Proliferative Activity Ki-67 Research Articles

Cervical spinal metastasis of unsuspected hepatocellular carcinoma on initial presentation

Abstract Introduction/Objective In this case, a 66-year-old female reported to the emergency room (ER) for severe worsening neck and shoulder pain bilaterally for one month. Associated symptoms included bilateral hand weakness, swelling of the hands, inability to pick up objects, and inability to press buttons. MRI and CT scan of the spine demonstrated irregular marrow signals within C5, C6, and C7 vertebral bodies associated with anterior epidural thickening and the C6 vertebral body extending along C4-C5 nerve roots. Further imaging demonstrated a distended hepatic lesion measuring 6.3 x 6.4 x 6.9 cm. CT-guided biopsy of right hepatic lobe mass was performed. The cuboidal tumor cells showed abundant clear cytoplasm and centrally located nuclei demonstrated high nuclear:cytoplasmic ratio, and trabecular architecture. Tumor was immunoreactive to CK-7, CK-20, and Hep par 1, consistent with HCC. The Ki-67 proliferative activity is at 10%. Additionally, AFP, Napsin A, Pax 8, and RCC stains were negative. CT- guided biopsy of the longus colli muscle and anterior cervical spine at the C6 vertebrae performed at the same time demonstrated tumor positive for Hep par 1, consistent for metastatic HCC from just established liver primary. Bone metastasis of hepatocellular carcinoma (HCC) on initial presentation is rare, with an incidence rate of 0.9%. Of these cases, most incidents involve the vertebrae, pelvis, ribs, and skull, with poor patient morbidity and mortality. The thoracic and lumbar spinal locations are common in the field of view of standard abdominal imaging protocols and possibly are the most commonly reported regions of HCC spinal metastasis. Methods/Case Report Case report. Results (if a Case Study enter NA) NA Conclusion This case report demonstrates an unusual clinical presentation of spinal radiculopathy initially thought secondary to degenerative changes, which led to additional diagnostic imaging revealing a hepatic mass biopsied positive for hepatocellular carcinoma with metastasis to the spine.

Spatial heterogeneity of peri-tumoural lipid composition in postmenopausal patients with oestrogen receptor positive breast cancer

Deregulation of lipid composition in adipose tissue adjacent to breast tumour is observed in ex vivo and animal models. Novel non-invasive magnetic resonance imaging (MRI) allows rapid lipid mapping of the human whole breast. We set out to elucidate the spatial heterogeneity of peri-tumoural lipid composition in postmenopausal patients with oestrogen receptor positive (ER +) breast cancer. Thirteen participants (mean age, 62 ± [SD] 6 years) with ER + breast cancer and 13 age-matched postmenopausal healthy controls were scanned on MRI. The number of double bonds in triglycerides was computed from MRI images to derive lipid composition maps of monounsaturated, polyunsaturated, and saturated fatty acids (MUFA, PUFA, SFA). The spatial heterogeneity measures (mean, median, skewness, entropy and kurtosis) of lipid composition in the peri-tumoural region and the whole breast of participants and in the whole breast of controls were computed. The Ki-67 proliferative activity marker and CD163 antibody on tumour-associated macrophages were assessed histologically. Mann Whitney U or Wilcoxon tests and Spearman’s coefficients were used to assess group differences and correlations, respectively. For comparison against the whole breast in participants, peri-tumoural MUFA had a lower mean (median (IQR), 0.40 (0.02), p < .001), lower median (0.42 (0.02), p < .001), a negative skewness with lower magnitude (− 1.65 (0.77), p = .001), higher entropy (4.35 (0.64), p = .007) and lower kurtosis (5.13 (3.99), p = .001). Peri-tumoural PUFA had a lower mean (p < .001), lower median (p < .001), a positive skewness with higher magnitude (p = .005) and lower entropy (p = .002). Peri-tumoural SFA had a higher mean (p < .001), higher median (p < .001), a positive skewness with lower magnitude (p < .001) and lower entropy (p = .012). For comparison against the whole breast in controls, peri-tumoural MUFA had a negative skewness with lower magnitude (p = .01) and lower kurtosis (p = .009), however there was no difference in PUFA or SFA. CD163 moderately correlated with peri-tumoural MUFA skewness (rs = − .64), PUFA entropy (rs = .63) and SFA skewness (rs = .59). There was a lower MUFA and PUFA while a higher SFA, and a higher heterogeneity of MUFA while a lower heterogeneity of PUFA and SFA, in the peri-tumoural region in comparison with the whole breast tissue. The degree of lipid deregulation was associated with inflammation as indicated by CD163 antibody on macrophages, serving as potential marker for early diagnosis and response to therapy.

Uterine tumor resembling ovarian sex-cord tumor - a rare gynecological neoplasm.

Uterine tumor resembling ovarian sex-cord tumor is a rare group of uterine neoplasms with unknown histogenesis and differentiation towards ovarian sex-cord elements. They are benign in nature with low malignancy potential. Diagnosis is based on immunohistochemistry and morphological features, and the distinction from other more malignant differentials is paramount to correctly individualizing treatment.

Assessment of Immunoexpression of Ki-67 and CD 105 in Oral Pyogenic Granuloma

Background: Pyogenic granuloma (PG) is one of the most prevalent tumor-like lesions in the mouth, with two distinct histological variants: Non-Lobular Capillary Hemangioma (NLCH) and Lobular Capillary Hemangioma (LCH). This study aims to evaluate and compare the immunohistochemical expression of Ki-67 (proliferative activity) and CD 105 (angiogenic activity) in both types to find the conflict between the two. Methods: Data from clinical information and microscopic findings were collected. The selection criteria, including sufficient tissue, minor bleeding and/or inflammation, and proper fixation, were used to examine 24 cases of PG (10 LCH, 14 NLCH) that performed hematoxylin and eosin (H&amp;E) staining and immunostaining of anti-Ki-67 antibodies and anti-CD105 antibodies. Results: Our study showed female predilection, as 66.7% of cases were female (10 cases in LCH and 6 cases in NLCH). The mean patient age was 32.71%±15.35 years. LCH type of PG showed moderate positive expression of Ki-67 in 9 cases (64.3%); only two cases (14.3%) had a negative expression, while in 6 cases (60%) of NLCH, mild positive expression was seen, and in 4 cases (40%) it was moderate. The average number of blood vessels measured in LCH and NLCH samples treated with the anti-CD105 antibody was (72.7857±39.21479) and (47.1600±30.02855) respectively, with no significant difference between the two types of PG for both markers. Conclusions: The results of the present study confirm that there are no differences between the LCH and NLCH types of PG in proliferative rate and angiogenesis activity, so both types seem to have the same biological behavior.

Recurrence of composite hemangioendothelioma of the kidney after surgical resection

Composite hemangioendothelioma is an extremely rare form of kidney tumor. The tumor mainly occurs in the extremities, head and neck; internal organs involvement is rarely reported. Patient, 61-year-old male, was admitted to the urology department for a left kidney tumor, which was found accidentally during an ultrasound examination. Magnetic resonance imaging showed an irregularly shaped tumor measuring 5.0 × 6.0 × 4.0 cm and located in the lower pole of the left kidney. The tumor was surgically removed with resection of the capsule of the kidney lower pole. Immunohistochemical study revealed diffuse bright expression of CD31 (clone JC70A), CD34 (clone QBEnd 10), ERG (clone ER111), FLI-1 (clone MRQ-1) in tumor cells. The index of proliferative activity Ki-67 (clone SP6) was 40 %. The morphological picture and immunophenotype of the tumor correspond to composite hemangioendothelioma of the retroperitoneal space. Magnetic resonance imaging of the retroperitoneal space on follow-up visit in 9 months visualized a tumor of the left kidney measuring 8.3 × 8.4 × 7.8 cm. Radical nephrectomy was performed. Pathology examination showed that tumor tissue was mainly represented by solid fields of the spindle cell component. In samples of the border between the tumor and fatty pararenal tissue, tumor invasion was observed up to the adjacent striated muscles, tumor growth into the tissue of the kidney gate was also found. Taking into account the morphological picture and the earlier immunohistochemical study, the removed tumor corresponds to composite hemangioendothelioma.Composite hemangioendothelioma is a tumor of low malignant potential. It is extremely rare for this tumor to affect the kidney. At the same time, in the described case, the tumor was initially located in the retroperitoneal space, with involvement of the kidney capsule, and was assessed as a benign lesion. After 9 months, there was a recurrence of the tumor localized in the kidney with damage to the elements of the renal sinus, retroperitoneal tissue, and lumbar muscles. In this case, the tumor has significant malignant potential.

Analysis of the regional clinical use of CDK4/6 inhibitor ribociclib as a mechanism of integration of a research approach in drug provision

Introduction. Implementation of data from registration studies into clinical practice often presents a number of problems due to the heterogeneity of the patient population, the lack of uniformity of thinking among clinicians, and organizational difficulties. Using the example of studying the algorithm for prescribing ribociclib in a cohort of patients from one region in modern realities and the possibilities of drug provision, we have shown the main controversial points in the implementation of the results of clinical trials in the daily practice of an oncologist.Aim. The purpose of this study was to analyze our own preliminary results of the treatment of patients with hormone-receptorpositive Her-2-negative metastatic breast cancer using ribociclib in the routine practice of prescribing CDK4/6 inhibitors outside of clinical trials, taking into account the peculiarities of regional drug supply.Materials and methods. A retrospective analysis of the results of treatment of patients (n = 56) who took ribociclib in terms of combined hormone therapy for metastatic hormone-dependent Her-2 negative breast cancer in the practice of oncologists in the Krasnodar Territory from 2019 to 2022 was carried out.Results. At the time of data collection and analysis, with a total follow-up time of 29 months, the median overall survival was not achieved, 52 patients (92.9%) were alive and continued to follow up. The median progression-free survival was also not reached: disease progression was recorded in 19 patients (33.9%), 37 patients (66.1%) continued treatment. A total of 14 out of 56 patients (25.1%) received ribociclib therapy in combination with drugs for endocrine therapy in the first and second lines. The best results were demonstrated by patients with a high level of expression of progesterone receptors in the tumor (p = 0.005), a low level of Ki67 proliferative activity index (p = 0.035), without metastatic visceral lesions (p = 0.034), who received the minimum number of lines of therapy before the appointment of ribociclib (p = 0.029). The results of the clinical part of the study became available due to the timely optimization of regional drug supply processes with the creation and constant monitoring by clinicians of a stable cohort of patients in the form of updated registers.Conclusions. The introduction of the experience and knowledge of clinical oncologists into the process of drug supply management and its optimization, taking into account the understanding of data on drug efficacy and toxicity, is a promising direction and requires further discussion.

DNA aneuploidy identifies a subset of Luminal subtype breast carcinoma patients with worse clinical outcome.

In breast carcinoma (BC), the relationship between the ploidy pattern and molecular subtyping is still unknown. We aim to investigate the prognostic impact of DNA ploidy within molecular subtypes of a large cohort of BC patients. The series involved 520 BC patients with no neoadjuvant therapy and a median follow-up of 115.5 months. Immunohistochemical assessment of hormonal receptors, ERBB2 (HER2) status and Ki67 proliferative activity was the basis of the surrogate molecular subtyping. Ploidy was evaluated by DNA flow cytometry in fresh/frozen tumour samples. Kaplan-Meier (K-M) survival estimation was used for prognostic statistical analysis. Luminal A subtype had the lowest prevalence of disease recurrences (23.6%) and deaths from disease (18.3%), while Luminal B (42.2%/37.9%), Triple-negative (46.4%/40.6%), and HER2-positive (55.9%/50.0%) subtypes had the highest. The Triple-positive subtype shows an intermediate/low frequency of adverse events (29.4% of disease recurrences and 17.6% of deaths from disease). Luminal A tumours were mostly diploid (55.3%), while Triple-negative and HER2-positive tumours showed a high incidence of aneuploidy (82.6% and 88.2%, respectively). Luminal B and Triple-positive tumours had an intermediate percentage of aneuploidy (63.8% and 70.6%, respectively). K-M survival curves showed that DNA aneuploidy is significantly associated with shorter disease-free survival and overall survival in Luminal A and Luminal B molecular subtypes. DNA aneuploidy identifies a subset of Luminal BC patients with worse clinical outcome, potentially eligible for more aggressive adjuvant therapy.

Comparative characteristics of the regeneration of the femur bone of rats at intramedullary osteosynthesis using medical steel and carbon-carbon composite material

The aim of this study was to compare the morphological features of rat femoral bone regeneration during intramedullary osteosynthesis using medical steel and carbon-carbon composite material. Materials and methods. All animals were divided into two groups. A fracture of the thighbone was simulated by surgical intervention. In the first group, medical steel was used for intramedullary fixation of fragments; in the second group, fragments were fixed using a carbon-carbon composite material. The morphological, morphometric, histological, histochemical, immunohistochemical and X-ray methods was used, the bone regenerate was studied on the 30th day, 6 and 12 months after the surgical intervention. There were established expression of immunohistochemical markers CD-34 and Ki-67 using the ImageJ program. The statistical analysis of the obtained results was performed by the methods of variational statistics using the program Statistica 13.0. Results. In the group of animals where composite material was used, on the 30th day after surgery, a statistically significant increase in the expression of the relative area occupied by CD-34+ structures compared to the second group of animals was established (4.80 ± 0.40 in the group in which the composite material was used and 2.80 ± 0.30 in group in which the medical steel was used). Also a statistically significant increase in the expression of the Ki-67+ marker was established (5.20 ± 0.36 in the group in which the composite material was used and 2.48 ± 0.32 in group in which the medical steel was used). With inspection microscopy, faster rates of osseointegration and regeneration of the fracture site were observed in the group of animals in which the composite material had been used compared to the other group of animals due to the stimulation of vascular endothelium growth. The data of the histological examination coincide with the data of the X-ray examination at all the periods of observation. Conclusions. The use of carbon-carbon composite material during intramedullary osteosynthesis accelerates bone regeneration pace due to the angiogenic effect, which is confirmed by increase in the expression of markers of proliferative activity Ki-67+ and the marker of vascular endothelium CD-34+ in the group of experimental animals in 30 days.

Histopathological and immunohistochemical analysis of predictive and prognostic markers in spontaneous canine mammary cancer

The study investigates the interspecies similarities between canine and human mammary cancer in the sense of innovative predictive and prognostic tumour markers. Surgical resection specimens with diagnosed spontaneous primary mammary cancer obtained from 100 female canine patients were included in this study. Expression of carbonic anhydrase IX (CAIX) enzyme and human epidermal growth factor receptor 2 (HER2) expression was evaluated immunohistochemically. The study was completed with investigation of Ki67 expression and proliferation with marker of myogenous differentiation. Histopathological grading was performed using the Nottingham/modified Bloom-Richardson system. As in humans, our analysis of canine mammary cancer has shown that CAIX positivity in tumour cells significantly correlates with higher levels of HER2 immunoreactivity (P = 0.001), and increased tumour grade (P &lt; 0.001). The percentage of smooth muscle actin (SMA) positive cases was significantly higher (P = 0.002) in the group of mammary carcinomas with CAIX positivity compared to the tumours that were negative. Using antibody Ki67 proliferative activity was not significantly different between mammary tumours that were CAIX positive and CAIX negative. Canine mammary gland carcinomas may, therefore, represent valuable animal models for the study of hypoxic signaling pathways involved in mammary carcinogenesis in humans. Further research investigating this possibility is required.

Multiplexed Imaging Reveals the Spatial Relationship of the Extracellular Acidity-Targeting pHLIP with Necrosis, Hypoxia, and the Integrin-Targeting cRGD Peptide.

pH (low) insertion peptides (pHLIPs) have been developed for cancer imaging and therapy targeting the acidic extracellular microenvironment. However, the characteristics of intratumoral distribution (ITD) of pHLIPs are not yet fully understood. This study aimed to reveal the details of the ITD of pHLIPs and their spatial relationship with other tumor features of concern. The fluorescent dye-labeled pHLIPs were intravenously administered to subcutaneous xenograft mouse models of U87MG and IGR-OV1 expressing αVβ3 integrins (using large necrotic tumors). The αVβ3 integrin-targeting Cy5.5-RAFT-c(-RGDfK-)4 was used as a reference. In vivo and ex vivo fluorescence imaging, whole-tumor section imaging, fluorescence microscopy, and multiplexed fluorescence colocalization analysis were performed. The ITD of fluorescent dye-labeled pHLIPs was heterogeneous, having a high degree of colocalization with necrosis. A direct one-to-one comparison of highly magnified images revealed the cellular localization of pHLIP in pyknotic, karyorrhexis, and karyolytic necrotic cells. pHLIP and hypoxia were spatially contiguous but not overlapping cellularly. The hypoxic region was found between the ITDs of pHLIP and the cRGD peptide and the Ki-67 proliferative activity remained detectable in the pHLIP-accumulated regions. The results provide a better understanding of the characteristics of ITD of pHLIPs, leading to new insights into the theranostic applications of pHLIPs.

Malignant insulinoma: Can we predict the long-term outcomes?

Insulinomas are the most frequent type of functional pancreatic neuroendocrine tumors with a variety of neuroglycopenic and autonomic symptoms and well-defined diagnostic criteria; however, prediction of their clinical behavior and early differentiation between benign and malignant lesions remain a challenge. The comparative studies between benign and malignant cases are limited, suggesting that short clinical history, early hypoglycemia during fasting, high proinsulin, insulin, and C-peptide concentrations raise suspicion of malignancy. Indeed, malignant tumors are larger with higher mitotic count and Ki-67 proliferative activity, but there are no accurate histological criteria to distinguish benign from malignant forms. Several signaling pathways have been suggested to affect the pathophysiology and behavior of insulinomas; however, our knowledge is limited, urging a further understanding of molecular genetics. Therefore, there is a need for the identification of reliable markers of metastatic disease that could also serve as therapeutic targets in patients with malignant insulinoma. This opinion review reflects on current gaps in diagnostic and clinical aspects related to the malignant behavior of insulinoma.

THE EXPERIENCE OF OBTAINING A CELL CULTURE OF BREAST CARCINOMA FROM A TUMOR LUMINAL B SUBTYPE

The paper describes a case of obtaining a primary culture of breast carcinoma from tumor cells of the luminal B subtype. The aim of the study. Assess the cell morphology and changes in the receptor apparatus when obtaining a primary cell culture and further maintaining it during five passages Methodology. The paper describes the case of obtaining a primary culture of breast cancer. The level of expression for the following markers was determined: pancytokeratin, vimentin, the level of proliferative activity of Ki-67. Results. The data on the polyformism of cells in culture are presented, the levels of cell proliferation are estimated, the epithelial nature of the cells is determined during five passages. At the fourth passage, signs of an epithelial-mesenchymal transition were noted. The level of Ki-67 proliferative activity differed at different passages and was higher or lower than the initially established level in the primary material. The study of the primary culture and the first passages of the cell line is important for creating a further relevant model for the tumor in vivo. Conclusion. It is necessary that such a model be as close as possible in terms of cellular composition and receptor apparatus to the primary tumor.

А New Combination of Prognostic Markers in Follicular Lymphoma That Influences the Choice of Therapy

Background: Follicular lymphoma (FL) is characterized by clinical and morphological heterogeneity. It is based on the pathogenetic mechanisms of the development of tumor cells. The identification and assessment of risk factors associated with the course of the disease and treatment outcome in FL is an important task, as it allows to evaluate and predict the effectiveness of therapy.Objective: Identify and estimate risk factors for overall survival (OS) and progression free survival (PFS) in FL.Patients and Methods: The prospective exploratory study conducted at National Research Center for Hematology (Moscow) from 01/2017 to 04/2021 included patients (pts)(in total, 80) with FL. Morpho-immunohistochemical, cytogenetic and molecular studies were performed on biopsies of lymph nodes taken before the start of therapy. The mutational status of exon 16 and intron polymorphism rs_2072407 of the EZH2 gene were investigated by Sanger sequencing. 18q21/BCL-2 rearrangements were determined by conventional cytogenetic analysis and/or FISH study. The results obtained in a blind study were compared with the effect of the therapy.Results: Of the 80 pts 34 were male: Me (median) age 50 years (range 30-72) and 46 were female: Me 56 (range 21-81). The median follow-up (FU) time was 53 months.As a result of the study in the multivariate Cox regression model (likelihood-ratio test, p=0.01) of significant factors, selected in the previously univariate analysis, the following statistically significant (Wald test) risk factors for OS and PFS (the events: progression, relapse, or death) were obtained:• BCL-2 gene rearrangements (no vs yes)• EZH2 gene genotypes (AA/AG vs GG)• proliferation index Ki-67 (>35%)• morphological grade (3А vs 1/2)• tumor size (>6 cm /bulky/) (Tab. 1, Fig. 1)The BCL-2 rearrangements were found in 45 from 80 pts (56%; 95 % CI 45-66). The probability of BCL-2 rearrangements is estimated to be about 0.5 (50%). According to the results of Cox-regression analysis (by OS) in the absence of BCL-2 rearrangements, the risk of death in FL was generally significantly (p = 0.01) higher than in the group with its presence: HR = 4.3 (95 % CI 1.5-13.0) (Fig. 2)Mutations in the 16th exon of the EZH2 gene (mutEZH2) were found in 10/80 (13%) pts. Analysis of EZH2 gene mutations with BCL-2 rearrangements revealed that in the mutEZH2 group with the presence of BCL-2 rearrangements, the number of deaths associated with progression is significantly less than in the control initial groups (mutEZH2 with BCL-2 rearrangements - 0/6, mutEZH2 without BCL-2 rearrangements - 2/4, wEZH2 with BCL-2 rearrangements - 3/39 (8%), wEZH2 without BCL-2 rearrangements - 11/31 (35%)) .The prognostic significance of EZH2 genotypes in lymphomas was studied for the first time in this study. The frequencies of rs_2072407 genotypes were: AA - 24% (19), AG - 42% (34), and GG - 34% (27). AA and AG genotypes of the EZH2 gene in pts with FL were associated with an increased risk of death (compared to the GG genotype) : HR = 2.9 (95% CI: 1.2-10.6), p = 0.01 (Fig. 3). The GG variant in most cases was associated with wEZH2 (26/27 (96%)) with BCL-2 rearrangements (16/26 (62%)) and a favorable prognosis (26/27 (96%)) (p = 0.01).Index of proliferative activity Ki-67> 35% (n = 40) and Ki-67 ≤ 35% (n = 40) were equally common in the study group. With a Ki-67> 35%, the probability of death is 2.9 (95% CI 1.1-9.7) times higher.The frequency distribution of morphological grade was as follows: grade 3A - 53% (n = 43) and grade 1-2 - 47% (n = 37). At grade 3A, the probability of death is 2.5 (95% CI 1.1-7.8) times higher.The number of pts with tumor size >6 cm (bulky) and ≤ 6 cm in the sample is approximately the same (41 and 39, respectively), the presence of bulky increased the mortality risk by 2.1 (95% CI 1.0-6.5) times.A short time from the manifestation of the disease to appeal to medical care is a predictor of poor prognosis, but this result we received earlier on a large sample of pts was not significant on a smaller sample.Conclusions: As a result of the multivariable Cox regression analysis, we identified and confirmed the previously obtained factors (bulky, grade 3A, Ki-67 > 35%, short medical history), and discovered new biogenetic factors (BCL-2 rearrangements and the GG rs2072407 genotype of the EZH2 gene). The model based on these independent risk factors improves the accuracy of predicting adverse events and allows to use more personalized treatment options for patients with FL. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Lymphocyte-macrophage colonization in various molecular biological types of endometrial cancer: comparison with the receptor status and proliferative activity of tumor tissue

Recent years have been marked by a gradual shift from the previous division of endometrial cancer (EC) into two main types to modern molecular biological classifications of this disease, one of which (at present, most likely, the most popular: Talhouk et al., 2017, 2019) is based on the use of a combination of genetic and immunohistochemical analysis.&#x0D; The study involved material from untreated EC patients, the number of which varied depending on the method used. The average age of patients was close to 55-60 years, and over 80% of patients were postmenopausal.&#x0D; Deparaffinized blocks of EC tissue were analyzed for POLE (DNA polymerase epsilon) mutations, evaluated by immunohistochemistry (IHC) the expression of the oncoprotein p53 and MMR (mismatch-repair) proteins / MLH1, MSH2, MSH6 and PMS2 /, and also helped to identify the type of disease without a characteristic molecular profile (WCMP).&#x0D; In addition to studying the expression of p53 and MMR proteins, the IHC method was also used to study the expression of estrogen (ER) and progesterone (PR) receptors, the Ki-67 proliferative activity index, and the severity of macrophage-lymphocytic infiltration of the EC tissue based on the analysis of the macrophage marker (CD68) and markers of lymphocytic cells (cytotoxic CD8 and regulatory FoxP3) using reagents from Ventana and Dako.

Low-molecular-weight fibroblast growth factor-2 — a viable prognostic factor for gastric gastrointestinal stromal tumors

Aim. To examine the expression of fibroblast growth factor-2 and its isoforms in gastrointestinal stromal tumors and assess the prognostic value of this marker.&#x0D; Methods. The study included 44 patients with gastric gastrointestinal stromal tumors of the stomach who were prescribed surgical or combined treatment with the targeted drug imatinib (imatinib mesylate). Immunohistochemistry (IHC)-staining and immunoblotting with monoclonal antibodies were used to assess the expression of FGF-2. Statistical analysis for differences in clinical and morphological parameters was performed by using Students, MannWhitneyWilcoxon and Fishers tests. Differences were considered significant at p 0.05.&#x0D; Results. Fibroblast growth factor-2 expression was assessed in tumor tissues in 39 out of 44 analyzed patients. The frequency of fibroblast growth factor-2 expression in the observed patients was 84.6% (33/39). The moderate and strong fibroblast growth factor-2 expression was detected in 21 (53.8%) patients with gastric gastrointestinal stromal tumors. High expression of low-molecular weight (18 kDa) fibroblast growth factor-2 isoform was found in all tumor samples from patients with high-risk gastrointestinal stromal tumor (prognostic group 6) (p=0.039), which indicated the active secretion of this ligand by its signalling pathway in the cancer cells. Patients with high levels of low‐molecular‐weight fibroblast growth factor-2 showed a higher level of Ki-67 proliferative activity (р=0.013) and tumor size (р=0.0017). Patients with increased expression of the low molecular weight isoform of fibroblast growth factor-2 in gastric gastrointestinal stromal tumor had a higher risk of recurrence, as well as larger tumor size and proliferative activity compared with patients without expression of this isoform. The level of fibroblast growth factor-2 expression in tumor samples, determined by immunohistochemistry-staining, increases after initiation of imatinib to based therapy, which may indicate the formation of resistance to this targeted drug and the progression of the disease.&#x0D; Conclusion. The results of the study suggest that FGF-2 might be an independent prognostic marker of gastric gastrointestinal stromal tumor and a viable therapeutic target.

Markers of Lymphocytic-Macrophagal Infiltration and Their Association With the Receptor Phenotype and Proliferative Activity of Tumor Tissue in Various Molecular-Biological Types of Endometrial Cancer

Background and Aims: The last years were characterized by a shift from the former subdivision of endometrial cancer (EC) into two main types [1, 2] to modern molecular biological classifications of this disease [3-5]. The purpose of this investigation was an attempt to compare such prognostic indicators for EC as features of lymphocytic [6] and macrophage infiltration of tumor tissue with markers of its hormonal sensitivity (receptor phenotype) and the proliferation index Ki-67 [7], taking into account the molecular biological type of the disease. Materials and Methods: The study involved material from untreated patients with endometrial cancer (a total of 219 people). The average age of patients was close to 55-60 years. Using classification of Talhouk et al. [5] allowed to perform a search for POLE mutations, evaluate by IHC the expression of the oncoprotein p53 and MMR (mismatch-repair) proteins /MLH1, MSH2, MSH6 and PMS2/, and also identify the type of disease without a characteristic molecular profile (WCMP). The IHC method was also used to study the rate of estrogen (ER) and progesterone (PR) receptors, Ki-67 proliferative activity index, as well as the severity of macrophage-lymphocytic tissue infiltration of EC based on the analysis of the macrophage (CD68) and lymphocytic cells (cytotoxic CD8 and regulatory FoxP3) markers using reagents from Ventana and Dako. Statistical assessment of the relationships of the studied indicators was carried out by the Spearman rank correlation coefficient. Results: FoxP3 (in contrast to CD8 and CD68) positively and significantly correlates (ρ varies from 0.2895 to 0.3477) more often with ER, but not with PR. Ki-67 index in EC tissue positively and reliably correlates with FoxP3 both in the MMR-D and WCMP groups and in the combined cohort of EC patients. In the latter case, a similar relationship with Ki-67 extends to other studied markers of lymphocytic-macrophage infiltration, namely CD8 and CD68 (ρ 0,1746-0,3294). Only in the entire group of EC patients there is a positive rank correlation (0.4119!) between ER and PR expression. Conclusions: In patients with certain types of EC the connection between the estrogenic signal and PR induction is lost; it is especially noticeable in the MMR-D group, as exemplified by the negative correlation (-0.2951) of FoxP3 and PR expression. Taken together with existing data this indicates an important role of the endocrine component for differentiating separate groups of patients with EC, that may also be of practical importance.

ASSOCIATION BETWEEN APPARENT DIFFUSION COEFFICIENT AND KI67 IN BRAIN TUMORS: A SYSTEMATIC REVIEW

Certain histological variants of tumors have a correlation between the values of the apparent diffusion coefficients (AdC), cell density and the proliferative activity index MIB-I (Ki67). The results of studies on the relationship between the values of the AdC and the Ki67 index in brain tumors are ambiguous and largely contradictory. The purpose of this study was to perform a systematic review based on the results of clinical studies that examined the relationship between AdC values and the Ki67 proliferative activity index in brain tumors. Material and Methods . Clinical studies were searched in the databases pubmed, EMBASE, Cohrane Library and eLibrary published from January 2000 to January 2020, which studied the relationship between AdC values and the Ki67 proliferative activity index in brain tumors. Results . A systematic review included 17 retrospective cohort nonrandomized clinical studies. The average value of the coefficient of reliable correlation between AdC and the mitotic index Ki67 in the group of meningiomas was -0.493. The indicated dependence was more often found in groups of typical (MI) and atypical (MII) brain meningiomas. The average coefficient of statistically significant correlation between the studied parameters in the group of brain gliomas was -0.443. The relationship between the AdC values and the Ki67 proliferative activity index was observed both in the glioma group of low (GI–II) and high (GIII–IV) grade of malignancy. In groups of patients with pituitary adenomas, primary lymphomas and brain metastases, the relationship between the studied parameters was not reliably confirmed. Conclusion. The use of diffusion-weighted magnetic resonance imaging techniques with subsequent calculation of AdC values can be recommended for use in the clinical practice of oncologists in order to assess the proliferative potential of brain meningiomas and gliomas.

Adrenocortical cancer: morphological variants, immunohistochemical characteristics

To provide a detailed description of the morphological variants of ACC with an emphasis on their histological characteristics and the expression of immunohistochemical markers. A total of 75 cases of ACC were analyzed in the adult population diagnosed as having the morphological variants in accordance with the International Histological Classification of Adrenal Tumors (WHO, 2017). Monoclonal antibodies to SF1, Inhibin A, Melan A, Ki-67, p53, and antimitochondrial antibodies were used for immunohistochemical diagnosis. The classic, oncocytic, and myxoid subtypes of ACC were found in 51 (68%), 15 (20%), and 9 (12%) cases, respectively. The functional activity of the tumors was observed in 43% (n=18) in the classic variant of ACC; moreover, the clinical picture was manifested by the symptoms of hypercorticism (38%) and virilization (5%). There were no significant differences in hormonal activity between different morphological variants. The characteristics of the above histological variants of the tumor was determined with a description of growth patterns that can improve the diagnosis of ACC. The diagnosis of ACC can be confirmed by an immunohistochemical study; the required minimum panel of markers should include SF1, Melan A, and Inhibin A. The Ki-67 proliferative activity index showed significant differences (p=0.0056) when it was determined in the morphological variants of ACC. Despite the determination of a minimal immunohistochemical panel to confirm the diagnosis of ACC, it is important to remember that each histological variant may be characterized by the different expression of immunohistochemical markers. The identification of morphological variants of ACC and the use of specific, sensitive, and prognostically significant immunohistochemical markers will allow clinicians and pathologists to more accurately judge the biological properties of this tumor and the clinical course of the disease.

Ki-67 Proliferative Activity in the Tumor Margins as a Robust Prognosis Factor in Glioblastoma Patients.

The infiltrative margin of glioblastomas (GBM) contains proliferative tumor cells difficult to estimate radiologically as they are included in the hyperintense signal of T2 sequences and they remain in the cavity margin after tumor resection. The amount of these cells could determine overall survival (OS) of these patients. From October 2007 to January 2010, patients whose MRI were suggestive of newly diagnosed, resectable high-grade glioma were operated using fluorescence-guided surgery (FGS). Separate samples were selectively taken from nonfluorescent white matter areas just adjacent to the border of the pale fluorescence and staining was made for Ki-67. OS was analyzed with Kaplan-Meier and Cox regression. Multivariate analysis included the following prognosis variables: age, extent of resection (EOR), O-6-methylguanine-DNA methyltransferase (MGMT) promoter methylation, and performance status index. Sample included 65 patients, comprising 37 men and 28 women, with a median Karnofsky Performance Score (KPS) of 80 (40-100) and mean age of 60 (34-78) years. Mean preoperative tumor volume was 35.8 mL. EOR was 100% in 52 patients (80%), with the lower EOR being 88%. For Ki-67, 39 patients had <5% and 26 had ≥5%. OS was 26.8 months (95% confidence interval [CI]: 18.9-28.2) for the Ki-67 low group versus 15.8 months (95% CI: 7.7-18.2) for the Ki-67 high group (p = 0.002). Proliferative activity in the normal-looking brain around the resection cavity measured with Ki-67 immunostaining is an important independent prognostic factor for GBM cases with complete resection of enhancing tumor. When complete resection is not reached, this factor is not relevant for prognosis.

Pathological and molecular features of liver metastases of colon adenocarcinoma

Aim. To study pathological and molecular features of liver metastases of colon adenocarcinoma. Material and methods . DNA mismatch repair (MMR), CXCR4 expression, Ki-67 proliferative activity were investigated in 125 cases of colon adenocarcinoma with liver metastases. First group consisted of 94 cases of tumor with liver metastases at diagnosis. The second group consisted of 31 cases with stage II disease at diagnosis, but subsequently these patient metastases. In second group KRAS mutation was investigated. The control group included 22 cases of stage II colon adenocarcinoma without disease progression. MMR was studied in 325 cases of colon adenocarcinoma without known stage. Results . MMR deficiency (dMMR) didn’t revealed in group 1 and 2. The frequency of deficiency MMR in the general population of colon adenocarcinoma was 8%. Low level of expression of CXCR4 in group I and II was revealed in 16% of cases, in control group – in 73%. Low level of Ki-67 was revealed in 5% of cases of liver metastases (group 1 and 2), the frequency of KRAS mutations was 45%. Conclusion. Colon adenocarcinoma with liver metastases is characterized by aggressive immunophenotype: high expression rates CXCR4, Ki-67, and preferentially retained MMR function.