-
Cancers Jun 2024Melanoma is the cancer with the highest risk of dissemination to the central nervous system (CNS), one of the leading causes of mortality from this cancer.
BACKGROUND
Melanoma is the cancer with the highest risk of dissemination to the central nervous system (CNS), one of the leading causes of mortality from this cancer.
OBJECTIVE
To identify patients at higher risk of developing CNS metastases and to evaluate associated prognostic factors.
METHODS
A cohort study (1998-2023) assessed patients who developed CNS melanoma metastases. Multivariate logistic regression was used to identify predictive factors at melanoma diagnosis for CNS metastasis. Cox regression analysis evaluated the CNS-independent metastasis-related variables impacting survival.
RESULTS
Out of 4718 patients, 380 (8.05%) developed CNS metastases. Multivariate logistic regression showed that a higher Breslow index, mitotic rate ≥ 1 mm, ulceration, and microscopic satellitosis were significant risk factors for CNS metastasis development. Higher patient age and the location of the primary tumor in the upper or lower extremities were protective factors. In survival analysis, post-CNS metastasis, symptomatic disease, prior non-CNS metastases, CNS debut with multiple metastases, elevated LDH levels, and leptomeningeal involvement correlated with poorer survival.
CONCLUSION
Predictive factors in the primary tumor independently associated with brain metastases include microscopic satellitosis, ulceration, higher Breslow index, and trunk location. Prognostic factors for lower survival in CNS disease include symptomatic disease, multiple CNS metastases, and previous metastases from different sites.
PubMed: 38927977
DOI: 10.3390/cancers16122272 -
Biomedicines Jun 2024Proliferative activity in cutaneous melanomas can be appreciated both histopathologically by counting mitotic figures and immunohistochemically through the Ki67 index,...
Proliferative activity in cutaneous melanomas can be appreciated both histopathologically by counting mitotic figures and immunohistochemically through the Ki67 index, but the prognostic value of each method is still a matter of debate. In this context, we performed a retrospective study on 33 patients diagnosed with cutaneous melanomas between 2013 and 2018 in order to evaluate progression-free survival and overall survival. Multivariate Cox proportional hazards regression was performed by considering both clinical histopathological and immunohistochemical features. The mitotic rate was significantly independently associated with both outcomes, while the Ki67 index was not an independent prognostic factor. However, the Ki67 predictive accuracy could be improved by establishing both a cut-off value and a standardized protocol for evaluating its expression. Until these desiderata are met, the mitotic rate remains superior to the Ki67 index for predicting prognosis in cutaneous melanomas, as also has the advantage of being easily interpreted in a standard histopathological examination regardless of the pathologist's experience and with no further financial expenses. Importantly, this is one of very few articles that has shown perineural invasion to be an independent prognostic factor for both progression-free survival and overall survival in cutaneous melanomas. As a consequence, this parameter should become a mandatory feature in the histopathological evaluation of cutaneous melanomas as it can improve the identification of patients who are at high risk for disease progression.
PubMed: 38927524
DOI: 10.3390/biomedicines12061318 -
European Journal of Cell Biology Jun 2024Chaperonin Containing Tailless complex polypeptide 1 (CCT) is a molecular chaperone composed of eight distinct subunits that can exist as individual monomers or as...
Chaperonin Containing Tailless complex polypeptide 1 (CCT) is a molecular chaperone composed of eight distinct subunits that can exist as individual monomers or as components of a double oligomeric ring, which is essential for the folding of actin and tubulin and other substrates. Here we assess the role of CCT subunits in the context of cell cycle progression by individual subunit depletions upon siRNA treatment in mammalian cells. The depletion of individual CCT subunits leads to variation in the distribution of cell cycle phases and changes in mitotic index. Mitotic defects, such as unaligned chromosomes occur when CCTδ is depleted, concurrent with a reduction in spindle pole-localised p150, a component of the dynactin complex and a binding partner of monomeric CCTδ. In CCTδ-depleted cells, changes in the elution profile of p150 are observed consistent with altered conformations and or assembly states with the dynactin complex. Addition of monomeric CCTδ, in the form of GFP-CCTδ, restores correct p150 localisation to the spindle poles and rescues the mitotic segregation defects that occur when CCTδ is depleted. This study demonstrates a requirement for CCTδ in its monomeric form for correct chromosome segregation via a mechanism that promotes the correct localisation of p150, thus revealing further complexities to the interplay between CCT, tubulin folding and microtubule dynamics.
PubMed: 38897036
DOI: 10.1016/j.ejcb.2024.151430 -
Journal of Comparative Pathology Jun 2024Canine ovarian cancer poses a significant diagnostic and therapeutic challenge. The heterogeneous nature of ovarian tumours makes accurate histological identification...
Canine ovarian cancer poses a significant diagnostic and therapeutic challenge. The heterogeneous nature of ovarian tumours makes accurate histological identification difficult, whilst treatment is limited to surgical excision. The tyrosine kinase receptor CD117 is neo-expressed in many tumours and represents a potential diagnostic and prognostic biomarker and therapeutic target. This study aimed to establish if CD117 is neoexpressed in canine ovarian tumours. Immunohistochemistry was employed to assess expression of CD117 in 29 canine ovarian tumour samples. CD117 labelling was assessed with a semiquantitative immunoreactivity score, and the location of labelling was recorded as membranous, focal cytoplasmic or diffuse cytoplasmic. Histological morphology was assessed and used to assign subgroups based on growth pattern. Cytokeratin 7 labelling was used to indicate the tumour type as epithelial or sex-cord stromal in origin. Mitotic index, percentage of necrosis and vascular invasion were also assessed and evaluated for association with CD117 expression. Overall, 81% of ovarian tumours neoexpressed CD117 and normal ovarian tissue did not express CD117. Positive immunolabelling was seen in a subset of cells in both ovarian carcinomas (n = 20) and ovarian granulosa cell tumours (n = 3). There was no association between CD117 expression and patient age, histological subtype, mitotic index, percentage of necrosis or vascular invasion. This is the largest study to identify the expression of CD117 in canine ovarian tumours, but further research is needed to elucidate its prognostic and therapeutic value.
PubMed: 38878529
DOI: 10.1016/j.jcpa.2024.05.001 -
ESMO Open Jun 2024Six thoracic pathologists reviewed 259 lung neuroendocrine tumours (LNETs) from the lungNENomics project, with 171 of them having associated survival data. This cohort...
BACKGROUND
Six thoracic pathologists reviewed 259 lung neuroendocrine tumours (LNETs) from the lungNENomics project, with 171 of them having associated survival data. This cohort presents a unique opportunity to assess the strengths and limitations of current World Health Organization (WHO) classification criteria and to evaluate the utility of emerging markers.
PATIENTS AND METHODS
Patients were diagnosed based on the 2021 WHO criteria, with atypical carcinoids (ACs) defined by the presence of focal necrosis and/or 2-10 mitoses per 2 mm. We investigated two markers of tumour proliferation: the Ki-67 index and phospho-histone H3 (PHH3) protein expression, quantified by pathologists and automatically via deep learning. Additionally, an unsupervised deep learning algorithm was trained to uncover previously unnoticed morphological features with diagnostic value.
RESULTS
The accuracy in distinguishing typical from ACs is hampered by interobserver variability in mitotic counting and the limitations of morphological criteria in identifying aggressive cases. Our study reveals that different Ki-67 cut-offs can categorise LNETs similarly to current WHO criteria. Counting mitoses in PHH3+ areas does not improve diagnosis, while providing a similar prognostic value to the current criteria. With the advantage of being time efficient, automated assessment of these markers leads to similar conclusions. Lastly, state-of-the-art deep learning modelling does not uncover undisclosed morphological features with diagnostic value.
CONCLUSIONS
This study suggests that the mitotic criteria can be complemented by manual or automated assessment of Ki-67 or PHH3 protein expression, but these markers do not significantly improve the prognostic value of the current classification, as the AC group remains highly unspecific for aggressive cases. Therefore, we may have exhausted the potential of morphological features in classifying and prognosticating LNETs. Our study suggests that it might be time to shift the research focus towards investigating molecular markers that could contribute to a more clinically relevant morpho-molecular classification.
Topics: Humans; Lung Neoplasms; Neuroendocrine Tumors; Female; Ki-67 Antigen; Male; Biomarkers, Tumor; Middle Aged; World Health Organization; Histones; Aged; Prognosis; Deep Learning
PubMed: 38878324
DOI: 10.1016/j.esmoop.2024.103591 -
Problemy Endokrinologii Oct 2023Currently, all pheochromocytoma/paraganglioma (PPGLs) are considered malignant due to metastatic potential. Consequently, PPGLs are divided into «metastatic» and... (Review)
Review
Currently, all pheochromocytoma/paraganglioma (PPGLs) are considered malignant due to metastatic potential. Consequently, PPGLs are divided into «metastatic» and «non-metastatic». Metastatic PPGLs can be with synchronous metastasis (metastases appear simultaneously with the identified primary tumor) or metachronous (metastases develop after removal of the primary tumor). The term metastatic PPGLs is not used in the presence of tumor invasion into surrounding organs and tissues, without the presence of distant metastases of lymphogenic or hematogenic origin. It is generally believed that about 10% of pheochromocytomas and about 40% of sympathetic paragangliomas have metastatic potential. On average, the prevalence of PPGLs with the presence of metastases is 15-20%. Risk factors for metastatic PPGLs are widely discussed in the literature, the most significant of which are groups of clinical, morphological and genetic characteristics. The review presents a discussion of such risk factors for metastatic PPGLs as age, localization and type of hormonal secretion of the tumor, the size and growth pattern of the adrenal lesion, the presence of necrosis and invasion into the vessels, the tumor capsule surrounding adipose tissue, high cellular and mitotic activity, Ki-67 index, expression of chromogranin B and S100 protein, the presence of genetic mutations of three main clusters (pseudohypoxia, kinase signaling and Wnt signaling).Over the past two decades, a number of authors have proposed various predictor factors and scales for assessing a probability of metastatic PPGLs. The review contains detailed description and comparison of sensitivity and specificity of such predictor scales as PASS, GAPP, M-GAPP, ASES and COPPS.
Topics: Humans; Pheochromocytoma; Adrenal Gland Neoplasms; Risk Factors; Paraganglioma; Neoplasm Metastasis
PubMed: 38796759
DOI: 10.14341/probl13331 -
Veterinary Sciences May 2024Twelve dogs with oral malignant melanomas (MM) were evaluated in this study, with demographic details indicating a balanced distribution of gender, age, and weight among...
Twelve dogs with oral malignant melanomas (MM) were evaluated in this study, with demographic details indicating a balanced distribution of gender, age, and weight among various breeds. Tumor locations varied, with diverse surgical procedures being performed, including mandibulectomies and maxillectomies. Lymphadenectomies were conducted, revealing a 16.66% metastatic rate in regional lymph nodes. At the time of surgery, clinical staging identified stages I, II, and III, with most cases having non-infiltrated margins and a high mitotic index. Follow-up revealed local recurrences and metastases, prompting additional surgeries and affecting survival rates. This study reports varying outcomes, with some dogs completing one year without recurrence, while others experienced progressive disease, leading to six oral melanoma-related deaths. The characteristics of melanotic melanoma and amelanotic melanoma are observed in order to study differences between them, the degree of aggressiveness, the mortality rate and the possibility of future therapeutic targets. Although high pigmentation has been correlated with a better outcome, we could not find any significant correlation between survival and achromia. Oral benign melanomas might exist, and this could justify variabilities between stage and survival; however, carefulness is required due to their unpredictable behavior. The findings underscore the complexity of oral melanoma cases and highlight the need for further research on effective management strategies.
PubMed: 38787198
DOI: 10.3390/vetsci11050226 -
Heliyon May 2024DNA methylation is one of induced changes under salinity stress causing reduction in the expression of several crucial genes required for normal plant's operation....
Exogenous application of 5-azacitidin, royal jelly and folic acid regulate plant redox state, expression level of DNA methyltransferases and alleviate adverse effects of salinity stress on L. plants.
DNA methylation is one of induced changes under salinity stress causing reduction in the expression of several crucial genes required for normal plant's operation. Potential use of royal jelly (RJ), folic acid (FA) and 5-azacitidine (5-AZA) on two Egyptian faba bean varieties (Sakha-3 and Giza-716) grown under saline conditions was investigated. Salinity stress affects negatively on seeds germination (G %), mitotic index, membrane stability and induced a significant increase in chromosomal abnormalities (CAs). DNA methyltransferases genes ( and ) were highly up-regulated (∼23 and 8 folds for and in shoots of Giza-716 stressed plants). On the other hand, down regulation of other studied stress related genes: superoxide dismutase (), catalase ), glutathione reductase (), heat shock protein () and proline-rich protein () were detected in stressed plants of both studied varieties. Treating plants with RJ and FA increase G%, chlorophyll content, improves membrane properties and reduces CAs compared to non-treated stressed plants. Exogenous application of 5-AZA, RJ and FA on salinity stressed plants was associated with a significant reduction in the transcription of and which was associated with significant up regulation in the expression of , , , and encoding genes. The Lowest expression of and were induced with 5-AZA treatment in both studied varieties. Exogenous application of the FA, RJ and 5-AZA modified the methylation state of stressed plants by regulation the expression of DNA methyltransferases, subsequently, modulated the expression of studied genes and could be proposed as a promising treatment to ameliorate hazardous effects of salt stress on different plants.
PubMed: 38784551
DOI: 10.1016/j.heliyon.2024.e30934 -
Digital Health 2024The mitotic activity index is an important prognostic factor in the diagnosis of cancer. The task of mitosis detection is difficult as the nuclei are microscopic in size...
OBJECTIVE
The mitotic activity index is an important prognostic factor in the diagnosis of cancer. The task of mitosis detection is difficult as the nuclei are microscopic in size and partially labeled, and there are many more non-mitotic nuclei compared to mitotic ones. In this paper, we highlight the challenges of current mitosis detection pipelines and propose a method to tackle these challenges.
METHODS
Our proposed methodology is inspired from recent research on deep learning and an extensive analysis on the dataset and training pipeline. We first used the MiDoG'22 dataset for training, validation, and testing. We then tested the methodology without fine-tuning on the TUPAC'16 dataset and on a real-time case from Shaukat Khanum Memorial Cancer Hospital and Research Centre.
RESULTS
Our methodology has shown promising results both quantitatively and qualitatively. Quantitatively, our methodology achieved an F1-score of 0.87 on the MiDoG'22 dataset and an F1-score of 0.83 on the TUPAC dataset. Qualitatively, our methodology is generalizable and interpretable across various datasets and clinical settings.
CONCLUSION
In this paper, we highlight the challenges of current mitosis detection pipelines and propose a method that can accurately predict mitotic nuclei. We illustrate the accuracy, generalizability, and interpretability of our approach across various datasets and clinical settings. Our methodology can speed up the adoption of computer-aided digital pathology in clinical settings.
PubMed: 38778869
DOI: 10.1177/20552076241255471 -
Experimental and Therapeutic Medicine Jun 2024Ossifying fibromyxoid tumor (OFMT) of the soft parts is a mesenchymal neoplasm of uncertain lineage. Fibromyxoid matrix and peripheral metaplastic bone are common...
Ossifying fibromyxoid tumor (OFMT) of the soft parts is a mesenchymal neoplasm of uncertain lineage. Fibromyxoid matrix and peripheral metaplastic bone are common histological features of this type of tumor. In the present study, a case of OFMT in a 33-year-old female was reported. The patient was referred to the First Affiliated Hospital of China Medical University (Shenyan, China) in January 2018. The patient had developed a mass in the left upper arm 6 months prior to presentation, which was slowly enlarging. The tumor was 1.5 cm in diameter, with hard texture. Histologically, the tumor showed a clear boundary with no invasion into the adjacent tissue. The majority of tumor cells were round and medium-sized, with abundant pale cytoplasm, without obvious atypia and densely arranged in sheets. The tumor tissue was characterized by cartilage-like morphology and fibromyxoid and hyalinization matrix. Mitotic index was <1/10 high-power fields. Additionally, tumor cells were positive for S-100 and vimentin expression, but negative for smooth muscle actin, CD34, cytokeratin, desmin, human melanoma black 45 and melanoma A. Ki67 index was ~1%. The patient underwent surgery and the tumor was totally removed. No recurrence was observed at the final 6-year follow-up. Based on the aforementioned findings, the patient was diagnosed as typical OFMT. Slow growth and clear boundaries often suggest an indolent nature to this type of tumor. However, close follow-up should be performed due to its malignant potential.
PubMed: 38756906
DOI: 10.3892/etm.2024.12549