Treatment Of Upper Gastrointestinal Cancers Research Articles

Causal association between metabolites and upper gastrointestinal tumors: A Mendelian randomization study.

Upper gastrointestinal (UGI) tumors, notably gastric cancer (GC) and esophageal cancer (EC), are significant global health concerns due to their high morbidity and mortality rates. However, only a limited number of metabolites have been identified as biomarkers for these cancers. To explore the association between metabolites and UGI tumors, the present study conducted a comprehensive two‑sample Mendelian randomization (MR) analysis using publicly available genetic data. In the present study, the causal relationships were examined between 1,400 metabolites and UGI cancer using methods such as inverse variance weighting and weighted medians, along with sensitivity analyses for heterogeneity and pleiotropy. Functional experiments were conducted to validate the MR results. The analysis identified 57 metabolites associated with EC and 58 with GC. Key metabolites included fructosyllysine [EC: Odds ratio (OR)=1.450, 95% confidence interval (CI)=1.087‑1.934, P=0.011; GC: OR=1.728, 95% CI=1.202‑2.483, P=0.003], 2'‑deoxyuridine to cytidine ratio (EC: OR=1.464, 95% CI=1.111‑1.929, P=0.007; GC: OR=1.464, 95% CI=1.094‑1.957, P=0.010) and carnitine to protonylcarnitine (C3) ratio (EC: OR=0.655, 95% CI=0.499‑0.861, P=0.002; GC: OR=0.664, 95% CI=0.486‑0.906, P=0.010). Notably, fructosyllysine levels and the 2'‑deoxyuridine to cytidine ratio were identified as risk factors for both EC and GC, while the C3 ratio served as a protective factor. Functional experiments demonstrated that fructosyllysine and the 2'‑deoxyuridine to cytidine ratio promoted the proliferation of EC and GC cells, whereas carnitine inhibited their proliferation. In conclusion, the present findings provide insights into the causal factors and biomarkers associated with UGI tumors, which may be instrumental in guiding targeted dietary and pharmacological interventions, thereby contributing to the prevention and treatment of UGI cancer.

Patient Experiences of Specialty Palliative Care in the Perioperative Period for Cancer Surgery

ContextThough patients undergoing treatment for upper gastrointestinal (GI) cancers frequently experience a range of sequelae and disease recurrence, patients often do not receive specialty palliative care soon after diagnosis and it is unknown in what ways they may benefit. ObjectivesTo understand patient experiences of specialty palliative care in the perioperative period for patients seeking curative intent upper GI oncologic surgery. MethodsAs part of a randomized controlled trial, we conducted in-depth interviews between November 2019 and July 2021 with 23 patients in the intervention arm who were undergoing curative intent treatment for upper GI cancers and who were also followed by the specialty palliative care team. ResultsWe found five themes that characterized patient experiences and perceptions of specialty palliative care. Patients typically had limited prior awareness of palliative care (theme 1), but during the study, came to understand it as a “talking” intervention (theme 2). Patients whose concerns aligned with palliative care described it as being impactful on their care (theme 3). However, most patients expressed a focus on cure from their cancer and less perceived relevance for integration of palliative care (theme 4). Integrating specialist palliative care practitioners with surgical teams made it difficult for some patients to identify how palliative care practitioners differed from other members of their care team (theme 5). ConclusionWhile receipt of specialty palliative care in the perioperative period was generally perceived positively and patients appreciated palliative care visits, they did not describe many needs typically met by palliative care practitioners. Trial Registrationclinicaltrials.gov registration: NCT03611309.

Factors of Organizing Surgical Treatment of Upper Gastrointestinal Cancers and Patient Survival: Real-World Data

Aim: to analyze the safety and effectiveness of the method of cold snaring resection with preliminary hydropreparation when removing superficially colorectal epithelial neoplasms with a diameter of 5 to 25 mm.Material and methods. The number of complications and disease recurrence after endoscopic excisions by “cold” snaring resection with preliminary hydropreparation of superficially neoplasms with a diameter of 5 to 25 mm was assessed.Results. Neoplasms were removed in a single block in 89/122 (72.95 %) cases. Neoplasms with a diameter of 5 to 9 mm were excisions in a single block in 100 % of cases, with a diameter of 9 to 14 mm in 28/30 (93.33 %) cases, with a diameter of 15 to 19 mm in 12/38 (31.57 %) cases. According to the results of a lifetime pathoanatomic examination of the removed material, serrated dysplasia (serrated dysplasia, low grade) was detected in 76 cases; micro vesicular hyperplastic polyps (Hyperplastic polyp, micro vesicular type MVHP) were established in 9 cases; hyperplastic polyps containing goblet cells (Hyperplastic polyp, goblet cell GCHP) were in 5 cases; tubular adenoma with dysplasia (Tubular adenoma, low grade) was in 32 cases. Delayed bleeding and perforation of the intestinal wall, both at the time of resection, and in the delayed period was not observed. No local recurrence was detected in the groups of patients with neoplasms diameters of 5-9 and 10-14 mm. One case of local recurrence was detected in a group of patients with a neoplasms diameter from 15 to 19 mm (1/38 = 2.63 %) and one case in a group with a neoplasms diameter of 20-25 mm (1/5 = 20 %).Conclusions. Cold endoscopic snaring resection of colorectal epithelial neoplasms with preliminary hydropreparation in the submucosa is a safe and effective method of excisions superficially epithelial neoplasms of the colon with a diameter of 5 to 19 mm.

Correlation analysis of age and microbial characteristics in saliva and feces of high-risk population of upper gastrointestinal cancer

Objective: To explore the correlation between age and diversity and microbial composition in saliva and feces microbiota in high-risk population of upper gastrointestinal cancer. Methods: Based on the national project on early diagnosis and early treatment of upper gastrointestinal cancer, 38 participants were enrolled in Linzhou in Henan province in August 2019. The participant information was collected by questionnaire. Saliva and feces specimens were collected from each participant for 16S rRNA sequencing and bioinformatics analysis. Spearman rank correlation was used to analyze the correlation between age and α diversity (Observed ASVs and Shannon index) and relative abundance of microbiota (phyla, genera, and species) in saliva and feces. Results: The median age (age range) of 38 participants was 54 (43-60) years old, and there were 16 males (42.1%). The Observed ASVs of saliva was negatively correlated with age (rs=-0.35, P<0.05), but the observed ASVs of feces was not correlated with age. In saliva, the relative abundance of Treponema (rs=‒0.44, P<0.05), Alloprevotella (rs=‒0.42, P<0.05), and Porphyromonas (rs=‒0.41,P<0.05) were significantly negatively correlated with age. At the species level, the relative abundance of Porphyromonas endodontalis, Alloprevotella tannerae, Haemophilus influenza, Moraxella bovoculi, Prevotella sp.oral clone ID019, and Prevotella sp.oral clone ASCG10 in saliva were significantly negatively correlated with age, and the rs values were -0.50, -0.40, -0.38, -0.35, -0.33 and -0.33 (P<0.05), respectively. In feces, the relative abundance of Enterobacteria (rs=-0.35, P<0.05), Escherichia (rs=-0.33, P<0.05), and Bifidobacteria (rs=0.33, P<0.05) were correlated with age. At the species level, the relative abundance of Romboutsia sedimentorum, Citrobacter murliniae, and bacteroides uniformis in feces were correlated with age, and the rs values were -0.42, -0.37 and 0.36 (P<0.05), respectively. Conclusion: Age of the high-risk population of upper gastrointestinal cancer is correlated with the relative abundance of microbiota in saliva and feces.

Immune-related adverse events and prognosis in patients with upper gastrointestinal cancer treated with nivolumab

Immune checkpoint inhibitors (ICIs) are increasingly being used for the treatment of upper gastrointestinal cancers [esophageal cancer and gastric cancer (GC)]. They cause imbalances in immunological tolerance, resulting in immune-related adverse events (irAEs). Although irAEs have been reported to be associated with the efficacy of ICIs in some cancers, the relationship between irAEs and prognosis of upper gastrointestinal cancers remains unknown. This study aimed to investigate the prognostic impact of irAEs in patients with advanced or recurrent upper gastrointestinal cancer treated with nivolumab. We retrospectively divided the patients (n=96) who received nivolumab into two groups: the irAEs group (n=41) and non-irAEs group (n=55), according to the Common Terminology Criteria for Adverse Events ver. 5.0. irAEs were significantly associated with good performance status and high serum albumin levels (all P<0.05). The irAEs group had a significantly longer overall survival (OS) than the non-irAEs group [log-rank P=0.003; univariate hazard ratio (HR) =0.36, 95% confidence interval (CI) =0.21-0.65, P<0.01; multivariate HR =0.47, 95% CI =0.26-0.88, P=0.018]. Importantly, in both esophageal cancer and GC, the irAEs group experienced favorable clinical outcomes compared with the non-irAEs group. In the multivariate analysis, male sex (P<0.01), presence of irAEs (P=0.018), and good pretreatment performance status (P<0.01) were independent prognostic factors. Among patients with upper gastrointestinal cancer treated with nivolumab, the prognosis of patients who developed irAEs was better than that of patients who did not develop irAEs. Long-term continuation of nivolumab by early detection of irAEs and an appropriate response to irAEs are important.

Satisfaction in population-based cancer screening in a Chinese rural high-risk population: the Yangzhong early diagnosis and treatment of upper gastrointestinal cancer

BackgroundScreening for upper gastrointestinal cancer (UGC) effectively reduces morbidity and mortality in gastric and esophageal cancers. It is considered one of the effective measures for cancer control in China, but studies on its functional quality are lacking. Our study assessed the quality of screening service funded by Upper Gastrointestinal Cancer Early diagnosis and treatment (UGCEDAT) and its correlation in Yangzhong People’s hospital, China.MethodsA cross-sectional study was conducted among 516 screening users at a screening centre in Yanghzong People’s hospital from April to July 2021. The service quality questionnaire (SERVQUAL) based on the service quality gap (SQG) model was adopted. We calculated the mean scores of perceptions and expectations and their gap. To determine the association between overall SQG and related features of participants, we used a multivariate logistic regression.ResultsThe average scores of screening service users’ perceptions and expectations were 4.05 and 4.55, respectively. The SQG of five dimensions (tangibles, reliability, responsiveness, assurance and empathy) were negative, and the overall SQG was -0.51. The responsiveness dimension had the largest gap, and tangibles had the smallest gap. Occupation status (AOR: 0.57; CI: 0.37–0.89), health self-assessment (AOR: 4.97; CI: 1.35–18.23), endoscopy experience (AOR: 0.55; CI: 0.38–0.81), distance from screening hospital (AOR: 1.85; CI: 1.25–2.73) and frequency of visit (AOR: 1.65; CI: 1.10–2.46) were associated with the overall SQG.ConclusionsWe observed a negative gap between perceptions and expectations of the function quality of screening service, implying a high dissatisfaction across different dimensions. Service providers should take adequate measures to bridge the dimension with the largest quality gap. Meanwhile, attention should be paid to identifying the influencing factors of the overall SQG and the characteristics of dimensional expectations and perceptions to improve the effectiveness of the screening program.

An analysis of mortality trends for upper gastrointestinal neoplasms in Qidong, 1972-2016

Objective: To describe the trend of upper gastrointestinal cancer mortality in Qidong between 1972 and 2016, and to provide guidelines for prevention and control measures and strategies. Methods: The upper gastrointestinal data was collected in Qidong cancer registration from 1972 to 2016. Crude mortality rate (CR), China age-standardized rate (CASR), world age-standardized rate (WASR), truncated rate (35-64 years old), cumulative rate (0-74 years old) and cumulative risk were calculated. Annual percent change (APC) was calculated by Joinpoint software. Age-period-cohort model was used to analyze the influence of age, period and birth cohort on the changes in the mortality trend of upper gastrointestinal cancer patients. Results: From 1972 to 2016, there were 20 658 deaths of upper gastrointestinal cancer in Qidong, accounting for 20.89% of all cancer deaths. The CR, CASR, WASR, truncated rate (35-64 years old), cumulative rate (0-74 years old) and cumulative risk were 40.85/100 000, 27.96/100 000, 27.69/100 000, 36.01/100 000, 3.30% and 3.25%, respectively. There were 13 429 male deaths, the CR, CASR, and the WASR were 53.81/100 000, 37.62/100 000, and 39.93/100 000; the female deaths were 7 229, and the CR, CASR, and WASR were 28.23/100 000, 18.87/100 000, 17.25/100 000, respectively. The APCs of the 45-year-old, 55-year-old and 65-year-old age groups were -2.94% (95% CI: -3.32%, -2.56%), -2.94% (95% CI: -3.22%, -2.66%) and -2.04% (95% CI: -2.39%, -1.69%), with significant difference (P<0.05), while without significance of 75-year-old group (P>0.05). From 1972 to 2016, the APCs of CR, CASR, and WASR in the gastrointestinal cancer were 0.65% (95%CI: 0.43%, 0.87%), -2.01% (95%CI: -2.24%, -1.77%) and -2.05% (95%CI: -2.28%, -1.81%). The age-period-cohort model showed that the mortality of upper gastrointestinal cancer was increased with age (P<0.05). Conclusions: The crude mortality of upper gastrointestinal cancer increases slightly in Qidong, while the CASR and WASR decrease significantly. However, with aged tendency of population, the early diagnosis and treatment of upper gastrointestinal cancer is still needed to be paid attention.

Exploring the Attitudes of Health Professionals Providing Care to Patients Undergoing Treatment for Upper Gastrointestinal Cancers to Different Models of Nutrition Care Delivery: A Qualitative Investigation.

Background: People with upper gastrointestinal cancer are at high risk for malnutrition without universal access to early nutrition interventions. Very little data exist on the attitudes and views of health professionals on providing nutrition care to this patient cohort delivered by electronic health methods. COVID-19 has fast-tracked the adoption of digital health care provision, so it is more important than ever to understand the needs of health professionals in providing health care via these modes. This study aimed to explore the perspectives of health professionals on providing nutrition care to upper gastrointestinal cancer patients by electronic methods to allow the future scaling-up of acceptable delivery methods. Methods: Semi-structured qualitative interviews were conducted face-to-face or by telephone and recorded, de-identified and transcribed. Thematic analysis was facilitated by NVivo Pro 12. Results: Interviews were conducted on 13 health professionals from a range of disciplines across several public and private health institutions. Thematic analysis revealed three main themes: (1) the ideal model, (2) barriers to the ideal model and (3) how to implement and translate the ideal model. Health professionals viewed the provision of nutrition interventions as an essential part of an upper gastrointestinal cancer patient’s treatment with synchronous, telephone-based internal health service models of nutrition care overwhelmingly seen as the most acceptable model of delivery. Mobile application-based delivery methods were deemed too challenging for the current population serviced by these clinicians. Conclusion: The use of novel technology for delivering nutrition care to people receiving treatment for upper gastrointestinal cancers was not widely accepted as the preferred method of delivery by health professionals. There is an opportunity, given the rapid uptake of digital health care delivery, to ensure that the views and attitudes of health professionals are understood and applied to develop acceptable, efficacious and sustainable technologies in our health care systems.

Attitudes of Australian Patients Undergoing Treatment for Upper Gastrointestinal Cancers to Different Models of Nutrition Care Delivery: Qualitative Investigation.

BackgroundAdults diagnosed with cancers of the stomach, esophagus, and pancreas are at high risk of malnutrition. In many hospital-based health care settings, there is a lack of systems in place to provide the early and intensive nutritional support that is required by these high-risk cancer patients. Our research team conducted a 3-arm parallel randomized controlled trial to test the provision of an early and intensive nutrition intervention to patients with upper gastrointestinal cancers using a synchronous telephone-based delivery approach versus an asynchronous mobile app–based approach delivered using an iPad compared with a control group to address this issue.ObjectiveThis study aims to explore the overall acceptability of an early and intensive eHealth nutrition intervention delivered either via a synchronous telephone-based approach or an asynchronous mobile app–based approach.MethodsPatients who were newly diagnosed with upper gastrointestinal cancer and who consented to participate in a nutrition intervention were recruited. In-depth, semistructured qualitative interviews were conducted by telephone and transcribed verbatim. Data were analyzed using deductive thematic analysis using the Theoretical Framework of Acceptability in NVivo Pro 12 Plus.ResultsA total of 20 participants were interviewed, 10 from each intervention group (synchronous or asynchronous delivery). Four major themes emerged from the qualitative synthesis: participants’ self-efficacy, low levels of burden, and intervention comprehension were required for intervention effectiveness and positive affect; participants sought a sense of support and security through relationship building and rapport with their dietitian; knowledge acquisition and learning-enabled empowerment through self-management; and convenience, flexibility, and bridging the gap to hard-to-reach individuals.ConclusionsFeatures of eHealth models of nutrition care delivered via telephone and mobile app can be acceptable to those undergoing treatment for upper gastrointestinal cancer. Convenience, knowledge acquisition, improved self-management, and support were key benefits for the participants. Future interventions should focus on home-based interventions delivered with simple, easy-to-use technology. Providing participants with a choice of intervention delivery mode (synchronous or asynchronous) and allowing them to make individual choices that align to their individual values and capabilities may support improved outcomes.Trial RegistrationAustralian and New Zealand Clinical Trial Registry (ACTRN) 12617000152325; https://tinyurl.com/p3kxd37b.

Analysis of the effects of esophageal cancer screening in Henan rural areas with cancer screening program, 2014-2018

Objective: To analyze the effects of esophageal cancer screening in Henan rural areas with cancer screening program from 2014 to 2018. Methods: From July 2014 to June 2019, according to the National Early Diagnosis and Treatment of Upper Gastrointestinal Cancer in Rural Areas Project, cluster sampling method was adopted in 16 counties/county-level cities in rural areas with high incidence of esophageal cancer in Henan province. Endoscopic iodine staining and indicative biopsy were used to screen esophageal cancer. The patients with mild and moderate dysplasia confirmed in screening were followed up. The distribution of esophageal diseases in the screening population was calculated, and Chi-square test was used to compare the differences of detection rate and early diagnosis rate between the primary screening population and the follow-up population. Results: The age of 116 630 primary screening population was (54.29±7.70) years old, and the proportion of males was 41.2% (48 108). In the primary screening population, patients with normal esophagus, mild to moderate dysplasia, severe dysplasia and above accounted for 92.91% (108 363), 6.03% (7 035) and 1.06% (1 232), respectively. The detection rate of esophageal cancer was 1.06% (1 232/116 630), and the rate of early diagnosis was 85.80% (1 057). Among the follow-up population of 6 154 people, those with normal esophagus, mild to moderate dysplasia, severe dysplasia and above diseases accounted for 63.45% (3 905), 33.13% (1 519) and 3.41% (210), respectively. The detection rate of esophageal cancer was 3.41% (210/6 154), and the rate of early diagnosis was 91.90% (1 939). Compared with the primary screening population, the risk of esophageal cancer was higher in the overall follow-up population, people either with mild or with moderate dysplasia diagnosed in primary screening, with OR values (95%CI) of 3.23 (2.78, 3.75), 1.85 (1.49, 2.29) and 8.13 (6.69, 9.88), respectively. Conclusion: From 2014 to 2018, in the early diagnosis and early treatment of upper digestive tract cancer project in rural areas of Henan Province, the detection rate of the follow-up population is significantly higher than that of the primary screening population. Improving follow-up rate and paying more attention to the screening of people who need follow-up could further improve the screening effect.

The Role of the Small Bowel in Unintentional Weight Loss after Treatment of Upper Gastrointestinal Cancers.

Upper gastrointestinal (GI) cancers are responsible for significant mortality and morbidity worldwide. To date, most of the studies focused on the treatments’ efficacy and post-treatment survival rate. As treatments improve, more patients survive long term, and thus the accompanying complications including unintentional weight loss are becoming more important. Unintentional weight loss is defined as >5% of body weight loss within 6–12 months. Malignancies, particularly GI cancers, are diagnosed in approximately 25% of patients who present with unintentional weight loss. Whereas some recent studies discuss pathophysiological mechanisms and new promising therapies of cancer cachexia, there is a lack of studies regarding the underlying mechanism of unintentional weight loss in patients who are tumor free and where cancer cachexia has been excluded. The small bowel is a central hub in metabolic regulation, energy homeostasis, and body weight control throughout the microbiota-gut-brain axis. In this narrative review article, the authors discussed the impacts of upper GI cancers’ treatment modalities on the small bowel which may lead to unintentional weight loss and some new promising therapeutic agents to treat unintentional weight loss in long term survivors after upper GI operations with curative intent.

Abstract 5805: Palbociclib synergistically enhances the anticancer activity of cisplatin in P53 mutant model of upper gastrointestinal cancers

Abstract Background: Upper Gastrointestinal Cancers (UGCs) respond poorly to conventional chemotherapy due to overactive intrinsic mechanisms that mediate cellular proliferation and drug resistance. Dysregulated cell division due to increased activity of cyclin-dependent kinases 4/6 (CDK4/6) is one such mechanism that drives progression of UGCs, making them an important therapeutic target. Palbociclib is a second generation cdk4/6 specific inhibitor approved for treatment of ER+ breast cancers. Since Cisplatin (CDDP) is a first line therapeutic agent frequently used for treatment of UGCs we hypothesized that Palbociclib would complement the DNA-damaging activity of CDDP. To test this hypothesis, we investigated the potential therapeutic benefit of Palbociclib alone and in combination with CDDP in P53 mutant model of UGCs. Methods: In this study, we evaluated the effect of Palbociclib treatment alone and/or in combination with CDDP on FLO-1 (P53 mutant) UGC cell viability, survival, and cell cycle progression, respectviely. The MTT cell viability assay and Compusyn mediated median effect plot analysis (MEPA)(Chou and Talaly) were used to determine synergistic drug combinations of Palbociclib and CDDP in FLO-1 UGC cells. Results: The cell viability data and MEPA indicated that Palbociclib and CDDP show significant synergistic anticancer activity in FLO-1 UGC cells at a ratio of 1:2 and 1:3, respectively. The clonogenic cell survival assay data showed that in comparison to treatment with Palbociclib (0.5µM) or CDDP (1.0 and 1.5µM) alone, the combination treatments (Palbociclib:CDDP) at a ratio of 1:2 and 1:3 exhibited significantly elevated (p&amp;lt;0.05) inhibition of cellular survival in FLO-1 UGC cell lines. In addition, the Combination Index (CI) values of 0.66 and 0.71 for the aforementioned combination ratios suggests a strong synergism between the two drugs. Furthermore, the cell cycle data exhibited a marked increase (p&amp;lt;0.05) in the percentage of FLO-1 cells in the sub-G1-phase (cell death) after treatment with Palbocicb and CDDP combinations for 72 hrs., respectively . Conclusions: Our in vitro data indicate that Palbociclib, as a single agent, is an effective therapeutic strategy for inhibiting UGC cells. Additionally, Palbociclib in combination with CDDP synergistically enhances the anti-tumor activity of CDDP against P53 mutant UGC cells[MM1] . The observed synergism can potentially translate into reduced individual drug dosages and toxicity for Palbociclib and/or CDDP when used in combination. Citation Format: Dhvanir Kansara, Amruta Samant, Priya Pancholi, Tanvi Visal, Shraddha Patel, Vikas Sehdev. Palbociclib synergistically enhances the anticancer activity of cisplatin in P53 mutant model of upper gastrointestinal cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5805.

Patient information needs in upper gastrointestinal cancer: what patients and their families want to know.

The treatment of upper gastrointestinal cancer (UGIC) patients is complex. Patients are often elderly, comorbid as well as nutritionally depleted and treatment involves multimodality therapy incorporating chemotherapy, radiation therapy and surgery. The pre-treatment information requirements of UGIC patients are not clear but crucially important in ensuring they complete treatment successfully. A systematic review of the English language literature was performed to determine the specific information needs of patients with UGIC. Following abstract review and comprehensive analysis six articles were included. UGIC patients nominated information regarding post-operative recovery, quality of life, expected survival, management of post-operative symptoms and coping strategies for insurance and financial issues, relationships and family as being most important to them. Patients' families nominated information on the effects of diagnosis on patient well-being over the ensuing months and detailed information on available support services as being most important. One-on-one consultations with senior medical staff were the preferred method of information transfer followed by web-based information services. For effective treatment of UGIC patients, physicians and surgeons must address issues pertaining to quality of life, finance and relationships and may require specific training, or administrative support, in these areas.

Abstract 4180: RS-41, a multi-targeted kinase inhibitor, induces cell cycle arrest and apoptosis in p53 mutant and wild type models of upper gastrointestinal cancers

Abstract Introduction: Upper Gastrointestinal Cancers (UGCs) are a leading cause of cancer-related mortality and account for approximately 1.1 million deaths worldwide. UGCs respond poorly to conventional chemotherapy due to constitutive over activity of multiple oncogenic signaling mechanisms, including the epidermal growth factor receptor (EGFR), ERBB2/HER-2, Aurora kinases, and JAK-STAT pathways. In addition, presence of mutant P53 further imparts resistance to conventional chemotherapeutic agents. Therefore, novel small molecule inhibitors that target multiple kinases associated with oncogenic progression could pave the way for improved chemotherapy and better therapeutic outcomes. In this study, we characterized the anticancer activity of RS-41, an investigational 4-phenylbenzamidopyrrolo[2,3-d]-pyrimidin-4-amine multi-kinase inhibitor, in P53 mutant and wild type models of UGC. Methods: Target kinase inhibition and selectivity screening assays were performed to determine potency and selectivity of kinase inhibition for RS-41. In addition, MTT-cell viability assay, clonogenic cell survival assay, cell cycle analyses, and western blot analyses were done to evaluated the effect of RS-41 treatment on cell viability, survival, cell cycle progression, and expression of apoptotic markers in P53 mutant (FLO-1) and P53 wild type (AGS) UGC cells, respectively. Results: The kinase selectivity screening assay characterized RS-41 for its selectivity against a panel of 90 human kinases. The kinase screening analyses showed that RS-41 selectively inhibits AURKA (IC50-0.96±0.03µM), JAK2 (IC50-1.21±0.17µM), and EGFR (IC50-5.92±0.75µM) kinases, respectively. The cell viability data indicate that treatment with RS-41 mediates significant (P≤0.05) inhibition of FLO-1 and AGS UGC cell viability. The clonogenic cell survival data showed that treatment with RS-41 for 24 hrs. suppresses subsequent formation of colonies in both FLO-1 and AGS UGC cells. The cell cycle data exhibited a marked increase (P≤0.05) in the percentage of FLO-1 and AGS cells in the sub-G1-phase (cell death) after treatment with RS-41 for 24 and 72 hrs., respectively. The western blotting data further confirmed induction of apoptosis in FLO-1 and AGS cells as evidenced by an increase in expression of various markers of apoptosis (P73/P53, cleaved PARP, and/or cleaved caspase 3) following treatment with RS-41 for 24 and 72 hrs. Conclusions: Our in vitro data indicate that inhibition of various oncogenic kinases with RS-41 is an effective therapeutic strategy for inducing apoptosis in both P53 mutant and wild type UGC cells. Our study suggests that RS-41 is a promising multi-kinase inhibitor with a potential to further enhance chemotherapeutic options for treatment of UGC. Citation Format: Tanvi Visal, Shraddha Patel, Priya Pancholi, Samhita Bapat, Amruta Samant, Dhvanir Kansara, Sonali Kurup, Vikas Sehdev. RS-41, a multi-targeted kinase inhibitor, induces cell cycle arrest and apoptosis in p53 mutant and wild type models of upper gastrointestinal cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4180. doi:10.1158/1538-7445.AM2017-4180

Analysis of the incidence and age characteristics of upper gastrointestinal cancer among 2003-2012 in the high incidence area of esophageal cancer, Cixian County, in Hebei Province

Objective: To investigate the overall incidence and age distribution of upper digestive tract cancer in Cixian county, and to provide a reliable basis of prevention and treatment for upper gastrointestinal cancer. Methods: Collected annual incidence rate among 2003-2012 from Cixian cancer registry and abstracted all incidence rate of upper digestive tract cancer. The age-standardized incidence rate by Chinese standard population (ASR China) was calculated using the national population composition of 2000. The age-standardized incidence rate by world standard population (ASR world) was calculated using the world population composition of 1964 of Segi's. The annual average change (APC) was used to estimate the growth rate of the last two years in comparision with the first two years, which was calculated by Joinpoint regression model. The data was divided into two sections (from 2003 to 2007, and from 2008 to 2012), and the rate difference of different age group was calculated. Results: The crude incidence rate of the digestive tract cancer from 2003 to 2012 was 165.36/100 000 (10 309/6 234 346), which dropped from 170.75/10 100 000 (1 029/602 638) of 2003 to 146.02/100 000 of 2012 (936/640 991).The PC and APC of the crude incidence rate of upper gastrointestinal cancer were-12.96%, and-1.54% (95%CI:-3.22%-0.07%), respectively. The PC and APC of ASR China were-10.83%, and-1.30% (95%CI: 2.54%-0.03%), respectively. The PC and APC of ASR world were-9.82%, and-1.13% (95%CI:-2.20%--0.03%), respectively. The incidence of upper gastrointestinal cancer decreased. The incidence rate of 2003-2007 and 2008-2012 were 171.55/100 000 (5 239/3 048 593), and 159.41/10 000 (5 070/3 180 514), respectively and the rate difference was-12.15/100 000. The decrease of rate difference of 70 to 74 years old was the most (-340.32/100 000) and the increase of rate difference over the age of 85 was the most (447.21/100 000). Conclusion: From 2003 to 2012, the crude incidence of upper digestive tract cancer in Cixian showed a decreasing trend, and the 70-74 years old age group shows the most obvious decline.

Upper gastrointestinal cancer burden in Hebei Province, China: A population-based study.

AIMTo investigate the incidence and mortality rates of upper gastrointestinal cancer (UGIC) in Hebei Province, China, and to identify high-risk populations to improve UGIC prevention and control.METHODSData for UGIC patients were collected from 21 population-based cancer registries covering 15.25% of the population in Hebei Province. Mortality data were extracted from three national retrospective death surveys (1973-1975, 1990-1992 and 2004-2005). The data were stratified by 5-year age groups, gender and area (high-risk/non-high-risk areas) for analysis. The age-period-cohort and grey system model were used.RESULTSThe crude incidence rate of UGIC was 55.47/100000, and the adjusted rate (Segi’s population) was 44.90/100000. Males in rural areas had the highest incidence rate (world age-standardized rate = 87.89/100000). The crude mortality rate of UGIC displayed a decreasing trend in Hebei Province from the 1970s to 2013, and the adjusted rate decreased by 43.81% from the 1970s (58.07/100000) to 2013 (32.63/100000). The mortality rate declined more significantly in the high-risk areas (57.26%) than in the non-high-risk areas (55.02%) from the 1970s to 2013. The median age at diagnosis of UGIC was 65.06 years in 2013. There was a notable delay in the median age at death from the 1970s (66.15 years) to 2013 (70.39 years), especially in the high-risk areas. In Cixian, the total trend of the cohort effect declined, and people aged 65-69 years were a population at relatively high risk for UGIC. We predicted that the crude mortality rates of UGIC in Cixian and Shexian would decrease to 98.80 and 133.99 per 100000 in 2018, respectively.CONCLUSIONUGIC was the major cause of cancer death in Hebei Province, and males in rural areas were a high-risk population. We should strengthen early detection and treatment of UGIC in this population.

Abstract 4776: Dichloro [4,40-bis(4,4,4-trifluorobutyl)-2,20-bipyridine] platinum, a novel Cisplatin analog, exhibits enhanced anticancer activity in preclinical models of upper gastrointestinal cancers

Abstract Background: Upper Gastrointestinal Cancers (UGCs) respond poorly to conventional chemotherapy due to variable P53 status and overactive mechanisms that mediate drug resistance. Platinum based compounds like Cisplatin (CDDP) are frequently used for treatment of UGCs. However, clinical use of CDDP is limited due to development of drug resistance and dose limiting side-effects resulting in nausea, vomiting, neutropenia, thrombocytopenia and renal toxicity. In this study we investigated the anticancer potency of a novel CDDP derivative (dichloro [4,40-bis(4,4,4-trifluorobutyl)-2,20-bipyridine] platinum) (DCTF-CDDP) and compared it to CDDP in P53 wild type and mutant models of UGCs. Methods: For this study, we evaluated the effect of CDDP or its derivative (DCTF-CDDP) on AGS (P53 wild type) and FLO-1 (P53 mutant) UGC cell viability, survival, and expression of apoptotic markers. Results: The cell viability data indicated that DCTF-CDDP treatment was comparatively more effective than CDDP at inhibiting AGS (CDDP IC50: 6.3 ± 0.2 μM; DCTF IC50: 1.7 ± 0.5μM) and FLO-1 (CDDP IC50: 2.5 ± 0.68 μM; DCTF IC50: 0.5 ± 0.6μM) UGC cancer cell viability. The clonogenic cell survival assay data also showed that DCTF-CDDP was significantly (p&amp;lt;0.05) more potent at suppressing UGC cell survival when compared to CDDP. Similarly, the western blot data also showed that treatment with increasing concentrations (1, 2.5, and 5 μM) of CDDP and DCTF-CDDP for 24h induced higher levels of P53/P73 and cleaved PARP with DCTF-CDDP treatment in UGC cells. Conclusions: Our in vitro data indicate that DCTF-CDDP is significantly more potent at inhibiting cell viability and inducing apoptosis in P53 wild type and mutant UGC cells. Our study suggests that DCTF-CDDP could be an effective CDDP derivative that can be used to achieve better therapeutic outcome at lower doses and toxic side effects. Citation Format: Samhita Bapat, Tanmay Dichwalkar, Priya Pancholi, Byron L. Bennett, Vikas Sehdev. Dichloro [4,40-bis(4,4,4-trifluorobutyl)-2,20-bipyridine] platinum, a novel Cisplatin analog, exhibits enhanced anticancer activity in preclinical models of upper gastrointestinal cancers. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4776.

Möglichkeiten und Grenzen der minimalinvasiven Chirurgie bei Resektion des Ösophagus und des Magens

Although minimally invasive surgery is being increasingly performed for the treatment of upper gastrointestinal cancers, the discussion on potential advantages and oncological accuracy is still controversial. In the framework of a literature survey, current trials on minimally invasive oesophageal resection and laparoscopic abdominal surgery have been analysed. Minimally invasive oesophagectomy and laparoscopic gastric resections for cancer are safe. Minimally invasive resections result in an improved short-term outcome postoperatively in view of less pain, less blood loss and shorter duration of hospital stay. While mortality is equal, morbidity following minimally invasive surgery is reduced. Especially pulmonary complications decrease on the application of minimally invasive oesophagectomy. Minimally invasive operations last longer than open procedures. The oncological results seem to be equal between open and minimally invasive operations. A few studies have shown that laparoscopic gastric resections may result in a reduced number of lymph nodes harvested. The long-term survival between open and laparoscopic resections did not differ in any study. Minimally invasive resections for oesophageal and gastric cancer are safe and show several advantages in short-term outcome. Oncological long-term results seem to be comparable. The potential risk of a reduced number of harvested lymph nodes during laparoscopic gastrectomy has to be addressed by an adequate surgical technique.

MET As a Potential Target for the Treatment of Upper Gastrointestinal Cancers: Characterization of Novel c-Met Inhibitors from Bench to Bedside

The receptor tyrosine kinase mesenchymal-epithelial transition factor (c-Met) plays a pivotal role in regulation of cell proliferation and migration. Abnormal expression of c-Met has been associated with poor prognosis in several cancer types, including upper gastrointestinal malignancies. Moreover, c-Met interaction with multiple signalling pathways involved in tumor growth and invasive/metastatic phenotype has gained substantial attention in the last few years, suggesting the therapeutic potential of this target. This has led to the development and evaluation of a number of c-Met inhibitors. Here we describe the critical role of the HGF/c-Met pathway in cancer, as well as the preclinical and clinical investigations on c-Met inhibitors in solid tumors, with particular emphasis on recent findings with small-molecule inhibitors in gastrointestinal cancers. Clinical trials with several of these novel inhibitors have been encouraging and one of them, crizotinib (dual c-Met/ALK inhibitor), has recently been approved for lung cancers with ALK-rearrangement. There are accumulating evidences on the therapeutic potential of this and other c-Met inhibitors for the treatment of other malignancies, such as gastric and pancreatic cancers. These inhibitors might be used in combination with chemotherapy as well as with other biological agents, in order to overcome different resistance mechanisms. However, further studies are needed to identify determinants of the activity of c-Met inhibitors, through the analysis of genetic and environmental alterations affecting c-Met and parallel pro-cancer pathways. These studies will be critical to improve the efficacy and selectivity of current and future anticancer strategies targeting c-Met.

Clinical presentation, endoscopic features, treatment and prognosis of synchronous upper gastrointestinal malignancies

To study the clinical presentation, endoscopic features and prognosis of patients with synchronous upper gastrointestinal (GI) cancers. A prospective database review of consecutive patients with synchronous upper GI malignancies was performed in a tertiary university hospital endoscopy unit. Gender, age, symptoms and cancer sites, endoscopic and pathological findings, as well as the long-term survival of these patients were analyzed. A total of 64 patients with a median age of 56 years were included, in which 81.3% were male, 71.9% presented with notable features, 68.8% had familial history of cancer, 56.3% of gastric cancers were at the gastric body, 92.9% of the duodenal malignancies at the duodenal bulb, all esophageal cancers at the middle and lower part of esophagus and a significant proportion of tumors in the synchronous malignancies group were poorly differentiated. In all patients, 20 underwent curative surgical treatment and the 5-year survival rate was only 20%. Patients with synchronous upper GI cancers are mainly male and present with different anatomic distribution and endoscopic features. They carry a poor prognosis as compared with single primary cancer patients. This case series describes the clinical profiles and emphasizes the necessity of a thorough examination for additional cancers before treatment of upper GI cancer.