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Gastrointestinal cancers are one of the most frequent cancers and a leading cause of cancer deaths worldwide. We provide an overview of the most important practice-changing trials that were either published or presented at the international scientific meetings in 2021–2023. Highlights included reports on three phase III trials (CONCORDE/PRODIGE 26, ARTDECO, and a study by Xu et al.) that evaluated dose escalation in the definitive setting for locally advanced oesophageal cancers, as well as two phase III trials that evaluated the role of chemotherapy (neo-AEGIS) and targeted therapy (NRG/RTOG 1010) in the neoadjuvant setting for adenocarcinoma oesophageal cancers or gastroesophageal junction cancer. CheckMate 577 evaluated nivolumab in patients who had residual pathological disease after neoadjuvant chemoradiation followed by complete resection. The use of radiation therapy for borderline and locally advanced pancreatic cancer is also discussed (SMART and CONKO-007 trials). Stereotactic body radiation therapy followed by sorafenib was compared to sorafenib alone in patients with hepatocellular carcinoma in the NRG/RTOG 1112 study. New options in the management of rectal cancer are emerging such as total neoadjuvant treatment (PRODIGE 23, RAPIDO, PROSPECT), organ preservation (OPRA, OPERA), and the role of immunotherapy in patients with DNA mismatch-repair deficient/microsatellite instability. Finally, preliminary results of the ACT 4 trial that evaluated de-escalation in anal cancer are presented. [ABSTRACT FROM AUTHOR]

Abstract Over the last 15 years there has been a change in how we understand the impact of the interaction between the tumour and the host on cancer outcomes. From the simplistic view that the make-up of tumours cells largely determines their aggressiveness to a more complex view that the interaction between the products of tumour and host cell signal transduction pathways is crucial in determining whether the tumour cell is eliminated or survives in the host. Of the host cells, those with an immune/inflammatory function are most well documented to inhibit or promote tumour cell proliferation and dissemination. It is only in the last few years that there has been greater recognition of the impact of intracellular, cellular and systemic immune/inflammatory phenotypes on patient outcomes independent of current tumour staging and that these phenotypes are useful in informing oncological research and practice. In the present review we will examine the importance of inflammatory phenotypes at the intra-cellular, cellular and systemic levels on outcomes in patients with gastrointestinal cancer with focus on colorectal cancer. Based on these phenotypes we will examine and discuss the prospects for therapeutic intervention. Highlights • The development and progression of colorectal cancer is heterogenous in nature. • Tumourogenesis occurs via systemic, cellular and intracellar mechanisms. • NF-κB and JAK-STAT signalling pathways represent key signalling cascades. • Components of signalling pathways are promising therapeutic targets. [ABSTRACT FROM AUTHOR]

Abstract High-performance submucosal injection materials (SIMs) contribute to the success of endoscopic therapy for early-stage gastrointestinal neoplasms. This study aimed to identify the most important factor (viscoelastic parameter) that determines SIM performance and the ease of injection. To determine the ideal viscoelastic parameters of SIMs, submucosal elevation heights (SEHs) and the ease of submucosal injection [characterized by injection pressures (IPs)] were evaluated using a newly developed ex vivo model, in which a constant tension was applied to the studied specimen. The strongest positive correlation was observed between the loss modulus determined at an oscillation frequency of 0.1 rad/s and SEH (correlation coefficient > 0.9) and between the loss modulus at 10 rad/s and IP (correlation coefficient > 0.9). SIMs with high loss moduli (0.1 rad/s) also contributed to maintenance of the submucosal elevation. Moreover, the SEHs of pseudoplastic fluid SIMs (whose loss moduli increased slightly with increasing angular frequency) were greater than those of Newtonian fluid SIMs (whose loss modulus increased drastically with increasing angular frequency). In this study, the ideal viscoelastic SIM parameters were clarified. The loss modulus (0.1 rad/s) was the most important viscoelastic factor affecting SIM performance. Additionally, the development of pseudoplastic fluid SIMs may lead to the creation of next-generation SIMs, with a performance superior to that of sodium hyaluronate, which is currently used widely in endoscopic treatments. Graphical abstract Unlabelled Image Highlights • Submucosal injection materials (SIMs) are important for endoscopic treatment. • The viscoelastic parameter that determines SIM performance was identified. • Loss modulus (0.1 rad/s) was the most important parameter affecting SIM performance. • Pseudoplastic fluid SIMs can be a major candidate for next-generation SIM. [ABSTRACT FROM AUTHOR]

Highlights • KRAS -mutant pancreatic and colorectal cancer is common and difficult to target. • Direct inhibition of K-Ras has been demonstrated in preclinical studies. • Combining MEK inhibitors with novel targeted agents may improve efficacy. • Immunotherapy has shown clinical promise in KRAS -mutant gastrointestinal cancers. Abstract KRAS mutations are common in pancreatic and colorectal cancers and are associated with lack of response to anti-epidermal growth factor receptor therapy. Ras is an established therapeutic target that has long eluded efforts to develop specific inhibitors, while targeting downstream signaling pathways has proven largely ineffective, highlighting a need for rational combination strategies to overcome resistance. Recently, renewed interest in directly targeting Ras has led to the development of several small-molecule inhibitors that bind directly to K-Ras or its effector proteins, downregulation of K-Ras expression using therapeutic antisense oligonucleotides or siRNAs, and targeting scaffold proteins such as kinase suppressor of Ras. Indirect approaches to inhibiting K-Ras include combining inhibitors of the mitogen-activated protein kinase pathway with novel targeted agents. Immunotherapy in early studies has also shown clinical promise. This review summarizes the current evidence for each of these approaches. [ABSTRACT FROM AUTHOR]

Inhibiting component of therapy with (−)-epigallocatechin-3-gallate (EGCG) is low bioavailability of fresh tea polyphenols that outcome from insecurity under stomach related circumstances, insufficient transcellular transport. As needs are, fucose- carboxymethyl chitosan (FU-CMC) graft EGCG with gold nanoparticles (GNPs) (FU-CMC-EGCG-GNPs) nanocomposites were prepared and managed peritumorally to assess their anticancer action. The physicochemical properties of as-prepared nanocomposite were evaluated by FTIR spectroscopy, UV–visible absorption spectra, XRD, FESEM-EDX and HRTEM-SAD. Additionally, the viability and cell uptake assays revealed that the as-prepared nanocomposite successfully repressed the propagation of gastric tumor cells. In vivo anticancer treatment of FU-CMC-EGCG-GNPs nanocomposites showed more anticancer action contrasted with pure EGCG. Immuno-histological investigations established a superior numeral of apoptotic tissues in the as-prepared FU-CMC-EGCG-GNPs nanocomposites contrasted with pure EGCG. Overall, the as-prepared FU-CMC-EGCG-GNPs nanocomposite affords a proficient medicine delivery stage for chemotherapy. [ABSTRACT FROM AUTHOR]

Cancer chemotherapy often induces gastrointestinal symptoms such as anorexia, nausea, and vomiting. Antiemetic agents are effective in inhibiting nausea and vomiting, but patients still experience anorexia. We previously reported that chemotherapeutic agent-induced anorexia is associated with an increase of inflammatory cytokines. Other studies also reported that antagonism of the histamine H 4 receptor is anti-inflammatory. In this study, we investigated the involvement of the H 4 receptor in the development of chemotherapy-induced anorexia in mice. Cisplatin-induced anorexia occurred within 24 h of its administration and continued for 3 days. The early phase (day 1), but not the delayed phase (days 2 and 3), of anorexia was inhibited by the daily injection of a 5-HT 3 receptor antagonist (granisetron). However, a corticosteroid (dexamethasone) or selective H 4 receptor antagonist (JNJ7777120) abolished the delayed phases of anorexia. Cisplatin significantly increased TNF-α mRNA expression in the hypothalamus and spleen, and the period of expression increase paralleled the onset period of anorexia. In addition, pretreatment with JNJ7777120 completely inhibited the increased expression. These results suggest that TNF-α mRNA expression via H 4 receptors may contribute to the development of cisplatin-induced anorexia, and that H 4 receptor antagonists are potentially useful treatments. [ABSTRACT FROM AUTHOR]

Aims Gastrointestinal cancers are a kind of deadly malignancy afflicting close to a million peoples worldwide. 5-Fluorouracil (5-Fu) is a main chemotherapeutic agent for cancer treatment. However, prolonged exposure of 5-Fu to cancer cells may cause chemoresistance and decrease the therapeutic potential of 5-Fu. Main methods Replication protein A (RPA) is a component of the origin recognition complex. In our study, we explored the role of RPA1 in hepatocellular carcinoma cell SMMC-7721, gastric cancer cell SGC-7901 and colorectal cancer HT-29 via lentiviral particles infection. Flow cytometry assay was used to examine the effect of RPA1 on cell proliferation, cell cycle and apoptosis. Western blot was employed to determine the role of RPA1 on Caspase 3 expression. Key findings Immunohistochemstry results showed that RPA1 was highly expressed in colorectal cancer tissues. Only 5-Fu or the knockdown of RPA1 suppressed cell clone formation, induced cell cycle arrest at the G1 phase and promoted cell apoptosis by regulating the protein level of Caspase 3. And the combination of the application of 5-Fu and RPA1 silencing significantly enhanced the above effects. Significance RPA1 serves as an oncogene during gastrointestinal cancers progression. These studies reveal a new target for gastrointestinal cancers therapy, and the combination of 5-Fu and silencing of RPA1 provides a new attractive therapeutic measure for gastrointestinal cancers. [ABSTRACT FROM AUTHOR]

Malnutrition in cancer patients – in both prevalence and degree – depends primarily on tumor stage and site. Preoperative malnutrition in surgical patients is a frequent problem and is associated with prolonged hospital stay, a higher rate of postoperative complications, higher re-admission rates, and a higher incidence of postoperative death. Given the focus on the cancer and its cure, nutrition is often neglected or under-evaluated, and this despite the availability of international guidelines for nutritional care in cancer patients and the evidence that nutritional deterioration negatively affects survival. Inadequate nutritional support for cancer patients should be considered ethically unacceptable; prompt nutritional support must be guaranteed to all cancer patients, as it can have many clinical and economic advantages. Patients undergoing multimodal oncological care are at particular risk of progressive nutritional decline, and it is essential to minimize the nutritional/metabolic impact of oncological treatments and to manage each surgical episode within the context of an enhanced recovery pathway. In Europe, enhanced recovery after surgery (ERAS) and routine nutritional assessment are only partially implemented because of insufficient awareness among health professionals of nutritional problems, a lack of structured collaboration between surgeons and clinical nutrition specialists, old dogmas, and the absence of dedicated resources. Collaboration between opinion leaders dedicated to ERAS from both the European Society of Surgical Oncology (ESSO) and the ERAS Society was born with the aim of promoting nutritional assessment and perioperative nutrition with and without an enhanced recovery program. The goal will be to improve awareness in the surgical oncology community and at institutional level to modify current clinical practice and identify optimal treatment options. [ABSTRACT FROM AUTHOR]

Background and aims Development of high-performance submucosal injection materials (SIMs) contribute to the advancement of endoscopic therapy for early-stage gastrointestinal neoplasms. This study aimed to develop a new ex vivo model that mimics the human gastrointestinal tract to evaluate the performance (the height and duration of the submucosal elevation) of various SIMs in detail. Methods A new ex vivo model that applies a constant tension to the tested specimen (the porcine gastric specimen) was developed. SIMs were injected into the submucosa at the center or edge of the tested specimen, and submucosal elevation heights (SEHs) were measured over time. Results The average value and standard deviation of SEH determined using the conventional model (the tested specimen was fixed with pins) were higher than those obtained using the new model, which showed that the new model could precisely measure the SEH of a given SIM. In addition, the performance (SEH) of SIMs decreased with increasing tension applied to the specimen, suggesting that the performance of SIMs deteriorates with the over-expansion of the gastrointestinal tract. The submucosal elevation formed at the specimen edge disappeared faster than that formed at the specimen's center. Conclusions The proposed new ex vivo model allows accurate SEH measurement under uniform conditions and detailed comparison of the performances of various types of SIMs and can contribute to the development of high-performance materials. [ABSTRACT FROM AUTHOR]

MiR-93-5p has been previously found to be associated with gastric cancer (GC) tumorigenesis; however, the current understanding of its function in this context remains largely incomplete. In the present study, we showed that miR-93-5p was upregulated in GC tissues. We also demonstrated that miR-93-5p overexpression promoted the proliferation, migration, invasion, and chemoresistance of SGC-7901 cells in vitro, and conversely, that endogenously silencing miR-93-5p expression induced the opposite effects in HGC-27 cells. Overexpression of miR-93-5p was found to inactivate the Hippo pathway, and furthermore, miR-93-5p knockdown activated Hippo signaling. MiR-93-5p upregulation was also shown to inhibit the expression of two well-characterized Hippo pathway regulators, protocadherin Fat 4 (FAT4), and large tumor suppressors 2 (LATS2), at both the mRNA and protein level. Additionally, the results of bioinformatics analyses and luciferase reporter assays indicated that miR-93-5p directly targets the 3′-UTR of FAT4 and LATS2. Taken together, these results demonstrate that miR-93-5p promotes GC-cell progression via the inactivation of the Hippo signaling pathway, and thus, represents a potential therapeutic target for the treatment of GC. [ABSTRACT FROM AUTHOR]

Aims Previous research suggests that patients undergoing upper gastrointestinal surgery are at high risk of poor postoperative outcomes. The aim of our study was to describe patient outcomes after elective upper gastrointestinal surgery at a global level. Methods Prospective analysis of data collected during an international seven-day cohort study of 474 hospitals in 27 countries. Patients undergoing elective upper gastrointestinal surgery were recruited. Outcome measures were in-hospital complications and mortality at 30-days. Results are presented as n(%) and odds ratios with 95% confidence intervals. Results 2139 patients were included, of whom 498 (23.2%) developed one or more postoperative complications, with 30 deaths (1.4%). Patients with complications had longer median hospital stay 11 (6–18) days vs. 5 (2–10) days. Infectious complications were most frequent, affecting 368 (17.2%) patients. 328 (15.3%) patients were admitted to critical care postoperatively, of whom 161 (49.1%) developed a complication with 14 deaths (4.3%). In a multivariable logistic regression model we identified age (OR 1.02 [1.01–1.03]), American Society of Anesthesiologists physical status III (OR 2.12 [1.44–3.16]) and IV (OR 3.23 [1.72–6.09]), surgery for cancer (OR 1.63 [1.27–2.11]), open procedure (OR 1.40 [1.10–1.78]), intermediate surgery (OR 1.75 [1.12–2.81]) and major surgery (OR 2.65 [1.72–4.23]) as independent risk factors for postoperative complications. Patients undergoing major surgery for upper gastrointestinal cancer experienced twice the rate of complications compared to those undergoing other procedures (224/578 patients [38.8%] versus 274/1561 patients [17.6%]). Conclusions Complications and death are common after upper gastrointestinal surgery. Patients undergoing major surgery for cancer are at greatest risk. [ABSTRACT FROM AUTHOR]

In this study, we aimed to investigate the antitumor effect of esculetin, a coumarin derivative extracted from natural plants, on human gastric cancer cells, and to illustrate the potential mechanisms. The results showed that esculetin exhibited anti-proliferative effects against gastric cancer cells and induced their apoptosis in a dose dependent manner with lower toxicity against normal gastric epithelial cells. Mechanism study indicated that esculetin induced gastric cancer MGC-803 cells apoptosis by triggering the activation of mitochondrial apoptotic pathway through reducing the mitochondrial membrane potential (MMP), increasing Bax/Bcl-2 ratio, activating caspase-3 and caspase-9 activity, and increasing cytochrome c release from mitochondria. Further study showed that the pro-apoptotic effects of esculetin were associated with down-regulation of insulin-like growth factor-1/ phosphatidylinositide 3-kinase/protein kinase B (IGF-1/PI3K/Akt) signaling pathway. Activation of IGF-1/PI3K/Akt pathway by IGF-1 abrogated the pro-apoptotic effects of esculetin, while inhibition of IGF-1/PI3K/Akt pathway by triciribine or LY294002 enhanced the pro-apoptotic effects of esculetin. In addition, esculetin inhibited in vivo tumor growth with no obvious toxicity following subcutaneous inoculation of MGC-803 cells in nude mice, and inhibited activation of IGF-1/PI3K/Akt pathway in tumor tissue. Conclusion These results indicate that esculetin could inhibit cell proliferation and induce apoptosis of gastric cancer cells through IGF-1/PI3K/Akt mediated mitochondrial apoptosis pathway, and may be a novel effective chemotherapeutic agent against gastric cancer. [ABSTRACT FROM AUTHOR]

The microbiota that inhabits the human body plays an important role in health and disease, by their fundamental role in food digestion, training of the immune system or protection against pathogen colonization. However, when the equilibrium with its host is altered, some diseases like cancer might be promoted. In this review we describe the information collected in recent studies between the microbiota and its association with cancer. We conducted the review of the relation of microbiome and cancer etiology focusing on the gastrointestinal and cervical cancer. The MEDLINE database was used for the search. The gastrointestinal tract harbours a diverse and site specific microbiota, and several studies have demonstrated that perturbation of these microbial communities might be associated with different types of cancer. In particular, alteration of the colorectal, gastric and oesophageal microbiota have been reported associated with cancer development. Likewise, cervical microbiome studies suggest that some members of the cervical microbiota are possible modifiers of the cytokine profile of the cervical microenvironment during the development of cervical lesions and cervical cancer. Larger prospective studies are needed to examine whether microbiome dysbiosis could cause cancer, and to evaluate the utility of microbiome profiles as biomarkers for prevention and early diagnosis. This is an important area of research if we consider that microbiota may be a modifiable factor by the use of pre- and probiotics, in order to prevent cancer evolution or even to potentiate cancer treatment. [ABSTRACT FROM AUTHOR]

Cisplatin (DDP) is the first line chemotherapeutic drug for several cancers, including gastric cancer (GC). Unfortunately, the rapid development of drug resistance remains a significant challenge for the clinical application of cisplatin. There is an urgent need to develop new strategies to overcome DDP resistance for cancer treatment. In this study, four types of human GC cells have been divided into naturally sensitive or naturally resistant categories according to their responses to cisplatin. PARP1 activity (poly (ADP-ribose), PAR) was found to be greatly increased in cisplatin-resistant GC cells. PARP1 inhibitors significantly enhanced cisplatin-induced DNA damage and apoptosis in the resistant GC cells via the inhibition of PAR. Mechanistically, PARP1 inhibitors suppress DNA-PKcs stability and reduce the capability of DNA double-strand break (DSB) repair via the NHEJ pathway. This was also verified in BGC823/DDP GC cells with acquired cisplatin resistance. In conclusion, we identified that PARP1 is a useful interceptive target in cisplatin-resistant GC cells. Our data provide a promising therapeutic strategy against cisplatin resistance in GC cells that has potential translational significance. [ABSTRACT FROM AUTHOR]

NF-κB is a critical target for cancer treatment due to its central role in facilitating cancer progression and desensitizing cancer cells to chemotherapeutic drugs. In this study, a series of chemically modified asymmetric curcuminoid analogs named S01–S15 were synthesized and evaluated for NF-κB inhibitory activity in gastric cancer cell lines. Cell growth inhibition assays revealed that most of these analogs effectively inhibited the growth of BGC-823, SGC-7901, and MFC cells. S06 was selected for further research. MTT assay, clonogenic assay, Hoechst 33258 staining assay, and western blotting revealed that S06 could exert anti-gastric cancer effects by downregulating NF-κB activity. Moreover, via its effects on NF-κB, S06 effectively enhanced the sensitivity of the gastric cancer cells to irinotecan. Together, this study provide a series of new curcuminoid analogs as promising cancer therapeutic agents. [ABSTRACT FROM AUTHOR]

Context: Patients with terminal illnesses often require surrogate decision makers. Prior research has demonstrated high surrogate stress, and that despite standards promoting substituted judgment, most patients do not want their surrogates to make pure substituted judgments for them. It is not known how best to help loved ones fulfill the surrogate role.Objectives: To test the effectiveness of an intervention to help surrogate decision makers.Methods: One hundred sixty-six patients (41% with amyotrophic lateral sclerosis and 59% with gastrointestinal cancers) and their surrogates at two university medical centers were randomized to an intensive nurse-directed discussion of the end-of-life decision control preferences of the patient (TAILORED) or a discussion of nutrition (CONTROL); 163 completed baseline interviews and underwent the intervention.Results: Twelve patients died during follow-up and 137 dyads completed the study. Post-intervention, using all available data, TAILORED patients and surrogates became more likely to endorse mutual surrogate decision making, that is, a balance of their own wishes and what the surrogate thinks best (adjusted odds compared with baseline for patients = 1.78, P = 0.04; adjusted odds for surrogates = 2.05, P = 0.03). CONTROL patients became 40% less likely to endorse mutual surrogate decision making (P = 0.08), and CONTROL surrogates did not change significantly from baseline (adjusted odds = 1.44, P = 0.28). Stress levels decreased for TAILORED surrogates (impact of events scale = 23.1 ± 14.6 baseline, 20.8 ± 15.3 f/u, P = 0.046), but not for CONTROL (P = 0.85), and post-intervention stress was lower for TAILORED than CONTROL (P = 0.04). Surrogates' confidence was uniformly high at baseline and did not change. Caregiver burden (Zarit) increased from 12.5 ± 6.5 to 14.7 ± 8.1 for TAILORED (P < 0.01), while not changing for CONTROL, yet satisfaction with involvement in decision making was higher at follow-up for TAILORED than for CONTROL (71% vs. 52%, P = 0.03).Conclusion: TAILORED patients and surrogates who completed the study adopted a more mutual decision-making style, balancing their own wishes with what the surrogate thinks would be best for them. Surrogates reported less stress and more satisfaction. Confidence was high at baseline and did not change. There was a modest increase in caregiver burden. These findings suggest that interventions like TAILORED might positively impact surrogate decision making. [ABSTRACT FROM AUTHOR]

Reirradiation (reRT) for locoregional recurrences poses unique challenges and risks; re-treatment using proton beam radiotherapy (PBT) could prove advantageous. Assessing clinical outcomes and toxicity profiles, this systematic review comprehensively evaluated available evidence regarding PBT reRT. Fourteen original investigations across central nervous system (CNS) ( n = 6), head/neck (H&N) ( n = 4), lung ( n = 2), and gastrointestinal ( n = 2) malignancies were analyzed. PBT for recurrent uveal melanoma achieved 5-year eye retention of 55%; for chordomas, reRT afforded a 2-year local control and overall survival (OS) of 85% and 80%, respectively. Multiple PBT reRT studies for adult gliomas illustrate no grade ≥3 toxicities. Two pediatric CNS tumor studies demonstrated the safety and efficacy of reRT, with one total grade 3 toxicity and achievement of longer-term OS. PBT for H&N malignancies shows appropriate local/locoregional control and favorable toxicity profiles versus historical photon-based methods, including low (9–10%) rates of feeding tube placement. PBT for recurrent lung cancer can achieve favorable survival with expected toxicities/complications of reRT, especially with concurrent chemotherapy and centrally located recurrences. Lastly, PBT reRT in gastrointestinal malignancies induced very few high-grade complications. Hence, based on the limited existing data, PBT is a notably safe reRT modality for effective salvage of recurrent disease. Institutional experiences must continue to be reported: dosimetric correlations, late toxicities, and advanced PBT techniques. [ABSTRACT FROM AUTHOR]

Although radiotherapy is a highly effective treatment for abdominal or pelvic cancer patients, it can increase the incidence of severe gastrointestinal (GI) toxicity. As an intestinal growth factor, glucagon-like peptide 2 (GLP-2) has been shown to improve the preclinical models of both short bowel syndrome and inflammatory bowel disease by stimulating intestinal growth. Teduglutide ([Gly 2 ]GLP-2), a recombinant human GLP-2 variant, has a prolonged half-life and stability as compared to the native GLP-2 peptide, but still requires daily application in the clinic. Here, we designed and prepared a new degradation-resistant GLP-2 analogue dimer, designated GLP-2②, with biotechnological techniques. The purity of GLP-2②reached 97% after ammonium sulphate precipitation and anion exchange chromatography purification, and the purification process was simple and cost-effective. We next confirmed that the GLP-2② exhibited enhanced activities compared with [Gly 2 ]GLP-2, the long-acting, degradation-resistant analogue. Notably, GLP-2② offers a pharmacokinetic and therapeutic advantage in the treatment of radiation-induced intestinal injury over [Gly 2 ]GLP-2. We further demonstrated that GLP-2② rapidly activates divergent intracellular signaling pathways involved in cell survival and apoptosis. Taken together, our data revealed a potential novel and safe peptide drug for limiting the adverse effect of radiotherapy on the gastrointestinal system. [ABSTRACT FROM AUTHOR]

Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) is one of the most effective cancer treatments owing to its ability to selectively kill cancer cells, without affecting normal cells. However, it has been reported that several gastric cancer cells show resistance to TRAIL because of a scarcity of death receptor 5 (DR5) expressed on the cell surface. In this study, we show that cyclopamine sensitizes gastric cancer cells to TRAIL-induced apoptosis by elevating the expression of DR5. Interestingly, survivin hampers the existence of DR5 protein under normal conditions and cyclopamine decreases the expression of survivin, thus acting as a TRAIL sensitizer. Mechanistically, cyclopamine induces endoplasmic reticulum (ER) stress via reactive oxygen species (ROS) and CHOP, the last protein of the ER stress pathway and it regulates the proteasome degradation of survivin. Taken together, our results indicate that cyclopamine can be used for combination therapy in TRAIL-resistant gastric cancer cells. [ABSTRACT FROM AUTHOR]

Introduction Certain surgical interventions, especially those involving upper GI tract remain challenging, due to high morbidity and mortality rates. The study of frailty in the surgical population has allowed the identification of those patients with a higher risk of poor postoperative outcomes. There remains a lack of evidence regarding the possibility of improving these results through a preoperative holistic management of the patients. The aim of this study is to evaluate whether preoperative treatment, in carefully selected patients, can improve the outcome following surgery. Patients and methods Between March 2015 and February 2016 patients affected by malignant tumors of the upper GI tract were enrolled at our Institution for major oncologic surgery. Amongst them, frail patients (Group 1) were identified using a validated scoring system and underwent a multidisciplinary preoperative management plan, composed of nutritional intervention, physical/respiratory enhancement and optimization of ongoing therapy. Short-term postoperative outcomes were then compared with a control group (Group 2) of patients with comparable frailty features and surgical indications, who had undergone surgery in the period from March 2013 to February 2014. Results 30-days and 3-months mortality, overall and severe complication rates were found to be significantly lower (p < 0.05) in Group 1 (41 patients) when compared with Group 2 (35 patents). No significant differences were recorded for the following outcomes: length of stay, referral to post-discharge institutionalisation and hospital re-admission. Discussion This study confirms advantages provided by preoperative treatment in frail patients, suggesting a new pathway for the improvement of postoperative outcomes. [ABSTRACT FROM AUTHOR]

A natural ursolic compound, 2α,3β-dihydroxy-urs-12-en-28-oic acid (corosolic acid, CRA) was isolated from the root of Actinidia valvata Dunn. ( A. valvata Radix). Since a large number of triterpenoid compound has marked anticancer effects toward various types of cancer cell lines in vitro , this study was carried out to investigate the anticancer effect of CRA in human gastric cancer cell line BGC823 cells and the underlying apoptotic mechanism of CRA was examined in BGC823 cell lines. The results showed that CRA significantly suppressed the viability of BGC823 cells in a concentration- and time-dependent manner. CRA also significantly increased the sub G1 population by cell cycle analysis in a concentration dependent manner. Exposure to CRA decreased p65, bcl-2, Fas, smac mRNA and protein expression, and increased IκBα, bax, survivin mRNA and protein expression. Results of immunofluorescence staining and EMSA further indicated CRA induced apoptosis by inhibiting nuclear translocation of nuclear factor NF-κB subunit p65. Consistently overall, our findings suggest that CRA induces apoptosis via inhibition of NF-κB (p65) expression level and activation of IκBα in BGC cells as a potent anticancer candidate for gastric cancer treatment. [ABSTRACT FROM AUTHOR]

Purpose: To perform a prospective trial testing the feasibility and utility of acquiring activity data as a measure of health status during concurrent chemoradiotherapy.Methods and Materials: Ambulatory patients who were planned for treatment with concurrent chemoradiotherapy with curative intent for cancers of the head and neck, lung, or gastrointestinal tract were provided with activity monitors before treatment initiation. Patients were asked to wear the devices continuously throughout the radiation therapy course. Step count data were downloaded weekly during radiation therapy and 2 and 4 weeks after radiation therapy completion. The primary objective was to demonstrate feasibility, defined as collection of step counts for 80% of the days during study subjects' radiation therapy courses. Secondary objectives included establishing step count as a dynamic predictor of unplanned hospitalization risk.Results: Thirty-eight enrolled patients were treated with concurrent chemoradiotherapy. Primary diagnoses included head and neck cancer (n=11), lung cancer (n=13), and a variety of gastrointestinal cancers (n=14). Step data were collected for 1524 of 1613 days (94%) during patients' radiation therapy courses. Fourteen patients were hospitalized during radiation therapy or within 4 weeks of radiation therapy completion. Cox regression modeling demonstrated a significant association between recent step counts (3-day average) and hospitalization risk, with a 38% reduction in the risk of hospitalization for every 1000 steps taken each day (hazard ratio 0.62, 95% confidence interval 0.46-0.83, P=.002). Inferior quality of life scores and impaired performance status were not associated with increased hospitalization risk.Conclusion: Continuous activity monitoring during concurrent chemoradiotherapy is feasible and well-tolerated. Step counts may serve as powerful, objective, and dynamic indicators of hospitalization risk. [ABSTRACT FROM AUTHOR]

Purpose: To review and assess ongoing proton beam therapy (PBT) clinical trials and to identify major gaps.Methods and Materials: Active PBT clinical trials were identified from clinicaltrials.gov and the World Health Organization International Clinical Trials Platform Registry. Data on clinical trial disease site, age group, projected patient enrollment, expected start and end dates, study type, and funding source were extracted.Results: A total of 122 active PBT clinical trials were identified, with target enrollment of >42,000 patients worldwide. Ninety-six trials (79%), with a median planned sample size of 68, were classified as interventional studies. Observational studies accounted for 21% of trials but 71% (n=29,852) of planned patient enrollment. The most common PBT clinical trials focus on gastrointestinal tract tumors (21%, n=26), tumors of the central nervous system (15%, n=18), and prostate cancer (12%, n=15). Five active studies (lung, esophagus, head and neck, prostate, breast) will randomize patients between protons and photons, and 3 will randomize patients between protons and carbon ion therapy.Conclusions: The PBT clinical trial portfolio is expanding rapidly. Although the majority of ongoing studies are interventional, the majority of patients will be accrued to observational studies. Future efforts should focus on strategies to encourage optimal patient enrollment and retention, with an emphasis on randomized, controlled trials, which will require support from third-party payers. Results of ongoing PBT studies should be evaluated in terms of comparative effectiveness, as well as incremental effectiveness and value offered by PBT in comparison with conventional radiation modalities. [ABSTRACT FROM AUTHOR]

The best available surgical strategy in the treatment of resectable esophago-gastric junctional (EGJ) cancer is a controversial topic. In this review we evaluate the current literature and scientific evidence examining the surgical treatment of locally advanced EGJ cancer by comparing esophagectomy with gastrectomy, transhiatal with transthoracic esophagectomy, minimally invasive with open esophagectomy, and less extensive with more extensive lymphadenectomy. We also assess endoscopic procedures increasingly used for early EGJ cancer. The current evidence does not favor any of the techniques over the others in terms of oncological outcomes. Health-related quality of life may be better following gastrectomy compared to esophagectomy. Minimally invasive procedures might be less prone to surgical complications. Endoscopic techniques are safe and effective alternatives for early-stage EGJ cancer in the short term, but surgical treatment is the mainstay in fit patients due to the risk of lymph node metastasis. Any benefit of lymphadenectomy extending beyond local or regional nodes is uncertain. This review demonstrates the great need for well-designed clinical studies to improve the knowledge in how to optimize and standardize the surgical treatment of EGJ cancer. [ABSTRACT FROM AUTHOR]

Recurrent esophago-gastric junction adenocarcinoma is not a rare event and its correct management is still debated. Many approaches for the treatment of these patients exist, but only few studies compare the different techniques. Most of the studies are retrospectives series and describe the experiences of single institutions in the treatment of recurrent esophageal and esophago-gastric junction cancers. Nowadays surgery is still the main and only curative treatment. Other alternative palliative therapies could be endoscopic stent placement and balloon dilation, photodynamic therapy, thermal tumor ablation (laser photoablation and Argon plasma coagulation), radiation therapy and brachytherapy, and chemotherapy. The aim of this review is to investigate the different rates, patterns and timings of recurrence of this tumor, and to explain the various approaches used for the treatment of recurrent esophago-gastric junction cancer. [ABSTRACT FROM AUTHOR]

Objective The aim of this study was to evaluate the use of plasma and saliva uracil (U) to dihydrouracil (UH 2 ) metabolic ratio and DPYD genotyping, as a means to identify patients with dihydropyrimidine dehydrogenase (DPD) deficiency and fluoropyrimidine toxicity. Methods Paired plasma and saliva samples were obtained from 60 patients with gastrointestinal cancer, before fluoropyrimidine treatment. U and UH 2 concentrations were measured by LC–MS/MS. DPYD was genotyped for alleles * 7 , * 2A , * 13 and Y186C . Data on toxicity included grade 1 to 4 neutropenia, mucositis, diarrhea, nausea/vomiting and cutaneous rash. Results 35% of the patients had severe toxicity. There was no variant allele carrier for DPYD . The [UH 2 ]/[U] metabolic ratios were 0.09–26.73 in plasma and 0.08–24.0 in saliva, with higher correlation with toxicity grade in saliva compared to plasma (r s = − 0.515 vs r s = − 0.282). Median metabolic ratios were lower in patients with severe toxicity as compared to those with absence of toxicity (0.59 vs 2.83 saliva; 1.62 vs 6.75 plasma, P < 0.01). A cut-off of 1.16 for salivary ratio was set (AUC 0.842), with 86% sensitivity and 77% specificity for the identification of patients with severe toxicity. Similarly, a plasma cut-off of 4.0 (AUC 0.746), revealed a 71% sensitivity and 76% specificity. Conclusions DPYD genotyping for alleles 7 , * 2A , * 13 and Y186C was not helpful in the identification of patients with severe DPD deficiency in this series of patients. The [UH 2 ]/[U] metabolic ratios, however, proved to be a promising functional test to identify the majority of cases of severe DPD activity, with saliva performing better than plasma. [ABSTRACT FROM AUTHOR]

Intensity-modulated radiotherapy (IMRT) is increasingly used in order to minimize the gastrointestinal, genitourinary, and hematological toxicity in cervical and uterine cancers. However, the benefit of this high-precision approach is detracted by the margins applied to the clinical target volume (CTV) to generate the planning tumor volume (PTV), taking into account tumor and surrounding organs movements, deformations, and volume changes. Adequate PTV margins should be large enough to prevent geographical misses, but not excessive, which might end the benefit from IMRT. The objectives of this review were: (a) to present the evidence available for the determination of CTV-PTV margin for uterine cancers; (b) to highlight the impact of these margins in the context of adaptive radiotherapy; and (c) to discuss the role of the PTV concept in intracavitary brachytherapy. [ABSTRACT FROM AUTHOR]

Growing evidence suggests the beneficial effect of aspirin against some types of cancer, particularly of the gastrointestinal tract, and it has been provided for an effect both in cancer prevention as well as in survival improvement of cancer patients. Aspirin benefits increase with duration of treatment, especially after 10 years of treatment. The inhibition of platelet activation at sites of gastrointestinal mucosal lesions could be the primary mechanism of action of low-dose aspirin. Indeed, the formation of tumor cell-induced platelet aggregates may favor immune evasion, by releasing angiogenic and growth factors, and also by promoting cancer cell dissemination. Moreover, platelets may contribute to aberrant COX-2 expression in colon carcinoma cells, thereby contributing to downregulation of oncosuppressor genes and upregulation of oncogenes, such as cyclin B1. Platelet adhesion to cancer cells leads also to an increased expression of genes involved in the EMT, such as the EMT-inducing transcription factors ZEB1 and TWIST1 and the mesenchymal marker vimentin. The aspirin-mediated inactivation of platelets may restore antitumor reactivity by blocking the release of paracrine lipid and protein mediators that induce COX-2 expression in adjacent nucleated cells at sites of mucosal injury. Thus, recent findings suggest interesting perspectives on “old” aspirin and NSAID treatment and/or “new” specific drugs to target the “evil” interactions between platelets and cancer for chemoprevention. [ABSTRACT FROM AUTHOR]

Cisplatin ( cis -diamminedichloroplatinum, CDDP) is one of the most effective chemotherapeutic drugs that are used for treatment of patients with gastrointestinal cancer cells, but its continuous administration often evokes the development of chemoresistance. In this study, we investigated alterations in antioxidant molecules and functions using a newly established CDDP-resistant variant of gastric cancer MKN45 cells, and found that aldo-keto reductase 1B10 (AKR1B10) is significantly up-regulated with acquisition of the CDDP resistance. In the nonresistant MKN45 cells, the sensitivity to cytotoxic effect of CDDP was decreased and increased by overexpression and silencing of AKR1B10, respectively. In addition, the AKR1B10 overexpression markedly suppressed accumulation and cytotoxicity of 4-hydroxy-2-nonenal that is produced during lipid peroxidation by CDDP treatment, suggesting that the enzyme acts as a crucial factor for facilitation of the CDDP resistance through inhibiting induction of oxidative stress by the drug. Transient exposure to CDDP and induction of the CDDP resistance decreased expression of peroxisome proliferator-activated receptor-γ (PPARγ) in MKN45 and colon cancer LoVo cells. Additionally, overexpression of PPARγ in the cells elevated the sensitivity to the CDDP toxicity, which was further augmented by concomitant treatment with a PPARγ ligand rosiglitazone. Intriguingly, overexpression of AKR1B10 in the cells resulted in a decrease in PPARγ expression, which was recovered by addition of an AKR1B10 inhibitor oleanolic acid, inferring that PPARγ is a downstream target of AKR1B10-dependent mechanism underlying the CDDP resistance. Combined treatment with the AKR1B10 inhibitor and PPARγ ligand elevated the CDDP sensitivity, which was almost the same level as that in the parental cells. These results suggest that combined treatment with the AKR1B10 inhibitor and PPARγ ligand is an effective adjuvant therapy for overcoming CDDP resistance of gastrointestinal cancer cells. [ABSTRACT FROM AUTHOR]

Gastric cancer is the third greatest global cause of cancer-related deaths. Despite its high prevalence, only recently have comprehensive genomic surveys shed light on its molecular alterations. As surgery is the only curative treatment strategy and chemotherapy has shown limited efficacy, new treatments are urgently needed. Many molecular therapies for gastric cancer have entered clinical trials but–apart from Trastuzumab and Ramucirumab–all have failed. We analyze the current knowledge of the genetic ‘landscape’ of gastric cancers, elaborating on novel, preclinical approaches. We posit that this knowledge lays the basis for identifying bona fide molecular targets and developing solid therapeutic approaches, requiring accurate patient selection and taking advantage of preclinical models to assist clinical development of novel combination strategies. [ABSTRACT FROM AUTHOR]

An immobilized biocatalyst with 2′- N -deoxyribosyltransferase (NDT) activity, Lactobacillus animalis NDT ( La NDT), was developed from cell free extracts. La NDT was purified, characterized and then immobilized by ionic interaction. Different process parameters were optimized, resulting in an active derivative (2.6 U/g) able to obtain 1.75 mg/g of 5-fluorouracil-2′-deoxyriboside, an antimetabolite known as floxuridine, used in gastrointestinal cancer treatment. Furthermore, immobilized La NDT was satisfactorily used to obtain at short reaction times other halogenated pyrimidine and purine 2′-deoxynucleosides such as 6-chloropurine-2′-deoxyriboside (4.9 U/g), 6-bromopurine-2′-deoxyriboside (4.3 U/g), 6-chloro-2-fluoropurine-2′-deoxyriboside (5.4 U/g), 5-bromo-2′-deoxyuridine (2.8 U/g) and 5-chloro-2′-deoxyuridine (1.8 U/g) compounds of pharmaceutical interest in antiviral or antitumor treatments. Besides, increasing the biocatalyst amount 8 times per volume unit allowed obtaining a 5-fold improvement in floxuridine biotransformation. The developed biocatalyst proved to be effective for the biosynthesis of a wide spectrum of nucleoside analogues by employing an economical, simple and environmentally friendly methodology. [ABSTRACT FROM AUTHOR]

Epigenetic alterations, including aberrant DNA methylation, play an important role in human cancer development. Importantly, epigenetic alterations are reversible and can be targets for therapy or chemoprevention for various types of human cancers. A field for cancerization, or a field defect, is formed by the accumulation of genetic and/or epigenetic alterations in normal-appearing tissues and can correlate with risk of cancer development. Thus, a better understanding of epigenetic field cancerization may represent a useful translational opportunity for cancer risk assessment, including previous history and exposure to carcinogenic factors, and for cancer prevention. In this article, we summarize current knowledge regarding epigenetic field cancerization and its clinical implications in gastrointestinal cancers, including colorectal cancer, gastric cancer and esophageal cancer. [ABSTRACT FROM AUTHOR]

Mucinous ovarian cancer represents approximately 3% of epithelial ovarian cancers (EOC). Despite this seemingly low prevalence, it remains a diagnostic and therapeutic conundrum that has resulted in numerous attempts to adopt novel strategies in managing this disease. Anecdotally, there has been a prevailing notion that established gold standard systemic regimens should be substituted for those utilised in cancers such as gastrointestinal (GI) malignancies; tumours that share more biological similarities than other EOC subtypes. This review summarises the plethora of small studies which have adopted this philosophy and influenced the design of the multinational GOG142 study, which was ultimately terminated due to poor accrual. To date, there is a paucity of evidence to support delivering ‘GI style’ chemotherapy for mucinous ovarian cancer over and above carboplatin-paclitaxel doublet therapy. Hence there is an urge to develop studies focused on targeted therapeutic agents driven by refined mutational analysis and conducted within the context of harmonised international collaborations. [ABSTRACT FROM AUTHOR]

Background This meta-analysis examined the impact of preoperative corticosteroids on interleukin 6 (IL-6), C-reactive protein (CRP), and complications following surgery for gastrointestinal cancer. Methods A systematic review was performed using appropriate keywords. Random-effects meta-analysis was performed. Results 11 RCTs with 474 patients, were included. Corticosteroids were significantly associated with lower IL-6 on postoperative day 1 (mean difference −148 pg/mL, 95% CI −205 to −92, p < 0.001), 2 (−33 pg/mL, 95% CI −58 to −8, p = 0.01), and 3 (−31 pg/mL, 95% CI −52 to −11, p = 0.002), lower CRP on day 3 (−45 mg/L, 95% CI −68 to −21, p < 0.001), and 7 (−14 mg/L, 95% CI −27 to −1, p = 0.04), and fewer postoperative infective complications (OR 0.47, 95% CI 0.26–0.83, p = 0.01). Conclusion Corticosteroids were associated with reduction in the postoperative systemic inflammatory response and complications following surgery for gastrointestinal cancer. [ABSTRACT FROM AUTHOR]

Gastrointestinal malignancies are a major health care challenge due to the high incidence and overall poor outcome. A biomarker is a molecular characteristic of a tumor that may be utilized in the initial risk assessment and the subsequent management of the patient. This review focuses on the most pertinent prognostic and predictive biomarkers used in the clinical management of gastric, pancreas, and colon cancer. The available assays, limitations and clinical use for each biomarker are reviewed. The clinical trials evaluating novel biomarkers in GI cancers are discussed. [ABSTRACT FROM AUTHOR]

Myelodysplastic syndromes (MDS) are oligoclonal hematopoietic disorders characterized by peripheral cytopenias with anemias being the most prevalent feature. The majority of patients will depend on regular transfusions of packed red blood cells (PRBC) during the course of the disease. Particularly patients with MDS and low risk for transformation into acute myeloid leukemia and low risk of early death will receive PRBC transfusions on a regular basis, which puts them at high risk for transfusional iron overload. Transfusion dependence has been associated with negative impact on organ function and reduced life expectancy. Recently, several retrospective but also some prospective studies have indicated, that transfusion dependent patients with MDS might benefit from consequent iron chelation with regard to morbidity and mortality. However, low treatment adherence due to adverse events mainly gastrointestinal in nature is an important obstacle in achieving sufficient iron chelation in MDS patients. Here, we will summarize and discuss the existing data on Deferasirox in low risk MDS published so far and provide recommendations for optimal management of gastrointestinal adverse events during iron chelation aiming at improving treatment compliance and, hence, sufficiently removing excess iron from the patients. [ABSTRACT FROM AUTHOR]

Spindle cell neoplasms are rare mesenchymal tumors of the gastrointestinal tract. GIST (Gastrointestinal stromal tumor) and leiomyosarcoma share similar clinical presentations, gross and microscopic characteristics making distinction difficult in the absence of immunohistochemical (IHC) studies. A multidisciplinary approach is required for treatment planning and ensuring best outcomes. Surgery remains the mainstay of curative treatment for both tumors. Significant advances in targeted molecular therapies have occurred in the past decade in the treatment of GIST with improvement in morbidity and mortality. Similar newer discoveries for treatment of leiomyosarcoma have failed to show any significant survival benefits as yet. Early diagnosis and R0 surgical resection offers the best long term outcome for leiomyosarcoma. Here in we review and discuss the concepts of genetic alterations, newer markers, possible cancer pathways and advances in treatment strategies for these sarcomas. [ABSTRACT FROM AUTHOR]

Background: In Japan, S-1 plus cisplatin has been used as first-line therapy for advanced gastric cancer (AGC). Patients with no response to first-line treatment with S-1 often receive a taxane-alone or irinotecan-alone as second-line treatment. However, second-line treatment with S-1 plus irinotecan is widely used in patients with AGC resistant to first-line S-1-based chemotherapy. The goal of this trial was to determine whether the consecutive use of S-1 plus irinotecan improves survival when compared with irinotecan-alone as second-line treatment for AGC. Patients and methods: Patients who had disease progression during first-line S-1-based chemotherapy were randomly assigned to receive S-1 plus irinotecan or irinotecan-alone. The S-1 plus irinotecan group received oral S-1 (40-60 mg/m²) on days 1-14 and intravenous irinotecan (150 mg/m²) on day 1 of a 21-day cycle. The irinotecan-alone group received the same dose of irinotecan intravenously on day 1 of a 14-day cycle. The primary end point was overall survival (OS). Results: From February 2008 to May 2011, a total of 304 patients were enrolled. The median OS was 8.8 months in the S-1 plus irinotecan group and 9.5 months in the irinotecan-alone group. This difference was not significant (hazard ratio for death, 0.99; 95% confidence interval 0.78-1.25; P = 0.92). Grade 3 or higher toxicities were more common in the S-1 plus irinotecan group than in the irinotecan-alone group. Conclusion: The consecutive use of S-1 plus irinotecan is not recommended as second-line treatment in patients who are refractory to S-1-based first-line chemotherapy. [ABSTRACT FROM AUTHOR]

Drug resistance remains one of the major reasons of therapy failure in gastric cancer patients. Although the mechanisms of anticancer drug resistance have been broadly investigated, they have not been completely understood. Accumulating reports have recently highlighted the involvement of endogenous non-coding RNAs, known as microRNAs, in the evolution of cancer cell drug resistance. MiRNAs have been characterized as major regulators of crucial genes implicated in the chemoresistance phenotype of gastric cancer cells. MiRNA-based therapy in the future may provide a new strategy to overcome drug resistance. This review summarizes the current knowledge on the role of miRNAs in regulating drug resistance in gastric cancer and their potential to develop targeted therapies and personalized treatment for managing drug resistant gastric cancers. [ABSTRACT FROM AUTHOR]

MicroRNAs have emerged as fundamental regulators in gene expression through silencing gene expression at the post-transcriptional and translational levels. In this study, miR-143 expression and biological functions in AGS/MNK28 cell lines was investigated. Results indicated that the expression of miR-143 was significantly down-regulated in cancer tissues and in gastric cancer (GC) cell lines. Target prediction algorithms (Target Scan and miRanda) showed that GABARAPL1 was a potential target gene of miR-143. GABARAPL1, also regarded as autophagy-related protein 8 (Atg8) is a ubiquitin-like protein required for the formation of autophagosomal membranes. Then, several different assays were conducted to detect autophagy in AGS/MNK28 after transfected with miR-143. In the present study, miR-143 was firstly identified as a autophagy inhibitor in GC cells via targeting GABARAPL1. Quercetin is one of the most prominent dietary antioxidants in human diet and lately it is grabbing some serious attention as a potentially powerful cancer fighter. However, the effect of Quercetin was unexpected decreased in GC cells on account of the appearance of Quercetin-induced autophagy. Therefore, applicable autophagy inhibitors might enhance the chemosensitivity of Quercetin. Furthermore, the therapeutic response of Quercetin in the combination of miR-143 was evaluated by MTT, Hochest and western blot, results suggesting that the chemosensitivity of Quercetin was enhanced when in combination with miR-143 in AGS/MNK28 cells. In conclusion, we determined miR-143 as a potent inhibitor of autophagy via targeting GABARAPL1 and miR-143 could improve the efficacy of Quercetin though autophagy inhibition in GC cell lines, thus representing a novel potential therapeutic target for gastric cancer. [ABSTRACT FROM AUTHOR]

The role of immunologic factors in the development of gastrointestinal (GI) neoplasia, made evident from the high degree of association of chronic intestinal or gastric inflammation with the development of cancer, has attracted much attention because it promises new ways of treating disease. Here we develop the idea that immunologic factors influence the appearance of GI cancer on two levels: (i) a basic and initiating level during which the epithelial cell is induced to undergo pre-cancerous molecular changes that render it prone to further cancer progression; and (ii) a secondary level that builds on this vulnerability and drives the cell into frank malignancy. This secondary level is uniquely dependent on a single epithelial cell signaling pathway centered on STAT3, and it is this pathway upon which stimulation of mucosal cytokine production and microbiota effects converge. [ABSTRACT FROM AUTHOR]

Advanced gastric cancer ranks second as the global leading cause of cancer-related death and improvements in systemic chemotherapy have reached a plateau. Advanced molecular sequencing techniques help identifying patients more likely to respond to targeted agents; nevertheless we are still far from major breakthroughs. Although antiangiogenic drugs have produced notable advances, redundant pathways or mechanisms of resistance may limit their efficacy. Novel compounds have been recently developed to specifically target VEGF receptors, PlGF, FGF, MET, and angiopoietin. Ramucirumab, a monoclonal antibody specifically directed against the VEGFR-2, has emerged as a novel therapeutic opportunity. REGARD and RAINBOW were the first phase III studies to report the value of this strategy in gastric cancer patients, and other ongoing trials are testing novel antiangiogenic compounds. The aim of our review is to present the state-of-the-art of novel antiangiogenic compounds in advanced gastric cancer, underlying the biology, their mechanism of action, and their clinical results. [ABSTRACT FROM AUTHOR]

Aberrant methylation of the transcription factor AP-2 epsilon (TFAP2E) has been attributed to 5-fluorouridine (5-FU) sensitivity. 5-Aza-2′-deoxycytidine (DAC), an epigenetic drug that inhibits DNA methylation, is able to cause reactive expression of TFAP2E by demethylating activity. This property might be useful in enhancing the sensitivity of cancer cells to 5-FU. However, the effect of DAC is transient because of its instability. Here, we report the use of intelligent gelatinases-stimuli nanoparticles (NPs) to coencapsulate and deliver DAC and 5-FU to gastric cancer (GC) cells. The results showed that NPs encapsulating DAC, 5-FU, or both could be effectively internalized by GC cells. Furthermore, we found that the NPs enhanced the stability of DAC, resulting in improved re-expression of TFAP2E. Thus, the incorporation of DAC into NPs significantly enhanced the sensitivity of GC cells to 5-FU by inhibiting cell growth rate and inducing cell apoptosis. In conclusion, the results of this study clearly demonstrated that the gelatinases-stimuli NPs are an efficient means to simultaneously deliver epigenetic and chemotherapeutic drugs that may effectively inhibit cancer cell proliferation. [ABSTRACT FROM AUTHOR]

Development of drug resistance to standard chemotherapy is a common phenomenon that leads to poor prognosis in patients. Thus, novel agents that can attenuate chemoresistance are urgently needed. Therefore, we analyzed whether isorhamnetin (IH), a 3′-O-methylated metabolite of quercetin, can enhance the potential efficacy of capecitabine in gastric cancer. The potential effect of IH on viability was analyzed by MTT assay, apoptosis by flow cytometric analysis, and NF-κB activation by DNA binding as well as Western blot assays. The in vivo effect of IH was also examined on the growth of subcutaneously implanted tumors in nude mice. IH inhibited the viability, potentiated the apoptotic effects of capecitabine, abrogated NF-κB activation, and suppressed the expression of various NF-κB regulated gene products in tumor cells. In a gastric cancer xenograft model, administration of IH alone (1 mg/kg body weight, i.p.) significantly suppressed the tumor growth alone as well as in combination with capecitabine. IH further reduced NF-κB activation and the expression of various proliferative and oncogenic biomarkers in tumor tissues. Overall, our results demonstrate that IH can significantly enhance the anti-tumor effects of capecitabine through the negative regulation of NF-κB regulated oncogenic genes. [ABSTRACT FROM AUTHOR]

A large body of evidence from epidemiological and preclinical studies have shown that nonsteroideal anti-inflammatory drugs (NSAIDs) have a chemopreventive effect on gastrointestinal cancers and, more specifically, in colorectal cancer. This review highlights recent advances in our understanding of the role of NSAIDs in colorectal cancer prevention and adjuvant treatment. Moreover, we have focused on randomized controlled studies assessing their efficacy to prevent adenoma recurrence and reduction of colorectal cancer incidence and mortality but also their gastrointestinal and cardiovascular side effects. Among NSAIDs, almost the unique agent with potential use as chemopreventive agent is aspirin at low dose since it has both no cardiovascular and low gastrointestinal risk. Furthermore, since aspirin has shown efficacy in secondary prevention of cardiovascular diseases, this drug carries a particular attractive intervention for selected populations. Nevertheless, before it can be prescribed, further studies are necessary to define some important questions, specially the most appropriate dose and time of aspirin use and the population who may benefit from it. [ABSTRACT FROM AUTHOR]

Background The purpose of this study was to determine the overall survival (OS) of patients with resectable gastric cancer treated with preoperative chemoradiation therapy and gastrectomy. Study Design The medical records of patients with gastric adenocarcinoma presenting to our institution (January 1995 to August 2012) were reviewed to identify patients who underwent diagnostic laparoscopy, preoperative chemoradiation, and gastrectomy. Associations between various clinicopathologic factors and OS were examined with Cox proportional hazards models. Results Of 192 patients who met inclusion criteria, 103 (54%) required total gastrectomy. One hundred sixty-eight patients (88%) had an extended lymph node dissection, 26 (14%) had resection of adjacent organs, and 178 (93%) had an R0 resection. Median follow-up time for surviving patients was 4.2 years. Median OS for all patients was 5.8 years, and 5-year OS rate was 56%. Multivariable Cox regression model results identified variables associated with diminished OS including age ≥ 65 years (hazard ratio [HR] 1.62; 95% CI 1.05 to 2.51), male sex (HR 1.76; 95% CI 1.13 to 2.74), adjacent organ resection (HR 1.97; 95% CI 1.16 to 3.35), R1 status (HR 2.29; 95% CI 1.17 to 4.48), pathologic N1 stage (HR 1.92; 95% CI 1.24 to 2.98), N2 stage (HR 2.58; 95% CI 1.01 to 6.58), and N3 stage (HR 6.54; 95% CI 2.69 to 15.93). Five-year OS rates for patients with pathologic N0, N1, N2, and N3 disease were 67%, 42%, 43%, and 0%, respectively. Conclusions Patients with gastric cancer who undergo diagnostic laparoscopy, preoperative chemoradiation, and gastrectomy have a high frequency of obtaining an R0 resection and excellent OS rates. Nodal status after surgery remains an important determinant of OS. [ABSTRACT FROM AUTHOR]