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Endocrine Pathology Dec 2020The exact prediction of outcome of patients with Merkel cell carcinoma (MCC) of the skin is difficult to determine, although several attempts have been made to identify... (Review)
Review
The exact prediction of outcome of patients with Merkel cell carcinoma (MCC) of the skin is difficult to determine, although several attempts have been made to identify clinico-pathologic prognostic factors. The Ki67 proliferative index is a well-known marker routinely used to define the prognosis of patients with neuroendocrine neoplasms. However, its prognostic value has been poorly investigated in MCC, and available published results are often contradictory mainly because restricted to small series in the absence of standardized methods for Ki67 evaluation. For this reason, we explored the potential prognostic role of Ki67 proliferative index in a large series of MCCs using the WHO standardized method of counting positive cells in at least 500 tumor cells in hot spot areas on camera-captured printed images. In addition, since MCC may be considered as the cutaneous counterpart of digestive neuroendocrine carcinomas (NECs), we decided to stratify MCCs using the available and efficient Ki67 threshold of 55%, which was found prognostic in digestive NECs. This choice was also supported by the Youden index analysis. In addition, we analyzed the prognostic value of other clinico-pathologic parameters using both univariate and multivariate analysis. Ki67 index appeared significantly associated with prognosis at univariate analysis together with stage IV, lack of MCPyV, and p63 expression, but not at the multivariate analysis, where survival resulted independently influenced by p63 expression and tumor stage, only.
Topics: Biomarkers, Tumor; Carcinoma, Merkel Cell; Humans; Ki-67 Antigen; Mitotic Index; Prognosis; Skin Neoplasms
PubMed: 32696301
DOI: 10.1007/s12022-020-09640-3 -
Management of uterine sarcomas and prognostic indicators: real world data from a single-institution.BMC Cancer Dec 2018Uterine sarcomas consist a heterogeneous group of mesenchymal gynecological malignancies with unclear therapeutic recommendations and unspecific but poor prognosis,...
BACKGROUND
Uterine sarcomas consist a heterogeneous group of mesenchymal gynecological malignancies with unclear therapeutic recommendations and unspecific but poor prognosis, since they usually metastasize and tend to recur very often, even in early stages.
METHODS
We retrospectively analyzed all female patients with uterine sarcomas treated in our institution over the last 17 years. Clinico-pathological data, treatments and outcomes were recorded. Kaplan-Meier curves were plotted and time-to-event analyses were estimated using Cox regression.
RESULTS
Data were retrieved from 61 women with a median age of 53 (range: 27-78) years, at diagnosis. Fifty-one patients were diagnosed with leiomyosarcoma (LMS), 3 with high grade endometrial stromal sarcoma (ESS), 5 with undifferentiated uterine sarcoma (UUS), 1 with Ewing sarcoma (ES) and 1 with Rhabdomyosarcoma (RS). 24 cases had stage I, 7 stage II, 14 stage III and 16 stage IV disease. Median disease-free survival (DFS) in adjuvant approach was 18.83 months, and median overall survival (OS) 31.07 months. High mitotic count (> 15 mitoses) was significantly associated with worse OS (P < 0.001) and worse DFS (P = 0.028).
CONCLUSIONS
Mitotic count appears to be independent prognostic factor while further insights are needed to improve adjuvant and palliative treatment of uterine sarcomas.
Topics: Adult; Aged; Disease Management; Female; Greece; Humans; Middle Aged; Mitotic Index; Prognosis; Retrospective Studies; Rhabdomyosarcoma; Sarcoma, Endometrial Stromal; Sarcoma, Ewing
PubMed: 30541504
DOI: 10.1186/s12885-018-5156-1 -
International Journal of Clinical and... 2015Glomus tumor is an uncommon tumor usually presenting in the dermis. Rarely, it occurred in visceral organs including stomach, liver and long. The majority of glomus... (Review)
Review
Glomus tumor is an uncommon tumor usually presenting in the dermis. Rarely, it occurred in visceral organs including stomach, liver and long. The majority of glomus tumors were benign. Herein, we present a case of glomus tumor located in the left lobe of the lung in a 49 year-old Chinese male. An irregular mass measuring 3 cm was detected by imaging examination because of his suffering from cough, dyspnea and chest pain. Histologically, the tumor is composed predominantly of sheets of ovoid to round cells with clear border, pale cytoplasm and fine granular chromatin. The mitotic count was less than 5 per 50 HPF. The tumor focally invaded the surrounding normal bronchial and alveolar tissue. Immunohistochemical staining showed that the cells were diffusely positive for SMA, caldesmon, and vimentin. The Ki-67 proliferation index was approximately 20%. Based on morphologic features and the immunohistochemical profile, the tumor was consistent with glomus tumor of uncertain malignant potential.
Topics: Biomarkers, Tumor; Biopsy; Cell Proliferation; Glomus Tumor; Humans; Immunohistochemistry; Lung Neoplasms; Male; Middle Aged; Mitotic Index; Neoplasm Invasiveness; Pneumonectomy; Tumor Burden
PubMed: 26823902
DOI: No ID Found -
Journal of Neuropathology and... Nov 2019Current histological grading recommendations for isocitrate dehydrogenase (IDH)-mutant astrocytoma are imprecise and not reliably predictive of patient outcome, while...
Current histological grading recommendations for isocitrate dehydrogenase (IDH)-mutant astrocytoma are imprecise and not reliably predictive of patient outcome, while somatic copy number alterations are emerging as important prognostic biomarkers. One explanation for this relative underperformance of histological grading is that current criteria to distinguish World Health Organization (WHO) grade III anaplastic astrocytomas from lower-grade diffuse astrocytomas (WHO grade II) are vague ("increased mitotic activity"). This qualitative approach ensures diagnostic uncertainty and a broad "gray zone" where both diffuse and anaplastic designations can reasonably be assigned. Thus, we hypothesized that interobserver variability and lack of defined mitotic thresholds for IDH-mutant astrocytomas underlies poor predictive accuracy of current histologic grading approaches. To test this hypothesis, we quantified total mitotic figures and maximum mitotic activity per 10 high-powered fields in an institutional cohort of IDH-mutant astrocytomas. In our cohort, there was no mitotic activity threshold that was reflective of progression-free or overall survival (OS). Furthermore, in a multivariate Cox regression model consisting of mitotic activity, molecular markers, and clinical characteristics, only CDKN2A homozygous deletion was identified as a relevant variant for poor OS. We conclude that lack of defined mitotic figure thresholds may not contribute to underperformance of histological grading for IDH-mutant astrocytomas.
Topics: Astrocytoma; Brain; Brain Neoplasms; Humans; Isocitrate Dehydrogenase; Mitosis; Mitotic Index; Mutation; Neoplasm Grading
PubMed: 31529048
DOI: 10.1093/jnen/nlz082 -
Laboratory Investigation; a Journal of... Nov 2019As part of routine histological grading, for every invasive breast cancer the mitotic count is assessed by counting mitoses in the (visually selected) region with the...
As part of routine histological grading, for every invasive breast cancer the mitotic count is assessed by counting mitoses in the (visually selected) region with the highest proliferative activity. Because this procedure is prone to subjectivity, the present study compares visual mitotic counting with deep learning based automated mitotic counting and fully automated hotspot selection. Two cohorts were used in this study. Cohort A comprised 90 prospectively included tumors which were selected based on the mitotic frequency scores given during routine glass slide diagnostics. This pathologist additionally assessed the mitotic count in these tumors in whole slide images (WSI) within a preselected hotspot. A second observer performed the same procedures on this cohort. The preselected hotspot was generated by a convolutional neural network (CNN) trained to detect all mitotic figures in digitized hematoxylin and eosin (H&E) sections. The second cohort comprised a multicenter, retrospective TNBC cohort (n = 298), of which the mitotic count was assessed by three independent observers on glass slides. The same CNN was applied on this cohort and the absolute number of mitotic figures in the hotspot was compared to the averaged mitotic count of the observers. Baseline interobserver agreement for glass slide assessment in cohort A was good (kappa 0.689; 95% CI 0.580-0.799). Using the CNN generated hotspot in WSI, the agreement score increased to 0.814 (95% CI 0.719-0.909). Automated counting by the CNN in comparison with observers counting in the predefined hotspot region yielded an average kappa of 0.724. We conclude that manual mitotic counting is not affected by assessment modality (glass slides, WSI) and that counting mitotic figures in WSI is feasible. Using a predefined hotspot area considerably improves reproducibility. Also, fully automated assessment of mitotic score appears to be feasible without introducing additional bias or variability.
Topics: Adult; Aged; Breast Neoplasms; Cohort Studies; Deep Learning; Diagnosis, Computer-Assisted; Female; Humans; Middle Aged; Mitotic Index; Netherlands; Neural Networks, Computer; Observer Variation; Prospective Studies; Reproducibility of Results; Retrospective Studies
PubMed: 31222166
DOI: 10.1038/s41374-019-0275-0 -
The American Journal of Pathology Nov 1990Flow cytometric analysis of murine erythroleukemic cells (MELC) exposed in vitro to 2.5 to 7.5 mumol/l (micromolar) methylmercury (MeHg) reveals a dose-dependent...
Flow cytometric analysis of murine erythroleukemic cells (MELC) exposed in vitro to 2.5 to 7.5 mumol/l (micromolar) methylmercury (MeHg) reveals a dose-dependent decrease in the rate of DNA synthesis (rate of passage through the S phase of the cell cycle), manifested as the accumulation of most of the cells in the S phase, and a modest accumulation of cells in the G2/M phase of the cycle. Light microscopy reveals a progressive increase in chromosomal damage (condensation, pulverization). At or above 10 mumol/l MeHg, progression through all the phases of the cell cycle is blocked and mitotic cells are arrested irreversibly in anaphase, with most exhibiting arrangement of chromosomes in a wreathlike ring formation. Also the cells exhibit both nuclear propidium iodide (PI) fluorescence (indicative of loss of viability) and concurrent cytoplasmic carboxyfluorescein (CF) fluorescence (viable cells exhibit CF fluorescence and exclude PI). In addition, there is a dose-dependent increase in cellular refractive index (90 degrees light scatter), an apparent decrease in cell volume (axial light loss), and progressive resistance to detergent (NP-40)-mediated cytolysis. Resistance to detergent-mediated cytolysis is indicative of fixation (protein denaturation, cross-linking, and so on) of the plasma membrane/cytoplasm complex. Our findings indicate that DNA synthesis is the primary target of MeHg cytotoxicity and that apparent targets and degree of cytotoxicity are a complex function of dose.
Topics: Animals; Cell Cycle; Cell Line; Cell Nucleus; Cell Survival; Chromosome Aberrations; Chromosomes; Dose-Response Relationship, Drug; Flow Cytometry; Karyotyping; Leukemia, Erythroblastic, Acute; Mathematics; Methylmercury Compounds; Mice; Mitotic Index
PubMed: 2240165
DOI: No ID Found -
Neurology India 2017The most reliable histological correlate of recurrence risk in meningiomas is increased mitotic activity. Proliferative index with Ki-67 immunostaining is a helpful...
BACKGROUND
The most reliable histological correlate of recurrence risk in meningiomas is increased mitotic activity. Proliferative index with Ki-67 immunostaining is a helpful adjunct to manual counting. However, both show considerable inter-observer variability. A new immunohistochemical method for counting mitotic figures, using antibody against the phosphohistone H3 (PHH3) protein was introduced. Similarly, a computer based automated counting for Ki-67 labelling index (LI) is available.
AIMS AND OBJECTIVES
To study the use of these new techniques in the objective assessment of proliferation indices in meningiomas.
MATERIALS AND METHODS
This was a retrospective study of intracranial meningiomas diagnosed during the year 2013.The hematoxylin and eosin (H and E) sections and immunohistochemistry (IHC) with Ki-67 were reviewed by two pathologists. Photomicrographs of the representative areas were subjected to Ki-67 analysis by Immunoratio (IR) software. Mean Ki-67 LI, both manual and by IR were calculated. IHC with PHH3 was performed. PHH3 positive nuclei were counted and mean values calculated. Data analysis was done using SPSS software.
RESULTS
A total of 64 intracranial meningiomas were diagnosed. Evaluation on H and E, PHH3, Ki-67 LI (both manual and IR) were done in 32 cases (22 grade I and 10 grade II meningiomas). Statistically significant correlation was seen between the mitotic count in each grade and PHH3 values and also between the grade of the tumor and values of Ki-67 and PHH3.
CONCLUSION
Both the techniques used in the study had advantage over, as well as, correlated well with the existing techniques and hence, can be applied to routine use.
Topics: Adolescent; Adult; Aged; Child; Female; Humans; Immunohistochemistry; Ki-67 Antigen; Male; Meningeal Neoplasms; Meningioma; Middle Aged; Mitotic Index; Retrospective Studies; Young Adult
PubMed: 29133712
DOI: 10.4103/0028-3886.217934 -
Developmental Biology Jan 2016Many organisms accumulate a pool of germline stem cells during development that is maintained in later life. The dynamics of establishment, expansion and homeostatic...
Many organisms accumulate a pool of germline stem cells during development that is maintained in later life. The dynamics of establishment, expansion and homeostatic maintenance of this pool are subject to both developmental and physiological influences including the availability of a suitable niche microenvironment, nutritional status, and age. Here, we investigated the dynamics of germline proliferation during stages of expansion and homeostasis, using the C. elegans germ line as a model. The vast majority of germ cells in the proliferative zone are in interphase stages of mitosis (G1, S, G2) rather than in the active mitotic (M) phase. We examined mitotic index and DNA content, comparing different life stages, mutants, and physiological conditions. We found that germ cells in larval stages cycle faster than in adult stages, but that this difference could not be attributed to sexual fate of the germ cells. We also found that larval germ cells exhibit a lower average DNA content compared to adult germ cells. We extended our analysis to consider the effects of distance from the niche and further found that the spatial pattern of DNA content differs between larval and adult stages in the wild type and among mutants in pathways that interfere with cell cycle progression, cell fate, or both. Finally, we characterized expansion of the proliferative pool of germ cells during adulthood, using a regeneration paradigm (ARD recovery) in which animals are starved and re-fed. We compared adult stage regeneration and larval stage expansion, and found that the adult germ line is capable of rapid accumulation but does not sustain a larval-level mitotic index nor does it recapitulate the larval pattern of DNA content. The regenerated germ line does not reach the number of proliferative zone nuclei seen in the continuously fed adult. Taken together, our results suggest that cell cycle dynamics are under multiple influences including distance from the niche, age and/or maturation of the germ line, nutrition and, possibly, latitude for physical expansion.
Topics: Aging; Animals; Caenorhabditis elegans; Cell Cycle; Cell Lineage; Cell Proliferation; DNA; Germ Cells; Larva; Mitotic Index; Mutation; Regeneration; Stem Cells; Time Factors
PubMed: 26577869
DOI: 10.1016/j.ydbio.2015.10.031 -
The Journal of Histochemistry and... Jul 2017Grading of pancreatic neuroendocrine tumors (pNETs) is currently based on mitotic rate and Ki67 proliferation index. Phosphohistone-H3 (PHH3) is an effective marker for... (Comparative Study)
Comparative Study
Grading of pancreatic neuroendocrine tumors (pNETs) is currently based on mitotic rate and Ki67 proliferation index. Phosphohistone-H3 (PHH3) is an effective marker for mitosis that has been proposed to use in grading various NETs. It remains unclear which method more accurately predicts grade and clinical outcome. Cases of pNET were evaluated using immunohistochemical stains for Ki67 and PHH3. In addition, each case was evaluated for necrosis, lymphovascular invasion, and perineural invasion and compared with stage. R project statistical analysis was used for comparisons. Sixty-three cases were included in the study including 29 males and 34 females (M:F 0.9) with a median age of 59 years (ranging 34-84). There was not a significant discrepancy in the stratification of tumor grades for Ki67 and PHH3. PHH3 significantly predicted lymph node metastasis ( p=0.041). Necrosis correlated with overall survival ( p=0.017). The results suggest that PHH3 is an effective marker for determining mitotic activity and can be used alternative to Ki67. In addition, necrosis may be included in the reporting of pNET as it may play a prognostic role. Larger scale studies are warranted to understand the biology and behavior of these tumors.
Topics: Adult; Aged; Aged, 80 and over; Biomarkers, Tumor; Female; Histones; Humans; Ki-67 Antigen; Male; Middle Aged; Mitosis; Mitotic Index; Neoplasm Grading; Pancreas; Pancreatic Neoplasms; Phosphorylation; Prognosis
PubMed: 28651471
DOI: 10.1369/0022155417708186 -
Plant Physiology Nov 1996Previous studies on the cell cycle of Arabidopsis thaliana have been hindered by the lack of synchronous cell culture systems. We have used liquid callus cultures and a...
Previous studies on the cell cycle of Arabidopsis thaliana have been hindered by the lack of synchronous cell culture systems. We have used liquid callus cultures and a cycloheximide-synchronized suspension culture of Arabidopsis to investigate changes in cyclin transcript levels in response to exogenous auxin, cytokinin, and nutrients, and during the cell cycle. CYCD1 (delta 1) transcript was virtually undetectable in liquid-cultured callus or suspension-culture cells. CYCD2 (delta 2) transcript levels were largely unaffected by the readdition of phytohormones or nitrate to the growth medium, and remained constant throughout the cell cycle in suspension-culture cells. CYCD3 (delta 3) transcript levels were strongly dependent on nitrate, and were induced at the G1/S transition following phytohormone readdition. In synchronized suspension-culture cells, CYCD3 transcript accumulated during the S phase, and remained constant thereafter. These results support the hypothesis that D cyclins function as part of the cellular machinery that integrates diverse signals impinging upon commitment to cell division. In synchronized cells transcripts of the mitotic cyclins CYC1, CYC2, and CYC3 reached a maximum with peak mitotic index, but CYC3 transcript levels increased earlier than those of CYC1 or CYC2. The kinetics of accumulation of CYC transcript levels support their classification as A-type (CYC3) and B-type (CYC1 and CYC2) cyclins, respectively.
Topics: Arabidopsis; Arabidopsis Proteins; Cell Cycle; Cell Division; Cells, Cultured; Cyclin D1; Cyclins; Cycloheximide; Cytokinins; DNA, Plant; Indoleacetic Acids; Kinetics; Mimosine; Mitotic Index; Nitrates; Oncogene Proteins; Transcription, Genetic
PubMed: 8938409
DOI: 10.1104/pp.112.3.1023