Cellular Proliferation Index Research Articles

Cutaneous melanocytic tumor with CRTC1::TRIM11 fusion: a case report

BackgroundCutaneous Melanocytic Tumor with CRTC1::TRIM11 Fusion (CMTCT) represents a novel and rare entity in the realm of dermatological oncology, characterized by distinct melanocytic differentiation. This particular tumor type has yet to be officially recognized by the World Health Organization (WHO). CMTCT is generally perceived as a tumor with a relatively indolent nature; however, it is not devoid of metastatic potential. Therefore, ensuring complete surgical excision of the tumor, coupled with rigorous long-term follow-up, is paramount for patient management. In this context, we report the case of an 18-year-old female patient who presented with a dull red nodule on her left leg. Initial surgical intervention led to a pathological diagnosis of CMTCT, but it was determined that the tumor had not been fully excised. Consequently, a second surgical procedure was undertaken to achieve complete removal of the tumor. During a follow-up period of six months post-surgery, the patient showed no signs of local recurrence or metastasis, indicating a successful outcome.Case presentationAn 18-year-old female patient noticed a dull red nodule on her left leg three years ago, which exhibited slow growth over time. She underwent a subcutaneous tumor resection. Histological examination under high-power magnification revealed that the neoplasm consisted of epithelioid cells arranged in nests, fascicles, bundles, or sheets. The tumor cells had round or ovoid nuclei with prominent nucleoli and visible mitotic figures. Notably, areas resembling nevus cell clusters were observed. Immunohistochemical analysis confirmed melanocytic differentiation. Next-generation sequencing (NGS) identified a CRTC1::TRIM11 fusion, and fluorescence in situ hybridization (FISH) for CRTC1 confirmed rearrangement. Consequently, a diagnosis of cutaneous melanocytic tumor with CRTC1::TRIM11 fusion was established.ConclusionsCMTCT is a rare tumor characterized by melanocytic differentiation. In this case, the tumor predominantly comprised epithelioid cells with localized nevus cell clusters. The expression of melanocyte markers could easily lead to a misdiagnosis as cutaneous melanoma. However, several distinguishing features were noted: the tumor was not connected to the epidermis, exhibited low cellular heterogeneity and proliferation index, and showed minimal cellular atypia. Additionally, tests for EWSR1 rearrangement (FISH) and BRAF V600E mutation (PCR-ARMS) were negative.This case underscores the importance of a comprehensive diagnostic approach when clinical, microscopic, immunohistochemical, and molecular findings do not align. The presence of nevus cell clusters morphology in the tumor cells enhances our understanding of this disease’s histological spectrum and aids in avoiding misdiagnosis or missed diagnosis.

Prognostic significance of grade of malignancy based on histopathological differentiation and Ki-67 in pancreatic ductal adenocarcinoma.

Tumor cell malignancy is indicated by histopathological differentiation and cell proliferation. Ki-67, an indicator of cellular proliferation, has been used for tumor grading and classification in breast cancer and neuroendocrine tumors. However, its prognostic significance in pancreatic ductal adenocarcinoma (PDAC) remains uncertain. Patients who underwent radical pancreatectomy for PDAC were retrospectively enrolled, and relevant prognostic factors were examined. Grade of malignancy (GOM), a novel index based on histopathological differentiation and Ki-67, is proposed, and its clinical significance was evaluated. The optimal threshold for Ki-67 was determined to be 30%. Patients with a Ki-67 expression level > 30% rather than ≤ 30% had significantly shorter 5-year overall survival (OS) and recurrence-free survival (RFS). In multivariate analysis, both histopathological differentiation and Ki-67 were identified as independent prognostic factors for OS and RFS. The GOM was used to independently stratify OS and RFS into 3 tiers, regardless of TNM stage and other established prognostic factors. The tumor-node-metastasis-GOM stage was used to stratify survival into 5 distinct tiers, and surpassed the predictive performance of TNM stage for OS and RFS. Ki-67 is a valuable prognostic indicator for PDAC. Inclusion of the GOM in the TNM staging system may potentially enhance prognostic accuracy for PDAC.

Effect of homologous recombination deficient (HRD) breast cancers on a distinct immune marker phenotype by comprehensive genomic and immune profiling (CGIP).

1029 Background: Preclinical evidence suggests that breast cancer with features of genomic instability may upregulate the host antitumor immune response by producing neoantigens through DNA damage and increasing interferon production through the stimulator of interferon genes (STING) pathway. In this study, we evaluated the association between features of genomic instability and immune response in a real-world breast cancer population. Methods: We analyzed retrospective comprehensive genomic and immune profiling (CGIP) results from 529 breast tumors tested in the real-world clinical setting. We defined the HRD phenotype as tumor with any single nucleotide variants (SNV), indels, copy number variations (CNV) or fusions in the following genes: ARID1A, ATM, ATRX, BAP1, BARD1, BLM, BRCA1/2, BRIP1, CHEK1/2, FANCA, MRE11A, NBN, PALB2, RAD50 and RAD51. Otherwise, they were considered HR-proficient (HRP). PD-L1 expression (CPS positive ≥10) and TMB (high ≥10 Mut/Mb) were determined using IHC and DNA sequencing, respectively. mRNA expression signatures of tumor inflammation (TIGS, strong/moderate/weak), cell proliferation (CP, high/moderate/poor) and cancer testis antigen burden (CTAB, high/low) were determined by RNA-sequencing from a 395-gene panel. We used over-representation and proportion analysis using chi-squared test to determine association of HRD to immune correlates. Results: Among 529 cases, the median patient age was 63.2 years (25.5-93.5). The majority of patients were female (519, 98%), and the most common tumor histology was invasive ductal carcinoma (287, 54%). A total of 405 (77%) and 124 (23%) of patients had HRD and HRP phenotypes, respectively. A greater proportion of HRD tumors (16%) had higher TMB compared to HRP (5.6%, p=0.003). HRP tumors showed a relatively low CP index, whereas HRD tumors were associated with a moderate CP index score (p = 0.007). HRD phenotype was associated with a significantly higher proportion of weakly inflamed tumors, as represented by lower TIGS scores (p=0.007). No significant difference in PD-L1 or CTAB was found between HRD and HRP phenotypes. Conclusions: Breast tumors with mutations in the HR genes demonstrated greater TMB and moderate cellular proliferation index of both tumor and immune cells, which suggest susceptibility to immune checkpoint inhibitors. Interestingly, this cohort lacked elevated markers of immune infiltration (TIGS), indicating a mechanism of potential tumor immune evasion. These results suggest that CGIP may allow for more informed treatment decisions in HRD breast cancers. Furthermore, assessment of HR status and immunotherapy susceptibility may support clinical trial selections for therapies targeting the complex interplay of genomic and immune components of breast cancer (e.g., a combination of PARP inhibitor and immunotherapy).

Measurement of Patient-Derived Glioblastoma Cell Response to Temozolomide Using Fluorescence Lifetime Imaging of NAD(P)H.

Personalized strategies in glioblastoma treatment are highly necessary. One of the possible approaches is drug screening using patient-derived tumor cells. However, this requires reliable methods for assessment of the response of tumor cells to treatment. Fluorescence lifetime imaging microscopy (FLIM) is a promising instrument to detect early cellular response to chemotherapy using the autofluorescence of metabolic cofactors. Here, we explored FLIM of NAD(P)H to evaluate the sensitivity of patient-derived glioma cells to temozolomide (TMZ) in vitro. Our results demonstrate that the more-responsive cell cultures displayed the longest mean fluorescence lifetime τm after TMZ treatment due to an increase in the protein-bound NAD(P)H fraction α2 associated with a shift to oxidative phosphorylation. The cell cultures that responded poorly to TMZ had generally shorter τm, i.e., were more glycolytic, and showed no or insignificant changes after treatment. The FLIM data correlate well with standard measurements of cellular drug response-cell viability and proliferation index and clinical response in patients. Therefore, FLIM of NAD(P)H provides a highly sensitive, label-free assay of treatment response directly on patient-derived glioblastoma cells and can become an innovative platform for individual drug screening for patients.

Symptomatic subgemmal neurogenous plaque in patients with COVID-19: Is there an association?

Subgemmal neurogenous plaques (SNP) are composed of neural structures found in the posterolateral portion of the tongue, rarely biopsied as most of them are asymptomatic or eventually only clinically managed. We aimed to investigate a case series of possible correlation of symptomatic subgemmal neurogenous plaque (SNP) with coronavirus disease 2019 (COVID-19). Eleven formalin-fixed paraffin-embedded cases from patients with previous confirmed COVID-19 (by RT-PCR) were retrieved from two pathology files. Histological sections were morphologically studied, and then submitted to immunohistochemical reactions against S-100 and neurofilament proteins, neuron-specific enolase, Glial fibrillary acidic protein (GFAP), synaptophysin, CD56, Ki67, cytokeratins (7, 8-18, 19, 20), nucleocapsid and spike proteins (SARS-CoV-1; and -2) and epithelial membrane antigen (EMA) antibodies. Clinical data were retrieved from the patients' medical files, including the symptoms and the complete history of the progression of the disease. The patients who had COVID-19 included in this study experienced painful lesions in the tongue that corresponded to prominent or altered SNP. Microscopically, neural structures were positive for S-100, GFAP and neurofilament protein. And the cellular proliferative index (by Ki-67) was very low. Thus, based on the current results, we hypothesize that symptomatic SNP may be a late manifestation of COVID-19 infection.

HucMSC exosomes attenuate partial bladder outlet obstruction-induced renal injury and cell proliferation via the Wnt/β-catenin pathway

Bladder outlet obstruction (BOO) can cause serious complications including kidney damage; nevertheless, there are currently no animal models for studying BOO-induced kidney damage. Mesenchymal stem cells (MSCs) are widely used in therapeutic studies of renal fibrosis. However, MSC-derived exosomes show improved safety profile and more controllable characteristics compared with those of MSCs. Herein, we established a kidney injury mouse model of partial bladder outlet obstruction (PBOO) and evaluated the effects of human umbilical cord MSC-derived exosomes (hucMSC-Exos) on PBOO-induced reflux kidney injury in this model. Exosomes were isolated from a hucMSC-conditioned medium, purified by ultracentrifugation, and examined. Living image was performed to indicate the distribution of hucMSC-Exos. The PBOO-treated mice interacted with PBS (phosphate-buffered saline) or hucMSC-Exos. Morphologic changes and expression of interstitial-fibrosis—related, cell proliferation and Wnt/β-catenin signaling-pathway indices were evaluated. At 7 days after induction of PBOO, structural destruction of renal tubules was observed. Expression of the interstitial markers and the cellular-proliferation index increased significantly in the PBOO group compared with the control group. The isolated exosomes were 30–150 nm in diameter, showing a round shape and bilayer membrane structure with CD63, TSG101, Alix expressed, enriched in the kidney of the PBOO group. Administering hucMSC-Exos to post-PBOO mice reversed renal injury and suppressed expression of Wnt/β-catenin signaling pathway-related proteins. hucMSC-Exos inhibited PBOO-induced kidney injury and cellular proliferation and suppressed the Wnt/β-catenin signaling pathway. Our findings will spur the development of novel hucMSC-Exo-mediated therapies for treating patients with renal fibrosis.

Radiomic features quantifying pixel-level characteristics of breast tumors from magnetic resonance imaging predict risk factors in triple-negative breast cancer.

e12612 Background: Computationally derived quantitative imaging (radiomic) features that describe tumor phenotypes at the pixel level have demonstrated associations with clinical characteristics in early investigations of other cancers. This implies that molecular differences among tumors may be reflected in their structure on the scales probed by 3D magnetic resonance imaging (MRI). We investigated whether radiomic features computed over tumor volumes from pre-treatment breast MRI could predict risk factors in triple-negative breast cancer (TNBC). Methods: We evaluated breast tumors on pre-treatment, post-contrast T1-weighted MRI from 156 patients with non-metastatic TNBC who underwent neoadjuvant chemotherapy. Tumor regions of interest were segmented by a convolutional neural network algorithm, with validation by breast radiologists. Features quantifying tumor shape and texture were extracted for the largest tumor present in each patient. We identified 23 principal components (PCs) describing these data within the original 364-dimensional feature space for further analysis. Tumor volume was also extracted for comparison with the shape and texture PCs, clinical variables and outcomes, but was kept separate from other radiomic features, since it directly correlates with clinical stage. We compiled for the cohort clinical variables including demographics, stage, grade, and, where available, absolute lymphocyte count (ALC) and Ki-67, a cellular proliferation index routinely used in clinical practice. We then performed a series of univariate and multivariate regression analyses to identify radiomic PCs and clinical variables that significantly predict patient outcomes, and radiomic PCs that predict established risk factors. Our multivariate analyses utilized 5-fold cross-validation and Monte-Carlo determination of p-values (based on 3000 random samplings from the null hypothesis), to ensure statistical rigor in identifying predictive relationships while correcting for multiple hypothesis testing. Results: Our univariate analyses confirmed expected correlations between: overall survival and pre-treatment tumor volume (p = 0.010); survival and ALC (p = 0.002); and clinical stage and tumor volume (p = 1.2⨉10-7). From our multivariate analysis, shape and texture radiomic features were predictive of: tumor volume (p < 0.001); clinical stage (p < 0.001); and Ki-67 (p = 0.02). We confirmed that Ki-67 was predictive of post-treatment residual cancer (p = 0.014), as has been previously reported. Conclusions: Radiomic features predict breast cancer risk factors that are significant for determining outcomes for TNBC patients. Combinations of radiomic shape and texture features track closely with tumor volumes, stage, and proliferative activity, potentially reflecting underlying molecular evolution.

MCM6 versus Ki-67 in diagnosis of luminal molecular subtypes of breast cancers

BackgroundCurrently, breast cancers are divided into four major molecular subtypes. The distinction between the luminal A and luminal B subtypes is mainly based on the cellular proliferation indices and is assessed by the Ki-67 scoring. Due to the limitations in the assessment and expression of Ki-67, we hypothesized that minichromosome maintenance protein 6 (MCM6) might be taken as a surrogate marker to differentiate molecular subtypes and aid in more precise grading of tumors.MethodsWe performed a retrospective, cross-sectional study on 124 samples of breast cancer and 40 samples of normal breast tissue. Relevant clinical information was retrieved from the Cancer Institute database.ResultsMCM6 could discriminate between various categories of histologic grades, tubule formation, mitotic indices, and nuclear pleomorphism (P = 0.002 for tubule formation and P < 0.001 for other). Moreover, the MCM6 score exhibited a significant correlation with the mitotic count (P < 0.001). However, the Ki-67 score could not discriminate subgroups of the mitotic index and nuclear pleomorphism. Compared to the luminal A subtype, luminal B exhibited a higher MCM6 score (P = 0.01). Besides, MCM6 scores were higher for certain subtypes with more aggressive behaviors, such as hormone receptor (HR)-negative disease, and human epidermal growth factor receptor 2 (HER2)-enriched and triple-negative breast cancers, as there was a significantly higher MCM6 mean score in the HR-negative in comparison to the luminal breast cancers (P < 0.001). Similarly, higher MCM6 scores were observed among samples with more advanced nuclear grades, tubule formation, and overall grades.ConclusionMCM6 can differentiate luminal A and luminal B subtypes and is correlated with mitotic counts. However, this study was unable to prove the superiority of MCM6 in differentiating between molecular subtypes compared to the Ki-67 score. Nevertheless, in our study, MCM6 was superior to Ki-67 in exhibiting correlations with the mitotic grade, tubule formation, and nuclear grades. More studies are needed to standardize its assessment methods, determine more robust cut-off values, and evaluate its associations with prognostic features of breast cancer.

Histopathological Correlations of Qualitative and Quantitative Temporopolar MRI Analyses in Patients With Hippocampal Sclerosis.

Hippocampal sclerosis (HS) is a common cause of pharmacoresistant focal epilepsy. Here, we (1) performed a histological approach to the anterior temporal pole of patients with HS to evaluate cortical and white matter (WM) cell populations, alteration of myelin integrity and markers of neuronal activity, and (2) correlated microscopic data with magnetic resonance imaging (MRI) findings. Our aim was to contribute with the understanding of neuroimaging and pathophysiological mechanisms of temporal lobe epilepsy (TLE) associated with HS. We examined MRIs and surgical specimens from the anterior temporal pole from TLE-HS patients (n = 9) and compared them with 10 autopsy controls. MRIs from healthy volunteers (n = 13) were used as neuroimaging controls. Histological techniques were performed to assess oligodendrocytes, heterotopic neurons, cellular proliferative index, and myeloarchitecture integrity of the WM, as well as markers of acute (c-fos) and chronic (ΔFosB) activities of neocortical neurons. Microscopic data were compared with neuroimaging findings, including T2-weighted/FLAIR MRI temporopolar blurring and values of fractional anisotropy (FA) from diffusion-weighed imaging (DWI). We found a significant increase in WM oligodendrocyte number, both in hematoxylin and eosin, and in Olig2-stained sections. The frequencies of oligodendrocytes in perivascular spaces and around heterotopic neurons were significantly higher in patients with TLE–HS compared with controls. The percentage of 2',3'-cyclic-nucleotide 3'-phosphodiesterase (CNPase; a marker of myeloarchitecture integrity) immunopositive area in the WM was significantly higher in TLE-HS, as well as the numbers of c-fos- and ΔFosB-immunostained neocortical neurons. Additionally, we demonstrated a decrease in axonal bundle integrity on neuroimaging, with a significant reduction in the FA in the anterior temporal pole. No differences were detected between individuals with and without temporopolar blurring on visual MRI analysis, considering the number of oligodendroglial cells and percentage of WM CNPase-positive areas. Also, there was no relationship between T2 relaxometry and oligodendrocyte count. In conclusion, our histopathological data support the following: (1) the hypothesis that repetitive neocortical neuronal activity could induce changes in the WM cellular constitution and myelin remodeling in the anterior temporal pole from patients with TLE-HS, (2) that oligodendroglial hyperplasia is not related to temporal blurring or T2 signal intensity on MRI, and (3) that reduced FA is a marker of increase in Olig2-immunopositive cells in superficial temporopolar WM from patients with TLE-HS.

S2436 Coincidence or Not? A Rare Case of a Mixed Adenoneuroendocrine Rectal Tumor in the Setting of Ulcerative Colitis

Introduction: For decades it has been known that patients with inflammatory bowel disease (IBD) are at an increased risk for colorectal cancer, with adenocarcinoma being the most common. Risk of colorectal malignancy increases with years since diagnosis of IBD. However, very rarely diagnosed are mixed adenoneuroendocrine carcinomas (MANEC), comprising of at least 30% adenoma and 30% neuroendocrine components. Less than 20 cases have been reported of a MANEC in ulcerative colitis (UC) patients in the literature. Some hypothesize that chronic colonic mucosal inflammation and distant cytokine release eventually lead to MANECs. We present a case of high grade MANEC diagnosed in the setting of UC. Case description/methods: An 85 year old male with a 4-year history of refractory pan-UC with failure of multiple biologics (TNF alpha inhibitors, monoclonal antibodies), mesalamine, and azathioprine presented with worsening diarrhea, fecal urgency, rectal bleeding, muccorhea, and failure to thrive. He was placed on a long steroid taper. Fecal calprotectin was 1380 μg/g. Colonoscopy revealed severe pan-UC and a 4 cm sessile, exophytic, polypoid lesion in the proximal rectum. Biopsies revealed a high grade large cell neuroendocrine tumor positive for chromogranin, synaptophysin, CDX2, and Ki-67 cellular proliferation index of 40-50%. Robotic subtotal proctocolectomy with end ileostomy was performed with rectal specimen pathology revealing a high grade large cell poorly differentiated neuroendocrine carcinoma with low grade adenocarcinoma, consistent with pT3N1a MANEC. Given a single lymph node was positive, the patient is currently seeking oncologic opinion for potential chemotherapy. Discussion: The incidence of MANEC in a UC patient is very rare. To our knowledge, there are only 20 cases describing a MANEC diagnosis in a UC patient. There is now discussion as to whether or not MANECs correlate with IBD, specifically UC. In addition, MANEC lesions are associated with poor survival rates due to diagnosis at advanced stages. The decision to proceed with subtotal proctocolectomy for MANEC in an elderly patient with refractory pan-UC without severe co-morbidities was made due to a higher MANEC related mortality rate compared to other causes. Given the aggressive nature of MANECs, further research should be conducted regarding association between MANECs and UC to guide future diagnosis and treatment.Figure 1.: A 4 cm sessile, exophytic, polypoid lesion in the proximal rectum on colonoscopy status post biopsies revealing a MANEC on pathology.

LncRNA MEG3 inhibits the proliferation of neural stem cells after ischemic stroke via the miR-493–5P/MIF axis

ObjectiveThe proliferation of neural stem cells (NSCs11NSCs: neural stem cells.), or lack thereof, can have profound effects on brain tissue remodeling for ischemic stroke (IS22IS: ischemic stroke.). In this study, we aimed to reveal the influence of the lncRNA MEG3/miR-493–5p/MIF axis on NSC proliferation after IS. MethodsWe established an oxygen glucose-deprivation/reoxygenation (OGD/R33OGD/R: oxygen and glucose confinement/reoxygenation.) in vitro model of IS in NSCs. We evaluated NSC isolation efficiency and proliferation by NESTIN, SOX2, and PCNA immunofluorescence staining. MEG3 and miR-493–5P levels were assessed by quantitative real-time polymerase chain reaction (qRT-PCR44qRT-PCR: quantitative real-time polymerase chain reaction.). Changes in MIF protein expression levels were analyzed using Western blotting. We then evaluated the role of MEG3 and miR-493–5p by transfection of si-MEG3, a miR-493–5p mimic, or miR-493–5p inhibitor. NSC proliferation was quantified using Cell Counting Kit-8 analysis. ResultsNESTIN and SOX2 were co-expressed in endogenous NSCs. Following OGD/R, MEG3 and miR-493–5P were significantly upregulated in NSCs, while MIF levels decreased and proliferation was inhibited. Knockdown of MEG3 inhibited miR-493–5p and rescued expression of MIF and PCNA, restoring cellular proliferation levels. In NSCs transfected with a miR-493–5p mimic or inhibitor, MIF levels were down- or upregulated, respectively. Consistently, transfection of a miR-493–5p mimic reduced NSC proliferation, while transfection with a miR-493–5p inhibitor or si-MEG3 rescued the inhibitory effect of OGD/R on NSC proliferation. After co-transfection of si-MEG3 and a miR-493–5p mimic of OGD/R-induced NSCs, levels of PCNA, an indicator of cellular proliferation, were significantly reduced. Conclusion MEG3 inhibits NSC proliferation of after IS via positive regulation of miR-493–5p and potential subsequent downregulation of MIF.

SEBACEOUS CARCINOMA OF THE ORAL MUCOSA: A CASE REPORT

We report a rare case of sebaceous carcinoma arising in the buccal mucosa of the mandibular region. A 51-year-old female presented with an ulcerated swelling with 2 months of evolution. Incisional biopsy was performed, and, microscopically, the lesion showed a proliferation of nests and cords of atypical and pleomorphic epithelial cells. The cytoplasm of the cells had clear changes and vacuoles. Some of them demonstrated clearly sebaceous differentiation. Immunohistochemical studies revealed positivity for cytokeratins 14 and 18, epithelial membrane antigen, and adipophilin. The cellular proliferative index (assessed by Ki-67-nuclear expression) was 70%. The patient was undergoing complete surgical excision and received chemotherapy (6 cycles of paclitaxel and carboplatin 3 times weekly) and died 5 months after the treatment. Sebaceous carcinoma is exceedingly rare in the oral mucosa, and the immunohistochemistry, particularly adipophilin, is essential to its diagnosis. We report a rare case of sebaceous carcinoma arising in the buccal mucosa of the mandibular region. A 51-year-old female presented with an ulcerated swelling with 2 months of evolution. Incisional biopsy was performed, and, microscopically, the lesion showed a proliferation of nests and cords of atypical and pleomorphic epithelial cells. The cytoplasm of the cells had clear changes and vacuoles. Some of them demonstrated clearly sebaceous differentiation. Immunohistochemical studies revealed positivity for cytokeratins 14 and 18, epithelial membrane antigen, and adipophilin. The cellular proliferative index (assessed by Ki-67-nuclear expression) was 70%. The patient was undergoing complete surgical excision and received chemotherapy (6 cycles of paclitaxel and carboplatin 3 times weekly) and died 5 months after the treatment. Sebaceous carcinoma is exceedingly rare in the oral mucosa, and the immunohistochemistry, particularly adipophilin, is essential to its diagnosis.

EVALUATION OF FATTY ACID SYNTHASE ENZYME IMMUNOHISTOCHEMICAL EXPRESSION IN SALIVARY GLAND CARCINOMAS

Introduction: The general mechanism of neoplastic development and progression is complex and has been extensively studied. Besides genetic alterations, metabolic imbalances involving fatty acid synthesis arise early in tumor development. In this scenario, the fatty acid synthase enzyme (FASN) overexpression in cancer cells has been highlighted. Several studies have shown that FASN-associated tumors act as a reservoir of anabolic energy, providing advantages to the tumor cells. FASN expression had not been widely investigated in salivary gland carcinomas. Objective: Analysis of FASN expression in samples of salivary glands carcinomas. Study Design: A total of 92 samples of salivary gland carcinomas were subdivided into high and low aggressiveness degree. FASN expression and cellular proliferation index (Ki-67) were verified through immunohistochemical reactions. Results: FASN was expressed in salivary duct carcinomas (100%), salivary gland secretory carcinomas (100%), acinar cell carcinomas (61.1%), high-grade mucoepidermoid carcinomas (40%), and high-grade adenoid cystic carcinomas (27.3%). Ki67 was significant in high grade mucoepidermoid carcinomas (21.2%), salivary duct carcinomas (14.9%), and high-grade adenoid cystic carcinomas (13.4%). No correlation between FASN and Ki-67 was found. Conclusion: Expression of FASN in salivary gland tumors is related to high degree of malignancy and secretory differentiation.

Effect of neoadjuvant therapy on breast cancer biomarker profile

BackgroundBreast cancer clinical management requires the assessment of hormone receptors (estrogen (ER) and progesterone receptor (PR)), human epidermal growth factor receptor 2 (HER2) and cellular proliferation index Ki67, by immunohistochemistry (IHC), in order to choose and guide therapy according to tumor biology. Many studies have reported contradictory results regarding changes in the biomarker profile after neoadjuvant therapy (NAT). Given its clinical implications for the disease management, we aimed to analyze changes in ER, PR, HER2, and Ki67 expression in paired core-needle biopsies and surgical samples in breast cancer patients that had either been treated or not with NAT.MethodsWe included 139 patients with confirmed diagnosis of invasive ductal breast carcinoma from the Colombian National Cancer Institute. Variation in biomarker profile were assessed according to NAT administration (NAT and no-NAT treated cases) and NAT scheme (hormonal, cytotoxic, cytotoxic + trastuzumab, combined). Chi-squared and Wilcoxon signed-rank test were used to identify changes in biomarker status and percentage expression, respectively, in the corresponding groups.ResultsWe did not find any significant variations in biomarker status or expression values in the no-NAT group. In cases previously treated with NAT, we did find a statistically significant decrease in Ki67 (p < 0.001) and PR (p = 0.02605) expression. When changes were evaluated according to NAT scheme, we found a significant decrease in both Ki67 status (p = 0.02977) and its expression values (p < 0.001) in cases that received the cytotoxic treatment.ConclusionsOur results suggest that PR and Ki67 expression can be altered by NAT administration, whereas cases not previously treated with NAT do not present IHC biomarker profile variations. The re-evaluation of these two biomarkers after NAT could provide valuable information regarding treatment response and prognosis for breast cancer patients.

A practical predictor of the growth potential of benign meningiomas: Hypointensity of surface layer in T2-weighted magnetic resonance imaging

BackgroundAccurate evaluation of proliferative potential is particularly important in the clinical management of individual patients with meningiomas. We introduce a new feature in the parenchyma of meningioma, namely, hypointensity of the surface layer (HSL), on T2-weighted MR images and compare it with a cellular proliferation index and growth speed. Materials and methodsWe retrospectively analyzed the records of consecutive patients with WHO grade I meningiomas in two institutes: an operated group with 124 meningiomas resected in one institute, and an observed group with 89 meningiomas monitored without surgery in the other. Proliferative potential was evaluated using the MIB-1 labeling index (MIB-1 LI) for the operated group and using the relative growth rate on serial MR images for the observed group. ResultsIn the operated group, 60 (48.4%) meningiomas exhibited HSL. HSL-positive meningiomas were significantly smaller in size and more often calcified than HSL-negative ones. Univariate analysis showed that HSL negativity, large size, no calcification, and surrounding brain edema were significantly associated with high MIB-1 LI (p < 0.05). Multivariate analysis demonstrated that only HSL was significantly related to MIB-1 LI (p = 0.001). HSL did not correlate with tumor recurrence after resection. In the observed group, 43 (48.3%) meningiomas exhibited HSL and they presented a significantly slow relative growth rate. ConclusionsHSL is a simple and new radiological feature indicative of low proliferative potential and a low risk of enlargement of meningiomas. The presence or absence of HSL may serve as a key parameter for the selection of aggressive treatment or active observation.

Quantitative assessment of Ki67 expression in correlation with various breast cancer characteristics and survival rate; cross sectional study.

BackgroundKi-67 is a cellular proliferative index that has variable expression during cell cycle. The absence of Ki-67 in the quiescent tissues and its expression in the proliferating cells had linked its possible role in the proliferative capacity of the tissues.Materials and methodsThis retrospective study included 314 patients with breast cancer who underwent various types of breast surgeries. Analyzed was done to find any possible correlation between the level of Ki67 and various patient and tumor characteristics and the survival rates.ResultsThe mean age was 48.73 years, the overall survival was 30.77 months, 90.8% of the patients were alive and 8.3% died from breast cancer. In 85.67% no recurrence was reported and 5% had local and axillary recurrences, the commonest sites of metastases were bones and the vertebrae (2.2% and 1.9%) respectively. The mean size of the tumor was 34.39 mm and the mean number of the positive axillary nodes was 4. The expression of Ki67 was around 5–10% in the majority of patients, the mean expression was 28.54%. There was significant correlation between the level of Ki67 and the histopathological grade of the tumor, p value 0.003, and there was no significant correlation with other variables. There was no relation between the overall survival and the Ki67 level.ConclusionKi67 is correlated with the grade of the tumor, and is not a predictor for the survival of breast cancer patients. It may predict aggressive behavior of the tumor and higher histopathological grades.

Computerized Evaluation of the Immunoexpression of Ki-67 Protein in Odontogenic Keratocyst and Dentigerous Cyst.

Evaluation and comparison of odontogenic keratocysts and detigerous cysts immunoexpression and immunostaining intensities of Ki-67 antigen by assessing the whole extent of the epithelium (all epithelium layers in combination) and each layer individually. Ki-67 immunoexpression was evaluated in 15 odontogenic keratocysts and 6 dentigerous cysts using automated methods and the Aperio Technologies Inc. computer system. No statistically significant differences were observed in immunoexpression nor in immunostaining intensities between both lesions. Also, no statistically significant differences were found between odontogenic keratocysts from maxilla versus mandible nor primary versus recurrent. However, odontogenic keratocyst showed a significantly higher cellular proliferation index in the suprabasal layers compared to the basal layer. Assessment of the cellular proliferation index through a computerized system enabled the evaluation of all epithelial tissue without field selection. The increased Ki-67 immunoexpression in suprabasal layers of odontogenic keratocyst suggests a different biological behavior and more aggressive proliferation potential when compared to dentigerous cyst. The same result was found in recurrent odontogenic keratocysts when compared with primary ones. The odontogenic keratocysts of the maxilla and mandible have similar Ki-67 immunoexpression. The evaluation of cellular proliferation only by immunohistochemical analysis with Ki-67 antigen does not provide enough data to elucidate the biological behavior of odontogenic keratocyst.

Chromogranin-A Expression as a Novel Biomarker for Early Diagnosis of Colon Cancer Patients.

Colon cancer is one of the major causes of cancer death worldwide. The five-year survival rate for the early-stage patients is more than 90%, and only around 10% for the later stages. Moreover, half of the colon cancer patients have been clinically diagnosed at the later stages. It is; therefore, of importance to enhance the ability for the early diagnosis of colon cancer. Taking advantages from our previous studies, there are several potential biomarkers which have been associated with the early diagnosis of the colon cancer. In order to investigate these early diagnostic biomarkers for colon cancer, human chromogranin-A (CHGA) was further analyzed among the most powerful diagnostic biomarkers. In this study, we used a logistic regression-based meta-analysis to clarify associations of CHGA expression with colon cancer diagnosis. Both healthy populations and the normal mucosa from the colon cancer patients were selected as the double normal controls. The results showed decreased expression of CHGA in the early stages of colon cancer as compared to the normal controls. The decline of CHGA expression in the early stages of colon cancer is probably a new diagnostic biomarker for colon cancer diagnosis with high predicting possibility and verification performance. We have also compared the diagnostic powers of CHGA expression with the typical oncogene KRAS, classic tumor suppressor TP53, and well-known cellular proliferation index MKI67, and the CHGA showed stronger ability to predict early diagnosis for colon cancer than these other cancer biomarkers. In the protein–protein interaction (PPI) network, CHGA was revealed to share some common pathways with KRAS and TP53. CHGA might be considered as a novel, promising, and powerful biomarker for early diagnosis of colon cancer.

Cell Cycle-Dependent Expression of Bk Channels in Human Mesenchymal Endometrial Stem Cells

The study of ion channels in stem cells provides important information about their role in stem cell fate. Previously we have identified the activity of calcium-activated potassium channels of big conductance (BK channels) in human endometrium-derived mesenchymal stem cells (eMSCs). BK channels could have significant impact into signaling processes by modulating membrane potential. The membrane potential and ionic permeability dynamically changes during cycle transitions. Here, we aimed at verification of the role of BK channels as potassium transporting pathway regulating cell cycle passageway of eMSCs. The functional expression of native BK channels was confirmed by patch-clamp and immunocytochemistry. In non-synchronized cells immunofluorescent analysis revealed BK-positive and BK-negative stained eMSCs. Using cell synchronization, we found that the presence of BK channels in plasma membrane was cell cycle-dependent and significantly decreased in G2M phase. However, the study of cell cycle progression in presence of selective BK channel inhibitors showed no effect of pore blockers on cycle transitions. Thus, BK channel-mediated K+ transport is not critical for the fundamental mechanism of passageway through cell cycle of eMSCs. At the same time, the dynamics of the presence of BK channels on plasma membrane of eMSCs can be a novel indicator of cellular proliferation.

Clinicopathological significance of tumor cyclin D1 expression in oral cancer

ObjectiveTo evaluate the association of cyclin D1 overexpression with clinicopathological parameters classically considered of prognostic value in OSCC (T, N, M, clinical stage, degree of differentiation, invasive morphology and, cellular proliferation index). DesignA retrospective immunohistochemical study was conducted of cyclin D1 and ki-67 expression in 68 OSCCs from 54 patients. Cases were scanned using a digital pathology system. The tumor expression of markers was assessed in four randomly selected fields (40x), and a semi-automatized count was conducted of cyclin D1-positive and -negative cells. ResultsCyclin D1 overexpression was found in 28.7% of the cases of OSCC. It was significantly and positively associated with the following clinicopathological parameters: low tumor differentiation degree (p = 0.030), invasive morphology (p = 0.045), and proliferative phenotype according to tumor cell ki-67 expression (p = 0.018). ConclusionsCyclin D1 overexpression is an event of oral carcinogenesis associated with clinicopathological parameters classically associated with a poor prognosis in patients with OSCC.