Advanced Gastrointestinal Carcinoma Research Articles

The genomic landscape of advanced gastrointestinal (GI) neuroendocrine tumors (NET) and carcinomas (NEC).

656 Background: The impact of specific genomic alterations in advanced GI neuroendocrine malignancies on prognosis and treatment decisions has not been fully characterized. In this study, we seek to evaluate next-generation sequencing (NGS) panels and corresponding clinical outcomes in patients with metastatic GI NET/NEC. Methods: Patients with GI-NET/NEC were identified from a database of NGS reports performed at the Cleveland Clinic, and clinical variables were extracted by chart review through an IRB-approved protocol. We provide an analysis of this cohort. Results: Of a total n=45 patients, 53% were male. Median age at diagnosis was 60 (range: 35-90 years) and 82% were non-Hispanic white, while 9% were black. There were n=25 GI-NETs, mostly intermediate or high grade (11 G3, 7 G2), and n=20 GI-NECs. There was a balanced distribution of primary sites, including colorectal (27%), pancreas (24%), small intestine (18%), unknown primary (24%) and a single case of biliary primary. High grade GI-NETs and GI-NECs were over-represented in the colorectal primary group vs other sites. (n=10 of 12; p=0.021). The majority of patients (73%) had at least one somatic variant, including 12 patients (27%) with one or more mutations deemed actionable, but only one patient (with MSH2 mutation) has received a mutation-matched drug (pembrolizumab). Some recurrent alterations appeared to co-segregate with aggressive histology (NEC vs NET), including 12 of 13 TP53 mutations (p<0.05 by Fisher Exact Test), 7 of 8 RB1 (p<0.05), and 5 of 6 APC (p=0.074). The most common mutations per person based on primary site is shown. Microsatellite instability high was rare (n=1) and median tumor mutational burden (TMB) was 3/mb, with TMB lower in NETs vs NECs. A number of patients (35%) underwent germline testing, with 6 of 16 having a pathogenic germline variant. Conclusions: As 42% of the 12 patients with actionable mutations were alive at time of analysis, it is possible that additional patients could be treated with mutation-matched therapies. More input will be needed from providers as to the role played by alternative effective treatments and barriers such as insurance coverage and prior authorization to implementing mutation-matched therapies. Given the overall low TMB of GI-NETs, with several tumors having zero or 1 reported mutation on targeted NGS, whole genome sequencing may prove useful. Finally, certain mutations such as RB1 and TP53 were associated with more aggressive histology (i.e. NEC). Lastly, only 9% of our cohort with NGS were black, a significant under-representation based on epidemiological data, which raises concerns about disparate accessibility and barriers to NGS testing. Further studies are needed to address any possible racial disparity.[Table: see text]

392P Updated data of biodistribution and activity of oncolytic virus TG6002 after intravenous administration in patients with advanced gastrointestinal carcinomas

In a report on 15 pts included in TG6002.02 dose-escalation trial (ESMO 2021, Abstract #3550), we showed that TG6002, an oncolytic vaccinia virus deleted in 2 genes to selectively replicate in tumor cells and encoding FCU1, an enzyme converting 5-FC into 5-FU, was biodistributed and replicated in tumor tissue after IV administration and expressed a functional payload. Herein, we report the data with 15 additional pts treated with either higher doses of TG6002 or a more intensive schedule of administration.

O12-1 Ramucirumab-containing chemotherapy for gastrointestinal neuroendocrine carcinoma: RAM-NEC study (WJOG13420G)

Second-line chemotherapy (CTx) for advanced gastrointestinal neuroendocrine carcinoma (GI-NEC) after platinum-based CTx is adopted according to the guidelines of GI adenocarcinoma or small cell lung cancer in daily practice. Recently, some reports suggested that vascular endothelial growth factor receptor-2 highly expressed in tumor vessels of GI-NEC. In this study, we evaluated the efficacy of ramucirumab (RAM)-containing CTx.

The Roles of Non-Coding RNAs in Radiotherapy of Gastrointestinal Carcinoma.

Radiotherapy (RT), or radiation therapy, has been widely used in clinical practice for the treatment of local advanced gastrointestinal carcinoma. RT causes DNA double-strand breaks leading to cell cytotoxicity and indirectly damages tumor cells by activating downstream genes. Non-coding RNA (including microRNAs, long non-coding RNAs (ncRNAs), and circular RNAs) is a type of RNA that does not encode a protein. As the field of ncRNAs increasingly expands, new complex roles have gradually emerged for ncRNAs in RT. It has been shown that ncRNAs can act as radiosensitivity regulators in gastrointestinal carcinoma by affecting DNA damage repair, cell cycle arrest, irradiation-induced apoptosis, cell autophagy, stemness, EMT, and cell pyroptosis. Here, we review the complex roles of ncRNAs in RT and gastrointestinal carcinoma. We also discuss the potential clinical significance and predictive value of ncRNAs in response to RT for guiding the individualized treatment of patients. This review can serve as a guide for the application of ncRNAs as radiosensitivity enhancers, radioresistance inducers, and predictors of response in RT of gastrointestinal carcinoma.

Multicenter retrospective study of ramucirumab-containing chemotherapy for gastrointestinal neuroendocrine carcinoma patients previously treated with platinum-based chemotherapy: RAM-NEC study (WJOG13420G).

511 Background: Platinum-based systemic chemotherapy (CTx) is recommended for poorly differentiated advanced gastrointestinal neuroendocrine carcinoma (GI-NEC). As second-line CTx various regimens are adopted according to the guidelines of GI adenocarcinoma or small cell lung cancer in daily practice. Recently, some clinical and preclinical reports suggest that vascular endothelial growth factor (VEGF) inhibitors are effective against NEC. In this study, we evaluated the efficacy of ramucirumab (RAM, anti-VEGF receptor 2 antibody)-containing CTx. Methods: We retrospectively evaluated gastric (G-) or colorectal (C-) NEC patients previously treated with first-line platinum-based CTx followed by second-line CTx between March 2015 and June 2020 (G-NEC) or between May 2016 and June 2020 (C-NEC). The main inclusion criteria were ECOG performance status (PS) of 0–2, pathologically diagnosed as G or C- NEC or mixed adenoneuroendocrine carcinoma. We compared the efficacy of RAM-containing CTx as second- or later-line treatment (Group A) with that of CTx without RAM as second-line treatment (Group B). A Cox proportional hazard model and inverse probability weighting of propensity scores were used to adjust the background factors between the two groups. Results: From 25 facilities, 139 patients were included in this study. Group A and B contained 50 (G/C, 43/7 patients) and 89 (G/C, 58/31 patients) patients, respectively. Patient characteristics were as follows (Group A/Group B): median age (range), 70 (28–83)/68 (39–86); ECOG PS 1–2, 66/69%, more than two prior regimens, 46/0%; response to previous platinum-based CTx, 46/38%. The regimen in combination with RAM in Group A was paclitaxel/nab-paclitaxel/FOLFIRI (62/26/12%). Second-line CTx in Group B were commonly amrubicin (58%) and irinotecan (11%). The efficacy (Group A/Group B) after a median follow-up time of 7.5/5.5 months were as follows: median overall survival (mOS), 8.6/5.8 months (HR, 0.68; 95% CI, 0.45–1.01; p = 0.058); median progression-free survival, 4.3/1.9 months (HR, 0.57; 95% CI, 0.39–0.84; p = 0.004); objective response rate, 50/8% ( p < 0.0001); disease control rate, 70/24% ( p < 0.0001); mOS in G-NEC, 8.6/5.3 months (HR, 0.62; 95% CI, 0.39–0.99; p = 0.047); and mOS in C-NEC, 5.4/6.8 months (HR, 0.66; 95% CI, 0.26–1.66; p = 0.378). The most common grade 3 or higher treatment-related adverse event that occurred in more than 5% of patients in Group A was neutropenia (32%). Conclusions: This study suggests that RAM-containing CTx as second- or later-line treatment is effective for GI-NEC patients, especially for G-NEC. Central pathological review and biomarker analyses using pretreated tissue specimens are ongoing. We will present updated data in the congress. Clinical trial information: UMIN000043200.

486P Bioavailability and activity of oncolytic virus TG6002 after intravenous administration in patients with advanced gastrointestinal carcinomas

Armed oncolytic viruses (OV) are a promising modality for the treatment of solid tumors. OVs exert their antitumoral activity through a selective replication in tumor cells and expression of therapeutic molecules. The use of OV in the clinic is limited by the intra-tumoral route. TG6002 is an OV of the Vaccinia Copenhagen strain, with two deletions in key viral genes to enhance replication selectivity in tumor cells, and expressing FCU1, an enzyme converting 5-FC into 5-FU. As part of a dose-escalation phase I trial, we showed that TG6002 was distributed and delivered its payload in tumor after IV administration in patients with advanced GI carcinomas.

Abstract LB179: Oncolytic virus TG6002 locates to tumors after intravenous infusion and induces tumor-specific expression of a functional pro-drug activating enzyme in patients with advanced gastrointestinal carcinomas

Abstract Objective: TG6002 is a vaccinia virus deleted for Thymidine Kinase/Ribonucleotide Reductase and encoding the FCU1 enzyme that converts 5-Fluorocytosine (5-FC) to 5-Fluorouracil (5-FU). In a dose-escalation phase I study combining intravenous TG6002 and oral 5-FC in patients with advanced gastrointestinal carcinomas, exploratory analyses were performed to document TG6002 pharmacokinetic (PK) and biodistribution, and FCU1 function. Methodology: A total of 10 patients, median age 60 years (range 50-69), received TG6002 infusions on days 1, 8 and 15 at the dose of 3x108 pfu (n=3) (low dose, LD) or 1x109 pfu (high dose, HD) (n=7) combined with 5-FC (4 times 50 mg/kg/day) on days 5 to 7, 12 to 14, and 19 to 28 for colorectal (n=6), esophagus (n=1), gastric (n=1), pancreatic (n=1) and ampulla of Vater (n=1) carcinomas. Blood was sampled 30 min, 3h and 24h after TG6002 infusion on day 1 and 15 for plasma TG6002 PK and one hour after intake of 5-FC at screening (single dose of 50 mg/kg) and on days 5, 7, 14 and 28 for serum 5-FC and 5-FU measurements. A metastasis biopsy was performed on day 5 along with synchronous blood sampling. Virus presence was assessed by qPCR and plaque assay, and 5-FC and 5-FU quantified using HPLC-MS. Neutralizing antibodies (NAb) titers were assessed using a plaque inhibition assay at baseline, days 28 and 43. Results: TG6002 was detected by qPCR in plasma and was rapidly cleared with no patients showing trace of the virus beyond 3 hours after administration. On day 5, despite very scarce availability of biomaterial, the virus was detected in tumoral tissue in 1/3 and 2/7 patients of the LD and HD cohorts, respectively. 5-FC to 5-FU conversion was detected in tumor of all patients and the highest tumor concentrations of 5-FU (65 and 227 pg/mg of tissue, respectively) were found in 2 of the 3 patients in which virus was detected in the tumor. The other patients had tumor 5-FU concentrations ranging from 0.8 to 8.7 pg/mg. Those patients with highest tumor 5-FU levels had the highest level of serum 5-FU on day 5 (352 and 417 ng/mL, respectively). All other patients had levels of 5-FU ranging from 2 to 42 ng/mL, reflecting FCU1 activity. No 5-FU was detected after the intake of 5-FC during the screening period, excluding endogenous 5-FC to 5-FU conversion. Overall, blood 5-FU concentrations were 89±144, 50±96, 7±9 and 1±0.6 ng/ml on days 5, 7, 14 and 28, respectively, with no apparent differences between LD and HD cohorts. NAbs were developed by all patients on day 28 and could explain the decrease in blood 5-FU over the study course. In conclusion, despite the sensitivity challenges associated with direct detection of viral particles in patient tumor tissue, our data suggest that TG6002 locates to tumors after intravenous administration, remains active and effectively express an active recombinant payload selectively in tumor tissue. The study is continuing with escalating doses of virus. Citation Format: Kaidre Bendjama, Philippe Cassier, Victor Moreno, Bernard Doger, Emiliano Calvo, Maria de Miguel, Christiane Jungels, Philippe Erbs, Damien Carpentier, Alain Sadoun. Oncolytic virus TG6002 locates to tumors after intravenous infusion and induces tumor-specific expression of a functional pro-drug activating enzyme in patients with advanced gastrointestinal carcinomas [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr LB179.

Abstract 3162: Early change in peripheral blood CD4+T cells associated with the clinical outcome in gastrointestinal cancer patients receiving immune checkpoint inhibitors

Abstract Purpose: Predictive biomarkers for immune checkpoint inhibitors (ICIs) are urgently needed in advanced gastrointestinal (GI) carcinoma. Methods: Peripheral blood lymphocyte, lymphocyte subset and early dynamic changes of them were retrospectively analyzed in patients with GI cancer treated with ICIs. Cox regression and Kaplan-Meier analyses were conducted to analyze survival. Results: Eighty patients were enrolled. According to whether tumor progression occurred by 6 months after the initial ICI, patients were divided into two cohorts, 6m-progressive disease (PD) (N=40) and 6m-non-PD (nPD) (N=40).BaselineCD4+/CD8+ T cell (CD4/CD8) ratio was higher in the 6m-nPD cohort than in the 6m-PD cohort. Lymphocyte subsets were obtained both at baseline and before the second dose of ICIs in 61 patients. In total, 54.1% (33/61) of patients experienced tumor progression within 6 months of the initial ICI treatment, and these patients showed significant declines in CD4+ T cell counts (CD4-C1-decline) (p=0.0002) and the CD8+ T cell counts (CD8-C1-decline) (p=0.045) after the first dose of ICIs. In multivariate analyses, CD4-C1-decline (HR=12.66; 95% CI: 2.17-73.91; p=0.005) was an independent prognostic factor for OS. Furthermore, Stratified analyses indicated that CD4-C1-decline was a poor prognostic factor for tumor progression in patients with a deficient mismatch repair (dMMR)/microsatellite instability-high (MSI-H). Conclusion: Early change in CD4+ T cell counts in peripheral blood samples may help as prognostic biomarkers for GI cancer patients treated with ICIs. Further prospective studies are needed to validate this conclusion. Citation Format: Zhi-Hao Lu, Chang Liu, Yan-ni Wang, Shuang Li, Xi Jiao, Jian-ling Zou, Zheng-hang Wang, Chang-song Qi, Xiao-tian Zhang, Jian Li, Lin Shen. Early change in peripheral blood CD4+T cells associated with the clinical outcome in gastrointestinal cancer patients receiving immune checkpoint inhibitors [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3162.

Diagnostic, clinicopathologic, therapeutic and prognostic value of Plasma Heat Shock Protein 90 levels in patients with advanced Gastrointestinal Carcinoma.

Purpose: Heat shock protein 90 (HSP90) is a critical molecular chaperone for protein folding, intracellular disposition and regulation of tumor biological behavior in the extracellular space. HSP90 has received much attention due to its specific effect in gastrointestinal cancer. This clinical study sought to determine whether HSP90 in plasma may serve as a biomarker in patients with advanced gastrointestinal carcinoma.Methods: Using human plasma samples of advanced gastrointestinal carcinoma, we investigated the specific value of HSP90 in gastrointestinal cancer from a clinical perspective.Results: In summary, plasma levels of HSP90 were shown to be higher in patients with gastric cancer (GC) or colorectal cancer (CRC) than in controls with benign gastrointestinal diseases. In both GC and CRC patients, HSP90 was significantly associated with live metastasis. Higher HSP90 levels were more frequent in CRC patients with hazardous or harmful alcohol consumption habits. Patients with RAS mutations had higher HSP90 levels in CRC. Compared with Carcinoembryonic Antigen (CEA) and Carbohydrate Antigen 19-9 (CA19-9), HSP90 benefited patients by enhancing diagnostic sensitivity and the Youden index. The levels of HSP90 were inversely associated with short-term efficacy in GC patients who had received fluorouracil/platinum-based advanced first-line treatment. When first-line therapy failed, plasma HSP90 levels in patients with GC were significantly increased. In terms of progression-free survival (PFS), patients with GC or CRC who had low levels of HSP90 were not significantly different from those with high levels of HSP90. Univariate and multivariate analyses demonstrated that HSP90 was not an independent prognostic predictor for GC and CRC patients with PFS. However, RAS mutation was an independent prognostic factor for poor PFS in CRC patients.Conclusions: Plasma HSP90 levels have potential diagnostic value in advanced gastrointestinal carcinoma and therapeutic predictive value in GC.

Advanced gastrointestinal carcinoma with massive ascites and hydrothorax during pregnancy

Rationale:Gastrointestinal carcinoma is rare during pregnancy. It is usually diagnosed at an advanced stage because special gastrointestinal symptoms are generally overlooked during pregnancy, and there are many limitations and contraindications for using diagnostic tools during pregnancy.Patient concerns:We present a case of a 29-year-old patient with 27 weeks and 5 days of gestation due to massive ascites and hydrothorax.Diagnoses:The patient was diagnosed with an advanced gastrointestinal cancer. Pathological report showed poorly differentiated tumor with the signet ring cell component.Interventions:Caesarean section was performed. At the same time, an abdominal exploration showed that the omentum was like biscuits . There were extensive and firm intestinal adhesions, and many tumor lesions were found on the surface of greater curvature of stomach, spleen, intestine, peritoneum, ascending colon and descending colon.Outcomes:Gastrointestinal surgeon was invited during operation, and palliative gastrectomy was not performed because of extensive metastases. The patient died 30 days after caesarean section.Lessons:This study present a case with advanced gastrointestinal cancer during pregnancy. We suggest that endoscopic exam is recommended if the patient is highly suspicious.

466 - Phase I study of ganetespib and ziv-aflibercept in patients with advanced gastrointestinal carcinomas, non-squamous non-small cell lung carcinomas, urothelial carcinomas, and sarcomas

466 - Phase I study of ganetespib and ziv-aflibercept in patients with advanced gastrointestinal carcinomas, non-squamous non-small cell lung carcinomas, urothelial carcinomas, and sarcomas

Induction of Apoptosis in Intestinal Toxicity to a Histone Deacetylase Inhibitor in a Phase I Study with Pelvic Radiotherapy.

PurposeWhen integrating molecularly targeted compounds in radiotherapy, synergistic effects of the systemic agent and radiation may extend the limits of patient tolerance, increasing the demand for understanding the pathophysiological mechanisms of treatment toxicity. In this Pelvic Radiation and Vorinostat (PRAVO) study, we investigated mechanisms of adverse effects in response to the histone deacetylase (HDAC) inhibitor vorinostat (suberoylanilide hydroxamic acid, SAHA) when administered as a potential radiosensitiser.Materials and MethodsThis phase I study for advanced gastrointestinal carcinoma was conducted in sequential patient cohorts exposed to escalating doses of vorinostat combined with standard-fractionated palliative radiotherapy to pelvic target volumes. Gene expression microarray analysis of the study patient peripheral blood mononuclear cells (PBMC) was followed by functional validation in cultured cell lines and mice treated with SAHA.ResultsPBMC transcriptional responses to vorinostat, including induction of apoptosis, were confined to the patient cohort reporting dose-limiting intestinal toxicities. At relevant SAHA concentrations, apoptotic features (annexin V staining and caspase 3/7 activation, but not poly-(ADP-ribose)-polymerase cleavage) were observed in cultured intestinal epithelial cells. Moreover, SAHA-treated mice displayed significant weight loss.ConclusionThe PRAVO study design implemented a strategy to explore treatment toxicity caused by an HDAC inhibitor when combined with radiotherapy and enabled the identification of apoptosis as a potential mechanism responsible for the dose-limiting effects of vorinostat. To the best of our knowledge, this is the first report deciphering mechanisms of normal tissue adverse effects in response to an HDAC inhibitor within a combined-modality treatment regimen.

Feasibility of an interactive electronic self-report tool for oral cancer therapy in an outpatient setting.

The introduction of oral anti-cancer agents provides a convenient administration route for chronic cancer treatment to outpatients. Health information technology through web-based applications or other electronic tools can offer a platform to improve treatment compliance, symptom management, and patient-provider communication. The purposes of this study were to test the feasibility and clinical utility of an electronic self-report device (RemeCoach) for patients or their caregivers and to register and prospectively evaluate the quality of data generated. Patients using Teysuno® (S-1) for advanced gastrointestinal carcinoma used a pre-programmed device in order to register compliance to treatment and six clinical parameters. Real-time data were collected onto a central platform, which processed the data by an algorithm. This algorithm stratified the data into different grades based on the Common Terminology Criteria for Adverse Events (CTCAE v4.0). From December 2013 to March 2014, 11 patients (5 men, 6 women) were enrolled. Compliance to the device was high, six patients (55%) registered timely intake of medication (demonstrating >95% treatment compliance). Agreement between patients' and clinicians' reported toxicity was substantial for nausea, but discrepant for fatigue, hand-foot syndrome, and mucositis. The use of an interactive self-report tool is feasible, reliable, and acceptable to outpatients. The RemeCoach and the algorithm devised will be further developed as an interactive patient-reported outcome (PRO) system, to improve early detection of side effects in an outpatient setting. Further studies are needed to confirm these data and to explore the relationship between optimal patient support and efficacy of treatment.

Phase I trials in patients with relapsed, advanced upper gastrointestinal carcinomas: experience in a specialist unit

Conventional therapeutic options for patients with advanced upper gastrointestinal cancers (UGIC) are limited. Following first-line treatments, some patients are offered experimental therapies, including participation in Phase I trials. This study aims to describe the experience of UGIC patients treated in a dedicated Phase I unit. Patient, tumour and treatment characteristics, and clinical outcomes of UGIC patients treated consecutively at the Drug Development Unit, Royal Marsden Hospital, between 2005 and 2009, were recorded. Ninety-six patients who previously received a median of 2 (range 1-4) lines of chemotherapies were treated in 30 Phase I trials. Of 81 evaluable patients, 9 achieved RECIST-objective response (11 %) with a 6-month clinical benefit rate of 14 %. Median progression free and overall survival were 7.7 weeks [95 %CI 7.7 (6.4-9.0)] and 19.1 weeks (95 %CI 17.5-20.8), respectively. Grade 3 or 4 toxicities were observed in 37 patients (39 %) and led to trial discontinuation in 9 (9 %); no toxicity-related death was recorded. In the multivariate analysis, serum albumin (<35 g/dl, HR2.0, p = 0.002) and lactate dehydrogenase (>192 μmol/l, HR1.7, p = 0.016) were prognostic of overall survival. Phase I clinical trials can be considered a reasonable option in selected patients with relapsed UGIC. The use of objective prognosticators may improve selection and risk/benefit profile of patients.

Application of traditional Chinese medical continuing nursing care in follow-up of patients with gastrointestinal carcinoma

Objective To study the application value of traditional Chinese medical continuing nursing care in follow-up of patients with gastrointestinal carcinoma .Methods Sixty-four patients with advanced gastrointestinal carcinoma from September 2010 to January 2013 were randomly divided into the control group （n=31） and the experimental group （n =33）.The control group received the routine follow-up, while the experimental group received routine follow-up plus traditional Chinese medical continuing nursing care including pressing the auricular point by magnetic beads , foot bath in the traditional Chinese medicine , massage at the plantar reflex zone and oral shiquandabu decoction .The quality of sleep , the intensity of pain , appetite and cancer-related fatigue （ CRF ） were evaluated before and four weeks after the follow-up in two groups. Results Before the follow-up, Pittsburgh sleep quality index （PSQI） was （10.39 ±177;3.84） in the control group, and （10.15 ±177;3.73） in the experimental group; the score of pain numerical rating scale was （2.26 ±177; 1.03） in the control group, and （2.21 ±177;1.05） in the experimental group;the cases of the mild, moderate and severe according to CRF score were respectively 8, 20, 3 cases in the control group , and respectively 10, 21, 2 cases in the experimental group , and the differences in the three indexes between two groups were not statistically significant （P＞0.05）.Four weeks after the follow-up, PSQI was （10.10 ±177;3.35） in the control group, and （8.48 ±177;2.50） in the experimental group, and the difference was statistically significant （t =2.170,P＜0.05）;the score of pain numerical rating scale was （2.19 ±177;0.83） in the control group, and （1.76 ±177;0.75） in the experimental group, and the difference was statistically significant （t =2.201,P ＜0.05）;the cases of the mild, moderate and severe according to CRF score were respectively 11, 16, 4 cases in the control group , and respectively 20, 13, 0 cases in the experimental group , and the difference was statistically significant （Z =-2.330,P ＜0.05）.Conclusions The traditional Chinese medical continuing nursing care can improve the symptoms in the follow-up of patients with advanced gastrointestinal carcinoma . Key words: Carcinoma; Gastrointestinal tract; Follow up study; Continuing nursing care; Traditional Chinese medical nursing

Outcome of patients (pts) with relapsed, advanced upper gastrointestinal (GI) carcinoma treated in a specialist oncology phase I unit.

45 Background: Conventional chemotherapy in advanced upper GI cancer after progression on first line therapy yields low response rates and no clear survival benefit. In this context, some pts are offered experimental treatments, including participation in Phase I clinical trials. Methods: Baseline pt and tumour characteristics, toxicity, response and outcome data of pts with upper GI cancers consecutively treated within the Drug Development Unit, Royal Marsden Hospital, from 2005 to 2009, were documented. Results: Ninety-six pts (median age 59 years [range 24-77]; male/female ratio 3.6, median of 2 [range 0-4] prior lines of chemotherapy) with oesophageal (42%), gastric (14.5%), pancreatic (26%) and oesphagogastric junction (7%) carcinomas were treated in 30 Phase I trials; of these, 36% participated in studies containing conventional cytotoxic chemotherapies. The overall response rate by RECIST was 11% with a disease control rate of 49%. The overall clinical benefit rate (i.e. no disease progression at 6 months) was 14%, respectively. In all pts, the median progression free survival (PFS) and overall survival (OS) were 7.0 weeks (95% CI: 5.6-8.4) and 19 weeks (95% CI: 17-21), respectively; these were not superior in pts who received chemotherapy-containing regimens (p=0.364, p=0.897). Pts with CBR ≥6 months a median OS of 55 weeks (95% CI: 46-64); 59% of them were treated with single-agent molecular targeting agents. Grade 3 or 4 toxicities were observed in 37 pts (39%) and led to trial discontinuation in nine (9%); no toxicity-related death occurred in these pts. In the multivariate analysis of baseline factors, serum albumin (&lt;35 g/dl, HR 2.0 [95%CI: 1.3-3.2] p=0.002) and serum lactate dehydrogenase (LDH) (&gt;192 umol/l, HR 1.7 [95% CI: 1.1-2.6], p=0.016) were prognostic of OS. Conclusions: Phase I clinical trials should be considered a valid option in pts with advanced upper GI cancers with disease relapse after first-line chemotherapy In our experience the risk of toxicity is low/moderate and there is the potential for clinical benefit.

Predictive and prognostic factors for treatment and survival in 305 patients with advanced gastrointestinal neuroendocrine carcinoma (WHO G3): The NORDIC NEC study

As studies on gastrointestinal neuroendocrine carcinoma (WHO G3) (GI-NEC) are limited, we reviewed clinical data to identify predictive and prognostic markers for advanced GI-NEC patients. Data from advanced GI-NEC patients diagnosed 2000-2009 were retrospectively registered at 12 Nordic hospitals. The median survival was 11 months in 252 patients given palliative chemotherapy and 1 month in 53 patients receiving best supportive care (BSC) only. The response rate to first-line chemotherapy was 31% and 33% had stable disease. Ki-67<55% was by receiver operating characteristic analysis the best cut-off value concerning correlation to the response rate. Patients with Ki-67<55% had a lower response rate (15% versus 42%, P<0.001), but better survival than patients with Ki-67≥55% (14 versus 10 months, P<0.001). Platinum schedule did not affect the response rate or survival. The most important negative prognostic factors for survival were poor performance status (PS), primary colorectal tumors and elevated platelets or lactate dehydrogenase (LDH) levels. Advanced GI-NEC patients should be considered for chemotherapy treatment without delay.PS, colorectal primary and elevated platelets and LDH levels were prognostic factors for survival. Patients with Ki-67<55% were less responsive to platinum-based chemotherapy, but had a longer survival. Our data indicate that it may not be correct to consider all GI-NEC as one single disease entity.

Single low-dose cyclophosphamide combined with interleukin-12 gene therapy is superior to a metronomic schedule in inducing immunity against colorectal carcinoma in mice

The use of conventional cytotoxic agents at metronomic schedules, alone or in combination with targeted agents or immunotherapy, is being explored as a promising anticancer strategy. We previously reported a potent antitumor effect of a single low-dose cyclophosphamide and interleukin-12 (IL-12) gene therapy against advanced gastrointestinal carcinoma, in mice. Here, we assessed whether the delivery of IL-12 by gene therapy together with metronomic cyclophosphamide exerts antitumor effects in a murine model of colorectal carcinoma. This combination therapy was able, at least in part, to reverse immunosuppression, by decreasing the number of regulatory T cells (Tregs) as well as of splenic myeloid-derived suppressor cells (MDSCs). However, metronomic cyclophosphamide plus IL-12 gene therapy failed to increase the number of tumor-infiltrating T lymphocytes and, more importantly, to induce a specific antitumor immune response. With respect to this, cyclophosphamide at a single low dose displayed a superior anticancer profile than the same drug given at a metronomic schedule. Our results may have important implications in the design of new therapeutic strategies against colorectal carcinoma using cyclophosphamide in combination with immunotherapy.

Xanthogranulomatous inflammatory reaction associated with endoscopic mucosal resections of gastric and colonic cancer

Background and aim: Xanthogranulomatous inflammatory reaction (XGI) is a rare diagnosis in the gastrointestinal tract. It could be misinterpreted as an invasive cancerous lesion. The pathogenesis of XGI in the gastrointestinal tract (GIXGI) is not well understood. We clinicopathologically studied six cases of GIXGI associated with endoscopic biopsy, mucosal resection, and submucosal dissection of gastric and colonic adenocarcinoma. Methods: Immunohistochemical, special histochemical stains, and tuberculosis-polymerase chain reaction (PCR) were performed. All radiological images and medical records of the patients were reviewed. Results: All cases showed XGI with foamy histiocytes, lymphocytes, and foreign body-type giant cells, which were positive for CD68 and negative for CD117, S-100, and cytokeratin. Acid-fast, Gomori's methenamine silver, periodic acid Schiff stains, and nontuberculous Mycobacterium and Mycobacterium tuberculosis-PCR were also negative. Two of four gastric adenocarcinomas were suspected to be advanced gastric cancer by computed tomography staging. However, the microscopic examination revealed only XGI with a mucosal carcinoma or without any residual tumor cells in the gastric wall. Conclusions: GIXGI may simulate advanced carcinoma clinicoradiologically. GIXGI should be included in the differential diagnosis in the case suggestive of a rapid transition to advanced gastrointestinal carcinoma within 12 weeks from the preoperative endoscopic procedure.

OVERALL ABSTRACT WINNER (CLINICAL OUTCOMES)

Background: Irinotecan (CPT-11) has demonstrated its potent efficacy in treating various malignancies, including advanced gastrointestinal cancers as a single agent, or in combination with chemotherapeutic and targeted agents. Yet, various degrees of dose-limiting toxicities, including diarrhea and neutropenia, were observed in some patients. It was reported that the incidence of such irinotecan-related adverse events was associated with polymorphism of the uridine diphosphate glucuronosyltransferases (UGTs) gene, and demonstrated an obvious ethnic diversity. Detection of these polymorphisms may guide the clinical decision for irinotecan dosage and the chemotherapeutic partner for individualized regimens. The aim of this study is to observe the frequency and severity of various adverse events in Han patients with advanced gastrointestinal cancer who were treated with irinotecan-based therapy. Simultaneously, the relationship between severe adverse events and the UGT1A1 gene promoter polymorphism (UGT1A1*28) was investigated. Methods: Sixty-six patients (42 men and 24 women; median age, 58 years; range, 30 –7 6 years) with advanced gastrointestinal carcinoma receiving irinotecan-based chemotherapy were enrolled. The inclusive criteria were: (1) pathologically/cytologically confirmed adenocarcinoma of the gastrointestinal tract, (2) expected survival time over 3 months, (3) no severe concomitant diseases of any vital organs, (4) no jaundice and digestive tract obstruction, (5) no acute infection. The adverse events during the course of chemotherapy, the pretreatment serum bilirubin level, as well as the time to grade 3 –4 toxicities were recorded. Genomic DNA was extracted from the peripheral blood to detect the polymorphism of UGT1A1*28 (TATA box thymine-adenine TA repeats). The relationship between the severity of adverse events and the UGT1A1*28 polymorphism, pretreatment bilirubin level, as well as the time to severe toxicity was investigated. Results: Of 66 enrolled patients, 55 patients (83.3%) were identified with the thymine-adenine (TA)6/(TA)6 genotype, and 11 patients (16.7%) were identified with the thymine-adenine (TA)6/(TA)7 genotype; no (TA)7/(TA)7 genotype was found. Twenty-six of the (TA)6/(TA)6 and 5 of the (TA)6/(TA)7 patients (47.3% vs 45.5%, P ¼ 1.000) developed grade 3 – 4 neutropenia, while 5 and 4 patients (9.1% vs 36.4%, P ¼ .036) experienced grade 3 – 4 diarrhea. The occurrence of grade 3 –4 diarrhea, but not neutropenia, was closely related with the (TA)6/(TA)7 genotype in the UGT1A1 promoter region in patients receiving irinotecanbased chemotherapy. The median time to severe toxicity of these 2 groups were 9 weeks (6 cycles) and 3 weeks (2 cycles), respectively (P ¼ .186). The pretreatment serum bilirubin levels in these 2 groups were (15.1+ 1.1) mmol/L and (20.8+ 5.1) mmol/L, respectively, which were not significantly associated with the occurrence of grade 3 – 4 diarrhea and neutropenia (P ¼ .09). Conclusion: The frequency of the UGT1A1*28 gene polymorphism in Han patients is 16.7%, which is lower than that reported in Western populations. The marked increase in grade 3 –4 diarrhea is related with the (TA)6/ (TA)7 genotype of UGT1A1 in patients receiving irinotecanbased chemotherapy. Detection of this gene polymorphism might help to select optional dosage and chemo-partner of irinotecan-based regimen in treating GI cancer patients in China.