Prognostic factors in advanced ovarian cancer

In this review, different factors with suspected effect on survival of patients with advanced ovarian cancer are analysed. The volume of residual disease after surgical debulking is one of the most important factors predicting outcome. However, the extent of cytoreduction may not be the only 'responsible' factor indicating a better prognosis; the underlying biology of those debulkable tumors may also play a role in defining the more favorable outcome. Seven reports have studied different prognostic factors by multivariate analysis: performance status, stage, age, grade, histology, tumor size, residual tumor, type of chemotherapy given, and ploidy status are the most common analysed parameters. A meta-analysis indicated that treatment with cisplatin and disease stage are the only independent prognostic variables. Some investigators have developed prognostic indexes with good predictive power, incorporating objective prognostic variables. This approach may be more useful than applying individual factors to each patient. The absolute titer of carbohydrate antigen 125, its decline after several courses of chemotherapy, or its half-life have been correlated with prognosis in some instances, but low sensitivity may be a problem. Other biologic factors with some prognostic potential in ovarian cancer are the expression of lung-resistance protein and the over-expression of c-erbB-2, both perhaps related to resistance to chemotherapy, the product of the metastasis suppressor gene nm23, the epidermal growth factor receptor, heat shock proteins (HSP-60), and plasma or ascites levels of macrophage colony-stimulating factor. Most of these predictors were explored in selected and often small series of patients, and their roles should be confirmed in well-designed confirmatory trials.     

Immunohistochemical research on breast cancer cell proliferation and hormonal receptor status with special emphasis on HER-2/neu expression

Breast cancer is the most frequent gynecological tumor. The HER-2/neu oncogene may play a role in the prognosis and management of patients with breast cancer. In a retrospective study on 100 patients, we correlated the expression of this oncogene with the classic clinical and pathological factors. 32 % of patients exhibited overexpression of HER-2/neu. There was no significant correlation with classic parameters. This finding could indicate that HER-2/neu expression is a new independent prognostic factor. Prospective studies correlating HER-2/neu overexpression with prognosis might provide additional data.     

Rewiew of ovarian cancer at the University of Texas Systems Cancer Center, M.D. Anderson Hospital and Tumor Institute

The records of 2,115 patients with ovarian cancer who were treated at the M.D. Anderson Hospital and Tumor Institute in Houston, Texas, during the 30 year period from 1944 to 1973 were reviewed. Ninety percent of the patients had an epithelial cancer of the ovary. The important prognostic factors include stage and grade of tumor and the presence or absence of ascites. Probably the most important prognostic factor, however, was the size of the largest tumor mass that remained after initial surgery. The patient's age and socioeconomic level were also influencing factors in the survival rate in this series of patients. Most of the patients had advanced disease when first examined and received some type of adjunctive postoperative treatment. The survival of patients who received postoperative irradiation, when compared by stage and size of the largest residual tumor mass, was improved over those who received chemotherapy.     

Procollagen-derived biomarkers in malignant ascites of ovarian cancer. Independent prognosticators for progression-free interval and survival

OBJECTIVE: Matrix formation is a hallmark of solid tumor biology. Circulating antigens of structural matrix proteins should reflect this fact, yet are subject to systemic variables. We propose that if measured regionally, in a cancer-induced extravascular fluid pool such as malignant ascites of ovarian cancer, the same antigens retain their conceptual advantage as surrogate markers for tumor biology. METHODS: In malignant ascites obtained at staging laparatomy of 35 women with ovarian cancer, the protein-normalized levels of the C-terminal propeptide of procollagen type I (pnPICP) and the N-terminal propeptide of procollagen type III (pnPIIINP) were determined. Using univariate and multivariate analysis, we examined these parameters, their (pnPIIINP/pnPICP) quotient, and clinical criteria (FIGO stage, age, residual tumor, histology, and tumor grade) for impact on progression-free interval and survival. RESULTS: The absolute level of pnPIIINP was the single most powerful independent factor impacting on survival, its P value being distinctly below (P = 0.0005 vs 0.003) and its risk ratio distinctly above (15 vs 2.5) residual tumor after debulking surgery. The relative level of pnPIIINP, i.e. (pnPIIINP / pnPICP), impacted on the likelihood of recurrence even more than residual tumor. By Kaplan-Meier analysis, cutoff values for the absolute or relative pnPIIINP level significantly discriminated patients with shortened survival or progression-free interval, respectively. CONCLUSIONS: Since malignant ovarian epithelium itself forms collagen type III, and since collagen type III is a solid-phase regulator of angiogenesis, we propose that ascitic pnPIIINP is a fluid-phase indicator for angiogenic activity in ovarian cancer and thus represents a tumor virulence index.     

长链非编码RNA在宫颈癌中的作用

宫颈癌是女性最常见的恶性肿瘤之一,我国的发病率和死亡率一直居高不下。人乳头瘤病毒的持续感染是宫颈癌的主要危险因素,但并非唯一因素,遗传和表观遗传因素与宫颈癌的关系不容忽视。近年有研究发现长链非编码RNA (long non-coding RNA,lncRNA)与宫颈癌的发生、发展有关。许多lncRNA可以作为竞争性内源RNA(competing endogenous RNA,ceRNA)广泛参与调控一些关键的信号通路,如Wnt/β-catenin依赖性途径、丝裂原活化蛋白激酶通路、磷脂酰肌醇3激酶/蛋白激酶B通路和Notch信号通路等,从而在宫颈癌的发生、发展中发挥致癌或抑癌作用,因此许多lncRNA已成为宫颈癌新的诊断和预后生物标志物。综述lncRNA的结构与功能,以及lncRNA在宫颈癌中的作用机制。     

Angiogenesis-prognostic factor in patients with endometrial cancer

Endometrial carcinoma is one of the most commonly found cancers. In numerous kinds of cancers, tumor microvessel density correlates with clinical stage of disease and is considered as an independent prognostic factor. Evaluation of angiogenesis intensity in endometrial cancer also seems to be an independent prognostic factor and statistically correlates with FIGO stage of disease, histological type and grade of tumor, depth of myometrial invasion and metastasis. Activity of angiogenic factors in human tissues and serum provides additional reference concerning the growth and progression of endometrial cancer.     

Tumor–stroma ratio is an independent predictor for survival in early cervical carcinoma

Objective

Tumor–stroma ratio (TSR) has recently been identified as an independent prognostic parameter for several solid tumors. The aim of the present study was to evaluate the prognostic role of TSR in early cervical cancer.

Methods

A cohort of 184 patients who had surgery for early stage cervical cancer (FIGO [International Federation of Gynecology and Obstetrics] stages IA2–IIA) were enrolled in this study. TSR was estimated on hematoxylin–eosin-stained tissue sections from the most invasive part of the primary tumor. Patients with less than 50% stroma were classified as stroma-poor and patients with ≥ 50% stroma were classified as stroma-rich. The relationship between TSR and survival time was statistically analyzed.

Results

The disease-free survival and overall survival rates were 88.44% and 92.52%, respectively, in the stroma-poor group, and 62.16% and 70.27%, respectively, in the stroma-rich group. Both the disease-free and overall survival rates in the stroma-poor group were significantly better than those in the stroma-rich group (p = 0.001). In a multivariate analysis, TSR was further confirmed as a significant prognostic factor for disease-free survival (hazard ratio 3.125; p = 0.005) and overall survival (hazard ratio 3.464; p = 0.003), independent of tumor size, FIGO stage and lymph node metastasis.

Conclusion

Our study identified that TSR was an independent prognostic factor of early cervical cancer. Patients with stroma-rich tumors had worse prognosis and higher risk of relapse compared with those with stroma-poor tumors. Considering its simplicity and availability for conventional clinical pathology, TSR may serve as a new prognostic histological characteristic in early cervical cancer.     

Expression of latent matrix metalloproteinase 9 (MMP-9) predicts survival in advanced ovarian cancer

OBJECTIVE: Matrix metalloproteinases (MMPs) are frequently expressed in malignant tumors and play an important role in tumor invasion and metastasis. MMP-2 and MMP-9 expression has been correlated with poor survival in some tumors, but data for ovarian cancer are lacking, despite clinical trials with MMP inhibitors. The aim of this study was to assess activity of MMP-2 and MMP-9 and correlate it to prognosis in ovarian cancer. METHODS: MMP-2 and MMP-9 gelatinolytic activity was analyzed in 84 patients with advanced ovarian cancer FIGO stage III and 19 benign ovarian tumors by gelatin zymography. MMP-9 immunoreactivity was detected by immunohistochemistry and gelatinolytic activity was localized in ovarian cancer tissue by in situ zymography. RESULTS: were correlated with patient survival, with a median follow-up period of 55 months. Results. Median pro-MMP-9 activity was at 0.00 U/microg protein in benign ovarian tissues and 4.82 U/microg protein in ovarian cancer (P = 0.001); activated MMP-9 was not detected. Pro-MMP-2 expression in benign ovarian tissue did not differ from that of malignant ovarian tissue, whereas active MMP-2 was present in 52% of ovarian cancers, but absent in benign ovarian tissues. Analyzing all patients high pro-MMP-9 activity was associated with short overall survival (P = 0.019) while pro-MMP-2 and activated MMP-2 did not predict overall survival. When analyzing the subgroups of patients with and without residual tumor mass at the time of surgery, pro-MMP-9 was of prognostic value only in the subgroup of patients with no residual tumor mass. In univariate analysis pro-MMP-9 activity, residual tumor mass, age, ascites volume, and grading were of prognostic significance for overall survival. However, in multivariate analyses, including all biological and clinicopathologic variables, only pro-MMP-9 and residual disease remained statistically independent prognostic factors. In situ zymography localized gelatinolytic activity predominantly to the tumor cell nests displaying MMP-9 immunoreactivity. CONCLUSIONS: Pro-MMP-9 gelatinolytic activity, but not active MMP-2 or MMP-9, serves as a useful statistically independent prognostic factor in ovarian cancer FIGO stage III, thus helping to identify ovarian cancer patients with an aggressive form of the disease.     

Biomolecular prognostic factors in breast cancer

PURPOSE OF REVIEW: To update clinicians on recent findings concerning the clinical usefulness of biomarkers in breast cancer, this review examines recently published papers dealing with promising prognostic/predictive biological factors. These factors can be classified according to their involvement in the main alterations characterizing tumor cells: self-sufficiency in growth signals, insensitivity to anti-growth signals, evasion of apoptosis, limitless replicative potential, sustained angiogenesis, and tissue invasion and metastasis. RECENT FINDINGS: Despite relevant research efforts and the identification of many putative good prognosticators, few of these factors are proving clinically useful for identifying patients at minimal risk of relapse, patients with a worse prognosis, or patients likely to benefit from specific treatments. Most of them, such as HER-2/neu, epidermal growth factor receptor, cyclin E, p53, bcl-2, vascular endothelial growth factor, urokinase-type plasminogen activator-1 and the recently discovered anti-apoptosis protein survivin, are suggested for possible inclusion in the category of biomarkers with a high level of clinico-laboratory effectiveness. However, no single biomarker was able to identify those patients with the best (or worst) prognosis or those which would be responsive to a given therapy. Novel findings derived from gene-expression analysis indicate that the simultaneous consideration of molecular alterations contributing to the hallmarks of cancer might provide clinically useful prognostic, and perhaps therapeutic, information. SUMMARY: Rapid translation of laboratory findings to clinical practice was hampered by many difficulties, including technical and statistical concerns, a lack of assay standardization and comparability, and the modest design of translational studies. Many studies are performed on too small series of patients to provide reliable results; the studies are often heterogeneous in terms of treatment, patients and tumor characteristics, and data may be evaluated using different analytical approaches and are thus not easily comparable. Adequately planned prospective studies are required to assess the clinical utility of biomarker determinations.     

微小RNA基因的DNA甲基化在卵巢癌中的研究

微小RNA(microRNA,miRNA)是一类短链非编码RNA,通过降解mRNA或抑制mRNA翻译的方式调控众多基因的表达。已有许多研究表明miRNA与卵巢癌的发生、发展、耐药和预后相关。DNA甲基化是表观遗传学的重要组成部分,与细胞的增殖、癌变等生命现象有着重大的关系,是目前肿瘤中研究最多的表观遗传学机制之一,与肿瘤的发生、发展、耐药和预后相关。研究卵巢癌中miRNA基因的DNA甲基化可能为卵巢癌诊治提供新的分子诊断和预后标记物,为化疗耐药分析和个性化治疗提供新的临床思路。     

Circulating tumor cells in breast cancer

PURPOSE OF REVIEW: To critically review the latest findings concerning the detection and characterization of circulating tumor cells in breast cancer. RECENT FINDINGS: Various studies have used different methods and markers for circulating tumor cell detection in breast cancer. Data on the prognostic value of circulating tumor cell monitoring by the CellSearch system are now available in patients with measurable metastatic breast cancer receiving chemotherapy, whereas no such data are still available for adjuvant or neoadjuvant settings. The detection of cytokeratin 19 mRNA-positive cells before the initiation of adjuvant chemotherapy was shown to be an independent prognostic factor for worse clinical outcome in patients with early breast cancer. Interestingly, this was mainly observed in patients with triple-negative and HER2-positive, but not estrogen receptor-positive/HER2-negative, early breast cancer. Finally, gene-expression profiling of single cells was reported to be feasible with important implications for eliminating circulating tumor cells. Pilot studies have shown that phenotyping of circulating tumor cells could be used to predict response to targeted therapies. SUMMARY: Circulating tumor cells might become a valuable tool to refine prognosis in early and metastatic breast cancer. Circulating tumor cell phenotyping/profiling may serve as a real-time tumor biopsy for individually-tailored targeted therapies.     

Circulating tumor cells (CTCs)--clinical significance in patients with ovarian cancer

Circulating tumor cells (CTCs) are cells released from the primary tumor and circulating in peripheral blood. CTCs are an important element in the process of understanding the biology of metastases. In the future CTCs may be used as biomarkers for the assessment of neoplastic process progression and recurrence. The CTCs presence in peripheral blood was described in various tumors, and the possibility of their use in clinical procedures was demonstrated. The appearance of CTCs is a sign of metastasis formation and its spread via the circulatory system. Ovarian cancer is a special type of tumor as it grows and recurs mainly in the abdominal cavity. Despite advances in therapeutic methods, more than half of the patients with ovarian cancer experience disease recurrence which cannot be cured. Therefore, it is important to seek better treatment strategies for patients with advanced disease. There is evidence that CTCs in patients with ovarian cancer may be associated with the appearance of recurrences, disease-free time and total survival time. Detection and molecular analysis of CTCs may also be a non-invasive test for detecting an early stage of the disease, impossible to diagnose using currently available diagnostic tools. Monitoring can also be a prognostic factor enabling the evaluation of the therapeutic response. CTCs detection will contribute to better patient outcomes by using an improved system of diagnosis and monitoring of patient therapy allowing for immediate implementation or change of the treatment when necessary.     

子宫内膜样腺癌MELF浸润模式的研究进展

子宫内膜癌是女性生殖系统常见的恶性肿瘤之一,其最常见的病理形态为子宫内膜样腺癌。早期子宫内膜癌预后较好,但仍有少部分患者预后不良。影响子宫内膜癌预后的不良因素包括肿瘤组织学分级、子宫肌层侵犯深度、淋巴脉管间隙浸润（lymphovascular space invasion,LVSI）、宫颈间质受累及淋巴结转移等。伴微囊性、伸长及碎片状（microcystic,elongated,fragmented,MELF）浸润是子宫内膜样腺癌的一种特殊的浸润子宫肌层的方式。多项研究证实MELF浸润模式与某些影响预后的不良病理因素相关,但是MELF浸润模式的预后意义尚不明确。现就MELF浸润模式的临床病理特征以及预后意义的研究进展进行综述,以期为未来MELF浸润模式的相关研究提供理论参考。     

Expression of indoleamine 2,3-dioxygenase predicts shorter survival in patients with vulvar squamous cell carcinoma (vSCC) not influencing on the recruitment of FOXP3-expressing regulatory T cells in cancer nests

Objective

Regulatory T cells (Tregs), and the enzyme indoleamine 2,3-dioxygenase (IDO), have potential regulatory properties for immune escape in cancer. Inhibitors of IDO are available and could potentially be used in vulvar cancer if IDO was proved to drive progression of the disease. The aim of this study was to evaluate the expression of factor forkhead boxP3 (FOXP3), a marker of Tregs, and IDO in vulvar squamous cell carcinoma (vSCC), and to verify their prognostic significance.

Methods

76 primary tumors and 35 lymph node metastases derived from 76 patients with full clinical history were analyzed. The intratumoral infiltration of Tregs and IDO expression within cancer were evaluated by immunohistochemistry.

Results

The number of Tregs in primary tumor and in corresponding lymph node metastasis was significantly correlated. Intensity of Treg infiltrates in the primary and metastatic sites was not correlated to IDO expression and had no influence on the overall patient survival. High IDO expression was associated with significantly worse overall survival among vSCC patients and was found to be an independent prognostic factor similarly to the tumor grade and patient's age.

Conclusions

The degree of intratumoral Treg infiltrates is an individual feature and remains stable throughout the course of the disease without impact on the patient's survival. IDO expression predicts shorter survival of vSCC patients. If immunologic tolerance of the tumor is promoted by the overexpression of IDO it will not influence the number of intratumoral Tregs. IDO expression seems to be an independent prognostic factor in patients with vSCC.     

The prognostic value of peritoneal cytology in ovarian cancer

We studied the significance of peritoneal cytology as a prognostic factor in primary epithelial ovarian cancer. Intraperitoneal specimens for cytological examination were taken from 73 patients at primary operation for ovarian cancer. The prognostic value of cytological findings was analyzed by the Kaplan-Meier method. It was also correlated to clinical stage, tumor histology, histopathological grade, residual tumor, presence of ascites and age by using the chi2-test. The value of cytology in relation to other factors was assessed by Cox-multivariate analysis. In univariate analysis peritoneal cytological findings correlated significantly to survival. In Cox-multivariate analysis peritoneal cytology, histopathological grade and the age of the patient were found to be significant independent prognostic factors in epithelial ovarian cancer. According to this data peritoneal cytology can be considered as an important prognostic factor in ovarian cancer. Therefore it should be evaluated routinely in association with surgery of ovarian tumors.     

The prognostic value of histopathologic grading parameters and microvessel density in patients with early squamous cell carcinoma of the uterine cervix.

Abstract. Graflund M, Sorbe B, Hussein A, Bryne M, Karlsson M.
The purpose of this study was to investigate the prognostic importance of clinical and histopathologic factors, including malignancy grading systems (MGS), partial index (PI), invasive front grading (IFG), and microvessel density. A complete geographic series of 172 early stage (FIGO I–II) cervical carcinomas treated by Wertheim-Meigs surgery during the period 1965–1990 was studied. The patients were followed up for at least 10 years. Significant prognostic factors for disease-free survival were lymph node status ( P < 0.0000001), radical surgical margins ( P = 0.00003), and tumor size ( P = 0.008). In a multivariate Cox analysis it was shown that lymph node status was the single most important prognostic factor with regard to disease-free survival. The total MGS and the PI scores were highly significantly ( P = 0.0001) associated with pelvic lymph node metastases and disease-free survival rate in squamous cell carcinomas. The MGS and the PI systems were superior to the IFG system in predicting lymph node metastases. The total IFG score was also a statistically highly significant ( P = 0.003) prognostic factor with regard to disease-free survival in both univariate and multivariate analyses. Microvessel density was a nonsignificant prognostic factor. There was a highly significant ( P = 0.002) association between vascular space invasion of tumor cells and the presence of lymph node metastases. In conclusion, histopathologic malignancy grading systems provide valuable prognostic information in patients with early stage squamous cell carcinomas of the uterine cervix.     

Magnetic resonance imaging in cervical cancer: a basis for objective classification

Conventional clinical staging of cervical cancer is subjective because it is based on palpatory findings and inadequate because it cannot assess the single most important prognostic factor--tumor size. To determine the exactitude of in vivo MRI measurements of tumor volume, 22 patients with invasive cervical cancer were studied before surgery. The volumes obtained by MRI correlated well (r = 0.983) with those obtained by histomorphometric analysis of the surgical specimens, but only weakly with clinical stage. MRI may provide a basis for precise classification of cervical cancer and for objective comparison of surgery and radiotherapy.     

The prognostic and predictive value of immunohistochemically detected HER-2/neu overexpression in 361 patients with ovarian cancer: a multicenter study

OBJECTIVE: The prognostic and predictive relevance of HER-2/neu dysregulation in epithelial ovarian cancer is controversial. The purpose of our study was to document HER-2/neu expression patterns and their correlation with clinicopathologic parameters and survival in a large and biologically homogenous Caucasian patient collective. METHODS: Expression of HER-2/neu in ovarian cancer tissue was assessed by immunohistochemistry. Immunohistochemical staining was performed according to established protocols. Results were correlated to clinical data. RESULTS: HER-2/neu overexpression was detected in 6.9% (25/361) of the tumor samples and was significantly associated with tumor stage (P = 0.03), but not with lymph node involvement (P = 0.5), tumor grade (P = 0.3), histological type (P = 0.6), residual tumor (P = 0.4), serum CA-125 before therapy (P = 0.2), and patient age (P = 0.8). We found no significant influence of HER-2/neu overexpression on overall and disease-free survival independent of FIGO stage, tumor grade, and residual tumor mass. In a subset of 73 suboptimally debulked patients, women with response to first-line chemotherapy (complete remission [CR] + partial remission [PR]) and no response to first-line chemotherapy (stable disease [SD] + progressive disease [PD]) showed significantly different rates of HER-2/neu overexpression (0% [0/51] vs. 14% [3/22]; P = 0.02). CONCLUSIONS: Tumor overexpression of HER-2/neu in women with advanced ovarian cancer is rare and provides no prognostic information in addition to that provided by established clinicopathologic parameters. This multicenter study, however, indicates that HER-2/neu overexpression is a predictive factor for the response to first-line chemotherapy in suboptimally debulked patients.     

上皮性卵巢癌DNA含量、细胞核形态及其对患者预后价值的探讨

目的：探讨ＤＮＡ含量、核形态参数对预测上皮性卵巢癌患者预后的价值。方法：应用计算机图像分析系统测定原发性上皮性卵巢癌３２例的细胞核ＤＮＡ含量、倍体水平、面积、周长及形状因子５个参数。结果：卵巢癌临床晚期及转移病例的ＤＮＡ含量明显增高，与早期及无转移组相比，差异均有显著性（Ｐ＜０．０２５）。６３％为异倍体肿瘤，３７％为二倍体肿瘤。组织学Ⅰ、Ⅱ、Ⅲ级的异倍体率分别为３８％、５７％、９０％，呈递增趋势。Ⅰ级与Ⅲ级相比，差异有显著性（Ｐ＜０．０５）。腹水阳性组及转移组的异倍体率明显增加，分别为７３％及７６％。ＰＣＮＡ阳性组及阴性组的核形状因子差异有显著性（Ｐ＜０．０５）。核面积和周长在诸预后因素间差异无显著性（Ｐ＞０．０５）。结论：细胞核ＤＮＡ含量和倍体水平是影响卵巢癌患者预后的重要因素；核形状因子亦可作为评估肿瘤生物学行为的一项指标。