Tumor Proliferative Potential Research Articles

Five latent factors underlie response to immunotherapy

Only a subset of patients treated with immune checkpoint inhibitors (CPIs) respond to the treatment, and distinguishing responders from non-responders is a major challenge. Many proposed biomarkers of CPI response and survival probably represent alternative measurements of the same aspects of the tumor, its microenvironment or the host. Thus, we currently ignore how many truly independent biomarkers there are. With an unbiased analysis of genomics, transcriptomics and clinical data of a cohort of patients with metastatic tumors (n = 479), we discovered five orthogonal latent factors: tumor mutation burden, T cell effective infiltration, transforming growth factor-beta activity in the microenvironment, prior treatment and tumor proliferative potential. Their association with CPI response and survival was observed across all tumor types and validated across six independent cohorts (n = 1,491). These five latent factors constitute a frame of reference to organize current and future knowledge on biomarkers of CPI response and survival.

WHO Histological Classification of Pituitary Tumors

The major changes in the upcoming 5th edition of the "2022 WHO Classification of Endocrine and Neuroendocrine Tumors" include:(1)evolution of the nomenclature: from pituitary adenoma to pituitary neuroendocrine tumour(PitNET),(2)detailed subtyping of a PitNET based on the tumor lineage, cell type, and related characteristics,(3)endorsement of the routine use of immunohistochemistry for pituitary transcription factors(PIT1, TPIT, SF1, GATA3, and ER-alpha),(4)introduction of some additional clinicopathologically distinct PitNET subtypes,(5)introduction of the term "metastatic PitNET" to replace the previous terminology "pituitary carcinoma," and(6)unifying posterior lobe tumors, the family of pituicyte tumors that invariably express TTF1, et al. Currently, no widely agreed grading or staging systems for PitNETs exist. Prognosis varies by tumor subtype and certain tumor subtypes are recognized as more aggressive(high-risk PitNETs)than others. Potentially aggressive PitNETs should be identified on an individual basis upon considering the tumor subtype, proliferative potential, and tumor invasion assessment.

Feasibility of predicting the evolution of cerebral gliomas based on study of microRNA expression levels in blood plasma and saliva

The management of cerebral glioma (CG) remains challenging. Recently, methods based on the study of the expression levels of miRNAs in blood plasma have proven to be promising. The volume of tumor tissue is known to correlate with increased expression levels of microRNA-21 and -210. MicroRNA-15, -16, -34, -126 and -342 are involved in the regulation of tumor proliferative potential, and microRNA-128 is involved in the regulation of metabolic activity.The aim of the study was to evaluate the extended protocol for assessing the expression of microRNA-15, -16, -21, -34, -126, -128, -210, and -342 in the plasma and saliva of CG patients.Material and Methods. The study group consisted of 24 patients with supratentorial glioma (8 men and 16 women aged 41 to 71 years, mean age: 56 years). The control group consisted of 30 volunteers. MicroRNA expression was studied in plasma and saliva according to the StemLoop-RealTime protocol, using fluorescently labeled samples with small miRNA U6 as a reference gene. Statistical analysis was carried out using nonparametric methods.Results. The lack of CG stabilization and the most probable progression of the tumor with a poor prognosis was related to an increase in microRNA-21 and -210 expression levels and decrease in microRNA-128 expression and at least four of microRNA 15, -16, -34, -126, and -342. Stabilization of CG with a high probability of progression was associated with an increase in microRNA-21 or microRNA210 expression levels, decrease in no more than three of microRNA-15, -16, -34, -126, -342 expression levels as well as decrease in microRNA-128 expression. Stabilization of the tumor with a low probability of progression was associated with a decrease in the expression of microRNA-21 and -210 and in no more than one of miRNA-15, -16, -34, -126, -342 below the reference level, with a simultaneous increase in miRNA-128 expression.Conclusion. The determination of microRNA expression in blood plasma and saliva can be one of the important criteria for assessing the prognosis of CG.

Evaluation of the malignant potential of gliomas using diffusion-weighted and gadolinium-enhanced magnetic resonance imaging

Objective: This study aimed to determine whether the apparent diffusion coefficients (ADCs) determined by diffusion-weighted imaging (DWI) of magnetic resonance imaging (MRI) could facilitate the malignancy grading of various gliomas. Methods: Sixty patients with a primary cerebral glioma underwent diffusion-weighted and gadolinium-enhanced (Gd) T1-weighted MRI using a 1.5-T MRI scanner. Scoring was performed based on signal intensities on DWI and Gd images. The mean and minimum ADC values were calculated, and Ki-67 staining was performed for each histological sample to evaluate their tumor proliferative potential. Then, the DWI, Gd, and combined scores were analyzed and compared with the Ki-67 staining index and malignant grade. The relationships among the mean and minimum ADC values, Ki-67 staining index, and malignant grade were also evaluated. Results: The minimum ADC was inversely correlated with the Ki-67 staining index, with a low minimum ADC suggestive of tumor malignancy. The qualitative evaluation of the D score of water molecule diffusion on DWI accurately reflected the pathological grades of gliomas, with an effectiveness that was at least as good as the quantitative analysis using the minimum ADC. The diagnostic value of Gd images in determining glioma malignancy grades was inferior to that of DWI. Conclusion: Both DWI and gadolinium-enhanced images of MRI should be considered essential for the diagnosis of tumor malignancy.

Hyperresistinemia in Obese Female Dogs With Mammary Carcinoma in Benign-Mixed Tumors and Its Correlation With Tumor Aggressiveness and Survival.

Resistin is associated with metabolic, inflammatory, and neoplastic disorders, and is also considered a prognostic marker in human oncology. Canine mammary tumors have epidemiological, clinical, biological, and genetic characteristics similar to those of women and are proposed as a comparative study model. Here, we evaluate the serum levels of resistin in female dogs with or without mammary carcinoma in mixed tumors (CBMT) and its correlation with the proliferative potential of the tumor, obesity, and survival. Eighty dogs grouped according to the presence (50) or absence (30) of CBMT, reproductive status and body condition were assessed for weight, fat percentage, and canine body mass index. The characteristic of the proliferative potential of the tumor (Ki-67) was evaluated. Ki-67 levels (p = 0.024), staging (p = 0.004), and grade (p = 0.016) influenced the survival of the female dogs. Through a multifactorial analysis, it could be seen that the parameters proliferation index (Ki-67) (p = 0.044) and staging (p = 0.036) influenced the survival of the animals. Neutered and overweight dogs from the control and CBMT groups showed hyperresistinemia. Ki-67 expression and resistin levels in dogs with CBMT were higher in overweight dogs than in dogs with normal weight (p = 0.0001). The survival rate of dogs with CBMT, obese and with high levels of resistin (8,400 μg L−1) was lower when compared to those with lower levels of resistin. These results showed an important relationship between hyperresistinemia, tumor proliferative potential and excessive body fat, suggesting that resistin levels may act as an interesting prognostic marker in patients with CBMT.

Pituitary macroadenoma: Accuracy of apparent diffusion coefficient magnetic resonance imaging in grading tumor aggressiveness.

The purpose of this study is to evaluate the accuracy of apparent diffusion coefficient magnetic resonance imaging in grading tumor aggressiveness using histogram apparent diffusion coefficient values. Eighteen patients with surgically proved pituitary macroadenomas were included in this study. Diffusion-weighted imaging with single-shot echo-planar sequence at 3-T with a 32-channel head coil was performed with b values of 0 and 1000 s/mm2. Calculated apparent diffusion coefficient maps were generated, and a 3-D volume of interest was placed on the tumor while superimposing contrast-enhanced magnetic resonance images. All apparent diffusion coefficient values within the volume of interest were used to compute the average apparent diffusion coefficient of the tumor. The apparent diffusion coefficient values were binned to construct the apparent diffusion coefficient histogram. Using the histogram, the mean, percentiles, skewness, and kurtosis of the apparent diffusion coefficient of the entire tumor were computed. Apparent diffusion coefficient histogram parameters were compared with the MIB-1 index, invasiveness, and recurrence for grading tumor aggressiveness of pituitary adenomas. The skewness of the apparent diffusion coefficient histogram only showed significant differences among MIB-1 indices ( p = 0.030). All apparent diffusion coefficient histogram parameters showed no significant differences between negative and positive invasion. The skewness and kurtosis of the apparent diffusion coefficient histogram showed significant differences between positive and negative recurrence (skewness p = 0.011, kurtosis p = 0.011). Receiver-operating characteristics analysis between positive and negative recurrence showed that both skewness and kurtosis of the apparent diffusion coefficient achieved area under the curve at 0.967. Skewness and kurtosis of the apparent diffusion coefficient histogram were the predictive parameters for assessing tumor proliferative potential and recurrence of pituitary adenomas.

Associations between apparent diffusion coefficient (ADC) and KI 67 in different tumors: a meta-analysis. Part 1: ADCmean.

Diffusion weighted imaging (DWI) is a magnetic resonance imaging (MRI) technique based on measure of water diffusion in tissues. This diffusion can be quantified by apparent diffusion coefficient (ADC). Some reports indicated that ADC can reflect tumor proliferation potential. The purpose of this meta-analysis was to provide evident data regarding associations between ADC and KI 67 in different tumors. Studies investigating the relationship between ADC and KI 67 in different tumors were identified.MEDLINE library was screened for associations between ADC and KI 67 in different tumors up to April 2017. Overall, 42 studies with 2026 patients were identified. The following data were extracted from the literature: authors, year of publication, number of patients, tumor type, and correlation coefficients.Associations between ADC and KI 67 were analyzed by Spearman's correlation coefficient. The reported Pearson correlation coefficients in some studies were converted into Spearman correlation coefficients.The pooled correlation coefficient between ADCmean and KI 67 for all included tumors was ρ = −0.44. Furthermore, correlation coefficient for every tumor entity was calculated. The calculated correlation coefficients were as follows: ovarian cancer: ρ = −0.62, urothelial carcinomas: ρ = −0.56, cerebral lymphoma: ρ = −0.55, neuroendocrine tumors: ρ = −0.52, glioma: ρ = −0.51, lung cancer: ρ = −0.50, prostatic cancer: ρ = −0.43, rectal cancer: ρ = −0.42, pituitary adenoma:ρ = −0.44, meningioma, ρ = −0.43, hepatocellular carcinoma: ρ = −0.37, breast cancer: ρ = −0.22.

The 2017 World Health Organization classification of tumors of the pituitary gland: a summary.

The 4th edition of the World Health Organization (WHO) classification of endocrine tumors has been recently released. In this new edition, major changes are recommended in several areas of the classification of tumors of the anterior pituitary gland (adenophypophysis). The scope of the present manuscript is to summarize these recommended changes, emphasizing a few significant topics. These changes include the following: (1) a novel approach for classifying pituitary neuroendocrine tumors according to pituitary adenohypophyseal cell lineages; (2) changes to the histological grading of pituitary neuroendocrine tumors with the elimination of the term "atypical adenoma;" and (3) introduction of new entities like the pituitary blastoma and re-definition of old entities like the null-cell adenoma. This new classification is very practical and mostly based on immunohistochemistry for pituitary hormones, pituitary-specific transcription factors, and other immunohistochemical markers commonly used in pathology practice, not requiring routine ultrastructural analysis of the tumors. Evaluation of tumor proliferation potential, by mitotic count and Ki-67 labeling index, and tumor invasion is strongly recommended on individual case basis to identify clinically aggressive adenomas. In addition, the classification offers the treating clinical team information on tumor prognosis by identifying specific variants of adenomas associated with an elevated risk for recurrence. Changes in the classification of non-neuroendocrine tumors are also proposed, in particular those tumors arising in the posterior pituitary including pituicytoma, granular cell tumor of the posterior pituitary, and spindle cell oncocytoma. These changes endorse those previously published in the 2016 WHO classification of CNS tumors. Other tumors arising in the sellar region are also reviewed in detail including craniopharyngiomas, mesenchymal and stromal tumors, germ cell tumors, and hematopoietic tumors. It is hoped that the 2017 WHO classification of pituitary tumors will establish more biologically and clinically uniform groups of tumors, make it possible for practicing pathologists to better diagnose these tumors, and contribute to our understanding of clinical outcomes for patients harboring pituitary tumors.

Overview of the 2017 WHO Classification of Pituitary Tumors.

This review focuses on discussing the main changes on the upcoming fourth edition of the WHO Classification of Tumors of the Pituitary Gland emphasizing histopathological and molecular genetics aspects of pituitary neuroendocrine (i.e., pituitary adenomas) and some of the non-neuroendocrine tumors involving the pituitary gland. Instead of a formal review, we introduced the highlights of the new WHO classification by answering select questions relevant to practising pathologists. The revised classification of pituitary adenomas, in addition to hormone immunohistochemistry, recognizes the role of other immunohistochemical markers including but not limited to pituitary transcription factors. Recognizing this novel approach, the fourth edition of the WHO classification has abandoned the concept of "a hormone-producing pituitary adenoma" and adopted a pituitary adenohypophyseal cell lineage designation of the adenomas with subsequent categorization of histological variants according to hormone content and specific histological and immunohistochemical features. This new classification does not require a routine ultrastructural examination of these tumors. The new definition of the Null cell adenoma requires the demonstration of immunonegativity for pituitary transcription factors and adenohypophyseal hormones Moreover, the term of atypical pituitary adenoma is no longer recommended. In addition to the accurate tumor subtyping, assessment of the tumor proliferative potential by mitotic count and Ki-67 index, and other clinical parameters such as tumor invasion, is strongly recommended in individual cases for consideration of clinically aggressive adenomas. This classification also recognizes some subtypes of pituitary neuroendocrine tumors as "high-risk pituitary adenomas" due to the clinical aggressive behavior; these include the sparsely granulated somatotroph adenoma, the lactotroph adenoma in men, the Crooke's cell adenoma, the silent corticotroph adenoma, and the newly introduced plurihormonal Pit-1-positive adenoma (previously known as silent subtype III pituitary adenoma). An additional novel aspect of the new WHO classification was also the definition of the spectrum of thyroid transcription factor-1 expressing pituitary tumors of the posterior lobe as representing a morphological spectrum of a single nosological entity. These tumors include the pituicytoma, the spindle cell oncocytoma, the granular cell tumor of the neurohypophysis, and the sellar ependymoma.

Parameters of simultaneous 18F-FDG-PET/MRI predict tumor stage and several histopathological features in uterine cervical cancer

The purpose of this study was to analyze associations between apparent diffusion coefficient (ADC) and standardized uptake values (SUV) values and different histopathological parameters in uterine cervical cancer. 21 patients with primary uterine cervical cancer were involved into the study. All patients underwent a whole body simultaneous18F-FDG PET/MRI. Mean and maximum SUV were noted (SUVmean and SUVmax). In all tumors minimal, mean, and maximal ADC values (ADCmin, ADCmean, and ADCmax) were estimated. Combined parameters were calculated: SUVmax/SUVmean, ADCmin/ ADCmean, SUVmax/ADCmin and SUVmax/ADCmean. In all cases the diagnosis was confirmed histopathologically by tumor biopsy. Histological slices were stained by hematoxilin and eosin, MIB 1 monoclonal antibody, and p16. All histopathological images were digitalized and analyzed by using a ImageJ software 1.48v. The following parameters were estimated: cell count, proliferation index KI 67, total and average nucleic areas, epithelial and stromal areas. Spearman's correlation coefficient was used to analyze associations between ADC and SUV values and histological parameters. P values ≤ 0.05 were considered as statistically significant. ADCmin and ADCmin/ ADCmean were statistically significant lower in N positive tumors. KI 67 correlated statistically significant with SUVmax (r = 0.59, p = 0.005), SUVmean (0.45, p = 0.04), ADCmin (r = −0.48, p = 0.03), SUVmax/ADCmin (r = 0.71, p = 0.001), SUVmax/ADCmean (0.75, p = 0.001). SUVmax correlated well with epithelial area (r = 0.71, p = 0.001) and stromal areas (r = −0.71, p = 0.001). SUV values, ADCmin, SUVmax/ADCmin and SUVmax/ADCmean correlated statistically significant with KI 67 and can be used to estimate the proliferation potential of tumors. SUV values correlated strong with epithelial area of tumor reflected metabolic active areas.

TROSATIVE STRESS PARAMETERS IN COLON CANCER TUMOR, ADJACENT AND HEALTHY TISSUE

Colorectal cancer is one of the most frequent human malignant diseases and one of the most common causes of malignant diseases death. Oxidative and nitrosative stress have an important role in cancer initiation and propagation. That is why this study is focused on the determination of oxidative and nitrosative stress markers in tumor, adjacent and health tissue, which are important for the estimation of tumor proliferative and angiogenic potential. The study encompassed 50 patients who underwent surgery due to colorectal cancer. In the tissue samples from resected colon preparation (tumor, adjacent and healthy tissue, at least 10 cm distant from tumor), oxidative and nitrosative stress markers, malondialdehyde (MDA) and nitric oxide (NO) were determined. The obtained results prove the presence of oxidative stress in tumor tissue. Highly significantly (p<0.001) increased MDA concentrations in both tumor and adjacent tissue (12.43±9.39 and 11.57±5.56 nmol/mg proteins) compared to healthy one (7.25±5.52) reflect higher tumor aggressiveness and metastatic capacity. Higher NO concentrations in adjacent tissue (85.100±37.972 nmol/mg prot.) compared to the tumor one (58.608±22.789) point out high angiogenic potential of tumor surrounding tissue, which could have the clinical importance in the assessment of tumor invasiveness and the probability of local recurrence. In conclusion, the determination of the intensity of reactive oxygen and nitrogen species generation in tumor and adjacent colon tissue of patients with colorectal carcinoma could be useful in the estimation of the cancer invasive and metastatic capacity related to the prognosis of the disease and the choice of adjuvant therapy.

Systems biology approach to studying proliferation-dependent prognostic subnetworks in breast cancer.

Tumor proliferative capacity is a major biological correlate of breast tumor metastatic potential. In this paper, we developed a systems approach to investigate associations among gene expression patterns, representative protein-protein interactions, and the potential for clinical metastases, to uncover novel survival-related subnetwork signatures as a function of tumor proliferative potential. Based on the statistical associations between gene expression patterns and patient outcomes, we identified three groups of survival prognostic subnetwork signatures (SPNs) corresponding to three proliferation levels. We discovered 8 SPNs in the high proliferation group, 8 SPNs in the intermediate proliferation group, and 6 SPNs in the low proliferation group. We observed little overlap of SPNs between the three proliferation groups. The enrichment analysis revealed that most SPNs were enriched in distinct signaling pathways and biological processes. The SPNs were validated on other cohorts of patients, and delivered high accuracy in the classification of metastatic vs non-metastatic breast tumors. Our findings indicate that certain biological networks underlying breast cancer metastasis differ in a proliferation-dependent manner. These networks, in combination, may form the basis of highly accurate prognostic classification models and may have clinical utility in guiding therapeutic options for patients.

Twist induces epithelial-mesenchymal transition in cervical carcinogenesis by regulating the TGF-β/Smad3 signaling pathway.

Epithelial-mesenchymal transition (EMT) is associated with the metastasis and poor prognosis of cervical cancer. However, the underlying mechanisms are poorly defined. In the present study, we investigated whether Twist plays a direct role in human cervical cancer using immunohistochemical and western blot analyses. Immunohistochemical analysis revealed that Twist is highly expressed in cervical cancer, which correlates with poor tumor pathological differentiation or lymph node metastasis (P<0.05). Depletion of Twist by stable shRNA-mediated knockdown decreased the migratory ability of cancer cell lines in vitro. Suppression or overexpression of Twist also resulted in an altered expression of the molecular mediators of EMT. Furthermore, exogenous TGF-β promoted EMT by upregulating the expression of Twist through the TGF-β/Smad3 pathway, and this effect was eliminated by Twist depletion in cancer cells as demonstrated in the in vitro study. The use of in vivo models revealed a decreased tumor proliferation potential in Twist-depleted cancer cells. The results suggested a novel function for Twist in the promotion of EMT via TGF-β/Smad3 signaling pathway. Thus, Twist constitutes a potential therapeutic target in human cervical cancer.

Evolution of proliferation and the angiogenic switch in tumors with high clonal diversity.

Natural selection among tumor cell clones is thought to produce hallmark properties of malignancy. Efforts to understand evolution of one such hallmark—the angiogenic switch—has suggested that selection for angiogenesis can “run away” and generate a hypertumor, a form of evolutionary suicide by extreme vascular hypo- or hyperplasia. This phenomenon is predicted by models of tumor angiogenesis studied with the techniques of adaptive dynamics. These techniques also predict that selection drives tumor proliferative potential towards an evolutionarily stable strategy (ESS) that is also convergence-stable. However, adaptive dynamics are predicated on two key assumptions: (i) no more than two distinct clones or evolutionary strategies can exist in the tumor at any given time; and (ii) mutations cause small phenotypic changes. Here we show, using a stochastic simulation, that relaxation of these assumptions has no effect on the predictions of adaptive dynamics in this case. In particular, selection drives proliferative potential towards, and angiogenic potential away from, their respective ESSs. However, these simulations also show that tumor behavior is highly contingent on mutational history, particularly for angiogenesis. Individual tumors frequently grow to lethal size before the evolutionary endpoint is approached. In fact, most tumor dynamics are predicted to be in the evolutionarily transient regime throughout their natural history, so that clinically, the ESS is often largely irrelevant. In addition, we show that clonal diversity as measured by the Shannon Information Index correlates with the speed of approach to the evolutionary endpoint. This observation dovetails with results showing that clonal diversity in Barrett's esophagus predicts progression to malignancy.

Role of Ki-67 labeling index as an adjunct to the histopathological diagnosis and grading of astrocytomas.

Ki-67 labeling index (LI) is used in the assessment of cell proliferating activity. It has been widely documented for various human tumors, including the brain neoplasms. The aim of the present study is to evaluate Ki-67 as proliferative index in the grading of astrocytomas in order to predict the biological behavior of the tumor and prognosis of patients. In the present study, a total of 105 patients with astrocytomas were included. Ki-67 LI was done on all the astrocytomas and was compared in correlation with World Health Organization histological grading of astrocytomas. The mean Ki-67 LI in Grade I astrocytomas was 3.36 ± 4.59 standard deviation (SD), 7.05 ± 4.16 SD in Grade II astrocytomas, 28.24 ± 6.23 SD in Grade III astrocytomas and 38.7 ± 7.19 SD in Grade IV astrocytomas. P values were significant between all grades of astrocytomas except between Grade I and Grade II tumors which was 0.5076. Assessment of astrocytic tumor proliferative potential provides important prognostic information that supplements standard histological grading. Ki-67 LI is the simplest and most reliable methods of all. This study demonstrates that, Ki-67 LI serves as an important prognostic marker in human astrocytomas. Ki-67 LI solely correlates with a grade of the tumor. Average level of Ki-67 LI varies between different grades of astrocytic tumors but some overlap of values does exist.

Glucose metabolism correlated with cellular proliferation in diffuse large B-cell lymphoma

Standardized uptake value (SUV) is a marker of tumor glucose metabolism detected by [18F]-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG-PET/CT). The maximum SUV of the whole-body (BmSUVmax) reflects the tumor aggressiveness in non-Hodgkin lymphoma. To evaluate the correlation between SUVmax at biopsy site (BxSUVmax) and proliferation potential of tumor cells in untreated diffuse large B-cell lymphoma (DLBCL), fifteen pre-therapy PET/CT scans in patients with histologically proven DLBCL were retrospectively analyzed together with Ki-67 proliferation index. The BmSUVmax and BxSUVmax were evaluated from the fused PET/CT images. Ki-67 proliferation index was measured in the biopsy specimens using an immunohistochemical technique in archival paraffin-embedded sections. The BmSUVmax was significantly higher than the BxSUVmax (mean 19.6 vs.16.6, p < 0.01). The BxSUVmax correlated with the Ki-67 proliferation index (r = 0.7, p < 0.01), but no correlation was detected between the BmSUVmax and the Ki-67 proliferation index. The results indicate that tumor proliferation potential might be predicted in vivo by FDG-PET/CT images. Thus, PET/CT is useful to guide biopsy by selecting sites with the BmSUVmax when clinically appropriate.

Serum thymidine kinase 1 activity in breast cancer

Thymidine kinase 1 (TK1) is an enzyme involved in DNA synthesis and an important proliferation marker. We explored the association of preoperative serum TK1 activity with clinicopathological parameters and prognosis in terms of recurrence-free survival (RFS) in breast cancer (BC) patients. TK1 activity in serum of 120 healthy women and 161 BC patients was measured by quantitative ELISA. Serum TK1 activity in BC patients was significantly higher than in healthy women (P < 0.0001). In BC patients elevated TK1 activity was significantly associated with advanced T stage (P = 0.015), higher grade (P = 0.013), presence of tumor necrosis (P = 0.006), vascular invasion (P = 0.002), and lack of estrogen receptor (ER) and progesterone receptor (PR) expression (P = 0.0004 and P = 0.003). Higher TK1 activity was found in patients with BRCA1/2 mutations compared to those without the mutation (P = 0.004). Multivariate Cox proportional hazards analyses demonstrated that TK1, adjusted for stage, grade, necrosis, ER and PR negativity was retained as an independent predictor of disease recurrence (Hazard Ratio = 3.9, 95%CI 1.3-11.6, P = 0.013). Elevated serum TK1 is an important risk factor indicating a high proliferation potential of tumors at the time of excision. In multivariate analysis TK1 activity was found to be an independent prognostic factor for RFS.

Metastatic Outcome of Estrogen Receptor (ER)-Negative Breast Cancer Appears Independent of Both Age-at-Onset and Tumor Proliferative Potential.

Abstract Breast cancers arising in younger women are associated with worse survival outcome when compared with stage-matched breast cancers diagnosed in older women; to date, however, the poorer outcome of these younger onset breast cancer cases has not been fully explained by prognostic biomarkers or biological mechanisms. Collecting age cohorts of node-negative, estrogen receptor (ER)-positive sporadic breast cancers, we recently showed that younger onset cases can be distinguished from older onset ER-positive cases by expression profiling but not by genomic profiling, revealing a predictive age signature and enrichment of a proliferation gene expression signature (Perou et al., 2000) among younger ER-positive breast cancer cases (Yau et al., 2007). To further explore the impact of age on the outcome and biology of early stage breast cancers stratified by ER status, we pooled outcome and expression microarray data on adjuvant-untreated, node-negative cases obtained from three sources (van de Vijver et al., 2002; Wang et al., 2005; Desmedt et al., 2007). Dichotomized age-at-onset cohorts were defined as either younger (Y) ≤ 39 y or older (O) ≥ 40 y cases. Gene expression data from 447 ER-positive (61 Y, 386 O) and 178 ER-negative (40 Y, 138 O) cases, generated from either of two microarray platforms (Affymetrix, Agilent), were mapped by gene symbol and combined using distance weighted discrimination (DWD), to produce pooled datasets for each ER subtype containing 6209 unique genes. Distant metastasis-free survival (DMFS) was plotted by Kaplan-Meier analysis out to 15 years for 563 of the pooled 624 cases (400 ER-positive: 52 Y and 348 O; 163 ER-negative: 36Y and 137 O), and log rank significance testing was performed. DMFS of all 163 ER-negative cases was significantly worse than that of all 400 ER-positive cases (p = 0.05); and DMFS of all 88 Y cases was significantly worse than that of all 475 O cases (p = 0.02). DMFS of ER-positive Y cases was significantly worse than ER-positive O cases (p = 0.02), but DMFS of ER-negative Y cases was not significantly different than that of ER-negative O cases (p = 0.66). Consistent with our earlier results, expression of a 38-gene proliferation signature was significantly enriched in ER-positive Y cases relative to ER-positive O cases. In contrast, this proliferation signature was not differentially enriched in ER-negative Y cases relative to ER-negative O cases. While high proliferation gene signature expression correlated with worse DMFS in ER-positive Y and O cases, it did not correlate with ER-negative DMFS in either Y or O cohorts. Thus, metastatic outcome analyses indicate that for node-negative breast cancers without systemic treatment, age is a prognostic factor only for ER-positive and not for ER-negative disease. Moreover, gene expression analyses indicate that the better prognosis of ER-positive breast cancers arising after age 39 may be attributed to their lower proliferative potential while the worse DMFS of younger onset ER-positive breast cancers may be attributed to their higher proliferative potential. In contrast, the metastatic outcome of ER-negative breast cancer appears independent of both age-at-onset and tumor proliferative potential. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 4051.

Correlation study between MR spectroscopic findings and cell proliferation in astrocytoma

目的 探讨星形细胞瘤质子MR波谱(1H-MRS)表现与肿瘤增殖潜力的相关性.方法 术前进行MRI和1H-MRS检查且经手术病理证实的34例星形细胞瘤患者,其中Ⅰ、Ⅱ级(低级别)26例,Ⅲ、Ⅳ级(高级别)8例.34例星形细胞瘤患者中有21例(低级别17例,高级别4例)为均质性肿瘤.增殖细胞核抗原(PCNA)免疫组织化学染色,研究PCNA在高、低级别星形细胞瘤中的表达水平,并与星形细胞瘤1H-MRS的胆碱(Cho)/N-乙酰天冬氨酸(NAA)、Cho/肌酸和磷酸肌酸(Cr)相比较,明确两者间的关系.结果 21例均质性肿瘤中,高级别星形细胞瘤的Cho/NAA、Cho/Cr(中位数分别为4.895、4.845)比低级别(中位数分别为2.920、2.000)明显升高(Z=-2.597,P=0.009;Z=-2.687,P=0.007);且Cho/NAA、Cho/Cr与PCNA的表达[吸光度(A)值中位数7.880]呈明显正相关(r=0.607,P=0.003;r=0.457,P-0.038).但全部34例星形细胞瘤中高、低级别Cho/NAA(中位数分别为3.965、2.890)、Cho/Cr(分别为3.080、1.960)的差异无统计学意义;Cho/NAA、Cho/Cr的比值与PCNA的表达(A值中位数为8.100)不相关(r=0.060,P=0.738;r=0.125,P=0.480).结论 运用1H-MRS检测均质性星形细胞瘤中Cho的含量对于术前活体预测星形细胞瘤的恶性程度很有价值,从而能间接判断星形细胞瘤的某些生物学行为及预后。

In vivo research in astrocytoma cell proliferation with 1H-magnetic resonance spectroscopy: correlation with histopathology and immunohistochemistry

Assessment of brain tumor proliferative potential provides important prognostic information that supplements standard histopathologic grading. Proton magnetic resonance spectroscopy ((1)H-MRS) gives completely different information, relating to cell membrane proliferation, neuronal damage, energy metabolism and necrotic transformation of brain or tumor tissues. The aim of this study was to investigate the relationship between (1)H-MRS and tumor proliferative potential in astrocytomas. We studied 34 patients with histologically verified astrocytomas using the (1)H-MRS protocol following routine MRI preoperatively. The tumor in 26 of these patients was classified as grade I/II (low grade), and the tumor in the remaining patients as grade III/IV (high grade) according to the World Health Organization classification criteria of nervous system tumors (2000). The tumor in 21 patients was homogeneous astrocytoma, and of these 17 were classified as low grade and 4 as high grade. Expression of proliferating cell nuclear antigen (PCNA) was determined immunohistochemically using streptavidin-biotin-peroxidase complex (SP) staining. The ratios of choline (Cho) to N-acetylaspartate (NAA) and Cho to creatine (Cr) in those with high-grade astrocytomas (n=4) were significantly higher than in those with low-grade astrocytomas (n=17) (t=2.899, P=0.009; t=3.96, P=0.001, respectively), and were found to be significantly correlated with the expression of PCNA in 21 patients with homogeneous astrocytomas (r=0.455, P=0.038; r=0.633, P=0.002, respectively). We conclude that (1)H-MRS may be a valuable method for predicting preoperatively the degree of malignancy of homogeneous astrocytomas by enabling the calculation of the Cho/NAA and Cho/Cr ratios in vivo, and indirect evaluation of the tumor proliferative potential and prognosis, which are not available using conventional magnetic resonance imaging (MRI).