High Mitotic Index Research Articles

Correlation between estrogen receptor, progesterone receptor, HER-2/neu status and other prognostic factors in carcinoma breast in Indian population

Background: Incidence of breast carcinoma (BC) is increasing all over the world. Contrary to the West where it is more common in the elderly; in India it is more common among the younger women. India accounts for nearly six percent of deaths, due to breast cancers in the world and also that one out of every 22 women in India is diagnosed with breast cancer every year. But no information is available on its biological characteristics in the Indian population. Our aim was to evaluate the estrogen receptor, progesterone receptor and HER-2/neu receptor in single institute patients and to compare the expression of these factors with other prognostic parameters such as menopausal state, size of tumor, grade, histological type, mitotic index, lymphovascular invasion and nodal metastases. Methods: This is a prospective study conducted in the Department of General Surgery at Sri Ramachandra Medical University Hospital, Chennai, India. A batch of 60 confirmed patients of BC, diagnosed in between 2012 to 2014, were included in this study. ER, PR and HER-2/neu status were studied by immune-histochemistry and were correlated with other prognostic factors. Results: ER negative and PR negative cases were comparatively high (61.7% and 70%) than the positive cases. 66.7% of the cases were post-menopausal group, 68.3% of cases were T2 tumor and 81.7% cases were ductal carcinoma. There was a significant correlation identified between ER, PR with tumor grade and Mitotic Index of the tumor. HER-2/neu positive cases tended to have significant higher axillary metastasis. There was no significant correlation between ER, PR and HER-2/neu with menopausal state, size, histological type and lymphovascular invasion. Conclusions: The ER, PR and Her2/neu expression in BC in our patients is comparable with the available international data. ER and PR negative expressions are strongly associated with some known bad pathological factors like high grade tumor and high Mitotic Index. HER-2/neu expression was high in advanced diseases like axillary node positive patients.

Giant solitary fibrous tumor from the lesser omentum causing a gastric outlet obstruction: A case report

Introduction: solitary fibrous tumors (sFts) are exceedingly rare tumors arising from the submesothelial mesenchymal layer. case report: A case of a 60-year-old male with paranoid schizophrenia presented with acute gastric obstruction secondary to a large, obstructive, mobile mass. surgical exploration revealed a 17x15x10.5 cm extraluminal, pedunculated mass originating from the lesser omentum extrinsically compressing the gastric antrum and duodenum. the mass was surgically resected with immediate relief of patient symptoms. Pathology revealed a spindle cell sarcoma with a high mitotic index. Immunohistochemical analysis was positive for cD34 and a newly elucidated nuclear marker that is sensitive and specific for sFt, stAt 6, was used to confirm the diagnosis of sFt. conclusion: to our knowledge, this is the largest described solitary fibrous tumor arising from the lesser omentum.

Relevant Role of Di-Fucosylated Ley Antigen in the Outcome of Locally Advanced Cervical Squamous Cell Carcinoma Patients Treated with Cisplatin Regimen

Background: Several mechanisms are involved in the development of resistance to therapy in LACSCC. Studies have shown that CD44 and Lewis Y antigen (LeY) form a complex that is associated with chemoresistance, tumor invasion and metastasis. We assessed the role of CD44 and LeY in the outcome of LACSCC patients (pts) treated with different chemotherapy regimens. Methods: A total of 126 LACSCC pts FIGO stages IIB-IVA were selected from GOCS databases: 74 pts included in three different prospective phase II trials in the neoadjuvant setting (vinorelbine, docetaxel, ifosfamide-vinorelbinecisplatin) and 52 pts treated with standard radio-chemotherapy based in cisplatin (RCBC). Clinical data at baseline, disease free survival (DFS) and overall survival (OS) were recorded. Univariate and multivariate Cox models were employed. Results: Median age was 45.6 years (range: 24.9 - 80.5). Sixty-three and 47 tumors were CD44+ and LeY+, respectively. Expansive growth tumors showed a higher grade (p=.0024), mitotic index (p=.0505), tumoral necrosis (p=.0191), LeY+ (p=.0034) and CD44+/LeY+ co-expression (p=.0334). CD44+ cells were present in 91.3% of those with local recurrence (p=.0317). Advanced stage was associated with LeY+ tumors (p=.0057). Pts treated with RCBC had worse DFS and OS when their tumors expressed LeY antigen (p=.0083 and p=.0137, respectively). Pre-treatment hemoglobin level, FIGO stage and tumor response remained the most significant prognostic factors in Cox regression. Conclusions: In our cohort of LACSCC pts, the co-expression of CD44+/LeY+ was not associated with worse outcome. However, in the subgroup of pts receiving RCBC, LeY expression was correlated with shorter DFS and OS.

Integrative analysis of high-throughput RNAi screen data identifies the FER and CRKL tyrosine kinases as new regulators of the mitogenic ERK-dependent pathways in transformed cells.

BackgroundCell proliferation is a hallmark of cancer and depends on complex signaling networks that are chiefly supported by protein kinase activities. Therapeutic strategies have been used to target specific kinases but new methods are required to identify combined targets and improve treatment. Here, we propose a small interfering RNA genetic screen and an integrative approach to identify kinase networks involved in the proliferation of cancer cells.ResultsThe functional siRNA screen of 714 kinases in HeLa cells identified 91 kinases implicated in the regulation of cell growth, most of them never being reported in previous whole-genome siRNA screens. Based on gene ontology annotations, we have further discriminated between two classes of kinases that, when suppressed, result in alterations of the mitotic index and provoke cell-cycle arrest. Extinguished kinases that lead to a low mitotic index mostly include kinases implicated in cytosolic signaling. In contrast, extinguished kinases that result in a high mitotic index mostly include kinases implicated in cell division. By mapping hit kinases in the PhosphPOINT phosphoprotein database, we generated scale-free networks consisting of 449 and 661 protein-protein interactions for kinases from low MI and high MI groups, respectively. Further analyses of the kinase interactomes revealed specific modules such as FER- and CRKL-containing modules that connect three members of the epidermal growth factor receptor (EGFR) family, suggesting a tight control of the mitogenic EGF-dependent pathway. Based on experimental studies, we confirm the involvement of these two kinases in the regulation of tumor cell growth.ConclusionBased on a combined approach of large kinome-wide siRNA screens and ontology annotations, our study identifies for the first time two kinase groups differentially implicated in the control of cell proliferation. We further demonstrate that integrative analysis of the kinase interactome provides key information which can be used to facilitate or optimize target design for new therapeutic strategies. The complete list of protein-protein interactions from the two functional kinase groups will provide a useful database for future investigations.Electronic supplementary materialThe online version of this article (doi:10.1186/1471-2164-15-1169) contains supplementary material, which is available to authorized users.

Anaplastic Childhood Meningioma in a 16-Year-Old Boy

Meningiomas account for 0.4-4.6% of all primary brain tumors in children. Childhood meningiomas have several different characteristics than those occurring in adults. Case: Here we report a 16 year old male presented with long-standing headache and incipient weakness on the left side. Magnetic resonance images revealed a 65x47x37 mm sized, right sided frontoparietal parasagittal extra-axial mass. Histopathologic examination showed monotonous, small cells with oval/round nucleus forming whorl-like structures. The tumor showed high mitotic index and Ki67 proliferation rate around 30%. Immunohistochemically tumor cells were positive with EMA, vimentin, BCL-2, progesterone receptor. The final diagnosis according to histopathological, radiological and immunohistochemical findings was anaplastic meningioma. Conclusion: High-grade meningiomas are rare in children. Appropriate grading is important, as high grade tumors with high proliferation index are associated with less favorable clinical outcomes and warrant more radical treatment.

The influence of Ki-67 proliferation index on Tc-99m-EDDA-HYNIC-TOC somatostatin receptor scintigraphy in patients with carcinoids

Abstract The aim of this paper is to determine the influence of Ki-67 proliferation index on somatostatin receptor scintigraphy (SSRS) with Tc-99m-EDDA-HYNIC-TOC (Tc-99m-Tektrotyd) somatostatin analogue in patients with carcinoid tumors. Sixty-one patients (31 female, 30 male; age range: 33-76 years) were examined: 13 patients highly suspected of having a carcinoid, and 48 patients who had undergone the surgical removal of the tumor. Whole body SSRS at 4 h postinjection, spot scintigrams and SPECT of the selected regions were obtained for all patients. Tc-99m-Tektrotyd scintigraphy was classified as true positive in 26 out of 30 and true negative in 24 out of 28 patients. The sensitivity of Tc-99mTc-Tektrotyd scintigraphy was found to be as high as 94.74% in the group of patients with low mitotic index Ki67 (<2%), and it progressively decreased in patients with higher mitotic index (77.78% for Ki67 2-15% and 20% for Ki67% >20%). The likelihood of Tc-99m-Tektrotyd scan being positive when a carcinoid is present was found to be inversely proportional to the value of Ki67 proliferation index. The results showed that Tc-99m-Tektrotyd SSRS is a sensitive method for diagnosing and staging patients with well-differentiated carcinoid tumors. However, in poorly differentiated tumors with high Ki67 proliferation index, additional analyses are necessary for precise staging.

Untangling the ATR-CHEK1 network for prognostication, prediction and therapeutic target validation in breast cancer

ATR-CHEK1 signalling is critical for genomic stability. ATR-CHEK1 signalling may be deregulated in breast cancer and have prognostic, predictive and therapeutic significance. We investigated ATR, CHEK1 and phosphorylated CHEK1 Ser345 protein (pCHEK1) levels in 1712 breast cancers. ATR and CHEK1 mRNA expression was evaluated in 1950 breast cancers. Pre-clinically, biological consequences of ATR gene knock down or ATR inhibition by the small molecule inhibitor (VE-821) were investigated in MCF7 and MDA-MB-231 breast cancer cell lines and in non-tumorigenic breast epithelial cells (MCF10A). High ATR and high cytoplasmic pCHEK1 levels were significantly associated with higher tumour stage, higher mitotic index, pleomorphism and lymphovascular invasion. In univariate analyses, high ATR and high cytoplasmic pCHEK1 levels were associated with poor breast cancer specific survival (BCSS). In multivariate analysis, high ATR level remains an independent predictor of adverse outcome. At the mRNA level, high CHEK1 remains associated with aggressive phenotypes including lymph node positivity, high grade, Her-2 overexpression, triple negative, aggressive molecular phenotypes and adverse BCSS. Pre-clinically, CHEK1 phosphorylation at serine345 following replication stress was impaired in ATR knock down and in VE-821 treated breast cancer cells. Doxycycline inducible knockdown of ATR suppressed growth, which was restored when ATR was re-expressed. Similarly, VE-821 treatment resulted in a dose dependent suppression of cancer cell growth and survival (MCF7 and MDA-MB-231) but was less toxic in non-tumorigenic breast epithelial cells (MCF10A). We provide evidence that ATR and CHEK1 are promising biomarkers and rational drug targets for personalized therapy in breast cancer.

The Case of the Missed Chest Radiograph: Bilateral Mammary Gland Metastases Mimicking Multifocal Primary Breast Cancer as the Initial Manifestation of Non–Small-Cell Lung Cancer

time, multiple nodular lesions were observed in the left thoracic wall, in front of the major pectoralis muscle, with the largest one corresponding to the fixed breast mass that was reported as the presenting sign of the patient (Fig. 3C, white arrows). A subse- quent computed tomography-guided biopsy of the thoracic mass confirmed the diagnosis of a poorly differentiated adenocarci- noma of the lung with a high mitotic index and a positive stain for TTF1. Morphological and immunohistochemical features of the breast lesions were consistent with metastases from the primary lung adenocarcinoma. Mutation analysis of the tumor specimen revealed no activating mutation of the EGFR gene and fluores- cence in situ hybridization analysis with break-apart probes for the ALK gene was negative for the presence of an ALK rearrange- ment. On the basis of these findings, the patient received first-line chemotherapy encompassing paclitaxel carboplatin and bevaci- zumab. After three cycles of chemotherapy, reevaluation showed progressive disease in both the primary tumor and the metastatic lesions to the breast. The patient is currently receiving second- line chemotherapy with pemetrexed. DISCUSSION

Clinicopathological Significance of ATM-Chk2 Expression in Sporadic Breast Cancers: a Comprehensive Analysis in Large Cohorts

ATM-Chk2 network is critical for genomic stability, and its deregulation may influence breast cancer pathogenesis. We investigated ATM and Chk2 protein levels in two cohorts [cohort 1 (n = 1650) and cohort 2 (n = 252)]. ATM and Chk2 mRNA expression was evaluated in the Molecular Taxonomy of Breast Cancer International Consortium cohort (n = 1950). Low nuclear ATM protein level was significantly associated with aggressive breast cancer including larger tumors, higher tumor grade, higher mitotic index, pleomorphism, tumor type, lymphovascular invasion, estrogen receptor (ER)−, PR−, AR−, triple-negative, and basal-like phenotypes (Ps < .05). Breast cancer 1, early onset negative, low XRCC1, low SMUG1, high FEN1, high MIB1, p53 mutants, low MDM2, low Bcl-2, low p21, low Bax, high CDK1, and low Chk2 were also more frequent in tumors with low nuclear ATM level (Ps < .05). Low ATM protein level was significantly associated with poor survival including in patients with ER-negative tumors who received adjuvant anthracycline or cyclophosphamide, methotrexate, and 5-fluorouracil–based adjuvant chemotherapy (Ps < .05). Low nuclear Chk2 protein was likely in ER−/PR−/AR−; HER-2 positive; breast cancer 1, early onset negative; low XRCC1; low SMUG1; low APE1; low polβ; low DNA-PKcs; low ATM; low Bcl-2; and low TOPO2A tumors (P < .05). In patients with ER+ tumors who received endocrine therapy or ER-negative tumors who received chemotherapy, nuclear Chk2 levels did not significantly influence survival. In p53 mutant tumors, low ATM (P < .000001) or high Chk2 (P < .01) was associated with poor survival. When investigated together, low-ATM/high-Chk2 tumors have the worst survival (P = .0033). Our data suggest that ATM-Chk2 levels in sporadic breast cancer may have prognostic and predictive significance.

Cellular stress responses in cancer and cancer therapy.

Cellular stress responses in cancer and cancer therapy.

Abstract NG01: Blockade of EGFR and HER3 enhances PI3K/Akt antitumor activity in triple negative breast cancer

Abstract NG01: Blockade of EGFR and HER3 enhances PI3K/Akt antitumor activity in triple negative breast cancer

128IN - Pet-Based Decisions in Non Hodgkin'S Lymphoma

ABSTRACT Patients with NHL vary in response to current therapies. Early identification of the non-responders is of utmost importance in order to maximise their chances of a successful second-line therapy. In the search for a predictor of outcome to distinguish responders from non-responders, FDG-PET interim response assessment has been identified as a very promising tool. It provides an excellent basis for ‘personalized medicine’, whereby patients whose tumour is not responding may be shifted early during treatment from the ineffective to an another therapy. Even though the value of FDG-PET for post-treatment response assessment in DLBCL is well established nowadays, its value as a tool for interim response assessment is highly debated. In clinical practice PET scans are typically interpreted by visual methods. The well-established International Harmonization Project) criteria dichotomize PET results into positive and negative relative to the intensity of tracer uptake. These criteria have been designed to assess end-of-therapy response and should not be used to evaluate interim-PET scans. A new visual approach to PET scoring in lymphoma include a 5-point scale, the so-called Deauville criteria. At any observation time during induction chemotherapy, FDG uptake reflects a metabolic state which is a balance between tumour cell kill of chemosensitive components and re-growth of resistant components. When interim-PET is performed after one or two cycles, it evaluates the response of the cells with the highest mitotic index, thereby providing an early evaluation of chemosensitivity. In studies that have been conducted on the predictive value of interim PET, timing of interim PET varies considerably, both between and within studies, ranging from PET having been performed after 1 to 4 treatment cycles. To maximise therapy effectiveness and to minimise delays, toxicity and costs, early response assessment seems an attractive way to go. Interim-PET seems a promising tool but important issues as impact of timing, criteria, therapies on test performance need to be clarified. Randomized clinical trials with interim PET-CT based treatment modifications must ultimately demonstrate whether this strategy will improve patient outcome. Disclosure: The author has declared no conflicts of interest.

Risk Factors and Features of Recurrence After Curative Resection of Gastrointestinal Stromal Tumor: Results of the Kinki Gist Registry Study

ABSTRACT Aim: To develop the optimal method of postoperative adjuvant therapy for gastrointestinal stromal tumor (GIST), it is necessary to estimate the risk of recurrence and to predict the prognosis after resection. Methods: Patients histologically diagnosed as GIST between Jan 2002 and Dec 2007 were enrolled into the GIST registry study by the Kinki GIST study group. A total of 570 patients in 40 institutiions who underwent curative resection of the tumor and were not given adjuvant therapy were investigated in this study. The prognostic factors and features of recurrence were assessed. And the patients were stratified by the modified-Flecher's (m-F) risk classification and validated for predicting the recurrence. Results: 73 patients developed tumor recurrences. 5-year overall survival (OS) and disease-specific recurrence-free survival (RFS) were 89.8%, 86.0%, and 10-year OS and RFS were 73.1%, 72.5%, respectively. The independent risk factors for recurrence were non-gastric location (HR: 2.63, 95%CI: 1.49-4.65), tumor size >5cm (HR: 3.70, 95%CI: 1.96-7.04), mitotic index (MI) >5/50HPF (HR: 5.49, 95%CI: 3.40-10.0), presence of tumor rupture (HR:3.90, 95%CI: 1.72-8.85). The median period of recurrence after resection was 541 (range 34-3128) days and 67% of the recurrence occurred within 2 years, 86% within 3 years, 95% within 5 years. Patients with high mitotic count or with tumor rupture developed signifcantly earlier recurrece (MI >5 vs. Conclusions: Modified-F classification discriminates the risk of recurrence of GIST properly. Patients classified as high risk by m-F criteria should be given adjuvant therpy. The high MI or tumor rupture are at particularly high risk of recurrence, thus, intensive precaution should be considered for the patients meeting these criteria. Disclosure: All authors have declared no conflicts of interest.

A prognosis based classification of undifferentiated uterine sarcomas: identification of mitotic index, hormone receptors and YWHAE-FAM22 translocation status as predictors of survival.

Undifferentiated uterine sarcomas (UUS) are rare tumors with a heterologous biology and a poor prognosis. The goal of this study was to examine clinicopathology, biomarkers and YWHAE-FAM22 translocation status, in the prognosis of these tumors. Twenty-six cases of UUS were included. All original slides were rereviewed and age at diagnosis, tumor stage, "Kurihara" diagnosis, mitotic index, presence of necrosis and grade of nuclear atypia were recorded. Additionally, a tissue microarray was constructed from 22 of the cases, and the protein biomarkers P53, P16, Ki-67, Cyclin-D1, ER, PR and ANLN were evaluated by immunohistochemistry. All tumors were evaluated for the presence of a YWHAE-FAM translocation; the translocation was demonstrated in the three Cyclin-D1 positive tumors. Follow-up data in the form of overall survival were available on all patients. These tumors could be divided into two prognostic groups, a high mitotic index group (10 cases, M = 36.8, SD = 5.4) and a low mitotic index group (16 cases, M = 8.7, SD = 5.8). These two groups showed a statistically significant difference in prognosis. The expression of ER, PR or presence of the YWHAE-FAM22 translocation correlated with low mitotic index and an additionally improved prognosis, although the number of cases was small. These results indicate that UUS can be divided into two prognostic groups using mitotic index as a primary criteria, followed by expression of either ER, PR or the presence of a YWHAE-FAM22 translocation as a secondary criteria. This study demonstrates the presence of statistically significant prognostic subgroups within UUS, and provides treatment insights.

Rapid analysis of chromosome aberrations in mouse B lymphocytes by PNA-FISH.

Defective DNA repair leads to increased genomic instability, which is the root cause of mutations that lead to tumorigenesis. Analysis of the frequency and type of chromosome aberrations in different cell types allows defects in DNA repair pathways to be elucidated. Understanding mammalian DNA repair biology has been greatly helped by the production of mice with knockouts in specific genes. The goal of this protocol is to quantify genomic instability in mouse B lymphocytes. Labeling of the telomeres using PNA-FISH probes (peptide nucleic acid - fluorescent in situ hybridization) facilitates the rapid analysis of genomic instability in metaphase chromosome spreads. B cells have specific advantages relative to fibroblasts, because they have normal ploidy and a higher mitotic index. Short-term culture of B cells therefore enables precise measurement of genomic instability in a primary cell population which is likely to have fewer secondary genetic mutations than what is typically found in transformed fibroblasts or patient cell lines.

Rapid Analysis of Chromosome Aberrations in Mouse B Lymphocytes by PNA-FISH

Defective DNA repair leads to increased genomic instability, which is the root cause of mutations that lead to tumorigenesis. Analysis of the frequency and type of chromosome aberrations in different cell types allows defects in DNA repair pathways to be elucidated. Understanding mammalian DNA repair biology has been greatly helped by the production of mice with knockouts in specific genes. The goal of this protocol is to quantify genomic instability in mouse B lymphocytes. Labeling of the telomeres using PNA-FISH probes (peptide nucleic acid - fluorescent in situ hybridization) facilitates the rapid analysis of genomic instability in metaphase chromosome spreads. B cells have specific advantages relative to fibroblasts, because they have normal ploidy and a higher mitotic index. Short-term culture of B cells therefore enables precise measurement of genomic instability in a primary cell population which is likely to have fewer secondary genetic mutations than what is typically found in transformed fibroblasts or patient cell lines.

Determinants of outcome of solitary fibrous tumors of the pleura: an observational cohort study.

BackgroundSolitary fibrous tumors of the pleura (SFTP) are rare and their long-term outcome is difficult to predict, as there are insufficient data which allow accurate characterization of the malignant variant. Thus the aim of this study was to describe the outcome and possible determinants of malignant behavior of SFTPs.MethodsData were collected retrospectively from medical records of patients treated at the University Hospital Zurich from 1992 to 2012. Kaplan-Meier and Cox regression analysis were performed to define disease-free survival time (defined as survival without tumor-recurrence or tumor-related death) using the classical histo-morphological criteria (tumor size, localization, pedunculation, tumor necrosis or hemorrhage, mitotic activity and nuclear pleomorphism) and immunohistochemical parameters.Results42 patients (20 males) with SFTP (median (IQR) age 62 (56–71) years) could be identified. SFTP were associated with symptoms in 50% of all cases. Complete resection was achieved by video-assisted thoracic surgery or thoracotomy in 20 and 22 patients, respectively. Three SFTP-related deaths (7.1%) and four tumor recurrences (9.5%) were observed. Mean disease-free survival time was 136.2 (±13.1) months, and 2-, 5- and 10-year disease-free survival was 91%, 84%, and 67%, respectively. Mean disease-free survival inversely correlated with the mean tumor diameter, number of mitotic figures and proliferation rate (Ki-67 expression). Other criteria (tumor necrosis, atypical localization, sessile tumor, and pleomorphism) were not statistically significant prognostic parameters.ConclusionsPatients with large SFTP with a high mitotic index and high proliferation rate should be followed-up closely and over a prolonged time period in order to recognize recurrence of the SFTP early and at a treatable stage. Future research on this topic should focus on the prognostic role of immunohistochemistry including Ki-67 expression and molecular parameters.

Targeted inactivation of Cerberus like-2 leads to left ventricular cardiac hyperplasia and systolic dysfunction in the mouse.

Previous analysis of the Cerberus like 2 knockout (Cerl2−/−) mouse revealed a significant mortality during the first day after birth, mostly due to cardiac defects apparently associated with randomization of the left-right axis. We have however, identified Cerl2-associated cardiac defects, particularly a large increase in the left ventricular myocardial wall in neonates that cannot be explained by laterality abnormalities. Therefore, in order to access the endogenous role of Cerl2 in cardiogenesis, we analyzed the embryonic and neonatal hearts of Cerl2 null mutants that did not display a laterality phenotype. Neonatal mutants obtained from the compound mouse line Cer2−/−::Mlc1v-nLacZ24+, in which the pulmonary ventricle is genetically marked, revealed a massive enlargement of the ventricular myocardium in animals without laterality defects. Echocardiography analysis in Cerl2−/− neonates showed a left ventricular systolic dysfunction that is incompatible with a long lifespan. We uncovered that the increased ventricular muscle observed in Cerl2−/− mice is caused by a high cardiomyocyte mitotic index in the compact myocardium which is mainly associated with increased Ccnd1 expression levels in the left ventricle at embryonic day (E) 13. Interestingly, at this stage we found augmented left ventricular expression of Cerl2 levels when compared with the right ventricle, which may elucidate the regionalized contribution of Cerl2 to the left ventricular muscle formation. Importantly, we observed an increase of phosphorylated Smad2 (pSmad2) levels in embryonic (E13) and neonatal hearts indicating a prolonged TGFβs/Nodal-signaling activation. Concomitantly, we detected an increase of Baf60c levels, but only in Cerl2−/− embryonic hearts. These results indicate that independently of its well-known role in left-right axis establishment Cerl2 plays an important role during heart development in the mouse, mediating Baf60c levels by exerting an important control of the TGFβs/Nodal-signaling pathway.

Adverse prognostic and predictive significance of low DNA-dependent protein kinase catalytic subunit (DNA-PKcs) expression in early-stage breast cancers.

DNA-dependent protein kinase catalytic subunit (DNA-PKcs), a serine threonine kinase belonging to the PIKK family (phosphoinositide 3-kinase-like-family of protein kinase), is a critical component of the non-homologous end-joining pathway required for the repair of DNA double-strand breaks. DNA-PKcs may be involved in breast cancer pathogenesis. We evaluated clinicopathological significance of DNA-PKcs protein expression in 1,161 tumours and DNA-PKcs mRNA expression in 1,950 tumours. We correlated DNA-PKcs to markers of aggressive phenotypes, DNA repair, apoptosis, cell cycle regulation and survival. Low DNA-PKcs protein expression was associated with higher tumour grade, higher mitotic index, tumour de-differentiation and tumour type (ps < 0.05). The absence of BRCA1, low XRCC1, low SMUG1, low APE1 and low Polβ was also more likely in low DNA-PKcs expressing tumours (ps < 0.05). Low DNA-PKcs protein expression was significantly associated with worse breast cancer-specific survival (BCSS) in univariate and multivariate analysis (ps < 0.01). At the mRNA level, similarly, low DNA-PKcs was associated with poor BCSS. In patients with ER-positive tumours who received endocrine therapy, low DNA-PKcs (protein and mRNA) was associated with poor survival. In ER-negative patients, low DNA-PKcs mRNA remains significantly associated with adverse outcome. Our study suggests that low DNA-PKcs expression may have prognostic and predictive significance in breast cancers.

Histopathological Characteristics of Triple-Negative Breast Cancer: An Iranian Issue

Background: Breast cancer is one of the most frequent malignancies among Iranian women. Triple-negative breast cancer (TNBC) is referred to a type of breast cancer which three biomarkers of estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2 (HER2), are negative.&#x0D; Materials and Methods: In this case control study, immunohistopathologic data of patients with TNBC were compared with non-TNBC patients. According to pathological reports, frequency, age, gender, type, size, and tumor grade, involvement and the number of involved lymph nodes, mitosis, Ki-67, necrosis, nuclear grade, tumor side, involvement of the margins, skin involvement, nipple involvement, tumor location, vascular invasion, perineural invasion, presence of in-situ compartment and the benign accompanied tumors, granulomatosis reaction, and calcification were compared between both groups.&#x0D; Results: Two hundred fourteen pathological samples of patients with breast cancer were evaluated. TNBC was seen in about 14% of breast cancers in this study on Iranian population. The mean age of TNBC group was 43±12 years and non-TNBC was 50±12 years (p=0.03). TNBC had significantly higher grade, high mitotic indices, more possibility of P53 positivity and higher level of Ki-67. Presence of vascular and nerve invasion and involvement of the margins at the time of diagnosis were seen in the TNBC group comparing with the non-TNBC group.&#x0D; Conclusion: Younger age, higher grading, neurovascular invasion, P53 positivity, and high levels of Ki-67, lead clinicians to evaluate the biomarkers of TNBC, and in case of confirming TNBC diagnosis, appropriate treatment methods should be added to the routine ones in breast cancer.