Top PDF Netrin-1 expression is an independent prognostic factor for poor patient survival in brain metastases.

Netrin-1 expression is an independent prognostic factor for poor patient survival in brain metastases.

Netrin-1 expression is an independent prognostic factor for poor patient survival in brain metastases.

The truncated DN-netrin-1 variant which localizes to the nucleolus has been shown to affect ribosome biogenesis resulting in cancer cell proliferation [14]. Beside the nucleolar expression of netrin-1, we observed a strong nuclear localisation in tumor cells which indicates a nuclear function beyond ribosome biogenesis as for instance as transcription factor or cofactor regulating target gene transcription or similar to EGFR as DNA repair mechanism in response to chemotherapy and ionizing radiation [30]. The nuclear epidermal growth factor receptor (EGFR) function was also associated with (I) poor patient survival in breast cancer patients and (II) with increased local recurrence in oropharyngeal squamous cell cancer [31,32]. Beside receptor-tyrosine kinases (RTKs) localizing to the nucleus thereby regulating cell cycle and target gene transcription [33,34] even typically secreted factors such as fibroblast growth factor bFGF [35] have the ability to localize to the nucleus. Similarly to its function on membrane- associated receptors, EGF also autophosphorylates its intranuclear receptors or receptors which are bound to the nuclear membrane [36]. In the case of nuclear/nucleolar netrin-1 expression, it is surprising that no significant correlation with the Ki67 prolifer- ation index could be observed since previous in vitro studies linked the intranuclear localisation of netrin-1 to an enhanced prolifer- ative activity [14]. Our data might not only have prognostic but also therapeutic impact since netrin-1 is involved in tumorigenesis in general and treatment strategies against netrin-1 have already been successfully tested in preclinical trials [20,21,37]. However, it is not known whether the current preclinical anti-netrin-1 approaches, which mainly focus on trapping external netrin-1 to induce tumor cell apoptosis, can be modified in a way to block also the intracellular action of netrin-1.
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FGFR1 is an independent prognostic factor and can be regulated by miR-497 in gastric cancer progression

FGFR1 is an independent prognostic factor and can be regulated by miR-497 in gastric cancer progression

Fibroblast growth factor receptor 1 (FGFR1) has been reported in gastric cancer to be a prognostic factor. However, miR-497- targeted FGFR1 has not been explored in the carcinogenesis of gastric cancer. The present study intended to revalidate the prognostic significance of FGFR1 in patients with gastric cancer, and the mechanism of miR-497-regulated FGFR1 was investigated in gastric cancer cell proliferation and apoptosis. The messenger RNA (mRNA) and protein levels were assayed by RT-qPCR and western blotting, respectively. The targeted genes were predicted by a bioinformatics algorithm and confirmed by a dual luciferase reporter assay. Cell proliferation was analyzed by CCK-8 assay. Annexin V-FITC/PI staining was used to evaluate the apoptosis in AGS and SGC-7901 cells. FGFR1 was frequently up-regulated in gastric cancer tissues and associated with poor overall survival in patients with gastric cancer. Interestingly, FGFR1 loss-of-function resulted in a significant growth inhibition and apoptosis in AGS and SGC-7901 cells. In addition, we found that miR-497 was inhibited in gastric cancer tissues and cell lines, while overexpression of miR-497 could suppress proliferation and induce apoptosis in AGS and SGC- 7901 cells. Importantly, bioinformatics analysis and experimental data suggested that FGFR1 was a direct target of miR-497, which could inhibit FGFR1 expression when transfected with miR-497 mimics. Furthermore, we found that overexpression of FGFR1 reversed the growth inhibition and apoptosis of miR-497 mimics in AGS and SGC-7901 cells. These findings suggested that overexpression of miR-497 inhibited proliferation and induced apoptosis in gastric cancer through the suppression of FGFR1.
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Co-Expression of TWIST1 and ZEB2 in Oral Squamous Cell Carcinoma Is Associated with Poor Survival.

Co-Expression of TWIST1 and ZEB2 in Oral Squamous Cell Carcinoma Is Associated with Poor Survival.

The occurrence of EMT has been shown to indicate an aggressive disease and therefore, we hypothesized that expression patterns of EMT-related proteins could be associated with worse prognosis in our OSCC patient cohort. Indeed, we observed a trend where TWIST1 and ZEB2 were associated with poor prognosis, although this did not reach statistical significance. As the EMT process is complex and often involves more than one EMT-related protein [2, 4, 50], it is likely that simultaneous overexpression of several EMT-related proteins are necessary for tumorigenesis. Taking into the account the co-expression of TWIST1 and ZEB2, we found that patients with expression of both proteins had significantly poorer survival compared to those whose tumor only expressed one or none of the 2 proteins. This effect was more apparent when we examined the expression of these 2 proteins amongst lymph node negative patients where individuals with co-expression of TWIST1 and ZEB2 are 3.8 times more likely to have a poor prognosis compared to those with the expression of either one or neither of the proteins indicating that the co-expression of these 2 markers is an independent prognostic factor for identifying aggressive disease particularly amongst lymph node negative patients. Emerging evidence suggest that EMT-related markers have other oncogenic roles in addition to driving the EMT process as measured by change of cell morphology and invasion. Although studying the functional role of EMT proteins is not within the scope of this study, previous studies dem- onstrated that TWIST1 and ZEB2 have other roles including repressing cellular senescence and conferring stem-like properties to cancer cells respectively [64, 65].
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ErbB2 and NFκB overexpression as predictors of chemoradiation resistance and putative targets to overcome resistance in muscle-invasive bladder cancer.

ErbB2 and NFκB overexpression as predictors of chemoradiation resistance and putative targets to overcome resistance in muscle-invasive bladder cancer.

The current study indicates that both erbB2 and NFkB are putative targets for treatments to overcome CRT resistance in MIBC. Among the small molecules currently being investigated in clinical studies, heat shock protein 90 (Hsp90) inhibitors can simultaneously block the activity of both of these oncoproteins [31]. Hsp90 is a ubiquitous molecular chaperone required for the stability and function of numerous client proteins, including a number of oncoproteins essential for the acquisition and maintenance of cancer hallmarks [31,32,33]. Hsp90 inhibitors destabilize Hsp90 clients by dissociating Hsp90-Hsp90 client complexes and thereby exerting antitumor activity [34]. Since both erbB2 and inhibitor of kB kinase b (IKKb), which mediates NFkB activation, are Hsp90 client proteins [31], adjunctive use of Hsp90 inhibitors is expected to efficiently sensitize MIBCs overexpressing erbB2 and/or NFkB to CRT. Indeed, we have confirmed that low-dose Hsp90 inhibitors effectually potentiate the effects of CRT on bladder cancer cells overexpressing erbB2 and NFkB in preclinical models [35].
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Intraocular pressure and ocular perfusion during hemodialysis

Intraocular pressure and ocular perfusion during hemodialysis

Continuous variables were expressed as mean ± standard devia- tion or as a percentage. Comparisons between the systolic arterial pressure (SAP) at the three time points during the HD session were evaluated using repeated measures analysis of variance (ANOVA). IOP and OPP at the three time points were analyzed using gene- ralized estimating equations (GEE) models to account for the de- pendence between eyes from the same patient. SPSS 17.0 for Win- dows (SPSS Inc, Chicago, Illinois, USA) was used for statistical analysis. All probabilities (p-values) were considered to be statistically signi- ficant if they were less than 0.05.
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Whole brain radiotherapy plus concurrent chemotherapy in non-small cell lung cancer patients with brain metastases: a meta-analysis.

Whole brain radiotherapy plus concurrent chemotherapy in non-small cell lung cancer patients with brain metastases: a meta-analysis.

Meta-analysis is based on the results of published articles and several steps of integration; thus, certain biases are inevitable. Also, 6 studies included in the meta-analysis were published in the period 1991–2013. Although the dose of WBRT for the treatment of multiple brain metastases did not change during this 22-year period, more precisely delineated target regional and advanced equipment would affect the effectiveness of treatment as technol- ogy advances. In addition, as more and more researchers focused their attention on the investigation of targeted drug combine with WBRT in the treatment of multiple brain metastases, and many chemoradiotherapy-related studies were retrospective study and single-arm study, limited RCT were included in this study. Furthermore, the methods of randomization, allocation conceal- ment, and blinding in most of the included studies are not clear. As Figure 4. Severe adverse event (P = 0.000).
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Cancer-associated fibroblasts in brain metastases

Cancer-associated fibroblasts in brain metastases

Metastases are responsible for about 90% of cancer deaths and a major problem in cancer management. In particularly, the incidence of brain metastases, which are often a sign of poor prognosis, diminished quality of life and short survival, are increasing due to the better control of primary tumours, the evolution of imaging techniques and the incidence rise of melanoma. Actual strategies include whole brain radiotherapy, stereotactic surgery, surgical resection and chemotherapy, which are very aggressive and with limited effectiveness for the patient .Tumour stroma is a key player that can determine overall outcome in cancers throughout the body. Indeed, cancer-associated fibroblasts (CAFs) have a complex and critical role in cancer progression, and there is still no specific biomarker for them. The main goal of this research project is to identify fibroblasts in tissue stroma of 138 formalin-fixed paraffin embedded samples of the most common brain metastases (lung, breast, colon, kidney and melanoma), using an extended panel of the following immunohistochemical markers: Collagen I, Collagen IV, Collagen VI, Collagen VII, anti-fibroblast TE-7, α-Smooth muscle actin and CD34. Our data provides compelling evidence for the presence of CAFs in most frequent brain metastases, as our findings are similar to previous published studies. A better understanding of the crosstalk between cancer cells and CAFs can lead to the development of novel therapeutic agents and strategies. The identification of these cells increases the oncobiological knowledge of brain metastases and, as stroma- targeted therapies are being exploited and becoming more popular in primary tumours and extra-cranial metastasis, its identification can arise new and useful strategies in brain metastases management.
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Arq. Bras. Cardiol.  vol.87 número3 en a11v87n3

Arq. Bras. Cardiol. vol.87 número3 en a11v87n3

Although the fact that the DSE results were made available to part of the physicians assisting the patients may have somehow biased their decision to refer patients to cinecoronariography, we must stress that this test was not included among the clinical events listed in this study. The cinecoronario graphy surely allowed the identification of severe lesions that prompted the indication of revascularization procedures. Additionally, the virtual impossibility of carrying out another complementary method with a similar accuracy, that is, myocardial Table 4 – Side effects during DSE
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Prognostic Factors after Liver Resection for Colorectal Liver Metastasis

Prognostic Factors after Liver Resection for Colorectal Liver Metastasis

CRLM and concomitant extrahepatic disease (EHD) submitted to surgery and concluded that the five negative prognostic factors for survival of this group of patients were: EHD-location other than lung metastases, EHD concomitant to CRLM recurrence, CEA ≥ 10 ng/mL, ≥ 6 liver metastases, and right colon cancer. Therefore, patients with CRLM with metachronous diagnosis of EHD, with < 6 liver metastases at diagnosis, presenting with isolated lung metastases and a CEA level < 10 ng/mL, and in whom the primary tumor is not located in the right colon, had a good long-term survival after complete resection of disease, and were considered optimal candidates for this treatment strategy. Taking into account that surgery of all resectable disease is the best chance of long-term survival, whenever technically possible, surgery should be discussed. However, in an external validation of the referred prognostic model made by Mavros et al, 25 none of these factors reached statistical significance,
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Further evidence of the prognostic role of pretreatment levels of CA 19-9 in advanced pancreatic cancer

Further evidence of the prognostic role of pretreatment levels of CA 19-9 in advanced pancreatic cancer

with single-agent gemcitabine had also received a second drug combined with gemcitabine (after tolerance to gemci- tabine had been ascertained) before disease progression, all such regimens were considered as first-line treatment during this analysis. The same was done in the case of patients who had initially been treated with a combination, and in whom gemcitabine had been maintained as a single-agent (in order to decrease toxicity) until the first documentation of disease progression. During treatment, chemotherapy doses were reduced according to usual guidelines, and treatment was continued until clinical or radiographic evidence of disease progression or unacceptable toxicity. In addition to chemotherapy, some patients had been treated after first-line with a molecularly targeted agent such as erlotinib, beva- cizumab and/or cetuximab. Since the oral tyrosine-kinase inhibitor erlotinib had been used more frequently, according to results of a phase III clinical trial, 23 only this molecularly
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Decreased expression of chromodomain helicase DNA-binding protein 9 is a novel independent prognostic biomarker for colorectal cancer

Decreased expression of chromodomain helicase DNA-binding protein 9 is a novel independent prognostic biomarker for colorectal cancer

Two-step immunohistochemistry assay was used in this study. Tissue sections were treated with EDTA buffer under high pressure at high temperature to retrieve antigen. Then, sections were incubated with primary antibody named anti-CHD9 (1:3000, 13402-1-AP, Proteintech, USA) at 4°C overnight. Sections were then washed with PBS after incubating with secondary antibody (HRP-labeled anti- rabbit antibody; DAKO, Denmark). Samples were visual- ized using diaminobenzidine system and hematoxylin re-dying, and analyzed under microscope (OLYMPUS CX41, Japan). Three random high-magnification fields of each specimen were chosen under optical microscope and more than 300 cells were selected for the evaluation. The CHD 9 expression was scored and grouped by posi- tive staining rate and intensity. The positive staining rate was defined according to the proportion of stained cancer cells: ‘‘Negative’’ is 0, ‘‘1–25%’’ is 1, ‘‘26–50%’’ is 2, ‘‘51–75%’’ is 3, ‘‘76–100%’’ is 4. The score for staining intensity was defined as follows: ‘‘Negative’’ is 0, ‘‘1+’’ is 1, ‘‘2+’’ is 2, ‘‘3+’’ is 3. Thus, patients were divided into low expression (p8) and high expression (48) groups according to the scores after multiplying ‘‘positive staining rate score’’ by the ‘‘staining intensity score’’.
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Endogenous Nmnat2 is an essential survival factor for maintenance of healthy axons.

Endogenous Nmnat2 is an essential survival factor for maintenance of healthy axons.

Of the three mammalian Nmnat isoforms, Nmnat2 did not initially appear the most obvious candidate for an endogenous axon survival factor, despite being the most abundantly expressed isoform in the nervous system at the mRNA level [23,34]. First, its predominant Golgi localization seemed inconsistent with an axonal location. However, a recent report shows axons in primary neuronal cultures contain Golgi components [42] and, as with Wld S [3], predominant localization may not reflect the site of its axon protective role. We have now clearly detected endogenous Nmnat2 in SCG neurites by immunoblotting and have shown that an Nmnat2-eGFP fusion localizes to distinct, rapidly transported particles in these neurites (Figure 7 and Video S1). It will be interesting to determine the precise nature of these particles. Second, the inability of Nmnat2 to protect 5-d lesioned axons in Drosophila, unlike the other Nmnat isoforms and Wld S , initially suggested it was either ineffective or by far the least potent isoform [2]. However, it has more recently been shown that exogenous expression of Nmnat2 can protect injured mammalian axons [26]. We propose that the short half-life of Nmnat2 could provide an explanation for this discrepancy, with the degree of protection being related to the levels of Nmnat2 expression achieved in the different systems. It is also possible that some protection of lesioned Drosophila axons might be evident at a less stringent time point (wild-type fly axons begin to degenerate just 1 d after injury). Thus, a short half-life, one of the most critical inherent properties of the endogenous survival factor in our model, might mask the capacity of exogenous Nmnat2 to protect in some situations. Conversely, greater stability probably underlies the ability of exogenous Nmnat1 and Nmnat3 to protect injured axons/neurites more robustly in this and other in vivo and/or in vitro situations [1,2,8,25].
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Arq. Bras. Cardiol.  vol.84 número3 en a08v84n3

Arq. Bras. Cardiol. vol.84 número3 en a08v84n3

Anemia is a comorbidity whose prognostic importance has been well recognized in a series of cardiovascular diseases, acute myo- cardial infarction included. In heart failure, anemia has only recen- tly received attention, and its prevalence has ranged from 16 to 48%, depending on the age of the patients studied, the severity of the disease, and the criteria used for the diagnosis of anemia. In our study, a high prevalence of anemia (63%) was found, which may be explained by the predominance of elderly patients with advanced heart failure, although that prevalence may have been overestimated by the limitations of a retrospective study.
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J. Bras. Patol. Med. Lab.  vol.49 número1

J. Bras. Patol. Med. Lab. vol.49 número1

The statistical analysis considered data descriptive measures, including frequencies and percentages for categorical variables, mean, median, minimum values, maximum values and standard deviation for quantitative measures. Student’s t test and non parametric Mann- Whitney test were used for comparison of groups deined by clinical pathological variables and clinical course in relation to quantitative variables. As to dichotomous nominal variables, the groups were compared through Fisher’s exact test. The association level between two markers was calculated by Spearman’s rank correlation coeficient and by Kappa coeficient. Kaplan-Meier curves were build to assess survival rates and comparison between curves was conducted by log-rank test. p values < 0.05 showed statistical signiicance. We employed SPSSV8 ® statistical analysis program.
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Prognostic impact of lymphocytes in soft tissue sarcomas.

Prognostic impact of lymphocytes in soft tissue sarcomas.

The applied antibodies were subjected to in-house validation by the manufacturer for IHC analysis on paraffin-embedded material. Ventana Benchmark, XT automated slide stainer (Ventana Medical System, France) was used for IHC. Sections were deparaffinized with xylene and rehydrated with ethanol. Antigen retrieval was performed by placing the specimens in 0.01 M citrate buffer at pH 6.0 and exposing them to two repeated microwave heatings of 10 minutes each at 450W. The DAKO Envision+ System-HRP (DAB) kit was used as endogen peroxidase blocking. As negative staining controls, the primary antibodies were replaced with the primary antibody diluents. Primary mouse monoclonal antibodies were incubated for 16 minutes (CD20, clone L26 Ventana), 20 minutes (CD4, clone 1F6 Novocastra, dilution 1:5) and 32 minutes (CD8, clone 1A5 Ventana) at room temperature. The Ventana antibodies were pre-diluted from the manufacturer. Biotinylated goat anti-mouse IgG and mouse anti-rabbit IgM were used as secondary antibodies. The DAB was used to visualize the antigens. This was followed by application of liquid diaminobenzidine and substrate-chromogen, yielding a brown reaction product at the site of the target antigen. Finally, slides were counterstained with hematoxylin to visualize the nuclei. For each antibody, including negative controls, all TMA staining was performed in a single experiment.
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Int. braz j urol.  vol.32 número3

Int. braz j urol. vol.32 número3

We report a case of bilateral metastatic renal hemangiopericytoma. A 37-year-old Caucasian male presented in 1993 with intracranial hemangiopericytoma. Subsequent metastatic disease noted years later include bilateral renal hemangiopericytoma 10 years after initial presentation. To our knowledge, this is only the second reported case of bilateral metastatic renal hemangiopericytoma.

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The clinical implication of cancer-associated microvasculature and fibroblast in advanced colorectal cancer patients with synchronous or metachronous metastases.

The clinical implication of cancer-associated microvasculature and fibroblast in advanced colorectal cancer patients with synchronous or metachronous metastases.

Carcinoma cells in different tissue areas have distinct characteristics [32]. In central areas of the tumor, carcinoma cells maintain an epithelial cell phenotype, but carcinoma cells in the invasive front acquire a more malignant and mesenchy- mal phenotype and are thought to have an increased migratory capacity and contribute to metastatic diseases. These metastatic cells may restore the epithelial phenotype at metastatic sites [33]. In addition to carcinoma cells themselves, microenviron- ment is suggested to be uneven within a given tumor because tumor formation and progression involve the co-evolution of cancer cells and microenvironments [34]. The present study demonstrated that the cancer-associated microenvironment also had distinct characteristics in different areas. Of the sites examined, LVD was highest in the center of the primary cancer. MVD was slightly higher in center than at the periphery of the primary cancer, but this difference was not statistically significant. Interestingly, the amount of CAFs in distant metastases was significantly lower than in center and periphery of the primary cancer. We show that the stromal microenvi- ronment has regional heterogeneity both within the primary tumor and between the primary site and its related metastases. Furthermore, our data suggests that the stromal heterogeneity might be attributable to tumor heterogeneity. Therefore, it would be beneficial to consider both stromal and tumor cell heterogeneity in order to manage CRC patients better.
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Prognostic nomograms for predicting survival and distant metastases in locally advanced rectal cancers.

Prognostic nomograms for predicting survival and distant metastases in locally advanced rectal cancers.

European phase III clinical trials [16]. Postoperative ypT stage and ypN stage were most relevant to overall survival. However, as downstaged by preoperative CRT, the two most important prognostic factors (ypT and ypN classfications) could not be well applied to patients treated with curative surgery prior to adjuvant treatment. Otherwise, the decision of neoadjuvant CRT mainly relies on preoperative staging of the primary tumor. The accuracy of T and N stage by preoperative MRI or endorectal ultrasound varies, especially in N stage. A number of patients with locally advanced rectal cancer will be under-staged preoperatively and undergo surgery first. The postoperative treatment and outcome prediction for this group of patients are currently lacking. Moreover, although perioperative CRT or CT has been proved to be effective in rectal cancer, in real clinical circumstance, there are still a part of patients with locally advanced rectal cancer undergoing surgery alone. According to a large-scale population- based study through the California Cancer Registry, there were still 33% and 18.6% of patients with stage II and stage III rectal cancer undergoing surgery alone from the year 1994 to 2008 [23]. Similarly, 57.4% and 13.0% of patients with stage II and stage III rectal cancer underwent surgery alone in our study. Currently, we are lacking of studies in defining characteristics of patients who Table 2. Cont.
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Int. braz j urol.  vol.36 número1

Int. braz j urol. vol.36 número1

Results: PNI was found in 188 (15%) patients, and was signiicantly associated with aggressive pathology and biochemical progression. On multivariate analysis, PNI was signiicantly associated with extraprostatic extension and seminal vesicle invasion (P < 0.001). Biochemical progression occurred in 10.5% of patients with PNI, vs 3.5% of those without PNI (unadjusted hazard ratio 3.12, 95% conidence interval 1.77-5.52, P < 0.001). However, PNI was not a signiicant independent predictor of biochemical progression on multivariate analysis. Finally, nerve-sparing did not adversely affect biochemical progression even among men with PNI. Conclusion: PNI is an independent risk factor for aggressive pathology features and a non-independent risk factor for biochemical progression after RP. However, bilateral nerve-sparing surgery did not compromise the oncological outcomes for patients with PNI on biopsy.
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Dissertaçao Sandra Antunes

Dissertaçao Sandra Antunes

In order to establish an adequate treatment it is important to obtain the histological classification, the grading and the staging of the tumour, since most of the MTs present local and distant metastasis at the time of the diagnosis. Tumours of the feline mammary gland are histologically classified according to the diagnostic criteria proposed by the World Health Organization (WHO). This classification is based on descriptive morphology and divides MTs into four main groups: mammary hyperplasia/dysplasia; benign tumours, malignant tumours, and unclassified tumours. The histological grade is determined according to an adaptation of the classification used by Elston and Ellis and is based on the degree of tubule formation, degree of nuclear and cellular pleomorphism, and mitotic count. The staging of feline MT is based on a modified WHO clinical staging system.
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