直肠腺癌中血管内皮生长因子和细胞增生核抗原的表达及其与放化疗敏感性的关系

Objective: To investigate the expressions of vascular endothelial growth factor (VEGF) and proliferating cell nuclear antigen (Ki-67) in patients with rectal adenocarcinoma and their associations with neoadjuvant therapy. Methods: The expressions of Ki-67 and VEGF in 32 cases of rectal adenocarcinoma, including both pretreatment tumor biopsies and postoperative specimen, were detected by immunohistochemistry using specific antibodies, and were correlated with clinico-pathological factors. Results: The intensity of VEGF staining was significantly correlated with lymph nodal metastasis (P = 0.033), depth of tumor invasion (P = 0.007) and tumor stage (P = 0.016), but not with histological types, tumor sizes, patients' ages and genders (P > 0.05). Low level of VEGF expression had significant correlation with the high sensitivity of response to neoadjuvant therapy (P = 0.016). The transient increase of VEGF expression could be seen after neoadjuvant therapy (P = 0.035). Ki-67 labeling index (Ki-67-LI) was significantly correlated with lymph node metastasis (P = 0.028), but not correlated to tumor sizes, patients' ages and genders (P > 0.05). Tumors with lower Ki-67-LI were more sensitive to neoadjuvant therapy (P = 0.032). The Ki-67 level decreased after neoadjuvant therapy, but no statistical significance was found (P > 0.05). Conclu-sion: Our results demonstrate that the expression of VEGF and Ki-67 in pretreatment rectal adenocarcinoma biopsies may be predictive of tumor response to neoadjuvant therapy.     

直肠腺癌中血管内皮生长因子和细胞增生核抗原的表达及其与放化疗敏感性的关系

目的 探讨血管内皮生长因子(VEGF)和细胞增生核抗原(Ki67)在直肠腺癌中的表达及其与放化疗敏感性的关系.方法 采用免疫组化二步法,检测接受新辅助放化疗的32例直肠腺癌患者的活检标本及手术切除标本中VEGF和Ki67的表达.结果 VEGF在直肠腺癌中的表达与肿瘤侵袭程度、淋巴结转移和TNM分期有关(均P＜0.05),与患者的性别、年龄、肿瘤大小及病理类型无关(均P＞0.05);VEGF阴性表达者对放化疗敏感(P=0.016);新辅助放化疗后,VEGF的表达升高(P＜0.05).Ki67在直肠腺癌中的表达与淋巴结转移有关(P=0.028),与患者的性别、年龄、肿瘤大小、病理类型、TNM分期和侵袭程度无关(均P＞0.05);Ki67阴性和低表达者对放化疗敏感(P=0.032);新辅助放化疗后,Ki67的表达有下降趋势,但并无统计学意义(P＞0.05).结论 VEGF和Ki67的表达可作为预测直肠腺癌患者对新辅助放化疗敏感性的参考指标.     

A Panel of Tumor Biomarkers to Predict Complete Pathological Response to Neoadjuvant Treatment in Locally Advanced Rectal Cancer

Pathological complete response after neoadjuvant chemoradiotherapy in locally advanced rectal cancer patients is related to a favorable prognosis. The identification of early biomarkers predictive of pathological complete response would help optimize the multimodality management of the patients. A panel of 11 tumor-related proteins was investigated by immunohistochemistry in the pretreatment biopsy of a group of locally advanced rectal cancer patients to identify early biomarkers of pathological complete response to neoadjuvant chemoradiotherapy. A mono-institutional retrospective cohort of 95 stage II/III locally advanced rectal cancer patients treated with neoadjuvant chemoradiotherapy and surgery was selected based on clinical–pathological characteristics and the availability of a pretreatment tumor biopsy. Eleven selected protein marker expression (MLH1, GLUT1, Ki67, CA-IX, CXCR4, COX2, CXCL12, HIF1a, VEGF, CD44, and RAD51) was investigated. The optimal cutoff values were calculated by receiver operating characteristic curve analysis. Classification and regression tree analysis was performed to investigate the biomarker interaction. Patients presenting either Ki-67 or HIF1a or RAD51 below the cutoff value, or CXCR4 or COX2 above the cutoff value, were more likely to get a pathological complete response. Classification and regression tree analysis identified three groups of patients resulting from the combination of Ki-67 and CXCR4 expression. Patients with high expression of Ki-67 had the lowest chance to get a pathological complete response (18%), as compared to patients with low expression of both Ki-67 and CXCR4 (29%), and patients with low Ki-67 and high CXCR4 expression (70%). Pretreatment Ki-67, CXCR4, COX2, HIF1a, and RAD51 in tumor biopsies are associated with pathological complete response after neoadjuvant chemoradiotherapy in locally advanced rectal cancer. A combined evaluation of Ki-67 and CXCR4 would increase their predictive potential. If validated, their optimal cutoff could be used to select patients for a tailored multimodality treatment.     

A Panel of Tumor Biomarkers to Predict Complete Pathological Response to Neoadjuvant Treatment in Locally Advanced Rectal Cancer

Pathological complete response after neoadjuvant chemoradiotherapy in locally advanced rectal cancer patients is related to a favorable prognosis. The identification of early biomarkers predictive of pathological complete response would help optimize the multimodality management of the patients. A panel of 11 tumor-related proteins was investigated by immunohistochemistry in the pretreatment biopsy of a group of locally advanced rectal cancer patients to identify early biomarkers of pathological complete response to neoadjuvant chemoradiotherapy. A mono-institutional retrospective cohort of 95 stage II/III locally advanced rectal cancer patients treated with neoadjuvant chemoradiotherapy and surgery was selected based on clinical–pathological characteristics and the availability of a pretreatment tumor biopsy. Eleven selected protein marker expression (MLH1, GLUT1, Ki67, CA-IX, CXCR4, COX2, CXCL12, HIF1α, VEGF, CD44, and RAD51) was investigated. The optimal cutoff values were calculated by receiver operating characteristic curve analysis. Classification and regression tree analysis was performed to investigate the biomarker interaction. Patients presenting either Ki-67 or HIF1α or RAD51 below the cutoff value, or CXCR4 or COX2 above the cutoff value, were more likely to get a pathological complete response. Classification and regression tree analysis identified three groups of patients resulting from the combination of Ki-67 and CXCR4 expression. Patients with high expression of Ki-67 had the lowest chance to get a pathological complete response (18%), as compared to patients with low expression of both Ki-67 and CXCR4 (29%), and patients with low Ki-67 and high CXCR4 expression (70%). Pretreatment Ki-67, CXCR4, COX2, HIF1α, and RAD51 in tumor biopsies are associated with pathological complete response after neoadjuvant chemoradiotherapy in locally advanced rectal cancer. A combined evaluation of Ki-67 and CXCR4 would increase their predictive potential. If validated, their optimal cutoff could be used to select patients for a tailored multimodality treatment.Key words: Rectal cancer, Neoadjuvant chemoradiotherapy (nCRT), Pathological complete response (pCR), Predictive biomarkers, Immunohistochemistry (IHC)     

Predictive effect of p53 and p21 alteration on chemotherapy response and survival in locally advanced adenocarcinoma of the esophagus

BACKGROUND: Cell cycle regulating proteins (p53/p21) and proliferation index Ki-67 have been associated with prognosis and response to chemotherapy. The aim of this study was to determine the significance of these molecular markers on tumor response and prognostic effect in a group of esophageal cancer patients treated with neoadjuvant chemotherapy. PATIENTS AND METHODS: Immunohistochemical expression of p53/p21 and Ki-67 was examined in pre-treatment biopsy specimen of 30 patients, in phase II neoadjuvant studies for locally advanced adenocarcinoma of the esophagus, who underwent surgery. Seven patients (23%) had progressive disease. Resection was achieved in all responders (n=23; 77%) and histochemical expression of the above-mentioned proliferating markers was examined in pre-treatment and resection specimens after chemotherapy. RESULTS: Responders had a significantly better survival compared to non-responders (p=0.001). Expression of p53, p21 and high Ki-67 in pre-treatment specimens was 73% (22/30), 63% (19/30) and 30% (10/30), respectively and was not related to response to chemotherapy. However, alteration in expression of p53-positivity in the pre-treatment specimens to p53-negativity in the resection specimens and p21-negativity to p21-positivity in 6 of the 23 (26%) resected tumors was correlated with better response and survival (p=0.011). CONCLUSION: Data from this study showed that alteration of p53 and p21 expression rather than the initial expression seems to be related to chemotherapy response and overall survival in patients with esophageal adenocarcinoma.     

Prognostic value of Smac expression in rectal cancer patients treated with neoadjuvant therapy

The objective was to evaluate expression of second mitochondria-derived activator of caspase (Smac) expression before and after treatment in patients treated with preoperative chemoradiotherapy (CRT) for locally advanced rectal cancer and to correlate the clinicopathological characteristics and level of Smac expression with pathologic response and outcome. Expression of biomarker was evaluated by immunohistochemistry in tumor samples from 98 patients with clinical Stage II and III rectal cancer treated with preoperative pelvic radiotherapy plus concurrent chemotherapy. All patients received a standardized total mesorectal excision procedure after a long interval of 4–6 weeks. For Smac, patients with a good response to neoadjuvant CRT tended to have higher pre-therapy levels (P = 0.007). The level of Smac expression decreased after neoadjuvant therapy (P = 0.016). High expression of Smac before CRT, and high Dworak’s tumor regression grade (TRG) were significantly associated with improved 5-year disease-free survival (P < 0.05). Pretreatment nodal status also was significantly associated with 5-year disease-free survival and 5-year local relapse-free survival (P < 0.05). Multivariate analysis confirmed that the pretreatment expression of Smac and Lymph nodal status were independent prognostic factors. Our study suggests that high expression of Smac before neoadjuvant CRT could predict good outcome in locally advanced rectal cancer patients.     

Platinum-Based Chemotherapy in Lung Cancer Affects the Expression of Certain Biomarkers Including ERCC1

Chemotherapies are widely used in the treatment of lung cancer. However, little is known about their effect in the expression of different tissue markers. Seventeen lung cancer tissue blocks obtained by bronchoscopic biopsies together with their corresponding surgical biopsies after neoadjuvant chemotherapy were studied. They included 9 adenocarcinomas (ADC) and 8 squamous cell carcinomas (SCC). Immunohistochemistry was performed on formalin-fixed, paraffin-embedded tissues to study the expression of Ki-67, p53, Bcl-2, Bax, Fas-ligand and ERCC1 (excision repair cross-complementation group 1). Out of 17 NSCLC 6 expressed proapoptotic markers and 4 expressed antiapoptotic markers, while in 7 cases the apoptotic markers did not show detectable changes after neoadjuvant chemotherapy. Six of 17 bronchoscopic NSCLC cases expressed increased level of Ki-67 after neoadjuvant treatment. Eight bronchoscopic NSCLC tissues (6 SCC, 2 ADC) expressed ERCC1. All but one ADC became ERCC1 negative after neoadjuvant therapy. There was no newly expressed ERCC1 positive case in the surgical biopsy group. Platinum-based neoadjuvant chemotherapy had no effect on the apoptotic activity of 17 patients’ tumor specimen, however, 6 of 17 bronchoscopic NSCLC cases expressed increased level of Ki-67 after neoadjuvant treatment, in 3 cases the level of Ki-67 became decreased, while 8 cases had no detectable change of proliferation activity. The results of the present study suggest that platinum-based chemotherapy probably induces a selection of tumor cells with more aggressive phenotype, and also affects the expression of tissue marker (ERCC1) that could have predictive value.     

Smac表达水平对预测直肠癌术前放疗敏感性的临床意义

背景与目的:直肠癌患者术前放疗效果个体差异大,寻找与放疗敏感性相关的生物学标志物,对于直肠癌的个体化治疗有着重要的临床意义。本研究旨在探讨Smac蛋白表达与直肠癌术前放疗病理反应程度的关系,评价Smac蛋白表达水平预测直肠癌术前放疗敏感性的价值。方法:收集我院2002年1月至2006年12月期间接受术前放疗的42例直肠癌病例资料,评价其放疗后病理反应程度,免疫组织化学方法检测手术治疗前活检标本和手术后切除标本中Smac蛋白的表达水平,分析活检组织中Smac蛋白表达水平与病理反应程度的关系,以及放疗前后蛋白表达水平的变化。结果:直肠癌术前放疗后病理反应良好,有效率达73.8%,联合放化疗者优于单纯放疗者(P<0.05);而直肠癌组织中Smac蛋白的表达水平与单纯术前放疗效果密切相关,Smac蛋白高表达者术前放疗有效率(83.3%)明显优于低表达者(25.0%),并且肿瘤组织放疗后Smac蛋白表达水平有明显下降。结论:直肠癌组织中Smac蛋白表达水平可作为术前放疗敏感性的预测因子。     

VEGF as a predictive marker of rectal tumor response to preoperative radiotherapy

BACKGROUND: Neoadjuvant radiotherapy for rectal cancer may result in tumor downstaging or complete tumor regression leading to greater sphincter preservation. The identification of molecular predictive markers of tumor response to preoperative radiotherapy would provide an additional tool for selecting patients most likely to benefit from treatment. The aim of this study was to determine whether VEGF expression in preirradiation tumor biopsies is a useful predictive marker of tumor response in patients with rectal cancer undergoing preoperative radiotherapy. METHODS: Immunohistochemistry for VEGF was performed on 59 preirradiation biopsies from patients with completely responsive (ypT0) or nonresponsive tumors after preoperative radiotherapy. VEGF positivity was evaluated using several scoring methods and the association between VEGF and tumor response was compared. The distribution of VEGF scores was obtained as well as the mean VEGF expression in the two response groups. RESULTS: The mean VEGF expression in nonresponsive tumors (NR) was significantly greater than in completely responsive tumors (CR) (P = 0.0035). Nearly half (47%) of all CR tumors had a VEGF expression of 10% or less. Eleven tumors were negative (0% immunoreactivity) for the protein and all of these (100%) were complete responders. Fifty-two percent of the NR tumors had VEGF scores of 80% or greater. The four scoring methods used to determine the association between VEGF and tumor response each produced significant results (P < 0.05). CONCLUSIONS: The results of this study indicate that VEGF assessed immunohistochemically from preirradiation tumor biopsies may be a useful marker of rectal tumor response to preoperative radiotherapy.     

Apoptosis as a cellular predictor for histopathologic response to neoadjuvant radiochemotherapy in patients with rectal cancer

BACKGROUND: Tumor shrinkage by preoperative radiochemotherapy (RCT) can markedly improve surgery in locally advanced (T4) rectal cancer with clear resection margins and may enable sphincter preservation in low-lying tumors. However, tumor response varies considerably, even among tumors treated according to the same protocol. If one is able to identify patients with highly radio-responsive tumors at the time of diagnosis, a selective and individualized policy of preoperative RCT might be pursued. METHODS: The apoptotic index (AI), Ki-67, p53, and bcl-2 were evaluated by immunohistochemistry on pretreatment biopsies from 44 patients treated uniformly according to a prospective neoadjuvant RCT protocol (CAO/AIO/ARO-94). Treatment response was assessed histopathologically in the resected surgical specimen, using a five-point grading system. Expression of each marker was correlated with tumor response and relapse-free survival after curative surgery. RESULTS: Tumors with complete (n = 3) or good (n = 28) response to RCT showed significantly higher pretreatment levels of apoptosis (mean AI: 2.06%) than tumors with moderate (n = 7), minimal (n = 5), or no regression (n = 1) from RCT (AI: 1.44%, p = 0.003). The AI was significantly related to Ki-67 (p = 0.05), but not to p53 and bcl-2 status. Tumor regression and AI best predicted relapse-free survival after combined modality treatment and curative surgery. CONCLUSION: Spontaneous apoptosis in rectal cancer may serve as an important predictor of tumor regression from RCT in rectal cancer and as a significant prognosticator of relapse-free survival. Thus, this molecular marker may finally help to tailor therapy with regard to (neo-) adjuvant treatment of rectal cancer.     

Gene Expression Profiles of Epidermal Growth Factor Receptor,Vascular Endothelial Growth Factor and Hypoxia-inducible Factor-1 with Special Reference to Local Responsiveness to Neoadjuvant Chemoradiotherapy and Disease Recurrence After Rectal Cancer Surgery

AimsTo establish a causal relationship between the gene expression profiles of angiogenetic molecular markers, including epidermal growth factor receptor (EGFR), vascular endothelial growth factor (VEGF) and hypoxia-inducible factor-1 (HIF-1), in rectal cancer and the local responsiveness to neoadjuvant chemoradiotherapy and subsequent disease recurrence.Materials and methodsWe examined the pre-treatment tumour biopsies (n = 40) obtained from patients with rectal adenocarcinoma (clinical International Union Against Cancer stage ll/III) who were scheduled to receive neoadjuvant 5-fluorouracil-based chemoradiotherapy for EGFR, VEGF and HIF-1 expression by quantitative real-time polymerase chain reaction.ResultsResponders (patients with significant tumour regression, i.e. pathological grades 2/3) showed significantly lower VEGF, HIF-1 and EGFR gene expression levels than the non-responders (patients with insignificant tumour regression, i.e. pathological grades 0/1) in the pre-treatment tumour biopsies. The elevated expression level of each gene could predict patients with a low response to chemoradiation. During the median follow-up of all patients (41 months; 95% confidence interval 28–60 months), 6/40 (15%) developed disease recurrence. Although local responsiveness to neoadjuvant chemoradiotherapy was associated with neither local nor systemic disease recurrence, lymph node metastasis and an elevated VEGF gene expression level were independent predictors of systemic disease recurrence. The 3-year disease-free survival rates of the patients with lower VEGF or EGFR expression levels were significantly lower than those of patients with higher VEGF or EGFR expression levels.ConclusionsAnalysing VEGF expression levels in rectal cancer may be of benefit in estimating the effects of neoadjuvant chemoradiotherapy and in predicting systemic recurrence after rectal cancer surgery.     

Predictive value of tumor Ki-67 expression in two randomized trials of adjuvant chemoendocrine therapy for node-negative breast cancer

Several small studies have reported that having a high percentage of breast tumor cells that express the proliferation antigen Ki-67 (ie, a high Ki-67 labeling index) predicts better response to neoadjuvant chemotherapy. However, the predictive value of a high Ki-67 labeling index for response to adjuvant chemotherapy is unclear. To investigate whether Ki-67 labeling index predicts response to adjuvant chemoendocrine therapy, we assessed Ki-67 expression in tumor tissue from 1924 (70%) of 2732 patients who were enrolled in two randomized International Breast Cancer Study Group trials of adjuvant chemoendocrine therapy vs endocrine therapy alone for node-negative breast cancer. A high Ki-67 labeling index was associated with other factors that predict poor prognosis. Among the 1521 patients with endocrine-responsive tumors, a high Ki-67 labeling index was associated with worse disease-free survival but the Ki-67 labeling index did not predict the relative efficacy of chemoendocrine therapy compared with endocrine therapy alone. Thus, Ki-67 labeling index was an independent prognostic factor but was not predictive of better response to adjuvant chemotherapy in these studies.     

细胞增殖标志物Ki-67与乳腺癌

分子标志物在乳腺癌的治疗中已经得到了广泛应用,细胞增殖标志物Ki-67的表达与乳腺癌的临床病理特征及预后相关联,并且在评估新辅助化疗及内分泌治疗的疗效方面具有重要的预测价值.Ki-67高表达可作为乳腺癌的不良预后因素,其与肿瘤的发展、转移和预后高度相关.     

Gene expression profiles of tumor regression grade in locally advanced rectal cancer after neoadjuvant chemoradiotherapy

Tumor regression grading (TRG) reportedly has prognostic value in rectal cancer patients after pre-operative chemoradiotherapy (CRT). The aim of this retrospective study was to differentiate gene expression profiles based on TRG in residual cancer cells after CRT. We evaluated pathological response using the criteria of four TRG systems: the Japanese Society for the Cancer of Colon and Rectum (JSCCR), Mandard, Dworak and R?del. Total RNA was obtained using microdissection from 52 locally advanced rectal cancer specimens from patients who underwent pre-operative CRT to examine the expression levels of 20 genes [PCNA, MKI67, CDKN1A (p21Cip1), CDK2, CHEK1, PDRG1, LGR5, PROM1 (CD133), CD44, SOX2, POU5F1 (OCT4), LKB1, VEGF, EGFR, HGF, MET, HIF1, GLUT1, BAX and BCL2] using real-time quantitative RT-PCR. Gene expression was compared across the four TRG systems. LGR5 gene expression levels in CRT non-responders were significantly higher than in responders in all four grading systems. Patients with elevated PDRG1 and GLUT1 gene expression had poor pathological response in three TRG systems (JSCCR, Dworak and R?del). MKI67 gene expression in non-responders was significantly higher than in responders in two grading systems (JSCCR and R?del). While, BAX gene expression in responders was significantly higher than in non-responders in the Mandard TRG system. The results of this study suggest that TRG may reflect characteristics, such as proliferative activity, stemness potency and resistance to hypoxia, of residual cancer cells following pre-operative CRT.     

Dynamic expression profile of p21WAF1/CIP1 and Ki-67 predicts survival in rectal carcinoma treated with preoperative radiochemotherapy.

PURPOSE: We investigated p53 and its downstream effectors p21WAF1/CIP1, BAX, and hMSH2 as well as the proliferation marker Ki-67 (mki-67/MIB-1) in patients undergoing preoperative radiochemotherapy for rectal carcinoma to identify prognostic and predictive factors. The focus of this study was on the dynamics of these genetic markers in a longitudinal study-that is, before and after radiochemotherapy. PATIENTS AND METHODS: Expression of p53, BAX, p21WAF1/CIP1, Ki-67, and hMSH2 was investigated by immunohistochemistry in pre- and posttherapeutic tumor samples in 66 patients. Tumor DNA was screened for p53 mutations by single-strand conformation polymorphism-polymerase chain reaction (SSCP-PCR). Paired tumor samples (pretherapy and posttherapy) were collected prospectively. RESULTS: Patients with a decrease in p21 expression following radiochemotherapy had better disease-free survival (P =.03). Similarly, patients with an increase in proliferative activity as measured by increased Ki-67 expression posttherapy had better disease-free survival (P <.005). In addition, we observed a significantly better prognosis for patients with high hMSH2 expression. In contrast, pretherapeutic levels of p53, BAX, or p21 expression and p53 mutation had no prognostic value, indicating that the combination of radiotherapy and chemotherapy might override defects in these genes. CONCLUSION: These findings are novel and support the clinical relevance of p21 in the suppression of both proliferation and apoptosis. Thus, the dynamic induction of p21WAF1/CIP1 was associated with a lower proliferative activity but an ultimately worse treatment outcome following neoadjuvant radiochemotherapy and tumor resection. Induction of p21, therefore, represents a novel resistance mechanism in rectal cancer undergoing preoperative radiochemotherapy.     

Predictive factors for the effectiveness of neoadjuvant chemotherapy and prognosis in triple-negative breast cancer patients

Purpose

Triple-negative breast cancers (TNBCs) do not derive benefit from molecular-targeted treatments such as endocrine therapy or anti-HER2 therapy because they lack those molecular targets. On the other hand, TNBCs have been shown to respond to neoadjuvant chemotherapy (NAC). In this study, we analyzed TNBC patients who were treated with NAC at Osaka National Hospital over a recent 5-year period to clarify the predictive factors for NAC and prognostic factors.

Patients and methods

Thirty-three TNBC patients underwent sequential NAC with anthracycline (FEC100: 5FU 500 mg/m², epirubicin 100 mg/m², and cyclophosphamide 500 mg/m²/q3w, 4 courses) and taxanes (paclitaxel 80 mg/m²/qw, 12 courses or docetaxel 75 mg/m²/q3w, 4 courses) from May 2003 to July 2008. Pre-therapeutical and surgical specimens were studied for expressions of ER, PgR, HER-2, EGFR, cytokeratin 5/6, Ki-67, p53 and androgen receptor by immunohistochemistry (IHC). We analyzed clinicopathological factors and molecular markers in regard to the response to NAC and prognosis.

Results

Pathological complete response (pCR) was achieved in 12 TNBC patients (36%). The pCR rate in the basal-like phenotype was significantly lower than in the non-basal-like phenotype (23 vs. 64%, respectively: P = 0.02). High pre-operative expressions of Ki-67 (≥50%) and HER-2 (2+) were considered as predictive factors for a better response from NAC. Pre-operative Ki-67 expression showed a significant correlation with disease-free survival (DFS) and a lower expression of Ki-67 (<50%) after NAC was favorable for DFS among non-pCR patients.

Conclusions

A non-basal-like phenotype and higher expressions of Ki-67 and HER-2 (2+) were favorable factors for NAC. However, a higher expression of Ki-67 on the surgical specimen after NAC was also a poor prognostic factor.     

Expression of Ki-67, p53 and VEGF in Pediatric Neuroblastoma

Background: Neuroblastoma (NB), is a neuroectodermal tumor derived from neural crest cells, and it is thesecond most common pediatric malignant tumor. The biological and clinical behavior of NB is very heterogeneous.This study was conducted to evaluate the expression of Ki-67, p53 and VEGF markers in tissues obtained fromNB patients with different histologic types and stage. Materials and Methods: Tissue microarray (TMA) blockswere constructed from paraffin blocks of the NB tissues. Immunohistochemical staining was performed on TMAsections to detect the expression of Ki-67, p53 and VEGF markers. The association between the expression ofthese markers and clinicopathological parameters were then analyzed. Results: We had 18 patients with NB,one patient with ganglioneuroblastoma (GNB) and one with ganglioneuroma. Ki-67 was expressed in 13 (65%)tumors, and negatively correlated with age, prognosis, histologic type and stage of NB (all p<0.05). High andmoderate expression of VEGF was found in 5% (1/20) and 65% (13/20) of the tumors, respectively; and it waspositively correlated with age, prognosis and histologic types (all p<0.05) and negatively correlated with MKI(mitosis-karyorrhexis index). p53 expression was observed in 10% (2/20) of the tumors, which showed a relativecorrelation with MKI (p value=0.07). Conclusions: VEGF as a candidate for anti-angiogenic targeted therapywas correlated with the development and progression of NB; therefore, VEGF along with Ki-67 can serve as avaluable marker for the prognosis of this tumor type.     

Molecular responses of rectal cancer to preoperative chemoradiation.

BACKGROUND AND PURPOSE: Some rectal cancers respond well to preoperative neoadjuvant therapy while others are inherently resistant or develop resistance during the treatment. To understand the mechanism underlying these differences, several markers that might be prognostic or predictive of downstaging in response to chemoradiotherapy in patients with rectal cancer were evaluated. MATERIAL AND METHODS: Thirty patients were enrolled in this study. All were treated with preoperative chemoradiation (45Gy in 25 fractions+5-FU). Paraffin-embedded sections obtained before and after therapy were stained by H&E, for COX-2, and Ki67. In addition, osteopontin and IL-6 concentrations were determined in blood samples obtained before, during, and after therapy. RESULTS: COX-2 expression increased in 67% (n=8/12) of the patients from a median of 0% before to 74% after therapy (p=0.009). Ki67 median positivity diminished from 90% to 45% in 83% (n=10/12) of cases (p=0.007). Osteopontin expression showed no significant changes during therapy, whereas IL-6 expression levels increased in 70% (n=19/27) of all patients (p<0.001). For osteopontin and IL-6, patients with a complete response tended to have lower pre-therapy levels. Moreover, osteopontin was much higher before (p=0.02) and after therapy (p=0.01) in patients who later developed metastases. CONCLUSIONS: Chemoradiotherapy seems to affect expression of COX-2 and Ki67 which indicates that these proteins might be of importance in predicting long-term outcome. Moreover, osteopontin might be a marker of metastases.     

Evaluation of ER and Ki-67 proliferation index as prognostic factors for survival following neoadjuvant chemotherapy with doxorubicin/docetaxel for locally advanced breast cancer

Background The aim of the study was to identify reliable predictive biological markers for treatment outcome following neoadjuvant adriamycin/docetaxel (AT) chemotherapy in locally advanced breast cancer patients. Materials and methods This study was a phase II study on AT neoadjuvant chemotherapy in locally advanced breast cancer patients. Patients received 50 mg/m² of doxorubicin intravenously (IV) over 15 min followed by docetaxel 75 mg/m² infused over 1 h, repeated every 3 weeks for three cycles. Surgery was performed within 3–4 weeks following the last cycle of chemotherapy. We analyzed the pre-treatment and post-treatment expression levels of ER, PgR, HER-2, Ki-67 proliferation index, and p53 and examined the correlation between the markers and clinical parameters with treatment response, overall survival and relapse-free survival following neoadjuvant treatment. Results From July 2001 to September 2004, 61 patients were enrolled. The meaningful parameters adversely influencing survival were post-treatment ER(−) status (P = 0.013) and post-treatment Ki-67 index above 1.0% (P = 0.013). At the multivariate level, the post-treatment Ki-67 proliferation index ≤ 1.0 was the only meaningful prognostic factor for better survival (P = 0.033). Notably, tumors with Ki-67 index ≤ 1.0 were more likely to express ER with statistical significance (P = 0.002). Tumors with ER(+) and Ki-67 index ≤ 1.0 showed the highest survival rate, followed by ER(+) and Ki-67 index > 1.0%, ER(−) and Ki-67 ≤ 1.0%, and ER(−) and Ki-67 > 1.0% with the worst survival (P = 0.033). Conclusion Collectively, post-treatment ER status and Ki-67 proliferation index were prognostic of overall survival following neoadjuvant AT chemotherapy.     

Neoadjuvant concurrent paclitaxel and radiation in stage II/III breast cancer.

PURPOSE: The aim of this study was to determine the safety and pathologic response rates following neoadjuvant paclitaxel and radiation in patients with stage II/III breast cancer and to evaluate the use of sequential biopsies to allow an in vivo assessment of biological markers as potential predictive markers of response to this regimen. PATIENTS AND METHODS: Patients with high-risk, operable breast cancer were treated with three cycles of paclitaxel 175 mg/m2 every 3 weeks, followed by twice-weekly paclitaxel 30 mg/m2 and concurrent radiation. Core biopsies were obtained at baseline and 24 to 72 hours after the first cycle of paclitaxel. After completing neoadjuvant treatment, patients underwent definitive surgery. The primary end point was pathologic complete response, which is defined as the absence of any invasive cancer at surgery. Potential markers of therapeutic response were evaluated including markers of proliferation, apoptosis, p21, HER2, estrogen receptor, and progesterone receptor status. RESULTS: Of the 38 patients enrolled, 13 (34%) had a pathologic complete response. There was no significant difference in baseline Ki-67 between responders (35%) and nonresponders (28%; P = 0.45). There was also no significant change in Ki-67 following paclitaxel administration. Despite this lack of immunohistologic change in proliferative activity, baseline mitotic index was higher for patients with pathologic complete response over nonresponders (27 versus 10, P = 0.003). Moreover, the increase in mitotic index following paclitaxel administration was associated with pathologic complete response. CONCLUSIONS: Neoadjuvant paclitaxel/radiation is effective and well tolerated. Tumor proliferation at baseline and response to chemotherapy as measured by mitotic activity may serve as an important indicator of pathologic response to neoadjuvant paclitaxel/radiation.