PML as a potential predictive factor of oxaliplatin/fluoropyrimidine-based first line chemotherapy efficacy in colorectal cancer patients

PML regulates a wide range of pathways involved in tumorigenesis, such as apoptosis, which is also one of the main mechanisms through which oxaliplatin and fluoropyrimidine exert their antineoplastic activity. The present study aims to investigate PML expression as a predictive factor of oxaliplatin/fluoropyrimidine therapy efficacy. Seventy-four metastatic colorectal cancer patients who received oxaliplatin/floropyrimidine-based first line therapy have been included in this retrospective study. PML expression was assessed by immunohistochemistry. PML down-regulation was detected in 39 (52.7%) patients (14 complete and 25 partial PML loss). RR was significantly lower (25.6%) in patients with PML down-regulation than in patients with preserved PML expression (60%) (P = 0.006). Median TTP was 5.5 months when PML was down-regulated versus 11.9 months in case of preserved PML expression (P < 0.0001). A statistical significant difference was also detected in OS (15.6 and 24.5 months, respectively, P = 0.003). The impact of PML down-regulation on TTP and OS was statistically significant also in a multivariate model. This study represents the first evidence of a possible correlation between PML protein expression and outcome of metastatic colorectal cancer patients treated with oxaliplatin/fluoropyrimidine-based first line therapy.     

Alterations in intestinal microbiota of colorectal cancer patients receiving radical surgery combined with adjuvant CapeOx therapy

An intricate relationship exists and interactions occur between gut microbiota and colorectal cancer(CRC). Radical surgery combined with adjuvant chemotherapy(AC) serves as the mainstream therapeutic scheme for most CRC patients. The current research was conducted to assess the effect of surgery or chemotherapy on gut microbiota. Forty-three CRC patients who received radical surgery and AC were enrolled. Fecal samples were collected preoperatively, postoperatively, and after the first to fifth cycles of postoperative chemotherapy. The microbial community of each sample was analyzed using high throughput 16S rRNA amplicon sequencing. Compared with preoperative samples, fecal samples collected postoperatively exhibited a significant decrease of obligate anaerobes, tumor-related bacteria, and butyric acid-producing bacteria. However, a significant increase of some conditional pathogens was observed. In addition, the AC regimen(CapeOx) was found to alter intestinal microbiota dramatically. In particular, several changes were observed after chemotherapy including an increase of pathogenic bacteria, the "rebound effect" of chemotherapy-adapted bacteria, the shift of lactate-utilizing microbiota from Veillonella to Butyricimonas and Butyricicoccus, as well as the decrease of probiotics. Both radical surgery and CapeOx chemotherapy exert a non-negligible effect on the gut microbiota of CRC patients. Microbiota-based intervention may be beneficial for patients during postoperative clinical management.     

Case-based prediction of survival in colorectal cancer patients

OBJECTIVE: To develop an approach to the prediction of survival in patients with colorectal cancer using nearest neighbor analysis and case-based reasoning. STUDY DESIGN: A total of 216 patients with full clinicopathologic records and five-year follow-up were the subjects of this study. They were divided into a core database of 162 cases and a test group of 54 cases, with follow-up on all patients. When the patient was still alive at the end of the follow-up period, censored survival time was used. For each of the test cases, the four closest neighbors from the database were retrieved and their median survival time recorded and used as the predicted estimate of survival. Case matching was based on a Euclidean multivariate distance measure for the three best predictor variables: patient age, Dukes stage and tubule configuration. Cases with the smallest distance from the test case were considered to be the most similar. The predicted survival times for the test cases were compared with the actual, observed survival in the test cases to determine the success of this approach. RESULTS: The results showed reasonable concordance between observed and predicted survival figures, although there was a large degree of spread. Classification of cases into < or = 60 and > 60 months' survival showed a correct classification rate of 63%. For the prediction of survival time, the distribution of differences between observed and predicted survival times for the uncensored test cases had a median value of--5 months but also showed a wide dispersion of values. Correlation of observed and predicted survival times, while not reaching statistical significance at P < .05, did show a strong positive association. CONCLUSION: Case-based approaches to the prediction of survival times in cancer patients are important. The results of the current study illustrate the difficulties in applying this approach to survival data and highlight the complexity of patient information and the inability to accurately predict patient outcome on a small subset of clinicopathologic features. While extensive work needs to be carried out to improve prediction power, this study illustrates the potential for case-based analyses. The ability to retrieve feature-matched cases from hospital patient databases has clear, independent advantages in patient management, but the ability to provide reliable, targeted prognostic estimates on individual cases should be a common goal in medical research.     

First efficacy results of capecitabine with anthracycline- and taxane-based adjuvant therapy in high-risk early breast cancer: a meta-analysis

Background

Capecitabine is effective and indicated for the salvage treatment of metastatic breast cancer. Therefore, it is essential to evaluate the efficacy of capecitabine in the adjuvant setting. There have been two large randomized studies to determine whether patients with high-risk early breast cancer benefit from the addition of capecitabine to standard chemotherapy, but they have yielded inconsistent results. We first undertook a meta-analysis to evaluate the efficacy of the addition of capecitabine over standard treatment.

Methods

PubMed, EBSCO, Web of Science, conference proceedings and key trials were searched from 1998 to 2011. The hazard ratio (HR) was used to evaluate the efficacy of a taxane-anthracycline regimen and a taxane-anthracycline-capecitabine regimen in early breast cancer. All of the data from each study use either fixed-effects or random-effects by Stata.

Findings

We found significant improvement in the additional capecitabine arm versus control in disease-free survival (DFS) (HR = 0.83, 95% CI: 0.71–0.98, P = 0.027), overall survival (OS) (HR = 0.71, 95% CI: 0.57–0.88, P = 0.002), distant recurrence (HR = 0.79, 95% CI: 0.66–0.94, P = 0.008) and the death from breast cancer only (HR = 0.65, 95% CI: 0.51–0.83, P = 0.001). Meanwhile, the subgroup analysis revealed that capecitabine improved the DFS in triple negative (HR = 0.71, 95% CI: 0.53–0.96, P = 0.028), hormone receptor negative (HR = 0.73, CI: 0.56–0.94, P = 0.017) and HER2 negative (HR = 0.81, CI: 0.67–0.98, P = 0.034) patients.

Conclusion

Due to the synergistic effect of taxane and capecitabine, taxane-anthracycline-capecitabine regimen may effectively improve the efficacy in the adjuvant setting and may be a novel generation of adjuvant chemotherapy regimen. The results of the current meta-analysis support this hypothesis and indicate that taxane-based regimen with capecitabine may be an effective, convenient, and well tolerated regimen in patients with early breast cancer.     

Gut microbiome in tumorigenesis and therapy of colorectal cancer

Colorectal cancer (CRC) is the malignant tumor with the highest incidence in the digestive system, and the gut microbiome plays a crucial role in CRC tumorigenesis and therapy. The gastrointestinal tract is the organ harboring most of the microbiota in humans. Changes in the gut microbiome in CRC patients suggest possible host–microbe interactions, thereby hinting the potential tumorigenesis, which provides new perspective for preventing, diagnosing, or treating CRC. In this review, we discuss the effects of gut microbiome dysbiosis on CRC, and reveal the mechanisms by which gut microbiome dysbiosis leads to CRC. Gut microbiome modulation with the aim to reverse the established gut microbial dysbiosis is a novel strategy for the prevention and treatment of CRC. In addition, this review summarizes that probiotic antagonize CRC tumorigenesis by protecting intestinal barrier function, inhibiting cancer cell proliferation, resisting oxidative stress, and enhancing host immunity. Finally, we highlight clinical applications of the gut microbiome, such as gut microbiome analysis-based biomarker screening and prediction, and microbe modulation-based CRC prevention, treatment enhancement, and treatment side effect reduction. This review provides the reference for the clinical application of gut microbiome in the prevention and treatment of CRC.     

Angiogenesis in metastatic colorectal cancer and the benefits of targeted therapy

Mesenchymal stem cells (MSC) have generated a great amount of enthusiasm over the past decade as a novel therapeutic paradigm for a variety of diseases. Currently, MSC based clinical trials have been conducted for at least 12 kinds of pathological conditions, with many completed trials demonstrating the safety and efficacy. This review provides an overview of the recent clinical findings related to MSC therapeutic effects. Roles of MSCs in clinical trials conducted to treat graft-versus-host-disease (GVHD) and cardiovascular diseases are highlighted. Clinical application of MSC are mainly attributed to their important four biological properties- the ability to home to sites of inflammation following tissue injury when injected intravenously; to differentiate into various cell types; to secrete multiple bioactive molecules capable of stimulating recovery of injured cells and inhibiting inflammation and to perform immunomodulatory functions. Here, we will discuss these four properties. Moreover, the issues surrounding clinical grade MSCs and principles for MSC therapeutic approaches are also addressed on the transition of MSCs therapy from bench side to bedside.     

金双歧辅助治疗小儿扁桃体炎的随访观察

目的探讨通过随访观察金双歧辅助治疗小儿扁桃体炎患儿的远期效果。方法选取2013年1月至2014年7月在本院儿科住院诊断为扁桃体炎患儿300例,采用随机数字表法,按入院先后顺序分为对照组和观察组,对照组常规给予抗生素(包括抗病毒药)和(或)对症治疗;观察组在对照组治疗的基础上,给予金双歧口服辅助治疗,出院后继续服用金双歧4周;两组患儿分别在出院后1个月、2个月、3个月均进行电话随访,3个月后均通过家庭访视进行观察,比较两组患儿出院后发生呼吸道感染和肠道感染的差异。结果观察组患儿在出院后3个月内呼吸道感染和肠道感染的发生率低于对照组,差异具有统计学意义(P0.05)。结论出院扁桃体炎患儿继续服用金双歧,可提高患儿机体免疫力,降低呼吸道和肠道感染的发生率;随访为观察患儿出院后健康状态,进行健康指导以及收集资料的重要手段。     

Recent results of irinotecan therapy in colorectal cancer

New results presented at ASCO Conference in 2003 added further important data to our knowledge on successful use of irinotecan in colorectal cancer (CRC). Irinotecan - just like oxaliplatin - given as neoadjuvant therapy with 5-FU - folinic acid (FUFA) can render originally unresectable liver or lung metastases of CRC resectable, giving the hope of long-term survival for a proportion of patients. Irinotecan combined with 5-FU is an essential part of the most successful palliative sequential chemotherapy of stage IV CRC. Sequential FOLFIRI before or after FOLFOX combination ensures the longest possible progression-free and overall survival for metastatic CRC patients in the palliative setting. In order to achieve the longest survival time, sequential use of both 5-FU, irinotecan and oxaliplatin is necessary. The French GERCOR Group achieved 26 months median overall survival with the sequential use of continuous infusional FUFA, oxaliplatin and irinotecan combinations in stage IV CRC. The analysis of large phase III trials using 5-FU, irinotecan and oxaliplatin revealed that the higher proportion of patients was treated with all three drugs, the longer overall survival was achieved. If applied with caution, toxicity and efficacy of irinotecan in elderly patients is not significantly different from that seen in younger population. The anti-VEGF bevacizumab increases the efficacy of first-line irinotecan therapy, while the addition of cetuximab restores irinotecan sensitivity in second line treatment of stage IV CRC. The combination of irinotecan with oral capecitabine is safe and effective in advanced CRC.     

The RAS paradox of the EGFR-targeted therapy in colorectal cancer

During the carcinogenesis of colorectal cancer in about half of the cases K-RAS, while much less frequently B-RAF mutation occur in early adenomas. While K-RAS mutant tumors are more likely present in male patients, B-RAF mutant tumors develop more frequently in females and are independent of the microsatellite status. Colorectal cancers are characterized by EGFR expression; the gene is not mutated, rarely amplified and increased copy number is due to chromosomal polysomy. This phenotype/genotype of colorectal cancer lent support to the introduction of anti-EGFR antibody therapies. For a while positive EGFR expression status of the tumor was the basis of patient selection for these targeted therapies in colorectal cancer. Monotherapies with the two available anti-EGFR antibodies of chemoresistant colorectal cancers resulted in appr. 10% objective response rate, which was independent of the level of EGFR expression. In case of panitumumab it was discovered that the efficacy of this targeted therapy depends on the K-RAS mutant status of the tumors. Furthermore, preliminary data suggest that cetuximab combined with chemotherapy is effective also exclusively in K-RAS wild-type tumors. Based on these data it is safe to say that K-RAS mutant status of colorectal cancer is a negative predictor for EGFR-targeted therapies of colorectal cancer. Accordingly, it is necessary to determine the K-RAS status of colorectal cancer before making therapeutic decisions.     

Novel biotechnology approaches in colorectal cancer diagnosis and therapy

With ever-increasing molecular information about colorectal cancer (CRC), there is an expectation to detect more sensitive and specific molecular markers for new advanced diagnostic methods that can surpass the limitations of current screening tests. Moreover, enhanced molecular pathology knowledge about cancer has led to the development of targeted therapies, designed to interfere with specific aberrant biological pathways in cancer. Furthermore, biotechnology has opened a new window in CRC diagnosis and treatment by introducing different application of antibodies, antibody fragments, non-Ig scaffold proteins, and aptamers in targeted therapy and drug delivery. This review summarizes the molecular diagnostic and therapeutic approaches in CRC with a focus on genetic and epigenetic alterations, protein and metabolite markers as well as targeted therapy and drug delivery by Ig-scaffold proteins, non-Ig scaffold proteins, nanobodies, and aptamers.     

Long-term influence of adjuvant therapy on natural killer cell activity in breast cancer

Summary Unstimulated IFN- and IL2-stimulated (NK) cell activities were investigated in patients with breast cancer who had received either local radiotherapy alone or adjuvant chemotherapeutic treatment with CMF combined with radiotherapy 12 to 18 months previously. When tested against the primarily NK-sensitive K562 cell line, patients who had received adjuvant chemotherapeutic treatment with CMF were shown to have a significantly decreased unstimulated and IFN-stimulated NK cell activity, as compared to both patients after radiotherapy only (P<0.002) and P<0.005, respectively) and healthy control persons (P<0.05). The former group of patients also had a significantly decreased IFN-stimulated NK cell activity, when tested against the primarily NK-insensitive Chang hepatoma cell line, as compared to patients after radiotherapy only (P<0.005) and healthy controls (P<0.05). Moreover, patients after radiotherapy only proved to have a significantly increased unstimulated (P<0.01) and IFN-stimulated NK cell activity (K562: P<0.05; Chang hepatoma cell line: P<0.05), as compared to healthy control individuals. In contrast, no difference in IL2-stimulated NK cell activity was detected. The investigation for the expression of CD3 and/or Leu 19 antigens as phenotypic markers of cells with non-MHC restricted cytotoxicity showed a significantly lower percentage of cells with the CD3+ phenotype in patients with breast cancer, irrespective of the chosen post-operative treatment, as compared to healthy controls (P<0.01). Finally, patients with breast cancer who had received radiotherapy only had a significant trend towards an increased percentage of CD³+/Leu 19+ PMNC, as compared to both patients after CMF treatment (P<0.05) and healthy controls (P<0.025). We conclude that patients with breast cancer vary on a long-term basis in their NK activity and in the phenotype of their PMNC depending on their post-operative adjuvant management.Abbreviations NK natural killer cells - IFN interferon - IL 2 interleukin 2 - CMF cyclophosphamide, methotrexate, fluorouracil - ER oestrogen receptor - PMNC peripheral blood mononuclear cells - MHC major histocompatibility complex - CTL cytotoxic T lymphocytes     

Incidence of radiation toxicity in cervical cancer and endometrial cancer patients treated with radiotherapy alone versus adjuvant radiotherapy

AimThe study was made to evaluate early and late toxicity in a diversified group of patients receiving definitive or adjuvant radiotherapy in terms of clinical diagnosis and treatment methods.BackgroundRadiotherapy is a standard way of treatment in cervical and endometrial cancer patients, both as definitive and adjuvant therapy. But every radiation treatment may be involved with toxicity.Materials and methodsA detailed analysis was performed of 263 patients with gynaecological cancer treated with definitive (90 patients with cervical cancer received radiochemotherapy or radiotherapy exclusively) and adjuvant radiotherapy (38 with cervical and 135 with endometrial cancer).ResultsAcute reactions were found in 51.3% and late reactions were found in 14.8% of patients. It was stated that early (p < 0.007) and late (p < 0.003) post radiation reaction appear more frequently in women treated with definitive than adjuvant radiotherapy. The analysis of the whole group revealed higher rate of toxicity, both early and late, in the gastrointestinal tract than in the urinary system (p < 0.004). Comparing the subgroups, it was found that intestinal reactions occurred more frequently in the definitive radiotherapy group than in the adjuvant one.The occurrence of side effects was associated with the prolongation of total irradiation time due to necessary interruptions of radiotherapy. The comparison of the subgroups showed that interruptions occurred more frequently in patients receiving definitive rather than adjuvant radiotherapy (17.7–2.9%).ConclusionsDefinitive radiotherapy compared with adjuvant treatment may by associated with higher percentage of side effects caused by dose of therapy and correlation with chemotherapy.     

Targeted therapy for colorectal cancer: mapping the way

In spite of the significant advances in conventional therapeutic approaches to colorectal cancer (CRC), most patients ultimately die of their disease. Dissecting the molecular mechanisms underlying CRC progression will not only accelerate the development of novel cancer-selective drugs but will also enable the therapeutic regimen to be personalized according to the molecular features of individual patients and tumors. Here, we report on the novel insights into CRC biology that are paving the way to the development of molecular therapies and summarize the results from recent clinical trials demonstrating that agents targeting tumor-specific molecular derangements can significantly improve the therapeutic efficacy of conventional chemotherapy. Only a broader clinical implementation of these concepts will provide patients with CRC the best chance of a cure.