早期乳腺癌保留乳房术后外照射加组织间插植放疗

12例早期乳腺癌患者行乳房肿瘤扩大切除术后,配合外照射加组织间插植高剂量率近距离放疗,患侧胸壁 外照射剂量40～57Gy,局部组织间插植近距离放疗剂量6～22Gy/1～4F。8例随访满5年,5年生存率8/8,局部控 制率91.7%(11/12),1例出现照射野内一处肋骨骨折,1例乳房胸壁纤维化,美容效果满意率91.7%(11/12)。初步 研究结果提示,早期乳腺癌保守手术后外照射加组织间插植近距离放疗生存率与根治术相同,而且美容效果好。     

Prognostic significance of breast relapse after conservative treatment in node-negative early breast cancer

The prognostic significance of local relapse after conservative treatment of early stage breast carcinoma has been controversial. To determine the incidence and the prognostic value of a breast relapse, we analyzed the results obtained in a series of patients with pT1pN0 presentation of breast carcinoma treated conservatively without adjuvant medical treatment. From 1976 to 1986, 202 patients with invasive breast carcinoma of less than 2 cm without lymph node involvement were treated with surgery and radiation therapy. The overall survival rate was 97.2% at 5 years. Locoregional relapses occurred in 16 patients (7.9%). In these patients, the overall survival rate was significantly decreased as compared to that of patients without local relapse (87.5% versus 98.3% at 5 years, p less than 0.001). The probability of remaining metastasis-free was also significantly decreased (80.2% vs 91.3%, p less than 0.001). Most relapses (94%) appeared at or close to the primary site. Salvage local treatment was possible in 14/16 patients (87.5%). Age, menopausal status, size and site of primary tumor, histological grade, and boost technique did not influence significantly the risk of local relapse occurrence. We concluded that the occurrence of a breast relapse after a successful local conservative treatment is a pejorative prognostic factor predictive of a high risk of distant metastasis development. There is a need to individualize factors that could allow discrimination of patients with a high probability of local relapse and subsequent metastasis.     

An early peak of relapse after surgery for breast cancer

There is great interest among oncologists concerning what we might learn by examining the pattern of relapse after breast cancer surgery. What you see depends upon how hard you look. Up to now, investigators have examined the hazard ratio for relapse every 6-12 months. In a research paper, published in this issue of Breast Cancer Research, the Milan group have looked at the hazard ratio every three months and have found, for the first time, a distinct, very early peak of relapse in a group of premenopausal, node-positive patients not given chemotherapy or hormone therapy. What is now needed is for other groups to repeat this observation and, if found, to examine the characteristics of the tumours producing this phenomenon in order to develop hypotheses about its cause and possible treatments.     

Overexpression of betaPix-a in human breast cancer tissues

Pak interacting exchange factor (betaPix) is a recently cloned protein that contains a multidomain with many potential binding sites and is known to be involved in the regulation of Cdc42/Rac GTPases and Pak kinase activity. These domains of betaPix appear to play a critical role in the regulation of the cytoskeletal organization. The overexpression of betaPix enhances the activation of p38, which is thought to be an important downstream effector of the Rho GTPase family (Rac, Cdc42), which are involved in increased membrane ruffling and cell motility. This increase of cell mobility is an important feature of cancer invasion. We examined the expression of betaPix-a in human breast cancer tissues and adjacent normal tissues obtained from 39 breast cancer patients. Immunoblot analysis and RT-PCR revealed that betaPix-a expression was significantly increased in 37 of the 39 breast cancer tissues (94.9%) versus normal breast tissues. Immunohistochemical analysis showed that breast cancer tissues have consistently stronger immunoreactivity to betaPix-a antibodies than normal tissues. betaPix-a overexpression was inversely associated with extensive intraductal component (P<0.001). In conclusion, betaPix-a expression was found to be higher in human breast cancer tissues than in normal breast tissues, which implies a role for betaPix-a in human breast tumorigenesis. We suggest that betaPix-a may be a useful marker of malignant disease in the breast.     

早期乳腺癌外科手术方式的选择

目的分析早期乳腺癌的手术方法。方法将79例早期乳腺癌病人随机分为2组，一组病人施行根治术，另一组施行简化根治术。随访5年，比较两组病人术后并发症和局部复发率与生存率，结果早期乳腺癌根治术和简化根治术两组病例术后5年生存率及局部复发率无统计差异，而根治术术后并发症显著增多。结论早期乳腺癌首选简化根治术。     

Overexpression of cyclinD1 predicts for poor prognosis in estrogen receptor-negative breast cancer patients

CyclinD1 plays a critical role in regulating cell cycle progression. CyclinD1 mRNA and protein are overexpressed in approximately 50% of primary breast cancer cases. However, its clinical significance as a predictive factor remains unclear. One hundred and seventy-three female patients diagnosed with invasive ductal carcinoma who had undergone a mastectomy (161 patients) or breast-conserving surgery (12 patients) were followed up for 6-119 months (median 86 months) postoperatively. Immunoreactivity for monoclonal anti-cyclinD1 antibody (clone DCS-6) with paraffin-embedded carcinoma tissues was investigated using a labeled streptavidin-biotin method. Overexpression of cyclinD1 was found in 42% (73 of 173), and strongly correlated with estrogen receptor (ER) expression (p < 0.000001). Univariate analysis revealed no association between overexpression of cyclinD1 and overall survival or relapse-free survival in all patient groups. However, in the ER-negative subgroup (n = 75), overexpression of cyclinD1 was significantly correlated with shorter overall survival (p = 0.018) and relapse-free survival (p = 0.014) as well as the lymph node status and tumor size. In contrast, there were no significant associations between overexpression of cyclinD1 and clinical outcome in the ER-positive subgroup. According to Cox's multivariate analysis in the ER-negative subgroup, overexpression of cyclinD1 had the most significant effect on overall survival (p = 0.02) and relapse-free survival (p = 0.0058), followed by nodal status and histologic grade. These findings suggest that overexpression of cyclinD1 is an independent prognostic indicator in ER-negative breast cancer patients.     

Patterns of breast relapse after local excision +/- radiotherapy for early stage breast cancer

One hundred patients with breast recurrence have been identified from patients at the Royal Marsden Hospital, treated by local excision +/- radiotherapy for early stage primary invasive breast cancer between 1961 and 1985. The mean follow-up was 58 months (range 1 month - 19 years). In 74/100 patients, breast recurrence occurred within the breast parenchyma, was not associated with systemic relapse and carried a relatively good prognosis with a median survival of 77 months from the time of breast relapse. In 67 patients with parenchymal relapse in whom the site of relapse could be reliably compared with that of the original tumour, 60 (90%) patients developed recurrent tumours at or close to the primary site. In 24/100 patients, breast recurrence occurred in the overlying skin and in only two of these patients (2% of total) did recurrence actually occur within the scar tissue. Skin relapse was associated with systemic relapse and carried a relatively poor prognosis with a median survival of 36 months from the time of recurrence. The pattern of breast relapse was similar in irradiated and unirradiated patients. Skin relapse appears to be a manifestation of metastatic disease while parenchymal relapse may represent regrowth of primary tumour. This pattern of breast relapse questions the requirement for radiotherapy to the whole breast after local excision for early stage breast cancer.     

Nuclear IRS-1 predicts tamoxifen response in patients with early breast cancer

Insulin receptor substrate-1 (IRS-1) is a cytoplasmic scaffolding protein that is phosphorylated by insulin-like growth factor-I receptor and recruits downstream effectors. Recent evidence suggests that IRS-1 has a nuclear localization and function. Here we investigated whether nuclear and cytoplasmic IRS-1 levels are associated with clinico-pathological characteristics and clinical outcome in breast cancer patients. Tissue microarrays from 1,097 patients with stage I–II breast cancer were stained by immunohistochemistry for IRS-1. Nuclear and cytoplasmic IRS-1 were scored separately according to the Allred score. Nuclear IRS-1 showed a positive association with estrogen receptor (ER) (r = 0.09, P = 0.003) and progesterone receptor (PR) (r = 0.08, P = 0.008) status and a negative correlation with lymph node involvement (r = −0.10, P = 0.001). Cytoplasmic IRS-1 did not correlate with ER or PR but showed a positive correlation with tumor size (r = 0.10, P = 0.001) and S-phase fraction (r = 0.16, P < 0.001). In univariate analysis, tamoxifen-treated patients with tumors showing positive nuclear IRS-1 had a better recurrence-free survival (RFS) (P = 0.009) and overall survival (OS) (P = 0.0007), while no association was shown between cytoplasmic IRS-1 and RFS or OS in the same group of patients. In multivariate analysis of patients receiving tamoxifen, negative nuclear IRS-1 showed a significantly reduced RFS (P = 0.046) and OS (P = 0.018). Combining both PR and nuclear IRS-1, tamoxifen-treated patients with PR+/IRS-1+ tumors had a better RFS (P = 0.0003) and OS (P < 0.0001) when compared with patients with PR−/IRS-1− tumors. In conclusion, nuclear IRS-1 may be a useful marker to predict tamoxifen response in patients with early breast cancer, particularly when assessed in combination with PR.     

Rational modified radical operation in early gastric cancer

Extended dissection of regional lymph nodes, omentobursectomy, splenectomy and thoracotomy, which are performed on cases with advanced gastric cancer, are not necessary in radical operation for early gastric cancer, for the early cancer was revealed to have the metastasis to lymph node of slight degree and no metastasis to the peritoneum. This modified operation can provide us a decrease of either intraoperative blood loss or operation time, which seems to contribute to diminish the operative death and to improve the quality of postoperative life. The result was satisfactory: 5-year relative survival rate after the operation was 100.0%. Diagnostic accuracy for early cancer was also sufficient.     

Gene expression profile predicts outcome after anthracycline-based adjuvant chemotherapy in early breast cancer

Prognosis of early beast cancer is heterogeneous. Today, no histoclinical or biological factor predictive for clinical outcome after adjuvant anthracycline-based chemotherapy (CT) has been validated and introduced in routine use. Using DNA microarrays, we searched for a gene expression signature associated with metastatic relapse after adjuvant anthracycline-based CT without taxane. We profiled a multicentric series of 595 breast cancers including 498 treated with such adjuvant CT. The identification of the prognostic signature was done using a metagene-based supervised approach in a learning set of 323 patients. The signature was then tested on an independent validation set comprising 175 similarly treated patients, 128 of them from the PACS01 prospective clinical trial. We identified a 3-metagene predictor of metastatic relapse in the learning set, and confirmed its independent prognostic impact in the validation set. In multivariate analysis, the predictor outperformed the individual current prognostic factors, as well as the Nottingham Prognostic Index-based classifier, both in the learning and the validation sets, and added independent prognostic information. Among the patients treated with adjuvant anthracycline-based CT, with a median follow-up of 68 months, the 5-year metastasis-free survival was 82% in the ??good-prognosis?? group and 56% in the ??poor-prognosis?? group. Our predictor refines the prediction of metastasis-free survival after adjuvant anthracycline-based CT and might help tailoring adjuvant CT regimens.     

保留乳头乳晕复合体的改良根治术治疗早期乳腺癌患者疗效分析

背景与目的：保留乳头乳晕复合体（nipple—areolar complex,NAG）对乳腺癌患者乳房重建的美容效果和术后生活质量有重要意义。但保留NAC改良根治术治疗早期（Ⅰ、Ⅱa期）乳腺癌的肿瘤学风险一直存在着争论。本研究比较保留NAC的改良根治术与传统改良根治性手术治疗早期乳腺癌疗效。方法：在1998年1月～2003年12月间在我院接受手术的早期乳腺癌患者中,根据发病年龄、腋窝淋巴结状态、激素受体情况、肿块大小和Her-2／neu的表达状态5个变量对42例接受保留NAC改良根治术患者和84例接受传统改良根治术患者的按1：2比例进行配对的回顾性队列研究。比较两组的局部区域复发率、远处转移率、总生存率和无瘤生存率。结果：保留NAC组中位随访时间为48个月,传统改良根治组为44个月。保留NAC组5年局部区域复发率为2．44％,传统改良根治组3．21％,两者差异无统计学意义（P=0．771）。保留NAC组5年远处转移率为5．64％,传统改良根治组为4．30％,两者差异无统计学意义（P=0．654）。保留NAC组和传统改良根治组5年总生存率分别为96．00％和98．18％,差异无统计学意义（P=0．694）;5年无瘤生存率分别为91．67％和92．26％,差异无统计学意义（P=0．597）。结论：在严格把握适应症基础上行保留NAC改良根治术治疗早期乳腺癌可以和传统的改良根治术取得相似的治疗效果,但可以增强患者乳房重建的美容效果和提高术后生活质量。     

早期乳腺癌根治术后放疗预后因素分析

目的 探讨早期乳腺癌患者根治术后是否需要接受放疗.方法 回顾性分析本院1998年根治术后经病理证实腋窝淋巴结0～3个阳性的乳腺癌患者270例,其中腋窝淋巴结阴性者156例,腋窝淋巴结转移1、2、3个的分别为60、30、24例(114例).定义预后指数≥4分者为高危患者,<4分者为低危患者.生存率计算采用Kaplan-Meier法并Logrank检验.结果 腋窝淋巴结阴性与1～3阳性者10年生存率、10年无瘤生存率、平均无瘤生存时间、局部复发率、远处转移率分别为75.0%与63.2%(χ~2=4.40,P=0.036),71.2%与59.6%(χ~2=3.90,P=0.048)、(97.03±2.53)个月与(87.01±3.80)个月(t=2.28,P=0.023)、7.7%与16.7%(χ~2=5.22,P=0.022)、12.8%与21.1%(χ~2=3.27,P=0.070).高危组中未放疗者和放疗者的10年生存率分别为56%和72%(χ~2=4.07,P:0.044),局部复发率分别为24%和5%(χ~2=11.16,P=0.001),远处转移率分别为26%和16%(χ~2=2.18,P=0.140).低危组未放疗和放疗者10年生存率分别为71%和81%(χ~2=1.57,P=0.210),局部复发率分别为11%和11%(χ~2=0.01,P=0.975),远处转移率分别为13%和13%(χ~2=0.00,P=1.000).结论 T_1～T_2期腋窝淋巴结1～3个阳性乳腺癌患者根治术后可考虑放疗,预后指数的应用似乎可选择那些复发概率较大患者,从而尽量减少一部分患者接受不必要放疗.     

乳腺癌改良根治术后即刻乳房再造不同方法的临床应用

目的:探讨乳腺癌改良根治术后即刻乳房再造不同方法的适应证、手术方法及优缺点.方法:本组37例乳腺癌患者,分别采用横形腹直肌肌皮瓣带蒂转移、腹壁下动脉穿支皮瓣吻合血管游离移植、背阔肌肌皮瓣带蒂转移、单纯乳房假体置入以及不同方法相结合进行术后即刻乳房再造.结果:除2例单纯TRAM皮瓣患者近腋窝皮瓣局部坏死,1例TRAM+DIEP联合皮瓣患者下腹正中局部皮瓣脂肪液化外,余34例皮瓣全部成活,形态满意.随访5个月-10年,无腹部薄弱或腹壁疝等并发症,患者生活质量均得到提高.结论:乳腺癌术后即刻再造安全可行,不同的方法各有优缺点,应根据患者具体情况选择适合患者本人的方法进行乳房再造.     

乳腺癌改良根治术后即刻乳房再造不同方法的临床应用

目的：探讨乳腺癌改良根治术后即刻乳房再造不同方法的适应证、手术方法及优缺点。方法：本组37例乳腺癌患者,分别采用横形腹直肌肌皮瓣带蒂转移、腹壁下动脉穿支皮瓣吻合血管游离移植、背阔肌肌皮瓣带蒂转移、单纯乳房假体置入以及不同方法相结合进行术后即刻乳房再造。结果：除2例单纯TRAM皮瓣患者近腋窝皮瓣局部坏死,1例TRAM＋DIEP联合皮瓣患者下腹正中局部皮瓣脂肪液化外,余34例皮瓣全部成活,形态满意。随访5个月-10年,无腹部薄弱或腹壁疝等并发症,患者生活质量均得到提高。结论：乳腺癌术后即刻再造安全可行,不同的方法各有优缺点,应根据患者具体情况选择适合患者本人的方法进行乳房再造。     

URC测试对消化道恶性肿瘤根治术后复发监测的临意义

目的:探讨癌症尿液筛查监测试剂(URC)测试对消化道恶性肿瘤术后复发监测诊断的临床意义。方法:对100例消化道恶性肿瘤根治术后病人每月一次URC测试,与实际复发情况,进行阳性符合率、阴性符合率、灵敏度、假阳性率统计分析。结果:两家医院2年内100例患者共测480次,阳性146次(30.4%),阴性334例次(69.6%),其中真阳性124次(25.8%),真阴性310次(64.6%),阳性符合率84.9%,阴性符合率92.8%。,灵敏度83.8%,假阳性率(误诊率)6.6%。结论:URC测试对消化道恶性肿瘤根治术后复发监测有临床实用意义,能对复发早诊断提供线索,灵敏度高、误诊率低,无创简便易行,值得临床进一步研究推广。     

Overexpression of RalBP1 in colorectal cancer is an independent predictor of poor survival and early tumor relapse

The non-ABC transport protein RalBP1 has been shown to be overexpressed in various cancer cell lines and implicated in the process of metastasis formation, but its expression in tissue samples and prognostic significance has not been shown. In this study matched tumor-mucosa tissue samples from 78 CRC patients were investigated. The RalBP1 mRNA and protein levels were quantified by real-time quantitative PCR (qPCR) and ELISA. RalBP1 was found to be overexpressed in tumor at the mRNA level both overall (p = 0.027), and for stages I (p = 0.024), II (p = 0.038) and IV (p = 0.004). At the protein level, RalBP1 was only significantly overexpressed in stage IV patients (p = 0.018). Expression of RalBP1 mRNA and protein were inversely correlated (r = 0.4173; p = 0.0004). Multivariate Cox regression analysis including sex, age, stage, grade, and nodal status as covariates showed that overexpression of RalBP1 protein, but not mRNA, was an independent predictor of both decreased disease free survival (p = 0.016, RR = 6.892) and overall survival (p = 0.039, RR = 5.986). These results suggest that RalBP1 protein is an independent predictor of poor survival and early relapse for CRC patients. Owing to its multifunctional intermediary role in cell survival, chemotherapeutic resistance, and metastasis formation, RalBP1 represents a promising novel therapeutic target.     

Overexpression of the cell cycle inhibitor p16INK4A in high-grade prostatic intraepithelial neoplasia predicts early relapse in prostate cancer patients.

Prostate cancer (PC) is the most commonly diagnosed male cancer in industrialized societies. No molecular markers of PC progression or outcome with proven clinical utility have been described. Because the loss of normal cell cycle control is an early event in the evolution of cancer, we sought to determine whether changes in expression of the cyclin-dependent kinase inhibitor, p16INK4A, predicted outcome in this disease. We screened a cohort of 206 patients with clinically localized PC treated with radical prostatectomy for overexpression of the INK4A gene, the product of which inactivates the G1-phase cyclin dependent kinases, Cdk4 and Cdk6. p16INK4A protein expression was evaluated by immunohistochemistry in areas of high-grade intraepithelial neoplasia (HGPIN), a precursor to invasive disease, and of cancer in the same specimen. Data were evaluated for disease relapse using the Kaplan-Meier method and in a Cox proportional hazards model by assessing p16INK4A status in areas of HGPIN and cancer with other variables of known clinical relevance. Overexpression of p16INK4A in HGPIN and cancer was correlated with, but independent of, pathological stage and was associated with early relapse in PC patients treated with radical prostatectomy (log-rank test, P < 0.001). In a multivariate model adjusted for Gleason grade, pretreatment prostate-specific antigen levels, pathological stage, and margin status, overexpression of p16INK4A in HGPIN was an independent predictor of disease relapse and increased the risk of recurrence 2.24-fold (95% confidence interval, 1.28-3.93). These data provide the first evidence for a prognostic marker in HGPIN. The clinical utility of p16INK4A status in stratifying patients for aggressive treatment very early in the disease process, potentially several years prior to the onset of invasive disease, requires further investigation.     

Overexpression of both CXC chemokine receptor 4 and vascular endothelial growth factor proteins predicts early distant relapse in stage II-III colorectal cancer patients.

PURPOSE: CXC chemokine receptor 4 (CXCR4) and vascular endothelial growth factor (VEGF) are implicated in the metastatic process of malignant tumors. However, no data are currently available on the biological relationship between these molecules in colorectal cancer. We studied whether CXCR4 and VEGF expression could predict relapse and evaluated in vitro the contribution of CXCR4 in promoting clonogenic growth, VEGF secretion, and intercellular adhesion molecule-1 (ICAM-1) expression of colorectal cancer cells. EXPERIMENTAL DESIGN: CXCR4 and VEGF were studied in colorectal cancer tissues and in Lovo, HT29, and SW620 colorectal cancer cell lines by immunohistochemistry. Correlations with baseline characteristics of patients and tumors were analyzed by chi2 test. VEGF secretion induced by CXCL12 was measured by ELISA. The effect of CXCL12 on ICAM-1 expression was evaluated by flow cytometry. Clonogenic growth induced by CXCL12 was determined by clonogenic assays. Functional effects induced by CXCL12 were prevented by the administration in vitro of AMD3100, a bicyclam noncompetitive antagonist of CXCR4. RESULTS: Seventy-two patients, seen between January 2003 and January 2004, were studied. CXCR4 was absent in 16 tumors (22.2%); it was expressed in < or = 50% of cells in 25 (34.7%) tumors and in >50% of cells in 31 (43.0%) tumors. VEGF was absent in 17 (23.6%) tumors; it was expressed in < or = 50% of cells in 16 (22.2%) tumors and in >50% of cells in 39 (54.2%) tumors. There was a significant association between CXCR4 expression and lymph nodal status (P = 0.0393). There were significant associations between VEGF and tumor invasion (P = 0.0386) and lymph nodal involvement (P = 0.0044). American Joint Committee on Cancer stage (P = 0.0016), VEGF expression (P = 0.0450), CXCR4 expression (P = 0.0428), and VEGF/CXCR4 expression (P = 0.0004) had a significant prognostic value for disease-free survival with univariate analysis. The predictive ability of the American Joint Committee on Cancer stage and of the concomitant and high expression of VEGF and CXCR4 was confirmed by multivariate analysis. Prognosis is particularly unfavorable for patients whose primary tumors express CXCR4 and VEGF in >50% of cells (median disease-free survival in relapsed patients, 5.8 months; hazard ratio of relapse, 8.23; 95% confidence interval, 7.24-14.29). In clonogenic assays, CXCL12 (20 ng/mL/d) significantly increased the number of clones in SW620, HT29, and Lovo cells at 7 and 14 days. Again, CXCL12 was able to stimulate VEGF secretion in SW620, HT29, and Lovo cells as well as up-regulated ICAM-1. These effects were prevented by the administration of AMD3100 (1 micromol/L). CONCLUSIONS: We have shown that concomitant and high expression of CXCR4 and VEGF is a strong and independent predictor of early distant relapse in colorectal cancer. CXCR4 triggers a plethora of phenomena, including stimulation of clonogenic growth, induction of VEGF release, and ICAM-1 up-regulation. These data support the inhibition of CXCR4 to prevent the development of colorectal cancer metastasis.