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Abstract Background Circulating tumor DNA (ctDNA)‐based minimal residual disease (MRD) detection, which can identify disease relapse ahead of radiological imaging, has shown promising performance. The objective of this study was to develop and validate OriMIRACLE S (Minimal Residual Circulating Nucleic Acid Longitudinal Detection in Solid Tumor), a highly sensitive and specific tumor‐informed assay for MRD detection. Methods Tumor‐specific somatic single nucleotide variants (SNVs) were identified via whole exome sequencing of tumor tissue and matched germline DNA. Clonal SNVs were selected using the OriSelector algorithm for patient‐specific, multiplex PCR‐based NGS assays in MRD detection. Plasma‐free DNA from patients with gastrointestinal tumors prior to and following an operation, and during monitoring, were ultradeep sequenced. Results The detection of three positive sites was sufficient to achieve nearly 100% overall sample level sensitivity and specificity and was determined by calculating binomial probability based on customized panels containing 21 to 30 variants. A total of 127 patients with gastrointestinal tumors were enrolled in our study. Preoperatively, MRD was positive in 18 of 26 patients (69.23%). Following surgery, MRD was positive in 24 of 82 patients (29.27%). The positivity rate for MRD was 33.33% (n = 18) for gastric adenocarcinoma and 32.26% (n = 62) for colorectal cancer. Twenty (20) of 59 patients (34.48%) experienced a change in MRD status over the monitoring period. Patients 8 and 31 responded to 3 cycles of systemic therapy, after which levels for all ctDNA dropped below the detection limit. Patient 53 was an example of using MRD to predict tumor metastasis. Patient 55 showed a weak response to treatments first and respond to new systemic therapy after tumor progression. Conclusion Our study identified a sensitive and specific clinical detection method for low frequency ctDNA, and explored the detection performance of this technology in gastrointestinal tumors.

Key Clinical Message: The case of a 44‐year‐old male with signet‐ring cell adenocarcinoma metastasis in the testis emphasizes the significance of immunohistochemistry in identifying the primary site of metastatic tumors. Further research is needed to establish effective treatment strategies for rare malignancies like small intestine signet‐ring cell carcinoma. Early diagnosis and appropriate treatment are crucial for improved patient outcomes. Metastasis to the testes is a rare occurrence, and identifying the primary site of origin can pose a significant challenge. Signet‐ring cell carcinoma (SRCC) is an uncommon subtype of adenocarcinoma typically found in the stomach but can also occur in other organs. This case report presents a 44‐year‐old male with signet‐ring cell adenocarcinoma metastasis in the right testis. The patient's initial clinical manifestation was testicular painful swelling, and subsequent immunohistochemical analysis using CK7, CK20, and CDX2 markers suggested a gastrointestinal origin. Normal upper and lower endoscopies rise suspicion of a small intestinal origin. The rarity of SRCC of the small intestine and the lack of clinical trials make treatment decisions difficult. This case highlights the importance of immunohistochemistry in determining the primary site of metastatic tumors and underscores the need for further research to establish optimal treatment strategies for rare malignancies like SRCC of the small intestine. As early diagnosis and appropriate treatment are critical for better patient outcomes. [ABSTRACT FROM AUTHOR]

Background: Circulating tumor DNA (ctDNA)‐based minimal residual disease (MRD) detection, which can identify disease relapse ahead of radiological imaging, has shown promising performance. The objective of this study was to develop and validate OriMIRACLE S (Minimal Residual Circulating Nucleic Acid Longitudinal Detection in Solid Tumor), a highly sensitive and specific tumor‐informed assay for MRD detection. Methods: Tumor‐specific somatic single nucleotide variants (SNVs) were identified via whole exome sequencing of tumor tissue and matched germline DNA. Clonal SNVs were selected using the OriSelector algorithm for patient‐specific, multiplex PCR‐based NGS assays in MRD detection. Plasma‐free DNA from patients with gastrointestinal tumors prior to and following an operation, and during monitoring, were ultradeep sequenced. Results: The detection of three positive sites was sufficient to achieve nearly 100% overall sample level sensitivity and specificity and was determined by calculating binomial probability based on customized panels containing 21 to 30 variants. A total of 127 patients with gastrointestinal tumors were enrolled in our study. Preoperatively, MRD was positive in 18 of 26 patients (69.23%). Following surgery, MRD was positive in 24 of 82 patients (29.27%). The positivity rate for MRD was 33.33% (n = 18) for gastric adenocarcinoma and 32.26% (n = 62) for colorectal cancer. Twenty (20) of 59 patients (34.48%) experienced a change in MRD status over the monitoring period. Patients 8 and 31 responded to 3 cycles of systemic therapy, after which levels for all ctDNA dropped below the detection limit. Patient 53 was an example of using MRD to predict tumor metastasis. Patient 55 showed a weak response to treatments first and respond to new systemic therapy after tumor progression. Conclusion: Our study identified a sensitive and specific clinical detection method for low frequency ctDNA, and explored the detection performance of this technology in gastrointestinal tumors. [ABSTRACT FROM AUTHOR]

Key Clinical Message The case of a 44‐year‐old male with signet‐ring cell adenocarcinoma metastasis in the testis emphasizes the significance of immunohistochemistry in identifying the primary site of metastatic tumors. Further research is needed to establish effective treatment strategies for rare malignancies like small intestine signet‐ring cell carcinoma. Early diagnosis and appropriate treatment are crucial for improved patient outcomes. Abstract Metastasis to the testes is a rare occurrence, and identifying the primary site of origin can pose a significant challenge. Signet‐ring cell carcinoma (SRCC) is an uncommon subtype of adenocarcinoma typically found in the stomach but can also occur in other organs. This case report presents a 44‐year‐old male with signet‐ring cell adenocarcinoma metastasis in the right testis. The patient's initial clinical manifestation was testicular painful swelling, and subsequent immunohistochemical analysis using CK7, CK20, and CDX2 markers suggested a gastrointestinal origin. Normal upper and lower endoscopies rise suspicion of a small intestinal origin. The rarity of SRCC of the small intestine and the lack of clinical trials make treatment decisions difficult. This case highlights the importance of immunohistochemistry in determining the primary site of metastatic tumors and underscores the need for further research to establish optimal treatment strategies for rare malignancies like SRCC of the small intestine. As early diagnosis and appropriate treatment are critical for better patient outcomes.

Digestive tract cancers, including esophageal, gastric, and colorectal cancers, are the major cause of death among cancer patients worldwide due to the heterogeneity of cancer cells, which limits the effectiveness of traditional treatment methods. Immunotherapy represents a promising treatment strategy for improving the prognosis of patients with digestive tract cancers. However, the clinical application of this approach is limited by the absence of optimal targets. Cancer/testis antigens are characterized by low or absent expression in normal tissues, but high expression in tumor tissues, making them an attractive target for antitumor immunotherapy. Recent preclinical trials have shown promising results for cancer/testis antigen-targeted immunotherapy in digestive cancer. However, practical problems and difficulties in clinical application remain. This review presents a comprehensive analysis of cancer/testis antigens in digestive tract cancers, covering their expression, function, and potential as an immunotherapy target. Additionally, the current state of cancer/testis antigens in digestive tract cancer immunotherapy is discussed, and we predict that these antigens hold great promise as an avenue for breakthroughs in the treatment of digestive tract cancers. [ABSTRACT FROM AUTHOR]

Objective: To assess and compare the diagnostic performance of gallium-68-labelled fibroblast activation protein inhibitor ([68Ga]FAPI-04) and fluorine-18 fluorodeoxyglucose ([18F]FDG) positron emission tomography/computed tomography (PET/CT) in gastrointestinal cancer. Methods: Fifty-one patients who underwent both [18F]FDG and [68Ga]FAPI-04 PET/CT for initial staging or restaging were enrolled. Histopathological findings, typical radiological appearances, and clinical imaging follow-up were used as the reference standard. The diagnostic performance of the two tracers was calculated and compared. The maximum standardised uptake value (SUVmax), mean SUV (SUVmean), tumour-to-mediastinal blood pool ratio (TBR), and tumour-to-liver ratio (TLR) of primary and metastatic lesions were measured and compared between two imaging modalities. Results: In patient-based analysis, [68Ga]FAPI-04 showed much better diagnostic sensitivity than [18F]FDG in detecting primary tumour (94.44% [17/18] vs. 61.11% [11/18]), postoperative recurrence and metastases (95.65% [22/23] vs. 69.57% [16/23]), and peritoneal carcinomatosis (100% [28/28] vs. 60.71% [17/28]) (all p < 0.05). In lesion-based analysis, [68Ga]FAPI-04 showed higher sensitivity than [18F]FDG for detecting lymph node metastases. In peritoneal carcinomatosis, the median SUVmax (12.12 vs. 7.18) and SUVmean (6.84 vs. 4.11) with [68Ga]FAPI-04 were significantly higher than those with [18F]FDG (all p < 0.005). The TBR and TLR of [68Ga]FAPI-04 were significantly higher than those of [18F]FDG for detecting primary tumour, lymph node, liver, and peritoneal metastases (all p < 0.005). Therapeutic management changed in 13 patients according to [68Ga]FAPI-04 PET/CT compared with conventional imaging. Conclusions: [68Ga]FAPI-04 is superior to [18F]FDG PET/CT for detecting primary tumour, postoperative recurrence and metastasis, and peritoneal carcinomatosis in gastrointestinal cancer. Key Points: • [68Ga]FAPI-04 PET/CT showed significantly higher sensitivity than[18F]FDG PET/CT in the detection of primary tumour and postoperative recurrence and metastasis in patients with gastrointestinal carcinoma. • [68Ga]FAPI-04 PET/CT had obvious advantages over[18F]FDG PET/CT in the detection of peritoneal carcinomatosis from gastrointestinal carcinoma with a much higher FAPI uptake value, TBR, and TLR. • Although the median SUVmax and SUVmean of[68Ga]FAPI-04 were similar to those of[18F]FDG for the primary tumour, lymph node metastases, and liver metastases in gastrointestinal carcinoma, the TBR and TLR of the SUVmax and SUVmean were significantly higher on[68Ga]FAPI-04 PET/CT, causing the lesions to be displayed more clearly. [ABSTRACT FROM AUTHOR]

Pituitary metastases are rare. Until now, few cases have been reported; about 50% of pituitary metastases originate from breast or lung cancers. We describe the clinical case of a primary colon carcinoma first presenting with a pituitary metastasis. A 76-year-old woman, with no history of malignancy, presented with headache, dizziness, and diplopia, at the Emergency Department. The neurologic examination was remarkable for complete left ophthalmoplegia with sensitivity deficit on the left side of the face. Radiologic investigations documented a voluminous sellar and suprasellar lesion, with extension in the left cavernous sinus and temporal lobe. Pituitary hormone levels were suggestive of anterior hypopituitarism and mild hyperprolactinemia. Subtotal surgical removal of the lesion was achieved through a trans-sphenoidal endoscopic endonasal approach. The histological examination disclosed a metastasis of gastrointestinal adenocarcinoma. A subsequent colonoscopy identified right colon cancer. A contrasted total-body computerized tomography ruled out other metastases. Postsurgical MRI showed a stable parasellar residual tumor. Conventional radiotherapy was scheduled. This case underlines the importance of considering pituitary metastases in the differential diagnosis of aggressive pituitary lesions, which should be managed in a pituitary tumor center of excellence through a multidisciplinary approach, for the complexity in diagnosis and therapeutic management of this rare condition. [ABSTRACT FROM AUTHOR]

Abstract N6‐methyladenosine (m6A) RNA methylation is correlated with carcinogenesis and dynamically possessed through the m6A RNA methylation regulators. This paper aimed to explore 13 m6A RNA methylation regulators' role in gastrointestinal cancer (GIC) and determine the risk model and prognosis value of m6A RNA methylation regulators in GIC. We used several bioinformatics methods to identify the differential expression of m6A RNA methylation regulators in GIC, constructed a prognostic model, and carried out functional enrichment analysis. Eleven of 13 m6A RNA methylation regulators were differentially expressed in different clinicopathological characteristics of GIC, and m6A RNA methylation regulators were nearly associated with GIC. We constructed a risk model based on five m6A RNA methylation regulators (METTL3, FTO, YTHDF1, ZC3H13, and WTAP); the risk score is an independent prognosis biomarker. Moreover, the five m6A RNA methylation regulators can also forecast the 1‐, 3‐ and 5‐year overall survival through a nomogram. Furthermore, four hallmarks of oxidative phosphorylation, glycolysis, fatty acid metabolism, and cholesterol homoeostasis gene sets were significantly enriched in GIC. m6A RNA methylation regulators were related to the malignant clinicopathological characteristics of GIC and may be used for prognostic stratification and development of therapeutic strategies.

N6‐methyladenosine (m6A) RNA methylation is correlated with carcinogenesis and dynamically possessed through the m6A RNA methylation regulators. This paper aimed to explore 13 m6A RNA methylation regulators' role in gastrointestinal cancer (GIC) and determine the risk model and prognosis value of m6A RNA methylation regulators in GIC. We used several bioinformatics methods to identify the differential expression of m6A RNA methylation regulators in GIC, constructed a prognostic model, and carried out functional enrichment analysis. Eleven of 13 m6A RNA methylation regulators were differentially expressed in different clinicopathological characteristics of GIC, and m6A RNA methylation regulators were nearly associated with GIC. We constructed a risk model based on five m6A RNA methylation regulators (METTL3, FTO, YTHDF1, ZC3H13, and WTAP); the risk score is an independent prognosis biomarker. Moreover, the five m6A RNA methylation regulators can also forecast the 1‐, 3‐ and 5‐year overall survival through a nomogram. Furthermore, four hallmarks of oxidative phosphorylation, glycolysis, fatty acid metabolism, and cholesterol homoeostasis gene sets were significantly enriched in GIC. m6A RNA methylation regulators were related to the malignant clinicopathological characteristics of GIC and may be used for prognostic stratification and development of therapeutic strategies. [ABSTRACT FROM AUTHOR]

The objectives were to define the maximum tolerated dose (MTD), safety profile and pharmacokinetics (PKs) of intraperitoneal oxaliplatin delivered by pressurised intraperitoneal aerosol chemotherapy (PIPAC) in patients with advanced peritoneal carcinomatosis from gastrointestinal tract cancers. PIPAC was applied every 4–6 weeks, for 5 cycles, in a phase I dose-escalation study using a 3 + 3 design. The first dose level was 90 mg/m2 with planned increases of 50 mg/m2 per level. Platinum concentration was measured in plasma, tissues and intraperitoneal fluid samples. The trial was registered at ClinicalTrials.gov (NCT03294252). Ten patients with 33 PIPAC sessions were included. No dose limiting toxicity (DLT) occurred at 90 mg/m2 and two at 140 mg/m2. The MTD was therefore set at 90 mg/m2. Overall treatment included a median number of three PIPAC sessions (range: 1–5) and secondary complete cytoreductive surgery for two patients. Overall safety showed 67 grade I–II and 11 grade III–IV toxicities, usually haematologic, digestive (nausea/vomiting, abdominal pain), and fatigue. Oxaliplatin concentrations were three- to four-fold higher in tissue in contact with aerosol than in muscle without contact. At 140 mg/m2, the plasma oxaliplatin concentration was high with Cmax and area under the curve (AUC) 0–48h of 1035 μg/l and 9028 μg h/L, respectively. The MTD of oxaliplatin during PIPAC is 90 mg/m2. PK data demonstrate a high tumour concentration and a significant systemic absorption. • The maximal dose of oxaliplatin during intraperitoneal aerosol is 90 mg/m2. • The median number of feasible PIPAC is three. • Some patients with major histological responses underwent a complete resection. • Platin concentrations are three- to four-fold higher in tumour than in muscle. • The systemic absorption of oxaliplatin is high. [ABSTRACT FROM AUTHOR]

In this work, design, synthesis, and screening of thiophene carboxamides 4–13 and 16–23 as dual vascular endothelial growth factor receptors (VEGFRs) and mitotic inhibitors was reported. All compounds were screened against two gastrointestinal solid cancer cells, HepG-2 and HCT-116 cell lines. The most active cytotoxic derivatives 5 and 21 displayed 2.3- and 1.7-fold higher cytotoxicity than Sorafenib against HepG-2 cells. Cell cycle and apoptosis analyses for compounds 5 and 21 showed cells accumulation in the sub-G1 phase, and cell cycle arrest at G2/M phase. The apoptotic inducing activities of compounds 5 and 21were correlated to the elevation of p53, increase in Bax/Bcl-2 ratio, and increase in caspase-3/7.Compounds 5 and 21 showed potent inhibition againstVEGFR-2 (IC50 = 0.59 and 1.29 μM) and β-tubulin polymerization (73% and 86% inhibition at their IC50 values).Molecular docking was performed with VEGFR-2 and tubulin binding sites to explain the displayed inhibitory activities.

Dyspeptic symptoms present a severe problem in gastrointestinal (GI) cancer patients. The aim of the study was to analyze an association between gastric myoelectric activity changes and dyspeptic symptoms in gastrointestinal cancer patients. The study included 80 patients (37 men and 43 women, mean age 61.2 ± 7.8 years) diagnosed with GI tract malignancies: colon (group A), rectal (group B) and gastric cancers (group C). Gastric myoelectric activity in a preprandial and postprandial state was determined by means of a 4-channel electrogastrography. Autonomic nervous system was studied based on heart rate variability analysis. The results were compared with the data from healthy asymptomatic controls. In a fasted state, GI cancer patients presented with lesser percentages of normogastria time (A:44.23 vs. B:46.5 vs. C:47.10 vs. Control:78.2%) and average percentage slow wave coupling (ACSWC) (A:47.1 vs. B:50.8 vs. C:47.2 vs. Control:74.9%), and with higher values of dominant power (A:12.8 vs. B:11.7 vs. C:12.3 vs. Control:10.9) than the controls. Patients did not show an improvement in the percentage of normogastria time, dominant power, dominant frequency and ACSWC in response to food. The severity of dyspeptic symptoms correlated with the values of electrogastrography parameters. Patients showed lower values of heart rate variability parameters than the healthy controls, that indicate abnormal autonomic nervous system activity. GI cancers affect the gastric myoelectric activity, decreasing normogastria and slow wave coupling. These patients do not show adequate gastric motility response to food. Impaired gastric electric motility may result from cancer-induced autonomic disturbances. [ABSTRACT FROM AUTHOR]

In this work, design, synthesis, and screening of thiophene carboxamides 4-13 and 16-23 as dual vascular endothelial growth factor receptors (VEGFRs) and mitotic inhibitors was reported. All compounds were screened against two gastrointestinal solid cancer cells, HepG-2 and HCT-116 cell lines. The most active cytotoxic derivatives 5 and 21 displayed 2.3- and 1.7-fold higher cytotoxicity than Sorafenib against HepG-2 cells. Cell cycle and apoptosis analyses for compounds 5 and 21 showed cells accumulation in the sub-G1 phase, and cell cycle arrest at G2/M phase. The apoptotic inducing activities of compounds 5 and 21were correlated to the elevation of p53, increase in Bax/Bcl-2 ratio, and increase in caspase-3/7.Compounds 5 and 21 showed potent inhibition againstVEGFR-2 (IC50 = 0.59 and 1.29 μM) and β-tubulin polymerization (73% and 86% inhibition at their IC50 values).Molecular docking was performed with VEGFR-2 and tubulin binding sites to explain the displayed inhibitory activities. [ABSTRACT FROM AUTHOR]

Background:PLOD1 (procollagen-lysine, 2-oxoglutarate 5-dioxygenase 1) is important for extracellular matrix formation and is involved in various diseases, including cancer; however, its role in gastrointestinal cancer is unclear. In this study, the expression of PLOD1 in gastrointestinal carcinoma and its relationships with patient survival were examined. Materials and Methods: Sample expression profiles were downloaded from the Gene Expression Omnibus database and methylation data were obtained from the Cancer Genome Atlas. Correlations between PLOD1 expression and clinicopathological features were analyzed by chi-square tests. Patient survival was evaluated by a Kaplan–Meier analysis. Results:PLOD1 expression was upregulated in gastric cancer and colorectal cancer compared with that in normal tissues. High PLOD1 levels indicated a poor prognosis. The high methylation group had a significantly lower level of PLOD1 expression. Conclusion: These results indicated that PLOD1 is highly expressed in gastrointestinal carcinoma and is a potential prognostic marker and therapeutic target. The data also indicate that hypomethylation contributes to PLOD1 upregulation in gastric and colon cancers. [ABSTRACT FROM AUTHOR]

More than 100 trillion microorganisms inhabit the human intestinal tract and play important roles in health conditions and diseases, including cancer. Accumulating evidence demonstrates that specific bacteria and bacterial dysbiosis in the gastrointestinal tract can potentiate the development and progression of gastrointestinal tract neoplasms by damaging DNA, activating oncogenic signaling pathways, producing tumor-promoting metabolites such as secondary bile acids, and suppressing antitumor immunity. Other bacterial species have been shown to produce short-chain fatty acids such as butyrate, which can suppress inflammation and carcinogenesis in the gastrointestinal tract. Consistent with these lines of evidence, clinical studies using metagenomic analyses have shown associations of specific bacteria and bacterial dysbiosis with gastrointestinal tract cancers, including esophageal, gastric, and colorectal cancers. Emerging data demonstrate that intestinal bacteria can modulate the efficacy of cancer chemotherapies and novel targeted immunotherapies such as anti-CTLA4 and anti-CD274 therapies, the process of absorption, and the occurrence of complications after gastrointestinal surgery. A better understanding of the mechanisms by which the gut microbiota influence tumor development and progression in the intestine would provide opportunities to develop new prevention and treatment strategies for patients with gastrointestinal tract cancers by targeting the intestinal microflora. [ABSTRACT FROM AUTHOR]

Endoscopic biopsies ( EBs) are the gold standard for diagnosing gastrointestinal carcinoma yet no guidelines address EB use for prognostic and predictive molecular testing. This review summarizes the reported quantity and quality of EBs, their relationship with molecular test failure rates and the resultant concordance between EB and resection specimen. Studies reporting molecular testing on gastrointestinal carcinoma EBs published between 2002 and 2014 were identified. Details regarding EB quantity, quality, tumour content, molecular test failure rates as well as causes and concordance with resection specimens were reviewed. Seventy-five studies were identified. Eighteen (24%) reported the mean EB number per patient (median: 2.1, range: 1-6.6 EBs). Sixty-one (81%) reported the frequency of test failure (median: 0%, range: 0-100%). Twenty-two (29%) investigated EB and resection specimen concordance (range: 0-100%). EB quantity and quality affected neither concordance nor failure rate. In summary, few studies currently report EB quantity, EB quality or EB and resection specimen concordance. Reliable molecular testing in EBs appears achievable, and can be representative of resection specimens. Concordance depends upon the testing methodology and biomarker heterogeneity within the tumour. To improve patient care, EB sampling, processing and reporting requires standardization and needs optimization for each biomarker individually. [ABSTRACT FROM AUTHOR]

background & objectives: Colorectal cancer (CRC) is second only to breast cancer as the leading cause of cancer-related deaths in Malaysia. In the Asia-Pacific area, it is the highest emerging gastrointestinal cancer. The aim of this study was to identify single nucleotide polymorphisms (SNPs) and environmental factors associated with CRC risk in Malaysia from a panel of cancer associated SNPs. methods: In this case-control study, 160 Malaysian subjects were recruited, including both with CRC and controls. A total of 768 SNPs were genotyped and analyzed to distinguish risk and protective alleles. Genotyping was carried out using Illumina's BeadArray platform. Information on blood group, occupation, medical history, family history of cancer, intake of red meat and vegetables, exposure to radiation, smoking and drinking habits, etc was collected. Odds ratio (OR), 95% confidence interval (CI) were calculated. results: A panel of 23 SNPs significantly associated with colorectal cancer risk was identified (p<0.01). Of these, 12 SNPs increased the risk of CRC and 11 reduced the risk. Among the environmental risk factors investigated, high intake of red meat (more than 50% daily proportion) was found to be significantly associated with increased risk of CRC (OR=6.52, 95% CI :1.93 - 2.04, p=0.003). Two SNPs including rs2069521 and rs10046 in genes of cytochrome P450 (CYp) superfamily were found significantly associated with CRC risk. For gene-environment analysis, the A allele of rs2069521 showed a significant association with CRC risk when stratified by red meat intake. interpretation & conclusions: In this preliminary study, a panel of SNPs found to be significantly associated with CRC in Malaysian population, was identified. Also, red meat consumption and lack of physical exercise were risk factors for CRC, while consumption of fruits and vegetables served as protective factor. [ABSTRACT FROM AUTHOR]

Gastrointestinal (GI) carcinoma is a common malignant disease worldwide. Its development and progression is a multistage process involving a multifactorial etiology. Although the detailed mechanisms of the development of GI carcinoma remain controversial, the elucidation of its molecular biology over the last few years has resulted in a better perspective on its epidemiology, carcinogenesis and pathogenesis. More significantly, it is currently possible to use biological indicators or biomarkers in differential diagnosis, prognostic evaluation and specific clinical interventions. In this review, we aimed to describe the biomarkers of pathogenesis, invasion, metastasis and prognosis of GI carcinoma and discuss their potential clinical applications. The majority of these biomarkers, such as tumor-associated antigens, oncogenes and tumor suppressor genes, metastasis-associated genes, cell adhesion molecules, cytokines, growth factors and microRNAs, are currently broadly applicable. [ABSTRACT FROM AUTHOR]

Background: The value of lymphadenectomy in most localized gastrointestinal (GI) malignancies is well established. Our objectives were to evaluate the time trends of lymphadenectomy in GI cancer and identify factors associated with inadequate lymphadenectomy in a large population-based sample. Methods: Using the National Cancer Institute's Surveillance Epidemiology and End Results Database (1998-2009), a total of 326,243 patients with surgically treated GI malignancy (esophagus, 13,165; stomach, 18,858; small bowel, 7,666; colon, 232,345; rectum, 42,338; pancreas, 12,141) were identified. Adequate lymphadenectomy was defined based on the National Cancer Center Network's recommendations as more than 15 esophagus, 15 stomach, 12 small bowel, 12 colon, 12 rectum, and 15 pancreas. The median number of lymph nodes removed and the prevalence of adequate and/or no lymphadenectomy for each cancer type were assessed and trended over the ten study years. Multivariate logistic regression was employed to identify factors predicting adequate lymphadenectomy. Results: The median number of excised nodes improved over the decade of study in all types of cancer: esophagus, from 7 to 13; stomach, 8-12; small bowel, 2-7; colon, 9-16; rectum, 8-13; and pancreas, 7-13. Furthermore, the percentage of patients with an adequate lymphadenectomy (49 % for all types) steadily increased, and those with zero nodes removed (6 % for all types) steadily decreased in all types of cancer, although both remained far from ideal. By 2009, the percentages of patients with adequate lymphadenectomy were 43 % for esophagus, 42 % for stomach, 35 % for small intestine, 77 % for colon, 61 % for rectum, and 42 % for pancreas. Men, patients >65 years old, or those undergoing surgical therapy earlier in the study period and living in areas with high poverty rates were significantly less likely to receive adequate lymphadenectomy (all p < 0.0001). Conclusions: Lymph node retrieval during surgery for GI cancer remains inadequate in a large proportion of patients in the USA, although the median number of resected nodes increased over the last 10 years. Gender and socioeconomic disparities in receiving adequate lymphadenectomy were observed. [ABSTRACT FROM AUTHOR]

Background: Bromelain is a pineapple stem extract with a variety of therapeutic benefits arising from interaction with a number of different biological processes. Several preclinical studies and anecdotal clinical observations have reported the anticancer properties of bromelain. In the present study, we investigated the cytotoxic effects of bromelain in four human cancer cell lines of gastrointestinal origin and the mechanisms involved. Methods: The gastric carcinoma cell lines (KATO-III and MKN45) and two chemoresistant subpopulations of the HT29 colon adenocarcinoma cell line (HT29-5M21 and HT29-5F12) were treated with a range of concentrations of bromelain, as well as with cisplatin as a positive control. The effect of bromelain on the growth and proliferation of cancer cells was determined using a sulforhodamine B assay after 72 hours of treatment. Expression of apoptosis-associated proteins in MKN45 cells treated with bromelain was analyzed by Western blotting. Results: Data from our sulforhodamine B assay showed that bromelain inhibited proliferation of HT29-5F12, HT29-5M21, MKN45, and KATO-III cells, with respective half maximal inhibitory concentration values of 29, 34, 94, and 142 μg/mL. Analyzing the expression of proapoptotic and antiapoptotic proteins in bromelain-treated MKN45 cells, we observed activation of the caspase system, cleavage of PARP and p53, overexpression of cytochrome C, attenuation of phospho-Akt and Bcl2, and removal of MUC1. Apart from the caspase-dependent apoptosis observed, emergence of cleaved p53 supports a direct, extranuclear apoptotic function of p53. Moreover, interrupted Akt signaling and attenuation of Bcl2 and MUC1 oncoproteins suggest impaired survival of cancer cells. Conclusion: Our findings collectively indicate that bromelain exerts cytotoxic effects in a panel of human gastric and colon carcinoma cells. Our study of MKN45 cells implicated different mechanisms in bromelain-induced cell death. While promoting apoptosis with involvement of the caspase system and extranuclear p53, bromelain also appears to impair cancer cell survival by blocking the Akt pathway and attenuating Bcl2 and MUC1 oncoproteins. [ABSTRACT FROM AUTHOR]

Abstract: Immunotherapy-based strategies for gastrointestinal carcinomas (GIC) have been exploited so far, but these approaches have to face strong mechanisms of immune escape induced by tumours. We previously demonstrated that sub-therapeutic doses of an adenovirus expressing IL-12 genes (AdIL-12) mediated a potent antitumour effect against subcutaneous (s.c.) colorectal carcinomas (CRC) in mice pre-treated with low doses of cyclophosphamide (Cy). In our study we used this combination to assess its impact on the immunosuppressive microenvironment. In s.c. CRC model we demonstrated that non-responder mice failed to decrease Tregs in tumour, spleen and peripheral blood. Reconstitution of Tregs into tumour-bearing mice treated with combined therapy abolished the antitumoural effect. In addition, Cy + AdIL-12 modified Tregs functionality by inhibiting the in vitro secretion of IL-10 and TGF-β and their ability to inhibit dendritic cells activation. Combined treatment decreased the number of myeloid-derived suppressor cells (MDSCs) in comparison to non-treated mice and, interestingly, administration of Tregs restored splenic MDSCs population. Furthermore, combined therapy potently generated specific cytotoxic IFN-γ-secreting CD4+ T cells able to eradicate established CRC tumours after adoptive transfer. Finally, we evaluated the combination on disseminated CRC and pancreatic carcinoma (PC). Cy + AdIL-12 were able to eradicate liver metastatic CRC (47%) and PC tumour nodules (40%) and to prolong animal survival. The results of this study support the hypothesis that Cy + AdIL-12 might be a valid immunotherapeutic strategy for advanced GIC. [Copyright &y& Elsevier]

Objective: To investigate the clinical effect of endoscopic submucosal dissection (ESD) on the treatment of gastrointestinal carcinoma in early stage and precancerous lesions. Methods: 79 patients with gastrointestinal carcinoma who were treated in our hospital from August 2013 to August 2014 were selected as the research subjects. According to the different operation methods, the selected patients were divided into the ESD group (49 cases) and the control group (30 cases). The patients in ESD group were treated with endoscopic submucosal dissection, and the patients in the control group were treated with conventional surgery. Then the operation time, curative resection rate, the whole complete resection rate, postoperative complication and recurrence and metastasis in the two groups were observed and compared. Results: The operation time in the ESD group was less than that of the control group, and the difference was statistically significant (p<0.05); The curative resection rate in the two groups were 100%, and there was no statistically significant difference (P>0.05); The whole complete resection rate in the ESD group was 63.27% which was lower than 86.67% of the control group, and the difference was statistically significant (p<0.05). The incidence of postoperative complications in the ESD group was 4.08% which was lower than 13.3% in the control group, and the difference was statistically significant (P<0.05). There was no metastasis and recurrence of primary lesions in the two groups after the operation for one year. Conclusion: The clinical effect of ESD on the treatment of gastrointestinal carcinoma and precancerous lesion is better. Compared with the conventional operation, ESD has less complications and higher safety, which is more suitable for clinical application. [ABSTRACT FROM AUTHOR]

Background/Aims: It has been demonstrated that substance P (SP) and neurokinin-1 (NK-1) receptor antagonist L-733,060 induces cell proliferation and inhibition, respectively, in several human cancer cell lines. At present, it is unknown whether such actions are exerted on human gastric and colon adenocarcinomas. We carried out an in vitro study of the growth-inhibitory capacity of L-733,060 against human gastric and colon adenocarcinomas. Methods: A coulter counter was used to determine viable cell numbers followed by application of the tetrazolium compound MTS. Immunoblot analysis was used to determine the NK-1 receptors and the DAPI method was applied to demonstrate apoptosis. Immunohistochemistry was used to demonstrate NK-1 receptors in primary human gastric and colon adenocarcinomas. Results: We observed the presence of several NK-1 receptor isoforms in human gastric and colon adenocarcinomas. Nanomolar concentrations of SP increased the growth of both cell lines and micromolar concentrations of L-733,060 inhibited the growth of such cell lines, with and without previous administration of SP. L-733,060 inhibited the growth of the 23132/87 and SW-403 cell lines in a dose-dependent manner. After administration of L-733,060, apoptosis was observed in both cell lines. In both human primary gastric and colon adenocarcinomas, a high density of NK-1 receptors was observed. Immunoreactivity, showing a diffuse cytoplasmic staining, was observed in the epithelial cells of normal and tumor glands and in numerous stromal elements. Conclusions: We demonstrated that NK-1 receptors were expressed in 23132/37 and SW-403 cell lines and in human primary gastric and colon adenocarcinomas, that SP is a mitogen and that the antitumor action of L-733,060 on both human cell lines occurs through the NK-1 receptor. Data also indicate that the cell death observed is produced by apoptosis. These data suggest that the NK-1 receptor is a new and promising target in the treatment of human gastrointestinal adenocarcinomas. Copyright © 2008 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

To investigate the effectiveness of stilamin in malignant bowel obstruction (MBO) due to advanced gastrointestinal carcinoma patients. 62 patients with MBO due to gastrointestinal carcinoma were randomly divided into two groups: routine therapy group (control group 30 patients) and stilamin group (32 patients). Stilamin group received routine therapy combined with stilamin (6 mg/d) by 24 hours continuous infusion for three to twelve days. The curative effectiveness was observed and compared between the two groups. After treatment, the clinical symptoms of abdominal distention and abdominal pain were relieved significantly in stilamin group compared with the control group (84.4% vs 57.6%; P < 0.05). The exhaust of anus was more earlier (62.1% vs 25.6%; P < 0.05), and the average volume of gastrointestinal decompression reduced more rapidly in stilamin group compared with the control group [(216 ± 158) mL/d vs (522 ± 184) mL/d; P < 0.001), smaller and less fluid-air in the intestinal and in the colon at the 81.3% of patients plain abdominal radiography were observed in stilamin group. Quality of life, evaluated with Karnofsky score (57 ± 7 vs 45 ± 9; P < 0.01), was improved significantly. The administration of stilamin, in combination with routine treatment can be very effective in the management of MBO. It can effectively relieve the symptoms of MBO and improve the quality of life in patients. [ABSTRACT FROM AUTHOR]

Recently, it was reported that exogenous bone morphogenetic protein (BMP)-2 acted as an antiproliferative agent in a variety of cell lines, including normal and cancerous gastric cell lines, indicating that BMP-2 plays an important role during cell growth. However, despite the loss of BMP-2 expression in several cancers, the underlying mechanism remains unknown. Epigenetic silencing through DNA methylation is one of the key steps during carcinogenesis. In this study, we found, through analysis by the methylation-specific polymerase chain reaction technique, CpG island methylation of the BMP-2 promoter region in gastric and colon cancer cell lines. BMP-2 mRNA was found to be activated after 5-aza-2′-deoxycytidine treatment of the methylation-positive cells. Moreover, 24 of the 56 (42.9%) gastric cancer tissues exhibited promoter methylation. Immunohistochemical staining revealed that 18 of the 24 (75%) gastric cancer tissues without methylation signals exhibited BMP-2 expression, whereas among 20 cancer tissues with strong methylation signals only four (20%) expressed BMP-2 (P=0.0003). These findings indicate that BMP-2 methylation is strongly associated with the loss of BMP-2 protein expression in the primary gastric carcinomas. BMP-2 methylation was more often observed in diffuse type (60.7%) than in intestinal type (25%) gastric carcinomas (P=0.007). Thus, aberrant BMP-2 methylation and the resultant loss of BMP-2 expression may be related to gastric carcinogenesis, particularly in the diffuse type.Oncogene (2006) 25, 2666–2673. doi:10.1038/sj.onc.1209297; published online 12 December 2005 [ABSTRACT FROM AUTHOR]

Abstract: Aim: To describe the role of nuclear factor-kappa B (NF-κB) in cancer treatment. Methods: We searched the Pubmed database (until Oct, 2004) with the keywords of gastrointestinal carcinoma, NF-κB, inhibitor, cancer treatment molecular target and chemoresistance. We reviewed the literature in the role of NF-κB activation in chemoresistance, tumour growth suppression and enhancement of apoptosis in gastrointestinal carcinomas. Conclusions: Several possible strategies for inhibiting NF-κB activation are identified. The importance of targeting NF-κB as a potential therapeutic approach in clinical medicine was discussed. [Copyright &y& Elsevier]

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Multiple genetic and epigenetic alterations of cancer-related genes and molecules are involved in the course of the development and progression of gastrointestinal cancers. These include telomerase activation, genetic instability, and abnormalities of oncogenes, tumor suppressor genes, cell cycle regulators, cell adhesion molecules and DNA repair genes. By analyzing these alterations in pathology specimens, we can improve differential diagnosis of cancer, obtain information of grade of malignancy, and identify patients at high risk for developing multiple primary cancers. Since 1993, a system of molecular–pathological diagnosis was established, and has been performed as a routine service in collaboration with Hiroshima City Medical Association Clinical Laboratory. More than 10 000 cases of gastrointestinal biopsy and surgery have been analyzed, and additional information of differential diagnosis, biological malignancy and tumor multiplicity could be obtained. Molecular–pathological diagnosis may provide a new approach to cancer diagnosis and novel therapeutics for the 21st century. Furthermore, the analysis of the genetic and epigenetic abnormalities in clinical materials may clarify the molecular mechanism of carcinogenesis and comparative morphological changes. From the analyses of p27KIP1 and telomerase in gastrointestinal adenomas, we have learned that morphological abnormality of the nucleus is an indicator for cells with immortality and malignant potential that must participate in super-early diagnosis (detection of true precancerous lesions) of gastrointestinal cancer. Molecular–pathological diagnosis thus contributes to detailed understanding of cancer histopathology and improves the histopathological diagnosis. [ABSTRACT FROM AUTHOR]

Preclinical and clinical studies have demonstrated that the circadian modulation of 5-FU delivery may reduce toxicities and improve antitumor activity. However, the relative importance of the timing of 5-FU delivery has not been clinically addressed. The aims of this study were to determine the toxicities, the maximum tolerable doses and the activity of a regimen with 5-fluorouracil (5-FU) and leucovorin (LV) administered as a 14-day continuous infusion according to a flat or three different chronomodulated rhythms in patients with metastatic gastrointestinal carcinomas. A total of 113 patients entered the study and their characteristics were comparable among the four groups. Toxicities included mainly stomatitis and diarrhea, and a reduced toxicity was observed in all the three chronogroups that allowed the delivery of higher dose intensities. Response rates were not significantly different among the four groups. These results suggest that a reduction in 5-FU+LV toxicity and an increase in 5-FU dose intensity can be obtained by a nonsinusoidally circadian modulated infusion. However, the reduction in toxicity observed seems to be dependent mainly on the quasi-intermittency and not on the timing of 5-FU+LV delivery. [ABSTRACT FROM AUTHOR]

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Background: Familial juvenile polyposis (JP) is an autosomal dominant condition in which affected individuals develop upper or lower gastrointestinal (GI) juvenile polyps, or both, and have a predisposition to cancer of the gastrointestinal tract. The risk of GI cancer has not been well defined because of the small number of these families and the lack of follow-up. The objective of this study was to determine the prevalence and age at diagnosis of GI polyposis and cancer in a large JP kindred. Methods: Medical records were reviewed, patients were interviewed, and histories were taken. Pathology reports and slides were reviewed by our pathologists. A database was created for analysis of clinical and pathologic factors. Results: This kindred contains 117 members, 29 of whom have had upper or lower GI polyps or cancer, or both. All those affected have had colonic juvenile polyps or cancer, except for two who died of advanced gastric cancer and never had colonic evaluation. Nine individuals have had both upper and lower GI polyps or cancer. Sixteen of 29 (55%) affected patients have developed gastrointestinal cancer. Eleven (38%) have had colon cancer, and six (21%) have had upper GI cancers. Conclusions: The risk of gastrointestinal malignancy in affected members of this JP kindred exceeds 50%. The high risk of GI cancer warrants frequent endoscopic screening of both affected and at-risk family members. Screening will soon be facilitated by presymptomatic genetic testing for the identification of gene carriers. [ABSTRACT FROM AUTHOR]

Adenosine triphosphatase (ATPase) activity and acid phosphatase activity in lymphocytes from patients with carcinoma of the gastrointestinal tract were determined in order to investigate whether or not changes in these enzyme activities has any relation to the immune reactivity of carcinoma-bearing patients. In patients with a performance status of more than 60%, the mean value of the total ATPase activity in lymphocytes differed little from that in controls, but the mean value of the oligomycin-sensitive ATPase activity decreased as compared to that in the controls. On the other hand, the mean values of the activities of both free and total acid phosphatase in lymphocytes increased as compared to those in controls. The mean values of the activities of both ATPase and acid phosphatase in lymphocytes from patients whose performance status was less than 50% decreased as compared to those from controls and patients whose performance status was more than 60%. The change of the activities of both ATPase and acid phosphatase in lymphocytes has relation to that of the immunological parameters of the patients with carcinoma of the gastrointestinal tract. These results indicate that both ATPase and acid phosphatase in lymphocytes may play an important role in the immune mechanism. [ABSTRACT FROM AUTHOR]

CEA-79 is a murine IgG2a type monoclonal antibody (MoAb) generated using purified CEA from culture supernatants of a human colon cancer cell line, LS174T. The association constant and immunoreactivity of the I-131 labeled CEA-79 ranged from 2.0 to 3.2 ×10 l/mole, and from 54 to 74 %, respectively. The purpose of this study was to evaluate the feasibility of radioimmunoscintigraphy employing MoAb CEA-79 in patients with advanced gastrointestinal carcinomas. Two mgs of MoAb CEA-79 was labeled with 111 MBq (3 mCi) of I-131, and infused intravenously in 6 stomach cancer and 16 colon cancer patients. Out of 6 patients with stomach cancer, immunoscintigraphy was able to detect the tumors in 4 cases. However, immunoscintigraphy found out tumors in all patients with colon cancer. Moreover, 1 patient with stomach cancer and 2 patients with colon cancer showed increased uptake of MoAb in the tumor lesions despite normal serum levels of CEA. We could conclude that this antibody has a potential as a new imaging agent for the diagnosis of gastrointestinal carcinoma. [ABSTRACT FROM AUTHOR]

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Copyright of Langenbecks Archiv fuer Chirurgie is the property of Springer Nature and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Massive lymphorrhea, containing transudative ascites due to a peritonectomy after undergoing surgery for gastrointestinal cancer, accompanied by an extended lymphadenectomy, has occasionally been observed but has usually improved spontaneously within a short period of time. The regeneration of the lymph vessels following lymphadenectomy for gastrointestinal cancer has been postulated. We investigated the regeneration of the lymph vessels in an animal experimental model undergoing a ligation and division of the mesenteric lymph trunk. Lymphangiographical studies were made on the first, fourth, and sixth postoperative day (POD 1, 4, 6). No regeneration of the lymph vessels was observed within 24h after the division. On POD 4, a recommunication due to regeneration was recognized in 60%. By POD 6, the lymphatics of all cases had recommunicated. This phenomenon of lymphatic regeneration was therefore confirmed in the medium-sized lymph vessels. [ABSTRACT FROM AUTHOR]

We report on our experience investigating the serum levels of the soluble domain of p185 and the neu protein expression in the corresponding tumour tissue in patients with advanced gastrointestinal carcinomas. The study included 32 patients who were treated with palliative chemotherapy. The serum levels of the neu protein were investigated by immunosorbent assay techniques. We used the alkaline phosphatase/anti-(alkaline phosphatase) method for investigating the corresponding tumour tissue immunohistochemically. Increased serum neu protein levels were found in 8 of 22 (36%) patients with colorectal carcinomas and in 2 patients with advanced abdominal adenocarcinoma of unknown primary. All other patients with advanced gastrointestinal cancers were serum- neu-protein-negative. All serum- neu-protein-positive patients with colorectal carcinomas showed also an elevated neu protein expression. The extent of serum neu protein expression corresponded to the clinical course and the tumour marker CA 19-9. The serum neu protein may be useful for monitoring patients with advanced colorectal carcinomas, particularly in cases of immunohistochemical neu-protein-positive primary tumours. [ABSTRACT FROM AUTHOR]

Abstract: Background: The rapid development of ascites in a patient without known liver disease is an uncommon occurrence in the Emergency Department. Initial stabilization may include therapeutic peritoneal lavage to reduce diaphragmatic pressure and halt the progression of respiratory compromise. In the absence of liver disease, the differential diagnosis should include a search for malignancy, which has been reported to account for up to 10% of all cases of newly diagnosed ascites. Objectives: To discuss the differential diagnosis, evaluation, and treatment options associated with the development of acute malignant ascites. Case Report: We report the case of an 86-year-old woman who presented with the chief complaint of an enlarging abdomen and worsening shortness of breath of 1 week''s duration. Bedside ultrasound rapidly revealed a large amount of intraperitoneal free fluid as a cause for her abdominal distension and respiratory compromise. Laboratory analysis of her blood along with computed tomography scan of her abdomen and pelvis were unremarkable. Diagnostic and therapeutic peritoneal lavage was done and the patient''s symptoms improved. Pathologic examination of the peritoneal fluid revealed metastatic gastrointestinal carcinoma. Conclusion: Rapidly progressing ascites may be the sole presenting symptom of metastatic gastrointestinal carcinoma. [Copyright &y& Elsevier]

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