α-muurolene (7.95%, ADEOs) and cis-anethol (9.11%, ADEOs). E-ligustilide (0.14%, APEOs & 81.14%, ASEOs), (-)-spathulenol (0.08%, FVEOs & 1.21%, ASEOs), (-)-terpinen-4-ol (4.91%, FVEOs), 2-butylthiolane (5.76%, APEOs) and α-bisabolol (3.80%, APEOs). This study showed that all the essential oils from the four studied Umbelliferae plants contained various lactones, including ligustrongolactone, trans-anisol and imperatorin. According to the results of the TPA induction test in the mouse ear edema model, the essential oils of four Umbelliferae plants reduced the levels of inflammatory cytokines TNF-α, COX-2, IL-6 and p65. All of them showed extraordinary biological activity in anti-inflammatory, so they have potential application value for biomedical products, pharmaceutical preparations, natural functional nutrients and cosmetic additives.

Asunto(s)

RESUMEN

Curcuma longa L. is one of the traditional Chinese herbs in the list of medicinal and food homology. Aromatic-turmerone is the main ingredient in turmeric essential oil. The aim of the present study is to investigate the treatment of Aromatic-turmerone on DSS-included colitis and its regulatory effect on intestinal flora disorder. Male KM mice supplemented with different concentration of aromatic-turmerone and mesalazine are subjected to 2% DSS in drinking water to induce colitis. Colon and cecum contents were collected for colitis lesion evaluation and inflammation-related gene analysis and colon contents for gut microbiota. The results show that treatments with Aromatic-turmerone significantly prevents colon shortening, alleviates the damage of colonic tissue, and reduces colonic inflammatory cytokines TNF-α and COX-2. Furthermore, the 16S rDNA gene sequence data indicate that Aromatic-turmerone improve the abundance of bacterial species, maintain some beneficial bacteria, and reduce harmful bacteria. Aromatic-turmerone downregulates the colonic inflammatory cytokines and modulates the abundance of intestinal flora, which is conductive to ameliorates DSS-induced colitis. Regularly intake of the edible herb may be help to prevent ulcerative colitis-related diseases.

Asunto(s)

RESUMEN

Rheumatoid arthritis (RA) is a chronic systemic autoimmune disease with predominant synovitis that has no complete cure or preventive treatment. Citrus essential oils, used in natural fragrances, contain a variety of functional ingredients that are worthy of investigation for their potential as natural anti-inflammatory drug sources. In this study, essential oils were hydro distilled from the peels of four citrus species: Citrus sinensis (L.) Osbeck (CSEOs), Citrus paradisi Macfad. (CPEOs), Citrus limon (L.) Osbeck (CLEOs) and Citri Reticulatae Pericarpium (CREOs). Altogether, 81 compounds were identified using gas chromatography-mass spectrometry (GC-MS), of which d-limonene (17.96%-94.66%) was an abundant component of all four oils. The stable 1,1-diphenyl-2-pyrrole hydrazine (DPPH) free radical test showed that all four essential oils had excellent antioxidant properties (IC50 , 0.76-13.86 µg/mL). Furthermore, the oils remarkably increased the first G1 phase of the cell cycle, which inhibited the pro-inflammatory factor expression. An immunohistochemical analysis indicated that the four essential oils inhibited the expression of tumor necrosis factor-α and cyclooxygenase-2 and they exhibited anti-inflammatory activity in a rat model that was similar to that of the common drug, Ibuprofen. These results show that the CSEOs, CPEOs, CLEOs, and CREOs have significant antirheumatic activities and thus have great potential in developing functional food or drugs for treating RA.

Asunto(s)

RESUMEN

Methods: This case-control study retrospectively reviewed the medical data of patients treated with primary percutaneous coronary intervention within 12 h after STEMI onset between January 2010 and January 2013 at the Department of Cardiology of the Beijing Anzhen Hospital. Results: A total of 902 patients were included in the analysis. The basic characteristics between the reflow and no-reflow groups were similar, except for time-to-hospital admission, heart rate, plasma glucose, high-sensitivity C-reactive protein (hsCRP)/prealbumin (PAB), neutrophil count, intraaortic balloon pump, and aspiration thrombectomy. The multivariable analysis showed that hsCRP/PAB (OR = 1.003, 95% CI: 1.000-1.006, P=0.022), neutrophil count (OR = 1.085, 95% CI: 1.028-1.146, P=0.003), plasma glucose levels (OR = 1.086, 95% CI: 1.036-1.138, P=0.001), diabetes mellitus (OR = 0.596, 95% CI: 0.371-0.958, P=0.033), Killip classification >1 (OR = 2.002, 95% CI: 1.273-3.148, P=0.003), intraoperative intraaortic balloon pump (IABP) use (OR = 3.257, 95% CI: 1.954-5.428, P=0.001), and aspiration thrombectomy (OR = 3.412, 95% CI: 2.259-5.152, P=0.001) were independently associated with no-reflow. Conclusion: hsCRP/PAB, neutrophil count, plasma glucose levels, diabetes mellitus, Killip classification, intraoperative IABP use, and aspiration thrombectomy were independent risk factors for no-reflow in patients with STEMI.

RESUMEN

Species of the genus Citrus are cultivated in many regions of China and are widely used for medicinal purposes. In the present study, essential oils (EOs) were extracted from four different Citrus species using steam distillation. The chemical components of these four essential oils were separated using gas chromatography-mass spectrometry, and 52 compounds were confirmed. D-limonene was found to be the most abundant compound. All four essential oils demonstrated varied but remarkable radical scavenging capacity (IC50 ; 0.77-13.9 %). Citrus paradisi essential oil exhibited excellent antioxidant activity. Compared to ibuprofen, topical application of the four Citrus spp. essential oils significantly inhibited ear edema formation in mice. Furthermore, essential oils from the four Citrus species reduced the expression levels of interleukin-6 (IL-6), cyclooxygenase-2 (COX-2) and nuclear transcription factor kappa B p65 (NF-κB) to different degrees. The cytotoxicity of the four essential oils on BV2 microglial cells was determined using the MTT assay (IC50 ; 321.37-1558.87 µg/mL), wherein Citrus limon essential oil showed the lowest cytotoxicity. The essential oils of Citrus limon, Citrus reticulata, and Citrus paradisi had an inhibitory effect on the lung cancer cell lines H1299 by inducing a G0/G1 cell cycle arrest. Cluster and principal component analyses were used to determine the relationship among the Citrus species. These results suggest that the four Citrus essential oils have potential for use as active ingredients in functional foods or cosmeceutical products.

Asunto(s)

RESUMEN

ETHNOPHARMACOLOGICAL RELEVANCE: Essential oils (EOs) are important active ingredients in Chinese herbal medicine. Cymbopogon citratus (DC.) Stapf, Cinnamomum cassia (L.) Presl, Salvia japonica Thunb., and Rosa rugosa Thunb. are used in local and traditional medicine to treat inflammation-related diseases. While the constituents and bioactivities of EOs of the above four Chinese herbals have been reported previously, but their anti-inflammatory and antioxidant activities have not been systematically evaluated. AIM OF THE STUDY: The purpose of this study was to research the chemical constituents, anti-inflammatory activities, and antioxidant activities of EOs of four Chinese herbal medicines. MATERIALS AND METHODS: Fresh plant materials were collected both in August 2018. The compositions of EOs were determined by the gas chromatography-mass spectrometry (GC-MS) method. TPA (12-O-tetradecylphophenol-13-acetate)-induced mouse ear model was evaluated the anti-inflammatory activities of EOs. The reduction of tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), cyclooxygenase-2 (COX-2) and RelA protein of the nuclear factor kappa-B (NF-κB) in the signal pathway (P65) were measured. The antioxidant activities of EOs from four plants were determined by using 2,2-diphenyl-1-picrylhydrazyl (DPPH) free radical scavenging method. RESULTS: A total of 217 compounds were separated and identified from four EOs, mainly including trans-cinnamylaldehyde (68.75%), citronellal (38.16%), linalool (1.02-33.73%), geraniol (19.39%) and citronellol (17.18%). All four EOs reduced the damage of the ear tissue and had certain anti-inflammatory effects, and the EOs of C. citratus (CyCEOs) and S. japonica (SJEOs) had the best anti-inflammatory activities among others, even better than ibuprofen. The four EOs exhibited different DPPH radical-scavenging activities (IC50, 0.101-1.017%), where most of them were much lower than that of EOs of C. citratus (CiCEOs) (IC50, 0.101%) and EOs of R. rugosa (RREOs) (IC50, 0.142%). CONCLUSIONS: The main components determine diverse propertise of these four EOs, our results suggested that four EOs presented anti-inflammatory and antioxidant effect via reducing the expression of TNF-a, IL-6, COX-2, and NF-κB p65, which may provide a new approach for development of new anti-inflammatory drugs.

Asunto(s)

RESUMEN

BACKGROUND: As the largest developing country in the world, China is still on its way towards building an adequate system of health insurance through continuous reforms. For the elderly in China, an effective medical security system might be especially helpful. OBJECTIVE: This study investigates the effect of medical insurance on outpatient visits by elderly Chinese in order to identify effective policies to improve the Chinese medical security system. METHODS: Based on data taken from the China Health and Retirement Longitudinal Study, eleven candidate models were analyzed, among which a finite mixture negative binomial model with two components was chosen as the theoretical foundation for an analysis of the effect of medical insurance on outpatient visits by elderly Chinese. RESULTS: The significant variables were found to be basic medical insurance (BMI), sex, surveyed area, education level, health status, economic area, income level, and the number of living children for the elderly aged 60-69 years; BMI, age, health status, number of household members, and income level for the elderly aged 70-79 years; and BMI, age, sex, and the presence of chronic disease for the elderly aged 80 years and above. CONCLUSION: Enrollment in BMI was found to be significantly associated with an increased number of outpatient visits, whereas supplementary medical insurance membership did not have a significant effect. The effects of BMI enrollment also differed by scheme and age. For those with a high rate of outpatient medical services utilization, the enhancing effect of BMI on the number of outpatient visits was not significant, so new medical insurance policies should be provided to the elderly population in China.

Asunto(s)

RESUMEN

Chemokine (C-X-C motif) ligand 1 (CXCL1) is a chemotactic cytokine known to regulate cancer progression and invasion. However, the prognostic significance of CXCL1 expression in colorectal cancer (CRC) has not been fully characterized. The present study explored the clinicopathological significance and potential role of CXCL1 in the carcinogenesis and progression of CRC. The protein expression of CXCL1 was measured immunohistochemically in tissue microarrays constructed from 276 CRC patients. CXCL1 expression levels and their associations with clinicopathological characteristics and patient survival were evaluated. The effect of CXCL1 on glycolysis was also examined. High CXCL1 expression was detected in 165 (59.8%) cases. CXCL1 expression was correlated with tumor diameter (P=0.002), T stage (P=0.044), N stage (P=0.005), M stage (P=0.001), lymphovascular invasion (P=0.010), and carcinoembryonic antigen status (P=0.019). High CXCL1 expression was validated as an independent prognostic factor for overall survival (OS) and disease-free survival (DFS) by both univariate and multivariate Cox regression analyses (both P<0.05). Experimentally, expression of CXCL1 was knocked down by stable transfected short hairpin RNA, resulting in a significantly decreased rate of glycolysis both in in vitro assays and in patients' samples (P<0.05). Silencing the expression of CXCL1 decreased the levels of the glycolytic enzymes GLUT1, HK2, and LDHA. In conclusion, by inducing glycolysis, CXCL1 plays a crucial role in both cancer progression and metastasis in CRC patients. The CXCL1 expression level is an independent prognostic factor for both OS and DFS. Moreover, CXCL1 may serve as a new biomarker and potential therapeutic target for CRC treatment.

Asunto(s)

RESUMEN

Negative lymph node (NLN) count has been validated as a protective predictor in various cancers after radical resection. However, the prognostic value of NLN count in the setting of stage IV gastric cancer patients who have received palliative resection has not been investigated. Surveillance, Epidemiology, and End Results Program (SEER)-registered gastric cancer patients were used for analysis in this study. Kaplan-Meier survival curves and multivariate Cox proportional hazards model were used to assess the risk factors for patients' survivals. The results showed that NLN count and N stage were independently prognostic factors in patients with stage IV gastric cancer after palliative surgery (P< 0.001). X-tile plots identified 2 and 11 as the optimal cutoff values to divide the patients into high, middle and low risk subsets in term of cause-specific survival (CSS). And NLN count was proved to be an independently prognostic factor in multivariate Cox analysis (P< 0.001). The risk score of NLN counts demonstrated that the plot of hazard ratios (HRs) for NLN counts sharply increased when the number of NLN counts decreased. Collectively, our present study revealed that NLN count was an independent prognostic predictor in stage IV gastric cancer after palliative resection. Standard lymph node dissection, such as D2 lymphadectomy maybe still necessary during palliative resection for patients with metastatic gastric cancer.