Combination with intravenous iron supplementation or doubling erythropoietin dose for patients with chemotherapy-induced anaemia inadequately responsive to initial erythropoietin treatment alone: study protocol for a randomised controlled trial.

INTRODUCTION: Erythropoietin (EPO) is a commonly used option in the treatment of chemotherapy-induced anaemia (CIA). However, ∼30-50% of patients fail to achieve an adequate response after initial treatment. Prior studies have demonstrated that intravenous iron might synergistically improve therapeutic response to EPO treatment in this patient population. METHODS AND ANALYSIS: We will perform this multicentre, randomised, open-label, parallel-group, active controlled non-inferiority study to compare the two combination therapies of EPO plus intravenous iron regimen versus doubling the dose of EPO in patients with CIA who have an inadequate response to initial EPO treatment at a routine dose. A total of 603 patients with an increase in haemoglobin (Hb) <1 g/dL will be enrolled and randomised to one of the three study treatment groups at a 1:1:1 ratio Group 1: EPO treatment at the original dose plus intravenous iron dextran 200 mg every 3 weeks (Q3W) for 15 weeks; Group 2: EPO treatment at the original dose plus intravenous iron dextran 100 mg, twice a week for 5 weeks; Group 3: the control group, doubling the EPO dose without preplanned iron supplementation. The primary outcome measure to compare is the Hb response rate at week 15 and the secondary end points involve therapeutic blood transfusions. Time-to-progression, adverse events and quality of life will also be evaluated. ETHICS AND DISSEMINATION: All participants will provide informed consent; the study protocol has been approved by the independent ethics committee of Shanghai East Hospital. This study would clearly demonstrate the potential benefit of combining epoetin treatment with intravenous iron supplementation. Findings will be shared with participating hospitals, policymakers and the academic community to promote the clinical management of CIA in China. TRIAL REGISTRATION NUMBER: NCT02731378.

Gene expression profiling-derived immunohistochemistry signature with high prognostic value in colorectal carcinoma.

OBJECTIVE: Gene expression profiling provides an opportunity to develop robust prognostic markers of colorectal carcinoma (CRC). However, the markers have not been applied for clinical decision making. We aimed to develop an immunohistochemistry signature using microarray data for predicting CRC prognosis. DESIGN: We evaluated 25 CRC gene signatures in independent microarray datasets with prognosis information and constructed a subnetwork using signatures with high concordance and repeatable prognostic values. Tumours were examined immunohistochemically for the expression of network-centric and the top overlapping molecules. Prognostic values were assessed in 682 patients from Shanghai, China (training cohort) and validated in 343 patients from Guangzhou, China (validation cohort). Median follow-up duration was 58 months. All p values are two-sided. RESULTS: Five signatures were selected to construct a subnetwork. The expression of GRB2, PTPN11, ITGB1 and POSTN in cancer cells, each significantly associated with disease-free survival, were selected to construct an immunohistochemistry signature. Patients were dichotomised into high-risk and low-risk subgroups with an optimal risk score (1.55). Compared with low-risk patients, high-risk patients had shorter disease-specific survival (DSS) in the training (HR=6.62; 95% CI 3.70 to 11.85) and validation cohorts (HR=3.53; 95% CI 2.13 to 5.84) in multivariate Cox analyses. The signature better predicted DSS than did tumour-node-metastasis staging in both cohorts. In those who received postoperative chemotherapy, high-risk score predicted shorter DSS in the training (HR=6.35; 95% CI 3.55 to 11.36) and validation cohorts (HR=5.56; 95% CI 2.25 to 13.71). CONCLUSIONS: Our immunohistochemistry signature may be clinically practical for personalised prediction of CRC prognosis.

Nuclear orphan receptor NR4A2 confers chemoresistance and predicts unfavorable prognosis of colorectal carcinoma patients who received postoperative chemotherapy.

BACKGROUND: NR4A2, an orphan nuclear receptor essential in neuron generation, has been recently linked to inflammatory and metabolic pathways of colorectal carcinoma (CRC). However, the effects of NR4A2 on chemo-resistance and postoperative prognosis of CRC remain unknown. METHODS: NR4A2 was transfected into CRC cells to investigate its effects on chemo-resistance to 5-fluorouracil and oxaliplatin and chemotherapeutics-induced apoptosis. We also investigated prostaglandin E2 (PGE2)-induced NR4A2 expression and its effect on chemo-resistance. Tissue microarrays including 51 adenoma, 14 familial adenomatous polyposis with CRC, 17 stage IV CRC with adjacent mucosa and 682 stage I-III CRC specimens were examined immunohistochemically for NR4A2 expression. Median follow-up time for stage I-III CRC patients was 53 months. RESULTS: Ectopic expression of NR4A2 increased the chemo-resistance, and attenuated the chemotherapeutics-induced apoptosis. Transient treatment of PGE2 significantly up-regulated NR4A2 expression via protein kinase A pathway and increased the chemo-resistance. NR4A2 expression in epithelials consecutively increased from adenoma, adjacent mucosa to CRC (P(trend)<0.001). In multivariate Cox regression analyses, high NR4A2 expression in cancer nuclei (immunoreactive score ≥ 4) significantly predicted a shorter disease-specific survival (DSS) of CRC patients (hazard ratio [HR]=1.88, P=0.024). High NR4A2 expression specifically predicted a shorter DSS of colon cancer patients (dichotomisation, HR=2.55, log-rank test P=0.011), especially for those who received postoperative 5-fluorouracil/leucovorin plus oxaliplatin (FOLFOX) chemotherapy (3-score range, HR=1.86, log-rank test P=0.020). CONCLUSION: High expression of NR4A2 in CRC cells confers chemo-resistance, attenuates chemotherapeutics-induced apoptosis, and predicts unfavorable prognosis of colon cancer patients, especially for those who received postoperative chemotherapy. NR4A2 may be prognostic and predictive for colon cancer.

[Clinical study on survival benefit for elderly patients with resected stage II or III colorectal cancer based on traditional Chinese medicine syndrome differentiation and treatment].

BACKGROUND: The incidence of colorectal cancer is high among the elderly. Traditional Chinese medicine (TCM) has been widely used in the treatment for colorectal cancer of old people. However, controlled trials with large sample size evaluating the effect of TCM are rare. OBJECTIVE: This research aimed to evaluate the survival benefit of using TCM syndrome differentiation treatment for elderly patients with stage II or III colorectal cancer. DESIGN, SETTING, PARTICIPANTS AND INTERVENTIONS: A total of 78 patients over 70 with resected stage II or III colorectal cancer were selected from the First Department of Oncology, Longhua Hospital of Shanghai University of Traditional Chinese Medicine, and Department of Anorectal Surgery, Changhai Hospital of Second Military Medical University. Patients were assigned to either integrated treatment group or Western medicine group by their own wills. MAIN OUTCOME MEASURES: Cox regression analysis was performed to determine all the potential factors which may affect prognosis such as gender, primary site, pathological type, TNM stage, chemotherapy period, radiotherapy and TCM therapy. RESULTS: A total of 78 cases were included in this study with 37 cases in integrated treatment group and 41 cases in Western medicine group. Cox regression analysis suggested that the TNM stage (P=0.001) and TCM therapy (P=0.021) were independent prognostic factors. The hazard ratio [Exp(ß)] of TCM therapy was 0.393, and 95% confidence interval (CI) was 0.178-0.870. Median disease-free survival (DFS) of Western medicine group was 41.293 months. DFS of integrated treatment group did not reach the median at the time of analysis. There was significant difference between the two groups (P=0.012). The 1-, 2-, 3-, 4-, and 5-year DFS rates of Western medicine group were 87.7 %, 69.6%, 63.4%, 46.5%, and 29.6%, respectively. The 1-, 2-, 3-, 4-, and 5-year DFS rates of integrated therapy group were 100%, 86.3%, 74.6%, 74.6%, and 74.6%, respectively. CONCLUSION: TCM syndrome differentiation and treatment is important for improving the prognosis of stage II or III colorectal cancer in elderly patients. Integrated treatment shows benefit for reducing relapse and metastasis rates, and prolonging survival for elderly patients. The influence of integrated treatment needs to be further evaluated.

[Diagnosis and surgical management for adult Hirschsprung's disease].

OBJECTIVE: To investigate the diagnosis and surgical management of adult Hirschsprung's disease. METHODS: Clinical data of 15 patients with adult Hirschsprung's disease were reviewed retrospectively from June 1992 to June 2004. RESULTS: Patients age ranged from 17 to 54 years old. The main manifestations included long-term (ranged from 9.5 month to 50 years) constipation and abdominal distention. Acute abdominal pain occurred in six patients, but no sign of de hydration and malnutrition occurred in all patients. Bowel stenosis and dilation could be examined by barium enema. Soave procedure was performed in 3 patients, subtotal colectomy with coloanal anastomosis was performed in twelve patients. The function of defecation was improved in all patients after operation. CONCLUSIONS: The diagnosis of adult Hirschsprung's disease mainly depends on the history of constipation from infant and barium enema. Subtotal colectomy with coloanal anastomosis is an effective and safe operative procedure.