Genome-wide copy number analysis in primary breast cancer

INTRODUCTION: Carcinogenesis is considered to be a multistep process that may involve cumulative genomic alterations. Loss of chromosomal material would inactivate tumor suppressor genes and gain of chromosomal material has the potential to activate tumor-promoting genes. AREAS COVERED: Recent intensive studies by array comparative genomic hybridization (aCGH) have demonstrated frequent alterations in multiple regions of the genome. This suggests that these regions contain a variety of oncogenes and tumor suppressor genes associated with breast cancer development. The patterns of copy number variations (CNVs) have been suggested to be associated with breast cancer subtypes, indicating the importance of genomic instability in the development of breast cancer. EXPERT OPINION: To further clarify the complexity of gene alterations, one approach is to employ a CNV-targeted platform that harbors a large number of direct CNV markers located in the repeat-rich unstable regions of the human genome. Next generation sequencing is another approach to overcome the limitations of aCGH such as the repeat-rich regions. Genomic analysis should be combined with expression analysis to elucidate individual genes relevant to breast cancer development and progression. The elucidation of the functions of the affected genes would lead to identification of new molecular targets for breast cancer eradication.     

Pharmacodynamic modeling of cardiac biomarkers in breast cancer patients treated with anthracycline and trastuzumab regimens

Trastuzumab is associated with cardiotoxicity, manifesting as a decrease of the left-ventricular ejection fraction (LVEF). Administration of anthracyclines prior to trastuzumab increases risk of cardiotoxicity. High-sensitive troponin T and N-terminal-pro-brain natriuretic peptide (NT-proBNP) are molecular markers that may allow earlier detection of drug-induced cardiotoxicity. In this analysis we aimed to quantify the kinetics and exposure–response relationships of LVEF, troponin T and NT-proBNP measurements, in patients receiving anthracycline and trastuzumab. Repeated measurements of LVEF, troponin T and NT-proBNP and dosing records of anthracyclines and trastuzumab were available from a previously published clinical trial. This trial included 206 evaluable patients with early breast cancer. Exposure to anthracycline and trastuzumab was simulated based on available dosing records and by using a kinetic-pharmacodynamic (K-PD) and a fixed pharmacokinetic (PK) model from literature, respectively. The change from baseline troponin T was described with a direct effect model, affected by simulated anthracycline concentrations, representing myocyte damage. The relationship between trastuzumab and LVEF was described by an indirect effect compartment model. The EC₅₀ for LVEF decline was significantly affected by the maximum troponin T concentration after anthracycline treatment, explaining 15.1% of inter-individual variability. In this cohort, NT-proBNP changes could not be demonstrated to be related to anthracycline or trastuzumab treatment. Pharmacodynamic models for troponin T and LVEF were successfully developed, identifying maximum troponin T concentration after anthracycline treatment as a significant determinant for trastuzumab-induced LVEF decline. These models can help identify patients at risk of drug-induced cardiotoxicity and optimize cardiac monitoring strategies.     

核苷酸切除修复交叉互补组基因 1和人类 X射线交错互补修复基因 1基因多态性与结直肠癌奥沙利铂疗效的相关性

目的 探讨核苷酸切除修复交叉互补组基因1(ERCC1)和人类X射线交错互补修复基因1(XRCC1)单核苷酸多态性(SNP)与接受以奥沙利铂为基础的化疗方案治疗晚期结直肠癌(CRC)疗效的关系.方法 选取2017年11月至2019年4月收治于荆门市第一人民医院经病理组织学确诊为晚期直肠癌病人95例,均接受含奥沙利铂为基础的化疗方案化疗至少3个周期后评价疗效.采用荧光染色原位杂交测序法对化疗病人外周血中ERCC1 Asn118Asn、XRCC1 Gln399Arg基因型进行检测,分析各基因型与CRC病人近期化疗疗效的相关性.结果 本研究所选取的病人中各多态性位点的基因型分布均符合Hardy-Weinberg平衡.病人的性别、年龄、结直肠癌分期(TNM分期)、肿块部位(结肠部位、直肠部位)和含奥沙利铂为基础的化疗方案疗效均差异无统计学意义(P>0.05).95例CRC病人中,携带ERCC1 Asn118Asn GG、AG+AA基因型的病人化疗后有效率分别为51.9％(28/54)和24.4％(10/41),ERCC1 Asn118Asn AG+AA基因型病人化疗失败的可能性是GG型的3.338倍,OR=3.338,95％CI为1.370～8.134,P<0.05;携带XRCC1 Gln399Arg CC、TC+TT基因型的病人化疗后有效率分别为52.0％(26/50)和26.7％(12/45),XRCC1 Gln399Arg TC+TT基因型病人化疗失败的可能性是CC型之间的2.979倍,OR=2.979,95％CI为1.257～7.060,P<0.05.结论 就含奥沙利铂为基础联合化疗失败的可能性而言,携带ERCC1 Asn118Asn AG+AA基因型比GG型高;携带XRCC1 Gln399Arg TC+TT基因型比CC型高.检测ERCC1 Asn118Asn和XRCC1 Gln399Arg单核苷酸多态性可以成为预测结直肠癌病人接受含奥沙利铂为基础的化疗方案疗效的指标.     

Impact of SHMT1 polymorphism on the clinical outcome of patients with metastatic colorectal cancer treated with first-line FOLFIRI+bevacizumab

The impact of thymidylate synthase (TYMS), methylenetetrahydrofolate reductase (MTHFR), and serine hydroxymethyltransferase 1 (SHMT1) gene polymorphisms and that of dihydropyrimidine dehydrogenase (DPD) enzyme activity, serum total homocysteine level, and estimated serum creatinine clearance on first-line 5-fluorouracil, leucovorin, irinotecan, and bevacizumab (FOLFIRI+bevacizumab) regimen efficacy in metastatic colorectal cancer patients was investigated. DNA was extracted from peripheral blood mononuclear cells. Genotyping was performed for TYMS 5'UTR variable number tandem repeat, TYMS 3'UTR ins/del, MTHFR C677T, and SHMT1 C1420T polymorphisms. The DPD activity of peripheral blood mononuclear cells was also determined. The univariate and multivariate analyses demonstrated that the SHMT1 1420T allele was associated with better response (P=0.025) and longer progression-free survival (PFS) (P=0.00004) and overall survival (OS) (P=0.034). Grade ≥2 hypertension was also an independent prognostic factor of longer progression-free survival and OS. Bevacizumab-related hypertension might be a predictive marker of treatment efficacy (P=0.0002 for OS) in the case of wild (CC) SHMT1 1420 genotypes only.     

氨茶碱不同给药方案的血药浓度比较

对氨茶碱不同给药方案进行血药浓度监测,为临床合理用药提供依据。方法：采用ＨＰＬＣ法测定血中不同时间的茶碱浓度,１０２例患者氨茶碱的给药方案分为口服组,静脉滴注组,静脉滴注＋口服组。结果：（１）口服０．２ｇ,ｑ８ｈ,或０．２ｇｔｉｄ的患者血药谷峰浓度在１０～２０μｇ·ｍｌ－１范围分别约占８７％和６５％。（２）静脉滴注０．５ｇ,ｑｄ,或静脉滴注０．２５ｇ,ｑｄ＋口服０．１ｇ,ｔｉｄ的患者血药谷峰浓度在１０～２０μｇ·ｍｌ－１范围分别约占７８％和８２％。（３）口服０．１ｇ,ｔｉｄ或０．２ｇ,ｑｎ的患者血药谷浓度＜１０μｇ·ｍｌ－１,分别约占９３％和８２％。３例发生毒性反应血药浓度均＞２０μｇ·ｍｌ－１。结论：对轻、中度哮喘的治疗和预防应使用较小剂量（０．１ｇ,ｔｉｄ或０．２ｇ,ｑｎ）,维持血药浓度在５～１０μｇ·ｍｌ－１即可。     

5-fluorouracil as a protracted continuous infusion plus irinotecan (CPT-11) in patients with advanced colorectal cancer treated with fluoropyrimidine-based regimens as first line

We carried out a single-center series with the combination of irinotecan (CPT-11) plus protracted 5-fluorouracil (5-FU) infusion as second-line chemotherapy for patients previously treated with a single-agent fluoropyrimidine as monotherapy or in combination with oxaliplatin. Twenty-five patients diagnosed with advanced colorectal cancer (CRC) received CPT-11 300 mg/m2 every 3 weeks plus 5-FU 250 mg/m2/day as a protracted infusion. Results were as follows. Twenty-four of 25 patients were evaluable for response. Two patients achieved a complete response and five a partial response, resulting in an overall response rate of 28%. Disease stabilization was obtained in 10 patients (40%), resulting in a tumor growth control rate of 68% (17 patients) and disease progression in seven (28%). Median progression-free interval was 6 months and median overall survival was 12 months. Neutropenia and diarrhea appeared as the most frequent adverse events, being grade 3/4 in 12 and 16% of patients, respectively. Mucositis, emesis, and hand and foot syndrome were mild. We conclude that protracted 5-FU infusion plus CPT-11 is an active and safe regimen for patients with advanced CRC. A phase III trial comparing this schedule with conventional CPT-11 monotherapy is warranted.     

以吉西他滨为基础的化疗方案治疗晚期胰腺癌的临床观察

目的评价单药吉西他滨或吉西他滨联合奥沙利铂治疗初治不可手术的局部晚期或转移性胰腺癌的疗效和毒性。方法共有36个胰腺癌病人进入本研究,其中16个病人接受吉西他滨(1000mg/m2静脉输注30min,每周1次,连续两周,休息1周重复),20个病人接受吉西他滨联合奥沙利铂方案(化疗第一天静脉输注吉西他滨1000mg/m230min,奥沙利铂100mg/m2120min,每两周重复)。结果没有完全缓解的病例,部分缓解有3例(8.3%),临床受益有9例(25.0%),中位生存时间是5.8个月,两组的毒性主要表现在血液学方面,毒性主要为1~2级,没有出现3度的周围神经毒性和治疗相关死亡。结论对于晚期胰腺癌病人,吉西他滨单药或吉西他滨联合奥沙利铂治疗是有效的,并有很好的耐受性。     

FOLFOX4方案化疗对结直肠癌患者免疫细胞数的影响

目的：探讨FOLFOX4方案治疗结直肠癌对患者免疫细胞数的影响及意义。方法：检测47例结直肠癌患者化疗前和化疗后的第1、4、7天T细胞亚群、NK细胞数目变化以及淋巴细胞的凋亡情况,并与正常对照组进行对比。结果：患者化疗前CD3、CD4、CD16＋56＋细胞及CD4/CD8的比值较正常对照组低（P〈0.05）,CD8水平无统计学差异。化疗结束后的1、4、7d,CD3、CD4、CD8、NK细胞的水平较化疗前降低,化疗后第4天下降到最低值,化疗后第7天各指标均有所回升,整个过程中CD4/CD8无显著变化。结论：FOLFOX4方案较为安全有效,但年老体弱者使用时需要注意检测和保护。     

Antiemetic effect and pharmacokinetics of high dose metoclopramide in cancer patients treated with cisplatin-containing chemotherapy regimens

Summary Fifteen cancer patients receiving cisplatin-containing chemotherapy participated in two antiemetic studies. In Study 1 they received standard antiemetics in low doses on demand, and in Study 2 the same patients participated in an open randomized cross-over study between metoclopramide 1 and 2 mg/kg i.v.×5.Serum metoclopramide was determined by HPLC. Self-reporting of nausea using a visual analogue scale (VAS) was compared with observer rated scores. Tolerability and volume vomited were assessed by nurse observers.The biological half-life of metoclopramide was 9.9 h, the volume of distribution was 9.9 l/kg and the clearance was 0.68 l/h/kg. The pharmacokinetics of high dose metoclopramide was linear in the range 0.15–2 mg/kg×5, with very little accumulation.Compared to standard antiemetics, both high dose regimens of metoclopramide had a significant effect on nausea, but no effect on the volume vomited. Self reports of nausea were significantly correlated with observer rated values. Tolerance of high dose metoclopramide was good except in 3 patients who left the study because of restlessness and trismus.It is concluded that high dose metoclopramide probably can be administered for several consecutive days without appreciable accumulation of the drug. Self-reporting of nausea by patients on VAS is a simple and feasible method of evaluation. The finding that metoclopramide affects nausea but not vomiting supports the hypothesis that nausea and vomiting should be evaluated separately in assessing antiemetic efficacy.     

19F-magnetic resonance spectroscopy in patients with liver metastases of colorectal cancer treated with 5-fluorouracil

The purpose of this study was to examine the uptake and metabolism of 5-fluorouracil (5-FU) in human liver metastases. Patients with liver metastases of colorectal cancer were treated with 5-FU (500/600 mg/m)+folinic acid with or without trimetrexate. The clinical application of F-magnetic resonance spectroscopy (MRS) of 5-FU in a random group of patients (n=17) was investigated. MR spectra of all patients showed 5-FU and catabolite resonances, and fluoronucleotides were also seen in seven patients. A correlation was found between maximum levels of 5-FU catabolites as measured by F-MRS and response in a group with larger metastases. However, such correlation was not observed in a group with smaller metastases, probably because of a significant contribution of normal liver tissue to the MR spectra.     

Reduced colorectal cancer incidence in type 2 diabetic patients treated with metformin: a meta-analysis

Context: Diabetic patients have a higher risk of colorectal cancer (CRC). The role of metformin in CRC incidence among type 2 diabetes mellitus (T2DM) remains controversial.

Objective: A meta-analysis was performed to evaluate the role of metformin treatment in the occurrence of CRC among T2DM patients.

Methods: Search was performed throughout PubMed, Embase, Springer databases up to November 2014. The search terms were (biguanides or metformin) and (bowel or colon or rectal or colorectal) and (cancer or neoplasm or neoplasia). Relative risk (RR) and 95% confidence interval (CI) was pooled using random-effects model or fixed-effect model basing on heterogeneity, which was calculated basing on Q statistics and χ² test. In addition, subgroup analyses were performed according to region, study design and control treatment. Finally, publication bias was evaluated using Egger’s regression test and trim and fill analysis.

Results: A total of 11 studies, including eight cohort studies and three case-control studies, were enrolled in the meta-analysis. Obvious heterogeneity was noted, and a 25% lower CRC incidence was found among diabetic patients treated with metformin (pooled RR=0.75, 95% CI: 0.66-0.86), using the random-effects model. Subgroup analyses showed that CRC incidence significantly reduced among T2DM in different regions, non-metformin treatment and cohort studies. Evidence supported significant publication for studies investigating from Egger’s regression test. Conversely, no missing data were found using trim and fill analysis.

Conclusion: In conclusion, the meta-analysis suggests metformin may reduce CRC incidence among diabetics, which is useful medical information for clinicians.     

A cell membrane correlate of tardive dyskinesia in patients treated with phenothiazines

Phenothiazine administration to psychiatric patients is associated with an increase in the structural order of platelet membranes as determined by steady-state fluorescence polarization measurements with 1,6-diphenyl-1,3,5-hexatriene (DPH), a fluorescent probe that localizes preferentially in the hydrocarbon region of cell membranes (Zubenko and Cohen 1984, 1985a, b). In this study, platelet membranes prepared from a group of psychiatric patients who developed tardive dyskinesia following chronic treatment with phenothiazines exhibited a significant elevation in DPH fluorescence polarization when compared to similar preparations from an otherwise matched group of patients who had no symptoms or history of tardive dyskinesia. The distribution of polarization values obtained for the tardive dyskinesia group displayed minimal overlap with that of an unmedicated, psychiatrically-healthy control group matched for age and gender. The fluorescence polarization of DPH-labelled platelet membranes was not significantly correlated with phenothiazine daily dose or serum cholesterol concentration in the phenothiazine-treated patient groups, or with dyskinesia severity (AIMS rating) in the tardive dyskinesia group. Patient gender and the presence of an affective disorder did not significantly correlate with DPH fluorescence polarization. The potential physiological and clinical significance of these findings is discussed.     

Detection of tumor mutant APC DNA in plasma of patients with sporadic colorectal cancer

The aim of this study was to detect mutant APC DNA of tumor origin in the plasma of patients with sporadic colorectal carcinomas. The polymerase chain reaction (PCR) and the single strand conformation polymorphism (SSCP) procedures were employed to detect DNA alterations using primers to amplify the mutation cluster region of the APC gene. APC mutations were observed in 7 out of 11 archival colonic tumor specimens examined. Matching mutations in free plasma DNA of tumor origin were detected in 3 of the 7 patients (42.8%). The results of this preliminary report indicated the presence of APC DNA in plasma harboring the identical abnormal molecular signature of tumor APC DNA. Detection methods of mutant APC DNA in blood may prove useful in the screening and monitoring of patients at risk of or with colorectal cancer.     

Platelet indices in patients with colorectal cancer

The interaction between cancer cells and platelets has been known for a long time. Although platelet indices have been also investigated in several clinical settings, it has not been exactly demonstrated in cancer patients. We investigated platelet indices in colorectal cancer patients and compared with healthy subjects. Two hundred and twenty-one colorectal cancer patients and 110 healthy subjects were enrolled into the retrospective study. Data were obtained from computerized medical records of our hospital. Medical record review was performed for all patients regarding thrombocyte indices. Platelet count (325.000/mm3 ± 265.000/mm3 vs 267.000/mm3 ± 67.000/mm3; p=0.025; respectively) and plateletcrit (Pct) (0.25% ± 0.10 vs 0.21 ± 0.05; p<0.001; respectively) were increased in patients compared with healthy subjects while mean platelet volume (MPV) and platelet distribution width (PDW) were similar. The platelet indices were not related to existence of metastasis or acute abdomen. Platelet count and Pct, but not MPV and PDW, are elevated in colorectal cancer patients. Future studies that investigate platelet morphology, function, and putative role of platelets in tumorigenesis and metatasis should be established.     

Ambient air pollution,blood mitochondrial DNA copy number and telomere length in a panel of diabetes patients

Abstract

Context: Several previous studies proposed a link between particulate matter (PM) pollution and mitochondrial DNA copy number (MtDNAcn) and telomere length (TL). However, this evidence is quite limited and inconsistent, especially on how the particle size affects the associations and on whether there exists such an association with gaseous pollutants.

Objective: We aimed to investigate the short-term associations of size-fractionated PM and gaseous pollutants with blood MtDNAcn and TL.

Methods: We conducted a longitudinal panel study involving 6 repeated measurements among 35 Type 2 diabetes patients in Shanghai, China from April to June 2013. We measured the real-time concentrations of size-fractionated PM (0.25–10?μm) and criteria gaseous pollutants. Blood MtDNAcn and TL were tested by a quantitative real-time PCR–based assay. Linear mixed-effect models were used to explore their short-term associations using multiple lag periods, after controlling for individual characteristics, time trends and weather conditions.

Results: In general, there were inverse but statistically non-significant associations between all pollutants and MtDNAcn. Coarse PM appeared to be more closely linked with MtDNAcn than smaller PM. The associations between various air pollutants and TL were generally positive but very weak. There were no clear lag patterns for these associations. The associations between air pollutants and MtDNAcn and TL were strengthened but still not significant among those who did not take statins regularly.

Conclusions: This study did not support short-term associations of PM or gaseous pollutants with blood MtDNAcn and TL in type 2 diabetes patients.     

Absence of DNA adduct in the leukocytes from breast cancer patients treated with toremifene

Tamoxifen (TAM) causes cancer in rat liver and human endometrium, whereas the carcinogenicity of its chlorinated analogue toremifene (TOR) has not been observed. To elucidate the genotoxicity of TOR, the capability of forming DNA adducts by TOR was examined in the leukocytes of patients treated with TOR. Leukocytes were collected from 27 breast cancer patients (57.7 +/- 11.4 years old) taking TOR (40 mg/day for 25 patients, 80 mg/day for one patient, and 120 mg/day for one patient; average duration, approximately 12 months) and 20 untreated breast cancer patients (58.2 +/- 12.3 years old). The DNA extracted was analyzed by (32)P-postlabeling/high-performance liquid chromatography. No DNA adducts were detected in the leukocytes of either TOR-treated or nontreated patients. Our results contrast to the previous observation detecting TAM-DNA adducts in several patients treated with TAM, indicating that TOR is less genotoxic to humans.