Tumor Proliferation Index Research Articles

Expresión de la mucina asociada a membrana MUC-1/ y su relación con Ki67 en el carcinoma mucoepidermoide de glándulas salivales

Background: Salivary gland tumors are rare and with different malignant potential. Immunohistochemistry is useful, especially Ki67, a marker of cell proliferation, for its prognostic information. On the other side, the mucin MUC-1 is overexpressed and loses its exclusively apical membranous localization and is aberrantly glycosylated in mucoepidermoid carcinoma of salivary glands. In the present work, we investigated the quantitative expression of tumor proliferative index and localization and overexpression of MUC-1 in the mucoepidermoid carcinoma of the human salivary glands, not studied is these organs, to determine their relationship with the histological grade and prognosis. Methods: H/E staining and immunohistochemistry with MUC-1 and Ki67 antibodies was performed on 10 cases. Results: The markings of the mucoepidermoid carcinoma depended on the histological grade; in low- grade tumors with MUC-1 only 10 to 25% of the cells were labeled, in contrast to high- grade tumors, with 75 to 90% labeled cells. They also differed in cell proliferation; in the low-grade tumors was 15% and in high-grade tumors it was greater than 30%. Conclusion: MUC-1 overexpression is significantly higher in high-grade mucoepidermoid carcinoma, as is Ki67 marking, results that are associated with tumor prognosis.

Comprehensive Metabolome Analysis Identified Novel Biomarkers for the Diagnosis and Prognosis of Diffuse Large B-Cell Lymphoma

Background Metabolic reprogramming is a major hallmark of cancer, providing tumor cells with vital energy and metabolites. Diffuse large B-cell lymphoma (DLBCL) is metabolically heterogeneous, and there was also evidence that altered metabolism is associated with tumor progression and prognosis. This study was aimed to assess the characteristics of metabolic reprogramming and novel biomarkers in DLBCL, thereby proposing a novel therapeutic strategy for DLBCL. Methods Serum sample were obtained from100 patients with newly diagnosed DLBCL and 70 age-gender matched healthy controls in the study. Non-targeted metabolomics studies were performed based on liquid mass spectrometry (LC-MS) technology. The normalized peak areas (normalized by IS) metabolites were introduced into SIMCA software for multivariate statistical analysis. Metabolomic pathway analysis of metabolic biomarkers was performed using MetbraAnalyst5.0. Results We first analyzed differential metabolite profiles in the serum of DLBCL patients. The metabolites detected in positive and negative ion modes were analyzed separately. Compared to the healthy control, DLBCL patients were featured with a specific metabolic profile, indicating the differential metabolism in disease state. We then established a model containing metabolic information by orthogonal partial least squares discriminant analysis (OPLS-DA) and tested its ability to identify new samples in seven cross-validations. The variable importance in the projection (VIP) was also calculated for each metabolite. We further screened for differentially expressed metabolites by plotting collapsed changes (fold change>1.5 or <0.667, p<0.05). In DLBCL patients, 33 up-regulated metabolomes and 48 down-regulated metabolites were detected in positive ion mode, while 19 up-regulated metabolites and 29 down-regulated metabolites were in negative ion mode. Enrichment analyses showed that differential metabolites were mainly enriched in D-Glutamine and D-glutamate metabolism, caffeine metabolism, and ascorbate and aldarate metabolism. We then attempted to verify whether the differential metabolites had diagnostic value in DLBCL patients. By using random forest analysis, 2-Phenylpropionicacid, 4-oxododecanedioicacid, cis-4-Hydroxy-D-proline, Hypoxanthine Octanedioicacid under positive ion mode, and Xanthosine, Subericacid, Diethyloxalpropionate, 4-Oxoproline Azelaicacid under negative ion mode, were screened out as potential biomarkers. Based on the above biomarkers, diagnostic models were developed and revealed the mean accuracies of 0.9460 in positive mode and 0.943 in negative mode. Receiver operating characteristic (ROC) curves then verified the significant sensitivity and specificity of the diagnostic models. Notably, the Area Under Curve（AUC）of the combined diagnostic model was superior to that of each metabolite, indicating that combined model values could significantly improve the diagnostic performance in DLBCL. Further investigations were aimed to explore the correlation of metabolite profiles with clinical features in DLBCL. Venn diagram profiled the differential metabolites between patients with GCB-like DLBCL and ABC-like DLBCL. Correlation analysis then suggested that the differential metabolites were correlated with clinical prognostic indicators in DLBCL patients. In particular, D-Glucuronic acid and Lignoceric acid were significantly associated with Ki-67 expression (tumor proliferation index), cis-4-Hydroxy-D-proline was significantly associated with LDH and β2-MG, and 2-Phenylpropionic acid significantly correlated with LDH, PLT and ALB. Conclusions Our study revealed the metabolic profile of DLBCL and found a relatively high diagnostic value of metabolite-based diagnostic models constructed. Furthermore, the combination with clinical data suggests that D-glucuronide, lignoceric acid, cis-4-hydroxy-D-proline and 2-phenylpropionic acid may be potential prognosis-related biomarkers in DLBCL. Targeting metabolic reprogramming is expected to provide novel strategies for the treatment of DLBCL. Keywords DLBCL, metabolomics, biomarkers, D-glucuronide, tumor Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Treatment Strategies for Residual Disease following Neoadjuvant Chemotherapy in Patients with Early-Stage Breast Cancer.

Breast cancer continues to be the most diagnosed cancer among women worldwide. Neoadjuvant chemotherapy is the standard of care for breast cancer patients with locally advanced disease and patients with poor pathological features, such as triple-negative (TN) or human epidermal growth factor receptor-2 (HER2)-positive subtypes. Neoadjuvant therapy offers several advantages, including better surgical outcomes, early systemic treatment for micro-metastases, and accurate tumor biology and chemosensitivity assessment. Multiple studies have shown that achieving pathological complete response (pCR) following neoadjuvant chemotherapy is associated with better prognosis and better treatment outcomes; almost half of such patients may fail to achieve pCR. Tumor proliferative index, hormone receptor (HR) status, and HER2 expression are the major predictors of pCR. Strategies to improve pCR have been dependent on augmenting neoadjuvant chemotherapy with the addition of taxanes and dual anti-HER2 targeted therapy in patients with HER2-positive tumor, and more recently, immunotherapy for patients with TN disease. The clinical management of patients with residual disease following neoadjuvant chemotherapy varies and depends mostly on the level of HR expression and HER2 status. Recent data have suggested that switching trastuzumab to trastuzumab-emtansine (T-DM1) in patients with HER2-positive disease and the addition of capecitabine for patients with HER2-negative and HR-negative subtype is associated with a better outcome; both strategies are incorporated into current clinical practice guidelines. This paper reviews available and ongoing studies addressing strategies to better manage patients who continue to have residual disease following neoadjuvant chemotherapy.

Evaluation of Tumor Grade and Proliferation Indices before and after Short-Course Anti-Inflammatory Prednisone Therapy in Canine Cutaneous Mast Cell Tumors: A Pilot Study.

Glucocorticoid administration is a common clinical practice that attempts to decrease the inflammation associated with and improve the resectability of canine mast cell tumors (MCTs). However, the impact of neoadjuvant glucocorticoids on the histological features and proliferation indices of canine MCTs is unknown. The objective of this study was to evaluate changes in tumor grade, mitotic count, Ki67, AgNOR, and AgNORxKi67 scores following short-course anti-inflammatory neoadjuvant prednisone in canine patients with MCTs. This was a prospective single-arm pilot study. Client-owned dogs with treatment-naïve cytologically confirmed MCTs were enrolled. Patients underwent an initial incisional biopsy followed by a 10–14-day course of anti-inflammatory prednisone and surgical resection. All histological samples were randomized, masked, and evaluated by a single pathologist. Unstained paired pre- and post-treatment samples were submitted to a commercial laboratory for Ki67 and AgNOR immunohistochemical analysis. There were 11 dogs enrolled with 11 tumors. There were no statistical differences between the pre- and post-treatment histological parameters of mitotic index, Ki67, AgNOR, or Ki67xAgNOR. There were no clinically significant alterations between pre-treatment and post-treatment in the assignment of tumor grades. A short course of anti-inflammatory prednisone does not appear to alter the histological parameters that affect grade determination or significantly alter the proliferation indices in canine MCTs.

Sinonasal Mucosal Melanoma: Role of Tumor Proliferative Indices and Pathological Factors in Survival.

The objective of this study is to determine the association of proliferation indices and pathologic biomarkers on overall and recurrence/metastasis-free survival (OS and RMFS) in patients with sinonasal mucosal melanoma (SNMM) and to assess the genetic mutational landscape of SNMM. This is a retrospective cohort study of 45 SNMM patients without neoadjuvant therapy who underwent surgical therapy with curative intent and had tumor tissue available for histopathologic review, molecular analysis, and genetic mutational assessment. The OS and RMFS were assessed for associations with numerous tumor and patient-related factors. Among proliferative indices, higher Ki67 and mitotic rates were associated with worsened OS and RMFS (Ki67: p=0.0007 and p < 0.0001; mitotic rate: p=0.005 and p=0.0009, respectively). The presence of brisk tumor-infiltrating lymphocytes (TILs) was associated with improved RMFS (p=0.007) and the presence of lymphovascular invasion was associated with worsened OS and RMFS (p=0.02 and p=0.04, respectively). Patients with amelanotic tumors were more likely to have higher T-stage (p=0.046), less likely to have brisk TILs (p=0.02) and had worsened RMFS (p=0.03). Patients on immunotherapy with tumor Ki67 < 40% had better 3-year OS compared to those with higher Ki67 index (p=0.004). Actionable genetic mutations such as BRAF V600E are rare and present in only 1 of 20 patients tested. In SNMM patients, pathologic and proliferation markers such as Ki67, mitotic rate and brisk TILs are associated with survival and may be considered in future staging systems. Clinical response to immunotherapy appears to correlate with the Ki67 index. Given the distinct genetic profile of SNMM, targeted therapies against the MAPK kinase pathway have limited utility. 3 Laryngoscope, 132:2350-2358, 2022.

A systematic study on phenotypical characteristics of invasive breast carcinoma and surrounding ductal carcinoma in situ in multifocal breast cancers

Multifocal breast cancers are heterogeneous in terms of histologic characteristics and molecular types. In this study, we annotated multiple foci of invasive lesions and ductal carcinoma in situ lesions of 17 cases of multifocal breast cancer and investigated their immunohistochemical phenotypes (estrogen receptor [ER], progesterone receptor [PR], human epidermal growth factor 2 [HER2], and Ki-67 proliferative index). Tumor histologic grade, proliferative index, and phenotypes were varied within each patient. We observed that there were some cases in which the treatment consideration could be changed due to different phenotypes of lesions. The proliferative index tended to be higher in areas where the histologic grade was higher. The triple-negative (TN) type had the highest Ki-67 index, followed by luminal B/HER2-, HER2, luminal B/HER2+, and luminal A types sequentially. As the luminal B lesions comprised a considerable portion of multifocal cancer, we subcategorized them according to several criteria. The proliferation index of the luminal B group was significantly (P<.001) higher in the low hormone receptor (HR) group than in the HR group. When compared by the phenotypes of the surrounding lesions, the proliferative index of luminal B lesions were intimately related to the coexisting phenotypes. In conclusion, the immunohistochemical phenotypes of multifocal breast cancer are heterogeneous, and luminal B type is the commonest of the heterogeneous phenotypes.

Platelet Activation and Platelet Indices as Markers for Disease Progression in Women with Breast Cancer

Background: Several studies reported the role platelet activation, platelet volume (MPV) and other Indices in breast cancer but the data is inconsistent and/or diverse. The aim of this study was to systematically evaluate the role of platelet activation and platelet volume indices in women with BC as predictors for cancer progression and poor prognosis. Methods: Patients were recruited from our local oncology center between 2019 to 2020 following ethics approval. 80 patients with locally invasive BC, 20 metastatic and 100 controls were recruited. ADP-induced platelet activation was assessed by light-transmission aggregometry. Platelet P-selectin (CD62P) expression with and without ADP stimulation was assessed by flow cytometry. A comprehensive analysis of platelet count and platelet volume indices (PVIs) (MPV, PDW, MPV/P and PDW/P) was conducted. Data were analyzed in relation to tumor pathology, hormone receptors (ER, PR, HER-2) and proliferation index Ki-67. Regression analyses were conducted for the prediction of poor prognosis, tumor aggression and metastatic potential. Results: We found a significant increase in platelet aggregation (MA), CD62P expression, CD62P+ADP, MPV, PDW, MPV/P and PDW/P in the metastatic group compared to the locally invasive group. Univariate regression analysis showed significance for ADP, MA, CD62P+ADP, MPV and PDW/P. Conclusion: MPV/P and PDW/P can be used as simple low-cost predictors for cancer progression and poor prognosis. We conclude platelet activation and specific platelet indices can help predict prognosis in females with BC.

Mutational Analysis of BRCA1 and BRCA2 Genes in Breast Cancer Patients from Eastern Sicily.

PurposeGermline mutations of BRCA1 and BRCA2 are associated with a defined lifetime risk of breast (BC), ovarian (OC) and other cancers. Testing BRCA genes is pivotal to assess individual risk, but also to pursue preventive approaches in healthy carriers and tailored treatments in tumor patients. The prevalence of BRCA1 and BRCA2 alterations varies broadly across different geographic regions and, despite data about BRCA pathogenic variants among Sicilian families exist, studies specifically addressing eastern Sicily population are lacking. The aim of our study was to investigate the incidence and distribution of BRCA pathogenic germline alterations in a cohort of BC patients from eastern Sicily and to evaluate their associations with specific BC features.Patients and MethodsMutational status was assessed in a cohort of 389 BC patients, using next generation sequencing. The presence of alterations was correlated with tumor grading and proliferation index.ResultsOverall, 35 patients (9%) harbored a BRCA pathogenic variant, 17 (49%) in BRCA1 and 18 (51%) in BRCA2. BRCA1 alterations were prevalent among triple negative BC patients, whereas BRCA2 mutations were more common in subjects with luminal B BC. Tumor grading and proliferation index were both significantly higher among subjects with BRCA1 variants compared to non-carriers.ConclusionOur findings provide an overview about BRCA mutational status among BC patients from eastern Sicily and confirm the role of NGS analysis to identify hereditary BC patients. Overall, these data are consistent with previous evidences supporting BRCA screening to properly prevent and treat cancer among mutation carriers.

The single-cell transcriptional landscape of lung carcinoid tumors.

Lung carcinoid tumors, also referred to as pulmonary neuroendocrine tumors or lung carcinoids, are rare neoplasms of the lung with a more favorable prognosis than other subtypes of lung cancer. Still, some patients suffer from relapsed disease and metastatic spread. Several recent single-cell studies have provided detailed insights into the cellular heterogeneity of more common lung cancers, such as adeno- and squamous cell carcinoma. However, the characteristics of lung carcinoids on the single-cell level are yet completely unknown. To study the cellular composition and single-cell gene expression profiles in lung carcinoids, we applied single-cell RNA sequencing to three lung carcinoid tumor samples and normal lung tissue. The single-cell transcriptomes of carcinoid tumor cells reflected intertumoral heterogeneity associated with clinicopathological features, such as tumor necrosis and proliferation index. The immune microenvironment was specifically enriched in noninflammatory monocyte-derived myeloid cells. Tumor-associated endothelial cells were characterized by distinct gene expression profiles. A spectrum of vascular smooth muscle cells and pericytes predominated the stromal microenvironment. We found a small proportion of myofibroblasts exhibiting features reminiscent of cancer-associated fibroblasts. Stromal and immune cells exhibited potential paracrine interactions which may shape the microenvironment via NOTCH, VEGF, TGFβ and JAK/STAT signaling. Moreover, single-cell gene signatures of pericytes and myofibroblasts demonstrated prognostic value in bulk gene expression data. Here, we provide first comprehensive insights into the cellular composition and single-cell gene expression profiles in lung carcinoids, demonstrating the noninflammatory and vessel-rich nature of their tumor microenvironment, and outlining relevant intercellular interactions which could serve as future therapeutic targets.

A Novel Role of Arrhythmia-Related Gene KCNQ1 Revealed by Multi-Omic Analysis: Theragnostic Value and Potential Mechanisms in Lung Adenocarcinoma.

The early diagnosis, prognostic prediction, and personalized therapy of lung adenocarcinoma (LUAD) remains a challenging issue. KCNQ1 (potassium voltage-gated channel subfamily Q Member 1) is implicated in long QT syndrome (LQTS) and cardiac arrhythmia, while its significance in LUAD remains unclear. In this study, we aimed to explore the significance of KCNQ1 in terms of clinical value, tumor immunity, underlying mechanisms, and a precision medicine approach by means of multi-omics analysis. The association of KCNQ1 with LUAD was first explored. Both altered variants and high expression of KCNQ1 in a TCGA-LUAD cohort indicated a favorable outcome. KCNQ1 levels had a negative correlation with tumor proliferation index Ki67 levels. siRNA-knockdown of KCNQ1 promoted the migration ability of lung cancer cells. KCNQ1 levels were decreased in LUAD tissue compared to normal tissue. A receiver operating characteristic (ROC) curve indicated good diagnostic efficiency of KCNQ1. High KCNQ1 is associated with an immunoactive profile of immune infiltration and immunomodulators and is involved in the inhibition of the cell cycle and DNA replication. Lapatinib was identified as a potent drug for LUAD in the context of low KCNQ1. This study unveiled the significance of KCNQ1 in diagnosis and prognosis and provided a corresponding precision medicine strategy for LUAD.

Midazolam exhibits antitumour and anti-inflammatory effects in a mouse model of pancreatic ductal adenocarcinoma

BackgroundAnaesthesia and perioperative management contribute to long-term outcomes of patients with cancer, including pancreatic ductal adenocarcinoma. We assessed the antitumour, anti-inflammatory, and analgesic effects of midazolam on LSL-KrasG12D/+;Trp53flox/flox;Pdx-1cre/+ transgenic mice with pancreatic ductal adenocarcinoma. MethodsSix-week-old transgenic mice were administered midazolam 30 mg kg−1 day−1 p.o. (n=13); midazolam 30 mg kg−1 day−1 with 1-(2-chlorophenyl)-N-methyl-N(1-methylpropyl)-3-isoquinoline carboxamide (PK11195) 3 mg kg−1 day−1 i.p., a peripheral benzodiazepine receptor antagonist (n=10); or vehicle (water; n=14) until the humane endpoint. Cancer-associated pain was evaluated using hunching score and mouse grimace scale. Tumour stage and immuno-inflammatory status were determined histopathologically. Anti-proliferative and apoptotic potentials of midazolam were investigated using mouse pancreatic ductal adenocarcinoma cell lines. ResultsMidazolam significantly inhibited tumour size and proliferative index of Ki-67 and cyclins in pancreatic ductal adenocarcinoma, which was blocked by administration of PK11195. Local myeloperoxidase+ tumour-associated neutrophils, arginase-1+ M2-like tumour-associated macrophages, and CD11b+Ly-6G+ polymorphonuclear myeloid-derived suppressor cells were reduced by midazolam, which was antagonised by administration of PK11195. Hunching and mouse grimace scale were improved by midazolam, whereas the scores increased with midazolam+PK11195 treatment. Plasma pro-inflammatory cytokines, such as interleukin-6 and CC chemokine ligand (CCL)2, CCL3, and CCL5, were reduced by midazolam, whereas these cytokines increased with PK11195. Midazolam inhibited pancreatic ductal adenocarcinoma proliferation through downregulation of cyclins and cyclin-dependent kinases and induced apoptosis in vitro. ConclusionsThese results suggest that midazolam inhibits pancreatic ductal adenocarcinoma proliferation and local infiltration of tumour-associated neutrophils, tumour-associated macrophages, and polymorphonuclear myeloid-derived suppressor cells, thereby inhibiting pancreatic ductal adenocarcinoma progression.

Correlation of REG1A, Claudin 7 and Ki67 expressions with tumor recurrence and prognostic factors in superficial urothelial urinary bladder carcinomas.

Superficial urothelial urinary bladder tumors are neoplasms that frequently recur and have a potential for invasion and metastasis. REG gene family is composed of various acute phase reactants, lectins, antiapoptotic factors, and growth factors that are effective on pancreatic island cells, neural cells, and epithelial cells. REG1A and REG1B are two forms of the human REG1 gene. It is reported that they are expressed in several cancers and are correlated with the prognosis of the patient. Claudins are integral transmembrane proteins that interconnect cells. However, their role in human tumorigenesis is extremely controversial. The aim of this study is to evaluate the relationship of REG1A, claudin 7 protein expressions, and Ki67 proliferation index in superficial urothelial urinary bladder tumors with well-known parameters of prognosis and tumor recurrence, and also to clarify whether these parameters are independent prognostic factors or not. A hundred and eleven patients diagnosed with superficial urothelial carcinoma between 2011 and 2016 years in our hospital and followed up in our urology clinic were included in this study. The slides prepared from paraffin blocks were immunohistochemically stained with REG1A, claudin 7, and Ki67 antibodies. REG1A showed positive staining in 37 (33%) and negative staining in 74 (67%) of urothelial tumors. Claudin 7 was positive in 24 (22%) and negative in 87 (78%) cases. REG1A expression showed a positive correlation with tumor stage and tumor recurrence; a high Ki67 proliferation index was positively correlated with tumor stage and grade. The loss of claudin 7 expression was related to tumor recurrence. Besides, tumors with REG1A expression and claudin 7 loss had a shorter survival independent of recurrence. In urothelial tumors, REG1A expression and loss of claudin 7 might be significant markers of prognosis that predict tumor recurrence.

ADD3 Deletion in Glioblastoma Predicts Disease Status and Survival.

Loss of heterozygosity (LOH) on chromosome 10 frequently occurs in gliomas. Whereas genetic loci with allelic deletion often implicate tumor suppressor genes, a putative tumor suppressor Adducin3 (ADD3) mapped to chromosome 10q25.2 was found to be preferentially downregulated in high-grade gliomas compared with low-grade lesions. In this study, we unveil how the assessment of ADD3 deletion provides clinical significance in glioblastoma (GBM). By deletion mapping, we assessed the frequency of LOH in forty-three glioma specimens using five microsatellite markers spanning chromosome 10q23-10qter. Data were validated in The Cancer Genome Atlas (TCGA) cohort with 203 GBM patients. We found that allelic loss in both D10S173 (ADD3/MXI1 locus) and D10S1137 (MGMT locus) were positively associated with tumor grading and proliferative index (MIB-1). However, LOH events at only the ADD3/MXI1 locus provided prognostic significance with a marked reduction in patient survival and appeared to have diagnostic potential in differentiating high-grade gliomas from low-grade ones. Furthermore, we showed progressive loss of ADD3 in six out of seven patient-paired gliomas with malignant progression, as well as in recurrent GBMs. These findings suggest the significance of ADD3/MXI1 locus as a promising marker that can be used to refine the LOH10q assessment. Data further suggest the role of ADD3 as a novel tumor suppressor, whereby the loss of ADD3 is indicative of a progressive disease that may at least partially account for rapid disease progression in GBM. This study revealed for the first time the downregulation of ADD3 on the genetic level resulting from copy number deletion.

Evaluation of the immunomodulatory activity of thalidomide on tumor-associated macrophages in the 4T1 murine metastatic breast cancer model

ABSTRACT The present work evaluated the immunomodulatory effect of thalidomide (Thal) at different doses on tumor-associated macrophages (TAMs) using a mouse model of human breast cancer. Mice were inoculated with 4T1 cells in the left flank and treated with Thal once a day at concentrations of 50, 100, and 150mg/kg body weight from the 5th day until the 28th day of tumor inoculation. The tumors were sized, proliferation index and TAMs count were evaluated in primary tumors and metastatic lungs. In addition, the metastasis rate was evaluated in the lungs. Thal at 150mg/kg significantly decreased tumor growth, proliferation index, and TAMs infiltration in primary tumors. Conversely, a higher number of TAMs and lower proliferation index were observed in metastatic lungs in mice treated with 150mg/kg of Thal. Furthermore, Thal at 150mg/kg significantly decreased the metastatic nodules in the lungs. Our findings demonstrated that Thal treatment considerably decreased the primary tumor and lung metastasis in mice associated with different TAM infiltration effects in these sites.

Can Apparent Diffusion Coefficient Predict the Grade, Genotype, or Proliferation Index of Oligodendrogliomas.

Background:Genetic subsets of oligodendrogliomas (OD) have distinct chromosomal and biophysical profiles. Pretherapeutic tumor grade and genotype analysis is a challenging aspect of management, with 1p/19q codeletion status and grade of oligodendroglioma among the most important considerations for clinical decision making.Methodology:Seventy-three patients with histopathological diagnosis of oligodendroglioma were selected, and their preoperative 1.5T magnetic resonance imaging (MRI) scans were reviewed through parameters including diffusion weighted image, susceptibility-weighted imaging, and apparent diffusion coefficient (ADC). These images were correlated with patients' histopathological and chromosomal testing. Tumor border irregularity, homogeneity, contrast enhancement, and other MRI characteristics were also studied. For analysis, descriptive statistics were generated, and normality was evaluated for ADC value, age, and Ki-67 tumor proliferation index.Objectives:The study aimed to determine the correlation of ADC with Ki-67, grade, and 1p/19q co-deletion in oligodendroglioma at a tertiary care hospital within a low-middle income country.Results:Ki-67 tumor proliferation index was high in 33 tumors. It was found to be statistically significant (P = 0.048) with respect to ADC, showing that 1p/19q co-deleted tumors have a difference in their Ki-67 index. Ki-67 also showed a significant relationship (P < 0.05) with grade of OD. However, there was no statistically significant relationship between 1p19q chromosomal co-deletion and ADC. Linear regression was carried out as the data set was continuous. Univariate analysis showed no significant result with all P values above 0.10.Conclusion:Mean ADC is a viable tool to predict Ki-67 and assist prognostic clinical decisions. However, mean ADC alone cannot predict 1p/19q codeletion and tumor grades in OD. Further supplementation with other radiological modalities may provide greater yield and positive results.

Automated assessment of Ki-67 proliferation index in neuroendocrine tumors by deep learning.

The Ki‐67 proliferation index (PI) is a prognostic factor in neuroendocrine tumors (NETs) and defines tumor grade. Analysis of Ki‐67 PI requires calculation of Ki‐67‐positive and Ki‐67‐negative tumor cells, which is highly subjective. To overcome this, we developed a deep learning‐based Ki‐67 PI algorithm (KAI) that objectively calculates Ki‐67 PI. Our study material consisted of NETs divided into training (n = 39), testing (n = 124), and validation (n = 60) series. All slides were digitized and processed in the Aiforia® Create (Aiforia Technologies, Helsinki, Finland) platform. The ICC between the pathologists and the KAI was 0.89. In 46% of the tumors, the Ki‐67 PIs calculated by the pathologists and the KAI were the same. In 12% of the tumors, the Ki‐67 PI calculated by the KAI was 1% lower and in 42% of the tumors on average 3% higher. The DL‐based Ki‐67 PI algorithm yields results similar to human observers. While the algorithm cannot replace the pathologist, it can assist in the laborious Ki‐67 PI assessment of NETs. In the future, this approach could be useful in, for example, multi‐center clinical trials where objective estimation of Ki‐67 PI is crucial.

The genomic landscape of 85 advanced neuroendocrine neoplasms reveals subtype-heterogeneity and potential therapeutic targets

Metastatic and locally-advanced neuroendocrine neoplasms (aNEN) form clinically and genetically heterogeneous malignancies, characterized by distinct prognoses based upon primary tumor localization, functionality, grade, proliferation index and diverse outcomes to treatment. Here, we report the mutational landscape of 85 whole-genome sequenced aNEN. This landscape reveals distinct genomic subpopulations of aNEN based on primary localization and differentiation grade; we observe relatively high tumor mutational burdens (TMB) in neuroendocrine carcinoma (average 5.45 somatic mutations per megabase) with TP53, KRAS, RB1, CSMD3, APC, CSMD1, LRATD2, TRRAP and MYC as major drivers versus an overall low TMB in neuroendocrine tumors (1.09). Furthermore, we observe distinct drivers which are enriched in somatic aberrations in pancreatic (MEN1, ATRX, DAXX, DMD and CREBBP) and midgut-derived neuroendocrine tumors (CDKN1B). Finally, 49% of aNEN patients reveal potential therapeutic targets based upon actionable (and responsive) somatic aberrations within their genome; potentially directing improvements in aNEN treatment strategies.

Dietary Melatonin and Glycine Decrease Tumor Growth through Antiangiogenic Activity in Experimental Colorectal Liver Metastasis.

Despite multimodal treatment strategies, clinical outcomes of advanced stage colorectal cancer (CRC) patients remain poor. Neoadjuvant/adjuvant chemotherapy efficacy is limited due to chemoresistance, toxicity, and negative side effects. Since both melatonin and glycine have anti-cancer activities without relevant side effects, this study was designed to investigate their combined effects in experimental CRC liver metastases. CRC metastasis with CC531 cells were induced in male Wistar rats. Melatonin and glycine alone or their combination were supplemented for 14 days (n = 100). Blood parameters, a micro-computed tomography scan (tumor volume over time), and immunohistochemistry for Ki67 and CD31 expression in tumor tissue were compared between groups. Melatonin and glycine alone significantly reduced the tumor volume by 63.2% (p = 0.002) and 43% (p = 0.044) over time, respectively, while tumor volume increased by 8.7% in the controls. Moreover, treatment with melatonin and glycine alone reduced the tumor proliferation index. Most interestingly, the combination therapy did not have any influence on the above-mentioned tumor parameters. The leukocyte count was significantly increased with melatonin at the end of the experiment (p = 0.012) which was due to a high lymphocytes count. Tumor microvascular density was significantly reduced in all treatment groups. The results of this study suggest an inhibitory function for melatonin and glycine alone in the case of CRC liver metastasis growth by acting as natural antiangiogenic molecules, followed by angiogenesis-dependent cancer proliferation and immunomodulation.

EVALUATION OF THE TUMOR PROLIFERATIVE ACTIVITY INDEX PCNA IN A VARIETY OF ROUTES OF DELIVERY OF CHEMOTHERAPEUTIC DRUGS IN PATIENTS WITH LOCALLY ADVANCED BREAST CANCER

Introduction. Breast cancer is one of the most live issue of the modern oncology, as it holds the leading position among the causes of female mortality and disability. A special place in the structure of this pathology is occupied by locally advanced forms of malignant tumor in which the effectiveness of the treatments used is unfortunately very low, therefore the prognosis is rather unfavorable. This determines there levance of them search for new methods of diagnosis and treatment in such patients. In the context of this research, we identified the role of neoadjuvant selective intra-arterial polychemotherapy in adverse primary inoperable forms of breast cancer. To determine and predict the effectiveness of this treatment, we used tumor proliferative activity. The research examined the expression of a PCNA nuclear proliferation marker for prognostic and diagnostic evaluation in the light of unsatisfactory literature on the subject in the context of determining similar parameters by other criteria. PCNA level was taken as the main dichotomous point of prognostic assessment of neoadjuvant therapy based on the results of retrospective analysis of the efficacy of preoperative treatment and determination of statistically significant difference between the results in the subgroups with lower and higher marker levels, which in our study were divided according to the median value of the immunohistochemical parameter level in the total sample of 25 %. Objective. Evaluation of the effectiveness of neoadjuvant treatment using systemic and selective intraarterial routes of chemotherapy administration in patients with locally advanced breast cancer using the tumor proliferative index based on the PCNA marker. Materials and methods. A retrospective analysis of the results of a comprehensive treatment of patients with initially inoperable locally advanced breast cancer based on selective and systemic routes of administration of chemotherapy was performed. The study included 63 patients. The sample was divided into 2groups depending on the selected type of neoadjuvant polychemotherapy: 1st group – control group were formed (based on systemic therapy) and 2nd group – study group (the selective intraarterial delivery route was used). The control group consisted of 22 patients, the study – 41 patients. All patients revealed stage IIIb of the disease. In accordance with the clinical manifestations, the patients were distributed as follows: control group include 12 patients with сT4bN1M0, 6 patients with сT4aN1M0 and 4 patients with сT4cN1M0; study group include 23 patients with сT4bN1M0, 7 patients with сT4aN1M0 and 11 patients with сT4cN1M0. All patients included in the study had luminal type B. In parallel with routine methods, the dynamics of proliferative activity of the tumor by the PCNA nuclear antigen was additionally studied in all patients. This study demonstrates the level of the PCNA marker at the start of treatment and after the completion of polychemotherapy (PCT). After PCT, all patients underwent surgical intervention. Taking into account the pathological examination, the patients were reassigned as follows: in the control group, 4 patients has pT4aN0M0, 2 patients – pT4aN1M0, 4 patients – pT4bN0M0, 8 patients – pT4bN1M0, 1 patient – pT4cN0M0 and 3 patients – pT4cN1M0; in the study group, 3 patients has PT4aN1M0, 4 patients – PT4aN0M0, 15 patients – PT4bN1M0, 8 patients – PT4bN0M0, 6 patients – PT4cN1M0 and 5 patients – PT4cN0M0. Since the patients belonged to the group with Luminal type of tumor, each of them received hormone therapy in an adjuvant regimen. Patients of reproductive age were treated with the group of estrogen antagonists, while postmenopausal patients received aromatase inhibitors. Targeted therapy was not used in the study. A statistical analysis was performed between the comparison groups; the median marker level in 25 % was taken as the critical value. Results. According to the degree of PCNA regression, it was determined that selective intra-arterial chemotherapy for breast cancer with a low proliferative activity index has a statistical advantage in overall survival and average life expectancy (p &lt; 0.05) compared with control group. Conclusions. Using the PCNA indicator, one can reliably evaluate the proliferative activity of the tumor, thus predicting the effect of neoadjuvant chemotherapy and choosing the optimal tactics of complex treatment. Keywords: locally advanced breast cancer, proliferative activity index, marker of nuclear antigen of proliferating cells, systemic polychemotherapy, selective intra-arterial polychemotherapy.

Comparative Characterization of Lymphoid Infiltration in Different Molecular-Biological Subtypes of Invasive Breast Cancer.

The morphometric study examined the cell profile of lymphoid structures and leukocytic infiltrates in mammary glands of women with different molecular-biological subtypes of invasive breast cancer (BC). A high degree of lymphoid infiltration with the formation of lymphoid nodules was typical of luminal B (LumB) subtype of BC characterized by high tumor proliferation index (Ki-67≥30%) and in triple negative BC with Ki-67 ranging 33-35%. In these BC subtypes, extensive necrotic foci and pronounced stromal fibrosis of the mammary glands were observed. Lymphoid clusters and nodules predominantly consisted of B cells (CD20+) and T helper cells (CD4+). Cytotoxic lymphocytes (CD8+) were mostly observed in interstitial infiltrates. Macrophages and plasma cells were primarily located near the tumor cells. The presence of lymphoid clusters in the form of lymphoid nodules and dense lymphoid infiltrates can be viewed as unfavorable sign during diagnosis of BC and prediction of the course of the tumor process.