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A phase 1 study of ADI-PEG 20 and modified FOLFOX6 in patients with advanced hepatocellular carcinoma and other gastrointestinal malignancies.
Harding, JJ, Do, RK, Dika, IE, Hollywood, E, Uhlitskykh, K, Valentino, E, Wan, P, Hamilton, C, Feng, X, Johnston, A, et al
Cancer chemotherapy and pharmacology. 2018;(3):429-440
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Abstract
PURPOSE Arginine depletion interferes with pyrimidine metabolism as well as DNA damage repair pathways. Preclinical data indicates that pairing pegylated arginine deiminase (ADI-PEG 20) with fluoropyrimidines or platinum enhances cytotoxicity in vitro and in vivo in arginine auxotrophs. METHODS This is a single-center, open-label, phase 1 trial of ADI-PEG 20 and modified FOLFOX6 (mFOLFOX6) in treatment-refractory hepatocellular carcinoma (HCC) and other advanced gastrointestinal tumors. A 3 + 3 dose escalation design was employed to assess safety, tolerability, and determine the recommended phase 2 dose (RP2D) of ADI-PEG 20. A RP2D expansion cohort for patients with HCC was employed to define the objective response rate (ORR). Secondary objectives were to estimate progression-free survival (PFS), overall survival (OS), and to explore pharmacodynamics and immunogenicity. Eligible patients were treated with mFOLFOX6 intravenously biweekly at standard doses and ADI-PEG-20 intramuscularly weekly at 18 (Cohort 1) or 36 mg/m2 (Cohort 2 and RP2D expansion). RESULTS Twenty-seven patients enrolled-23 with advanced HCC and 4 with other gastrointestinal tumors. No dose-limiting toxicities were observed in cohort 1 or 2. The RP2D for ADI-PEG 20 was 36 mg/m2 weekly with mFOLFOX6. The most common any grade adverse events (AEs) were thrombocytopenia, neutropenia, leukopenia, anemia, and fatigue. Among the 23 HCC patients, the most frequent treatment-related Grade ≥ 3 AEs were neutropenia (47.8%), thrombocytopenia (34.7%), leukopenia (21.7%), anemia (21.7%), and lymphopenia (17.4%). The ORR for this group was 21% (95% CI 7.5-43.7). Median PFS and OS were 7.3 and 14.5 months, respectively. Arginine levels were depleted with therapy despite the emergence of low levels of anti-ADI-PEG 20 antibodies. Arginine depletion at 4 and 8 weeks and archival tumoral argininosuccinate synthetase-1 levels did not correlate with response. CONCLUSIONS Concurrent mFOLFOX6 plus ADI-PEG-20 intramuscularly at 36 mg/m2 weekly shows an acceptable safety profile and favorable efficacy compared to historic controls. Further evaluation of this combination is warranted in advanced HCC patients.
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Multiple gastrointestinal metastases of squamous-cell lung cancer: A case report.
Li, X, Li, S, Ma, Z, Zhao, S, Wang, X, Wen, D
Medicine. 2018;(24):e11027
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Abstract
RATIONALE Gastrointestinal multiple metastases of lung cancer are extremely rare. The majority of gastrointestinal metastasis cases are diagnosed at a late stage and the prognosis is extremely poor. This report describes the clinical characteristics and outcomes of a patient with gastrointestinal multiple metastases from squamous-cell lung cancer, with special emphasis on the diagnosis and treatment of metastatic lung cancer. PATIENT CONCERNS A 61-year-old man who presented with progressive abdominal distention was admitted to our hospital. Radiological examinations showed changes of post-primary pulmonary tuberculosis and mechanical obstruction of the small bowl. Histopathological findings of gastroscopic examination and biopsy specimens showed a diagnosis of squamous-cell carcinoma in the body of the stomach. DIAGNOSES Postoperative histopathology confirmed a gastrointestinal multiple squamous-cell carcinoma in stomach and small bowl. Finally, squamous-cell lung cancer was confirmed by lung biopsy. INTERVENTIONS During his hospitalization urgent surgery was performed because of acute abdomen. The patient underwent a laparotomy with curative gastrectomy for gastric cancer and small bowel partial resection. The patient was recommended with combination chemotherapy of carboplatin and paclitaxel for 3 cycles. OUTCOMES Six months later after operation, the patient succumbed to respiratory failure. LESSONS We searched the related literature of gastrointestinal metastases from lung cancer and the clinical presentation, site of metastasis, diagnosis, treatment, and survival time in these cases were reviewed. The present study may increase the awareness of early diagnosis and appropriate treatment of metastatic lung cancer of gastrointestinal tract.
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Efficacy of Early Enteral Immunonutrition on Immune Function and Clinical Outcome for Postoperative Patients With Gastrointestinal Cancer.
Luo, Z, Wang, J, Zhang, Z, Li, H, Huang, L, Qiao, Y, Wang, D, Huang, J, Guo, L, Liu, J, et al
JPEN. Journal of parenteral and enteral nutrition. 2018;(4):758-765
Abstract
BACKGROUND Nutrition support is crucial for patients with gastrointestinal (GI) cancer after the operation. However, the controversy over the application of parenteral nutrition (PN) and early enteral immunonutrition (EEIN) has no determinate conclusion. MATERIALS AND METHODS We compared the effects of PN and EEIN on the postoperative nutrition condition, immune status, inflammation level, long-term survival, and quality of life of the patients with GI cancer. Seventy-eight patients were randomly divided into the PN group (n = 44) or EEIN group (n = 34). After an 8-day nutrition treatment, clinical and immunological parameters were evaluated. RESULTS The EEIN group had a significantly shorter hospital stay and higher body mass index level on postoperative day 30 than those in the PN group (P < .05). However, total hospital cost and incidences of short-term postoperative complications had no significant difference (P > .05). The percentages of CD4+ , natural killer, and natural killer T lymphocyte cells and the ratio of CD4+ /CD8+ in peripheral blood were significantly increased. Compared with the PN group, the EEIN group had a higher expression of activated cell surface markers such as CD27 and CD28. In addition, the secretion of interleukin (IL)-2 and interferon-γ was significantly higher, and the secretion of tumor necrosis factor-α and IL-10 was lower. Complication-free survival in the EEIN group were longer than those in the PN group (P = .04). CONCLUSION EEIN is superior to PN in improving nutrition status, enhancing immune function, and elevating quality of life.
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A process and mechanism of action evaluation of the effect of early and intensive nutrition care, delivered via telephone or mobile application, on quality of life in people with upper gastrointestinal cancer: a study protocol.
Furness, K, Huggins, CE, Hanna, L, Silvers, MA, Cashin, P, Low, L, Croagh, D, Haines, TP
BMC cancer. 2018;(1):1181
Abstract
BACKGROUND Cancers of the upper gastrointestinal tract commonly result in malnutrition, which increases morbidity and mortality. Current nutrition best practice lacks a mechanism to provide early and intensive nutrition support to these patients. A 3-arm parallel randomised controlled trial is testing the provision of a tailored, nutritional counselling intervention delivered using a synchronous, telephone-based approach or an asynchronous, mobile application-based approach to address this problem. This protocol outlines the design and methods that will be used to undertake an evaluation of the implementation process, which is imperative for successful replication and dissemination. METHODS A concurrent triangulation mixed methods comparative analysis will be undertaken. The nutrition intervention will be provided using best practice behaviour change techniques and communicated either via telephone or via mHealth. The implementation outcomes that will be measured are: fidelity to the nutrition intervention protocol and to the delivery approach; engagement; acceptability and contextual factors. Qualitative data from recorded telephone consultations and written messages will be analysed through a coding matrix against the behaviour change techniques outlined in the standard operating procedure, and also thematically to determine barriers and enablers. Negative binomial regression will be used to test for predictive relationships between intervention components with health-related quality of life and nutrition outcomes. Post-intervention interviews with participants and health professionals will be thematically analysed to determine the acceptability of delivery approaches. NVivo 11 Pro software will be used to code for thematic analysis. STATA version 15 will be used to perform quantitative analysis. DISCUSSION The findings of this process evaluation will provide evidence of the core active ingredients that enable the implementation of best practice nutrition intervention for people with upper gastrointestinal cancer. Elucidation of the causal pathways of successful implementation and the important relationship to contextual delivery are anticipated. With this information, a strategy for sustained implementation across broader settings will be developed which impact the quality of life and nutritional status of individuals with upper gastrointestinal cancer. TRIAL REGISTRATION 27th January 2017 Australian and New Zealand Clinical Trial Registry ( ACTRN12617000152325 ).
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Stent placement versus surgical palliation for adults with malignant gastric outlet obstruction.
Upchurch, E, Ragusa, M, Cirocchi, R
The Cochrane database of systematic reviews. 2018;(5):CD012506
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Abstract
BACKGROUND Malignant gastric outlet obstruction is the clinical and pathological consequence of cancerous disease causing a mechanical obstruction to gastric emptying. It usually occurs when malignancy is at an advanced stage; therefore, people have a limited life expectancy. It is of paramount importance to restore oral intake to improve quality of life for the person in a manner that has a minimal risk of complications and a short recovery period. OBJECTIVES To assess the benefits and harms of endoscopic stent placement versus surgical palliation for people with symptomatic malignant gastric outlet obstruction. SEARCH METHODS In May 2018 we searched the Cochrane Central Register of Controlled Trials, Ovid MEDLINE, Ovid Embase and Ovid CINAHL. We screened reference lists from included studies and review articles. SELECTION CRITERIA We included randomised controlled trials comparing stent placement with surgical palliation for people with gastric outlet obstruction secondary to malignant disease. DATA COLLECTION AND ANALYSIS Two review authors independently extracted study data. We calculated the risk ratio (RR) with 95% confidence intervals (CI) for binary outcomes, mean difference (MD) or standardised mean difference (SMD) with 95% CI for continuous outcomes and the hazard ratio (HR) for time-to-event outcomes. We performed meta-analyses where meaningful. We assessed the quality of evidence using GRADE criteria. MAIN RESULTS We identified three randomised controlled trials with 84 participants. Forty-one participants underwent surgical palliation and 43 participants underwent duodenal stent placement. There may have been little or no difference in the technical success of the procedure (RR 0.98, 95% CI 0.88 to 1.09; low-quality evidence), or whether the time to resumption of oral intake was quicker for participants who had undergone duodenal stent placement (MD -3.07 days, 95% CI -4.76 to -1.39; low-quality evidence).Due to very low-quality evidence, we were uncertain whether surgical palliation improved all-cause mortality and median survival postintervention.The time to recurrence of obstructive symptoms may have increased slightly following duodenal stenting (RR 5.08, 95% CI 0.96 to 26.74; moderate-quality evidence).Due to very low-quality evidence, we were uncertain whether surgical palliation improved serious and minor adverse events. The heterogeneity for adverse events was moderately high (serious adverse events: Chi² = 1.71; minor adverse events: Chi² = 3.08), reflecting the differences in definitions used and therefore, may have impacted the outcomes. The need for reintervention may have increased following duodenal stenting (RR 4.71, 95% CI 1.36 to 16.30; very low-quality evidence).The length of hospital stay may have been shorter (by approximately 4 to 10 days) following stenting (MD -6.70 days, 95% CI -9.41 to -3.98; moderate-quality evidence). AUTHORS' CONCLUSIONS The use of duodenal stent placement in malignant gastric outlet obstruction has the benefits of a quicker resumption of oral intake and a reduced inpatient hospital stay; however, this is balanced by an increase in the recurrence of symptoms and the need for further intervention.It is impossible to draw further conclusions on these and the other measured outcomes, primarily due to the low number of eligible studies and small number of participants which resulted in low-quality evidence. It was not possible to analyse the impact on quality of life each intervention had for these participants.
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Needleless Transcutaneous Electrical Acustimulation: A Pilot Study Evaluating Improvement in Post-Operative Recovery.
Zhang, B, Xu, F, Hu, P, Zhang, M, Tong, K, Ma, G, Xu, Y, Zhu, L, Chen, JDZ
The American journal of gastroenterology. 2018;(7):1026-1035
Abstract
BACKGROUND Functional gastrointestinal disturbance occurs after abdominal surgeries and could last for an extended period of time in some cases. This study was designed (1) to evaluate the effects of needleless transcutaneous electrical acustimulation (TEA) on postoperative recovery, and (2) to investigate the mechanisms involving autonomic function in postoperative patients after removal of gastrointestinal cancers. METHODS Forty-two patients (33 male, age: 69.5 ± 1.5 years) scheduled for abdominal surgical removal of gastrointestinal cancers were randomized to TEA (n = 21) and sham-TEA (n = 21). TEA was performed via acupoints ST36 and PC6 1 h twice daily from the postoperative day (POD) 1 to day 3. Sham-TEA was performed at non-acupoints. RESULTS (1) TEA improved major postoperative symptoms by about 30%, including a reduction in time to defecation by 31.7% (P < 0.01 vs. sham-TEA), time to first flatus by 35.9% (P < 0.001), time to ambulation by 42.8% (P < 0.01), time to resuming diet by 26.5% (P < 0.01) and hospital stay by 30% (P < 0.05) as well as pain score by 50% (P < 0.01). (2) TEA significantly increased vagal activity (P < 0.001) and decreased sympathetic activity on POD 4 (P < 0.001) compared with POD 1 as well as the serum level of NE (P < 0.05). (3) The vagal activity, high frequency assessed from the spectral analysis of heart rate variability, was negatively correlated with time to resuming diet, whereas the sympathetic measurement, serum norepinephrine was positively correlated with time to resuming diet and time to flatus. (4) TEA but not sham-TEA decreased TNF-α by 17.4% from POD 1 to POD 4. (5) TEA was an independent predictor of a shorter hospital stay. CONCLUSIONS Needleless TEA improves major postoperative symptoms by enhancing vagal and suppressing sympathetic activities.
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Cruciferous Vegetables and Risk of Cancers of the Gastrointestinal Tract.
Johnson, IT
Molecular nutrition & food research. 2018;(18):e1701000
Abstract
Cancers of the oropharyngeal tissues, oesophagus, stomach, and colorectum are amongst the most common causes of death from cancer throughout the world. Higher consumption of fruits and vegetables is thought to be protective, and cruciferous vegetables are of particular interest because of their unique role as a source of biologically active glucosinolate breakdown products. A literature review of primary studies and meta-analyses indicates that higher consumption of cruciferous vegetables probably reduces the risk of colorectal and gastric cancers by approximately 8% and 19%, respectively. Some studies support the hypothesis that the protective effect against colorectal cancer is modified by genetic polymorphisms of genes regulating the expression of enzymes of the glutathione S-transferase family, but due to contradictory findings the evidence is currently inconclusive. Despite these promising findings, future epidemiological research on the protective effects of cruciferous plants will depend critically upon accurate measurement of dietary exposure, both to the vegetables themselves, and to their active constituents. The development of sensitive chemical assays has facilitated the measurement of urinary excretion of isothiocyanate metabolites as an objective biomarker of intake, but sampling strategies need to be optimized in order to assess long-term exposures at the population level.
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Patient-derived organoid models help define personalized management of gastrointestinal cancer.
Aberle, MR, Burkhart, RA, Tiriac, H, Olde Damink, SWM, Dejong, CHC, Tuveson, DA, van Dam, RM
The British journal of surgery. 2018;(2):e48-e60
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BACKGROUND The prognosis of patients with different gastrointestinal cancers varies widely. Despite advances in treatment strategies, such as extensive resections and the addition of new drugs to chemotherapy regimens, conventional treatment strategies have failed to improve survival for many tumours. Although promising, the clinical application of molecularly guided personalized treatment has proven to be challenging. This narrative review focuses on the personalization of cancer therapy using patient-derived three-dimensional 'organoid' models. METHODS A PubMed search was conducted to identify relevant articles. An overview of the literature and published protocols is presented, and the implications of these models for patients with cancer, surgeons and oncologists are explained. RESULTS Organoid culture methods have been established for healthy and diseased tissues from oesophagus, stomach, intestine, pancreas, bile duct and liver. Because organoids can be generated with high efficiency and speed from fine-needle aspirations, biopsies or resection specimens, they can serve as a personal cancer model. Personalized treatment could become a more standard practice by using these cell cultures for extensive molecular diagnosis and drug screening. Drug sensitivity assays can give a clinically actionable sensitivity profile of a patient's tumour. However, the predictive capability of organoid drug screening has not been evaluated in prospective clinical trials. CONCLUSION High-throughput drug screening on organoids, combined with next-generation sequencing, proteomic analysis and other state-of-the-art molecular diagnostic methods, can shape cancer treatment to become more effective with fewer side-effects.
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Management of adverse events during treatment of gastrointestinal cancers with epidermal growth factor inhibitors.
Hofheinz, RD, Segaert, S, Safont, MJ, Demonty, G, Prenen, H
Critical reviews in oncology/hematology. 2017;:102-113
Abstract
The epidermal growth factor receptor (EGFR) is involved in development and progression of some gastrointestinal cancers, and is targeted by monoclonal antibodies (mAbs) and tyrosine kinase inhibitors (TKIs) used to treat these conditions. Targeted agents are generally better tolerated than conventional chemotherapy, but have characteristic toxicities that can affect adherence, dosing, and outcomes. Skin conditions are the most common toxicities associated with EGFR inhibitors, particularly papulopustular rash. Other common toxicities include mucosal toxicity, electrolyte imbalances (notably hypomagnesaemia), and diarrhoea, while the chimaeric mAb cetuximab is also associated with increased risk of infusion reactions. With appropriate prophylaxis, the incidence and severity of these events can be reduced, while management strategies tailored to the patient and the degree of toxicity can help to ensure continuation of anti-cancer therapy. Here, we review the main toxicities associated with EGFR-inhibiting mAbs and TKIs in patients with gastrointestinal cancers, and provide recommendations for prophylaxis and treatment.
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Optimal postoperative nutrition support for patients with gastrointestinal malignancy: A systematic review and meta-analysis.
Yan, X, Zhou, FX, Lan, T, Xu, H, Yang, XX, Xie, CH, Dai, J, Fu, ZM, Gao, Y, Chen, LL
Clinical nutrition (Edinburgh, Scotland). 2017;(3):710-721
Abstract
OBJECTIVE To improve clinical outcomes, parenteral nutrition, standard enteral nutrition and immuno-enhanced nutrition are widely used in the gastrointestinal tumor patients undergoing surgery, but the optimal management of postoperative nutrition support remains uncertain. METHODS We systematically searched the PUBMED, EMBASE and CNKI to identify latent studies which the effects of standard EN compared with PN or IEN on gastrointestinal tumor patients until the end of November, 2015. The quality of included trials was assessed according to the handbook for Cochrane reviewer. Statistical analysis was carried out by RevMan5.1 software. RESULTS 30 randomized controlled trials containing 3854 patients were contained in our meta-analysis, the results indicated that postoperative SEN could absolutely reduce the incidence of postoperative infectious (P < 0.00001) and non-infectious complications (P = 0.0003), together with its positive effect on the length of hospital stay (P < 0.00001). Additionally, enteral nutrition enhanced with immune stimulation was confirmed to be better, with a significant difference between groups in terms of total infectious (P < 0.00001) and non-infectious complications (P = 0.04), and IEN could also significantly shorten the length of hospital stay (P < 0.00001). CONCLUSION Early use of Enteral nutrition in digestive tumor patients after surgery could significantly reduce the postoperative complications and shorten the length of hospital stay, IEN should be the optimal management, while the use of parenteral nutrition should be restrict to few patients with severe intolerance to enteral nutrition.