Preclinical Chimeric Antibody Chimeric Antigen Receptor T Cell Progress in Digestive System Cancers.

Digestive system cancers, including hepatocellular carcinoma, colorectal and gastric tumors, are characterized by high rates of incidence and mortality. Digestive cancers are difficult to diagnose during the early stages, and the side effects of chemotherapy are often severe and may outweigh the therapeutic benefits. Chimeric antibody chimeric antigen receptor T cell (CAR-T) therapy, a novel immunotherapy, has achieved excellent results for the treatment of hematological tumors. However, CAR-T treatment of solid tumors has struggled due to a lack of target specificity, a difficult tumor microenvironment, and T cell homing. Despite the challenges, CAR-T treatment of digestive cancers is progressing. Combining CAR-T with other targets and/or modifying the CAR may represent the most promising approaches for future treatment of digestive cancers.

Feasibility, acceptability of enteral tube feeding and self-insertion of a nasogastric tube in the nutritional management of digestive cancers, impact on quality of life.

No study has evaluated the feasibility of enteral tube feeding (ETF) in undernourished patients with newly diagnosed gastrointestinal (GI) cancer. OBJECTIVES: Evaluate the acceptability of ETF in patients unable to increase their dietary intake and with a weight loss >10% or albuminemia <30 g/L or BMI <18.5 before surgery, or a weight loss >5% during chemotherapy. The feasibility of self-insertion of a nasogastric tube was also assessed. RESULTS: A total of 308 patients were nutritionally screened during a one-year period. ETF was indicated in 123 cases. Overall acceptability was 78.9% and was higher when weight loss was >10% (p < 0.0001) and before surgery (p < 0.0001), lower during chemotherapy (p < 0.0001), while not influenced by dietary intake or location of the cancer. Forty patients managed a daily self-insertion of the feeding tube (45.5%) and 48 had a nasogastric tube maintained in place. All Quality of Life (QoL) parameters were significantly improved, notably physical role functioning (+20.9% ± 24.0, p < 0.005) and mental health (+21.0% ± 17.7 p < 0.005). CONCLUSION: According to the present algorithm, ETF was indicated in 39.9% of cases and accepted in 78.9% of newly diagnosed patients with primary GI cancer while improving QoL. This study strengthens the place of self-insertion of feeding tubes in clinical practise.

Patients with head and neck cancer: Are they frailer than patients with other solid malignancies?

OBJECTIVE: We aimed to compare frailty status between patients with head and neck cancer (HNC) and other solid malignancies. METHODS: Data collection was prospective, and the following were compared between cohorts at baseline: patient and tumour characteristics, Charlson Comorbidity Index (CCI), Groningen Frailty Indicator (GFI), Mini Mental State Examination (MMSE), Activities of Daily Living (ADLs), Instrumental ADLs (IADLs), Timed Up and Go (TUG) and Quality of Life (QoL). Univariate and multivariate logistic regression analyses were performed, and odds ratios (ORs) with their 95% confidence intervals (95% CIs) were estimated. RESULTS: In total, 242 patients with HNC and 180 with other oncology diagnoses were enrolled, of whom 32.6% and 21.8% were frail according to the GFI respectively. Comorbidity scores were not significantly different between the cohorts (7.4% vs. 13.1%; OR 0.54; 95% CI 0.28-1.02). In the univariate analysis, the GFI was significantly worse in the HNC cohort (OR 1.74; 95% CI 1.11-2.71). However, in the multivariate analysis, the MMSE, TUG and global QoL were significantly worse in the HNC cohort, with ORs of 20.03 (95% CI 2.44-164.31), 11.56 (95% CI 1.86-71.68) and 0.98 (95% CI 0.97-1.00) respectively. CONCLUSION: Patients with HNC appear to be frailer than patients with other solid malignancies despite comparable levels of comorbidity.

Improved Survival With Higher Pre-diagnosis Cardiorespiratory Fitness in Men Who Developed Digestive System Cancers: A Prospective Pilot Study.

BACKGROUND/AIM: Digestive system cancers are the leading cause of cancer mortality and have poor survival particularly in men. The study aimed to assess the association between pre-diagnosis cardiorespiratory fitness (CRF) and cancer mortality in a pilot sample of men who developed digestive system cancers. PATIENTS AND METHODS: Pre-diagnosis CRF (treadmill exercise test) was assessed in 342 men (68.9±21.8 years) who developed digestive system cancers during 6.7±5 years from baseline evaluation. Cox multivariable hazard models were analyzed for total cancer mortality. RESULTS: During 7.2±5 years follow-up from baseline, 120 participants died from cancer. Compared to low CRF, moderate and high CRF levels were associated with 57% [0.43, 95%CI=0.24-0.74] and 73% [0.27, 95%CI=0.12-0.59] reduced risks for cancer mortality, respectively (p trend=0.002). Survival time from baseline was longer among those with moderate [13.5 (range=12.1-14.9) years] and high [16.1 (range=14.0-18.2) years] compared to low CRF [7.9 (range=5.7-10.1) years]. CONCLUSION: Higher pre-diagnosis CRF is independently associated with lower risk of cancer mortality and longer survival in men who later developed digestive system cancers.

Dynapenia could predict chemotherapy-induced dose-limiting neurotoxicity in digestive cancer patients.

BACKGROUND: FIGHTDIGO study showed the feasibility and acceptability of handgrip strength (HGS) measure in routine in 201 consecutive patients with digestive cancer treated with ambulatory chemotherapy. The present study focuses on the second aim of FIGHTDIGO study: the relationships between pre-therapeutic dynapenia and chemotherapy-induced Dose-Limiting Toxicities (DLT). METHODS: In this ancillary prospective study, DLT were analyzed in a sub-group of 45 chemotherapy-naive patients. Two bilateral consecutive measures of HGS were performed with a Jamar dynamometer before the first cycle of chemotherapy. Dynapenia was defined as HGS < 30 kg (men) and < 20 kg (women). DLT and/or Dose-Limiting Neurotoxicity (DLN) were defined as any toxicity leading to dose reduction, treatment delays or permanent treatment discontinuation. RESULTS: Two-thirds of chemotherapies were potentially neurotoxic (n = 31 [68.7%]) and 22 patients (48.9%) received FOLFOX (5FU, leucovorin plus oxaliplatin) regimen chemotherapy. Eleven patients (24.4%) had pre-therapeutic dynapenia. The median number of chemotherapy cycles was 10 with a median follow-up of 167 days. Twenty-two patients experienced DLT (48.9%). There was no significant association between pre-therapeutic dynapenia and DLT (p = 0.62). Nineteen patients (42.2%) experienced DLN. In multivariate analysis, dynapenia and tumoral location (stomach, biliary tract or small intestine) were independent risk factors for DLN (HR = 3.5 [1.3; 9.8]; p = 0.02 and HR = 3.6 [1.3; 10.0]; p = 0.01, respectively). CONCLUSIONS: Digestive cancer patients with pre-therapeutic dynapenia seemed to experience more DLN. HGS routine measurement may be a way to screen patients with frailty marker (dynapenia) who would require chemotherapy dose adjustment and adapted physical activity programs. TRIAL REGISTRATION: NCT02797197 June 13, 2016 retrospectively registered.

Recent developments in the diagnosis and therapy of well-differentiated neuroendocrine tumours.

Well-differentiated neuroendocrine tumours (NETs) of the digestive tract are being increasingly detected, which is partly explained by the increased use of endoscopic and cross-sectional imaging as well as improved recognition at histopathological evaluation. After the discovery of this relatively indolent type of epithelial malignancy over 100 years ago, their sporadic occurrence and divergent biological behaviour at multiple primary sites have hampered dedicated studies into NET pathogenesis and testing of drug efficacy in well-designed clinical trials. The last decade, however, has seen significant improvements in the NET field regarding our understanding of their pathophysiology. This has been substantiated by novel and exciting diagnostic and therapeutic options, including superior positron emission tomography imaging, treatment with unlabelled and radiolabelled somatostatin analogues and inhibitors of the mammalian target of rapamycin and vascular endothelial growth factor pathways. This review summarises contemporary studies within NET patients, which have enriched our clinical repertoire for this disease and have been instrumental in securing a remarkable improvement of overall survival within recent years.

Bile acid-microbiota crosstalk in gastrointestinal inflammation and carcinogenesis.

Emerging evidence points to a strong association between the gut microbiota and the risk, development and progression of gastrointestinal cancers such as colorectal cancer (CRC) and hepatocellular carcinoma (HCC). Bile acids, produced in the liver, are metabolized by enzymes derived from intestinal bacteria and are critically important for maintaining a healthy gut microbiota, balanced lipid and carbohydrate metabolism, insulin sensitivity and innate immunity. Given the complexity of bile acid signalling and the direct biochemical interactions between the gut microbiota and the host, a systems biology perspective is required to understand the liver-bile acid-microbiota axis and its role in gastrointestinal carcinogenesis to reverse the microbiota-mediated alterations in bile acid metabolism that occur in disease states. An examination of recent research progress in this area is urgently needed. In this Review, we discuss the mechanistic links between bile acids and gastrointestinal carcinogenesis in CRC and HCC, which involve two major bile acid-sensing receptors, farnesoid X receptor (FXR) and G protein-coupled bile acid receptor 1 (TGR5). We also highlight the strategies and cutting-edge technologies to target gut-microbiota-dependent alterations in bile acid metabolism in the context of cancer therapy.

The yield of endoscopic investigation for unintentional weight loss.

AIM: The aim of this study was to assess the yield of endoscopic evaluation in isolated unintentional weight loss (UWL) patients compared with patients with weight loss and additional symptoms or signs. PATIENTS AND METHODS: A retrospective review of all patients who underwent an endoscopic evaluation for the investigation of UWL at Soroka University Medical Center between 2006 and 2012. Data on clinical indication, endoscopic, and laboratory finding were retrieved. Severe inflammation, ulcers, achalasia, and neoplasias were considered clinically significant endoscopic findings (CSEF) that could explain weight loss. Detection rates of CSEF were compared between endoscopic studies for which UWL was the sole indication (group 1) and those performed for UWL and at least one other indication (group 2). RESULTS: During the study period, 1843 patients with UWL were evaluated with 2098 endoscopic procedures. Of these, 1540 underwent esophagogastroduodenoscopy (EGD) and 558 underwent colonoscopy. EGD was performed in 229 (14.8%) patients in group 1 (mean age: 60.9±16.4, 43.3% men), and in 1311 (85.2%) patients in group 2 (mean age: 60.5±18.5, 45% men). Pathological endoscopic findings were identified in 712 (46%) EGDs. Of these, 155 (10%) studies detected significant outcomes: six (3.9%) in group 1 and 149 (96.1%) in group 2. Of the 558 colonoscopies performed, 105 (18.8%) were performed in group 1 (mean age: 61.7±17.5, 43% men) and 453 (82.2%) in group 2 patients (mean age: 62.9±14.6, 49% men). Abnormal findings were found in 190 (33.8%) of the procedures. CSEF were found in 34 (6%) patients: two in group 1 and 32 in group 2. CONCLUSION: The diagnostic yield of endoscopy for investigation of patients with UWL is non-negligible, and should be considered as part of its baseline evaluation, especially in older individuals and those who present with other gastrointestinal manifestations.

[Microbiota and Cancer: a "pas de deux"?] / Gastrointestinale Mikrobiota und Tumorerkrankungen ­ ein "pas de deux"?

Malignant diseases pose an enormous challenge to today's health care system. Advanced pathophysiological understanding of gastrointestinal microbiota and a viable, causal relation to the development of malignant tumors is increasingly becoming the focus of medical research. The following article presents key pathomechanisms of reciprocal interaction between microbiota and malignancy and illustrates the associated role of diet.

Physiologic Response to HIPEC: Sifting Through Perturbation to Identify Markers of Complications.

CONTEXT: The postoperative physiologic response to hyperthermic intraperitoneal chemotherapy (HIPEC) has been poorly studied outside of the immediate perioperative time. OBJECTIVE: To characterize the physiologic response during the first 5 days after HIPEC and identify variables associated with major complications. METHODS: Patients undergoing HIPEC and cytoreductive surgery during a 14-month interval were retrospectively identified and their records reviewed for demographics, physiologic response, and major complications. Vital signs and laboratory results were recorded before the operation, immediately after the procedure, and for the first 5 postoperative days. RESULTS: Thirty-three patients were included. The mean body temperature and heart rate were elevated on postoperative day 1 compared with baseline (preoperative) status (37.1°C vs 36.6°C and 103 vs 78 beats/min, respectively) and remained elevated through postoperative day 5. The mean arterial pressure was lower on postoperative day 1 (73 mm Hg) but returned to baseline on postoperative day 3 (93 mm Hg). Mean creatinine level increased on postoperative day 1 (0.96 mg/dL) but returned to baseline on postoperative day 2 (0.87 mg/dL). Fourteen patients (42%) had major complications. The strongest predictors of major complications were a prolonged operative time (519 vs 403 minutes) and extreme changes in body temperature and renal function. CONCLUSIONS: Hyperthermic intraperitoneal chemotherapy results in a hypermetabolic response that partially returns to baseline around postoperative day 3. Elevated body temperature and impaired renal function are the best predictors of major complications.

Role of oncogene 24p3 neutrophil gelatinase-associated lipocalin (NGAL) in digestive system cancers.

Neutrophil gelatinase-associated lipocalin, known also as 24p3 lipocalin, lipocalin-2 or uterocalin (in mouse), is a small secretory protein binding small molecular weight ligands which takes part in numerous processes including apoptosis induction in leukocytes, iron transport, smell, and prostaglandins and retinol transport [19]. It was discovered in activated neutrophils as a covalent peptide associated with human gelatinase neutrophils [7]. Neutrophil lipocalin is secreted physiologically in the digestive system, respiratory tract, renal tubular cells, liver or immunity system. Systematic (circulated in plasma) neutrophil gelatinase come from multiple sources; it may be synthesized in the liver, secreted from activated neutrophils or macrophages, or derive from atherosclerosis or inflammatory endothelial cells [17]. NGAL is stored secondarily in granulates with lactoferrin, calprotectin or MAC-1, which take part in neutrophils' action and migration [13,19]. NGAL participates in acute and chronic inflammation (production of NGAL is indicated by factors conducive to cancer progression) [13,21]. NGAL levels increase in inflammatory or endothelial damage. NGAL level is measured in blood or urine. It is known as a kidney failure factor [7,20]. NGAL is therefore one of the most promising new generation biomarkers in clinical nephrology [6]. The role of NGAL in digestive system neoplasms has not been explored in detail. However, overexpression of this marker was proved in neoplasms such as esophageal carcinoma, stomach cancer, pancreatic cancer or colon cancer, which may indicate an association between concentration and neoplasm [3].

The association between biliary tract inflammation and risk of digestive system cancers: A population-based cohort study.

The relationship between biliary tract inflammation (BTI) and digestive system cancers is unclear. This study aimed to evaluate the association between BTI and the risks of digestive system cancers.Using the Taiwan National Health Insurance claims data, information on a cohort of patients diagnosed with BTI (n = 4398) between 2000 and 2009 was collected. A comparison cohort of sex-, age-, and index year-matched persons without BTI (n = 17,592) was selected from the same database. The disease was defined by the ICD-9-CM. Both cohorts were followed until the end of 2010 and incidences of digestive system cancers were calculated.The results revealed an increase in adjusted hazard ratio (aHR) of biliary tract cancer (24.45; 95% confidence interval [CI]: 9.20-65.02), primary liver cancer (1.53; 95% CI: 1.07-2.18), and pancreatic cancer (3.10; 95% CI: 1.20-8.03) in patients with both gallbladder and BTI. The aHR of stomach cancer was also found to be increased (2.73; 95% CI: 1.28-5.81) in patients with gallbladder inflammation only. There were no differences in esophageal cancer (aHR: 0.82; 95% CI: 0.23-2.87) and colorectal cancer (aHR: 0.92; 95% CI: 0.59-1.45). The aHR for digestive system cancers increased by 3.66 times (95% CI: 2.50-5.35) and 12.20 times (95% CI: 8.66-17.17) in BTI visits frequency averaged 2 to 4 visits per year and frequency averaged ≥5 visits per year, respectively.Patients with BTI have significantly higher risk of digestive system cancers, particularly biliary tract, pancreatic, and primary liver cancers, compared with those who are without it.

Feasibility of Exercise Training in Cancer Patients Scheduled for Elective Gastrointestinal Surgery.

BACKGROUND/AIMS: This study examines the feasibility of a preoperative exercise program to improve the physical fitness of a patient before gastrointestinal surgery. METHODS: An outpatient exercise program was developed to increase preoperative aerobic capacity, peripheral muscle endurance and respiratory muscle function in patients with pancreatic, liver, intestinal, gastric or esophageal cancer. During a consult at the outpatient clinic, patients were invited to participate in the exercise program when their surgery was not scheduled within 2 weeks. RESULTS: The 115 participants followed on average 5.7 (3.5) training sessions. Adherence to the exercise program was high: 82% of the planned training sessions were attended, and no adverse events occurred. Mixed model analyses showed a significant increase of maximal inspiratory muscle strength (84.1-104.7 cm H2O; p = 0.00) and inspiratory muscle endurance (35.0-39.5 cm H2O; p = 0.00). No significant changes were found in aerobic capacity and peripheral muscle strength. CONCLUSION: This exercise program in patients awaiting oncological surgery is feasible in terms of participation and adherence. Inspiratory muscle function improved significantly as a result of inspiratory muscle training. The exercise program however failed to result in improved aerobic capacity and peripheral muscle strength, probably due to the limited number of training sessions as a result of the restricted time interval between screening and surgery.

Important roles of P2Y receptors in the inflammation and cancer of digestive system.

Purinergic signaling is important for many biological processes in humans. Purinoceptors P2Y are widely distributed in human digestive system and different subtypes of P2Y receptors mediate different physiological functions from metabolism, proliferation, differentiation to apoptosis etc. The P2Y receptors are essential in many gastrointestinal functions and also involve in the occurrence of some digestive diseases. Since different subtypes of P2Y receptors are present on the same cell of digestive organs, varying subtypes of P2Y receptors may have opposite or synergetic functions on the same cell. Recently, growing lines of evidence strongly suggest the involvement of P2Y receptors in the pathogenesis of several digestive diseases. In this review, we will focus on their important roles in the development of digestive inflammation and cancer. We anticipate that as the special subtypes of P2Y receptors are studied in depth, specific modulators for them will have good potentials to become promising new drugs to treat human digestive diseases in the near future.

Halofuginone for fibrosis, regeneration and cancer in the gastrointestinal tract.

Organ fibrosis and architectural remodeling can severely disrupt tissue function, often with fatal consequences. Fibrosis is the end result of chronic inflammatory reactions induced by a variety of stimuli, and the key cellular mediator of fibrosis comprises the myofibroblasts which, when activated, serve as the primary collagen-producing cells. Complex links exist between fibrosis, regeneration and carcinogenesis, and the concept that all organs contain common tissue fibrosis pathways that could be potential therapeutic targets is an attractive one. Because of the major impact of fibrosis on human health there is an unmet need for safe and effective therapies that directly target fibrosis. Halofuginone inhibits tissue fibrosis and regeneration, and thereby affects the development of tumors in various tissues along the gastrointestinal tract. The high efficacy of halofuginone in reducing the fibrosis that affects tumor growth and tissue regeneration is probably due to its dual role in inhibiting the signaling pathway of transforming growth factor ß, on the one hand, and inhibiting the development of Th17 cells, on the other hand. At present halofuginone is being evaluated in a clinical trial for other fibrotic indication, and any clinical success in that trial would allow the use of halofuginone, also for all other fibrotic indications, including those of the gastrointestinal tract.

Raising public awareness.

Upper gastrointestinal (GI) cancer nurse specialist Claire Sedgwick from Newcastle upon Tyne Hospitals NHS Foundation Trust was concerned to find poor awareness of the symptoms of upper gastrointestinal and oesophageal cancers.

New insights into the role of chronic inflammation and cytokines in the etiopathogenesis of gastroenteropancreatic neuroendocrine tumors.

Although previously considered rare, recent epidemiological studies have revealed that the incidence (3.6/100,000) and prevalence (35/100,000) of gastroenteropancreatic neuroendocrine tumors (GEP-NETs) has increased over the past few decades. Despite the progress in the understanding of GEP-NET molecular biology, there is still little advance in the early diagnosis due to lack of specific tumor markers. As the tumors are mostly detected in their late stage, they are not well controlled by either biotherapy or conventional chemotherapy, and thus represent a significant clinical issue. Chronic inflammation has been implicated in the development of GEP-NETs. This review presents recent findings that link pro-inflammatory cytokines to the molecular basis of GEP-NET tumorigenesis, leading to a more personalized approach to disease management and therapy.

A practical guide for the diagnosis of primary enteric nervous system disorders.

OBJECTIVE: Primary gastrointestinal neuropathies are a heterogeneous group of enteric nervous system (ENS) disorders that continue to cause difficulties in diagnosis and histological interpretation. Recently, an international working group published guidelines for histological techniques and reporting, along with a classification of gastrointestinal neuromuscular pathology. The aim of this article was to review and summarize the key issues for pediatric gastroenterologists on the diagnostic workup of congenital ENS disorders. In addition, we provide further commentary on the continuing controversies in the field. RESULTS: Although the diagnostic criteria for Hirschsprung disease are well established, those for other forms of dysganglionosis remain ill-defined. Appropriate tissue sampling, handling, and expert interpretation are crucial to maximize diagnostic accuracy and reduce interobserver variability. The absence of validated age-related normal values for neuronal density, along with the lack of correlation between clinical and histological findings, result in significant diagnostic uncertainties while diagnosing quantitative aberrations such as hypoganglionosis or ultrashort Hirschsprung disease. Intestinal neuronal dysplasia remains a histological description of unclear significance. CONCLUSIONS: The evaluation of cellular quantitative or qualitative abnormalities of the ENS for clinical diagnosis remains complex. Such analysis should be carried out in laboratories that have the necessary expertise and access to their own validated reference values.

Propensity score analysis confirms the independent effect of parenteral nutrition on the risk of central venous catheter-related bloodstream infection in oncological patients.

BACKGROUND & AIMS: Parenteral nutrition is known as a high-risk factor for central venous catheter-related bloodstream infection (CVC-RBSI) in cancer patients. Owing to ethical and technical problems, the studies in the literature have nonrandomized designs and are therefore often confounded by biases. We performed a propensity score analysis to estimate the effect of parenteral nutrition on CVC-RBSI in digestive cancer patients who underwent chemotherapy. METHODS: Data were collected prospectively. A logistic regression model was used to calculate a propensity score, which was the probability of receiving parenteral nutrition. Kaplan-Meier survival and Cox regression model were used to estimate the effect of the parenteral nutrition on CVC-RBSI after adjustment for the propensity score. RESULTS: Before the propensity score analysis, the differences between patients with (n = 113) and without (n = 312) parenteral nutrition were identified including: male gender, body weight, weight loss, performance status, location of primary cancer, FOLFIRI, and previous long-term corticotherapy. After propensity score stratification, all of the covariates were balanced within each stratum. After adjustment, patients with parenteral nutrition were at a higher risk for CVC-RBSI. CONCLUSION: By using the propensity score analysis, this study confirmed that parenteral nutrition was an independent risk factor for CVC-RBSI in digestive cancer patients.

Involvement of liver-intestine cadherin in cancer progression.

Cadherins constitute a superfamily of Ca(2+)-dependent cell adhesion molecules that play critical roles in the maintenance of tissue structure and morphogenesis. Their dysregulation is commonly observed in a variety of cancers. Liver-intestine cadherin (LI-cadherin), which was so named in view of its sole expression in the liver and intestine of the rat, is a structurally unique member of the cadherin superfamily, possessing seven cadherin repeats within the extracellular cadherin domain and only 25 amino acids in the cytoplasmic domain. Its adhesive property does not require any interaction with cytoplasmic components such as catenins, and it responds to small changes in extracellular Ca(2+) below the physiological plasma concentration. In humans, the distribution of LI-cadherin is limited to the duodenum, jejunum, ileum, colon, and part of the pancreatic duct. Data accumulated from studies of the biological characteristics of LI-cadherin have shown that it plays an important role in the pathophysiology of human cancers. Here, we review recent information about LI-cadherin and its implications for cancer progression.