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BACKGROUND AND PURPOSE: Metaplastic breast carcinoma (BC-Mp) is an uncommon subtype that poses unique challenges. The limited information on patient prognosis and therapeutic strategies motivated our research initiative. We aimed to assess disease-free survival (DFS), overall survival (OS), and influential factors in patients with nonmetastatic BC-Mp. MATERIALS AND METHODS: In this multicenter retrospective cohort study, clinicopathological data for nonmetastatic BC-Mp patients treated at four oncology units in Poland (2012-2022) were gathered. RESULTS: Among 115 women (median age 61, range: 28-91), the median tumor size was 40 mm (range 20-130); 30% of patients exhibited positive local lymph nodes. The majority of patients presented with stage II (46%) and triple-negative breast cancer (TNBC) (84%). Radiotherapy was administered to 61% of patients. Surgical procedures included breast-conserving surgery in 31% of patients and mastectomy in 68%. Eighty-three per cent of patients received chemotherapy. The median estimated DFS and OS were 59 and 68 months, respectively. Multivariable analysis revealed that tumor size influenced DFS and OS (Hazard ratios [HR] = 1.02, 95%CI 0.01-0.03 for both endpoints) and taxanes application improved DFS (HR = 0.47, 95%CI 0.24-0.93), but other factors did not. For patients receiving neoadjuvant systemic therapy (N = 51), taxanes improved DFS and OS according to univariable analysis. INTERPRETATION: Our findings highlight poor DFS and OS regardless of receiving optimal treatment, emphasizing the need for tailored therapeutic strategies for BC-Mp patients. Taxanes appear promising in a neoadjuvant setting, particularly within the current standard of care for the TNBC subtype.
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Neoplasias de la Mama , Humanos , Femenino , Estudios Retrospectivos , Persona de Mediana Edad , Adulto , Anciano , Pronóstico , Neoplasias de la Mama/terapia , Neoplasias de la Mama/patología , Neoplasias de la Mama/mortalidad , Anciano de 80 o más Años , Resultado del Tratamiento , Supervivencia sin Enfermedad , Metaplasia/patología , Metaplasia/terapia , Mastectomía , Neoplasias de la Mama Triple Negativas/patología , Neoplasias de la Mama Triple Negativas/terapia , Neoplasias de la Mama Triple Negativas/mortalidadRESUMEN
INTRODUCTION: Hepatic visceral crisis (VC), characterized by a rapid total bilirubin increase with disease progression, poses a life-threatening risk in advanced breast cancer (ABC). International consensus guidelines define VC and touch on impending VC (IVC). Limited data exist on systemic treatments for hepatic VC/IVC. This study explores the safety and efficacy of cisplatin monotherapy in patients with Human Epidermal Growth Factor Receptor 2- negative breast cancer (BC) and hepatic IVC/VC. METHODS: In this retrospective single-center cohort study data of patients treated with cisplatin monotherapy (60-80 mg/m2, every 3-4 weeks) between 2016 and 2023 at a reference Cancer Centre in Southern Poland were analyzed. RESULTS: 33 female patients (24/33 hormonal-positive) with the mean age 53.84 years were included. Participants progressed on median 2 prior palliative systemic treatment lines. In 10/23 patients hepatic VC and in 23/33 IVC (rapid, symptomatic liver progression; extensive liver involvement; alanine or aspartate aminotransferase > 2 × normal limit; significant increases in lactate dehydrogenase, alkaline phosphatase, or gamma-glutamyl transferase) were identified. Median progression-free survival was 1.87 months and median overall survival 2.67 months. 33% of the patients presented stable disease or partial response. Eight patients experienced adverse events grade ≥ 3: in five the dose of cisplatin was reduced; two stopped the treatment. CONCLUSION: Due to the hepatotoxicity of BC-active drugs, specific recommendations for systemic treatment are scarce. Our study explored cisplatin's potential use, finding it to be a viable option in patients with performance status 0 or 1 experiencing hepatic IVC/VC, irrespective of liver function parameters and other factors.
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BACKGROUND: Melanoma is one of the most aggressive and deadliest skin tumor. Cholesterol content in melanoma cells is elevated, and a portion of it accumulates into lipid rafts. Therefore, the plasma membrane cholesterol and its lateral organization might be directly linked with tumor development. ATP Binding Cassette A1 (ABCA1) transporter modulates physico-chemical properties of the plasma membrane by modifying cholesterol distribution. Several studies linked the activity of the transporter with a different outcome of tumor progression depending on which type. However, no direct link between human melanoma progression and ABCA1 activity has been reported yet. METHODS: An immunohistochemical study on the ABCA1 level in 110 patients-derived melanoma tumors was performed to investigate the potential association of the transporter with melanoma stage of progression and prognosis. Furthermore, proliferation, migration and invasion assays, extracellular-matrix degradation assay, immunochemistry on proteins involved in migration processes and a combination of biophysical microscopy analysis of the plasma membrane organization of Hs294T human melanoma wild type, control (scrambled), ABCA1 Knockout (ABCA1 KO) and ABCA1 chemically inactivated cells were used to study the impact of ABCA1 activity on human melanoma metastasis processes. RESULTS: The immunohistochemical analysis of clinical samples showed that high level of ABCA1 transporter in human melanoma is associated with a poor prognosis. Depletion or inhibition of ABCA1 impacts invasion capacities of aggressive melanoma cells. Loss of ABCA1 activity partially prevented cellular motility by affecting active focal adhesions formation via blocking clustering of phosphorylated focal adhesion kinases and active integrin ß3. Moreover, ABCA1 activity regulated the lateral organization of the plasma membrane in melanoma cells. Disrupting this organization, by increasing the content of cholesterol, also blocked active focal adhesion formation. CONCLUSION: Human melanoma cells reorganize their plasma membrane cholesterol content and organization via ABCA1 activity to promote motility processes and aggressiveness potential. Therefore, ABCA1 may contribute to tumor progression and poor prognosis, suggesting ABCA1 to be a potential metastatic marker in melanoma.
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Melanoma , Humanos , Membrana Celular , Análisis por Conglomerados , Transportador 1 de Casete de Unión a ATPRESUMEN
BACKGROUND: Melanoma is one of the most aggressive and deadliest skin tumor. Cholesterol content in melanoma cells is elevated, and a portion of it accumulates into lipid rafts. Therefore, the plasma membrane cholesterol and its lateral organization might be directly linked with tumor development. ATP Binding Cassette A1 (ABCA1) transporter modulates physico-chemical properties of the plasma membrane by modifying cholesterol distribution. Several studies linked the activity of the transporter with a different outcome of tumor progression depending on which type. However, no direct link between human melanoma progression and ABCA1 activity has been reported yet. METHODS: An immunohistochemical study on the ABCA1 level in 110 patients-derived melanoma tumors was performed to investigate the potential association of the transporter with melanoma stage of progression and prognosis. Furthermore, proliferation, migration and invasion assays, extracellular-matrix degradation assay, immunochemistry on proteins involved in migration processes and a combination of biophysical microscopy analysis of the plasma membrane organization of Hs294T human melanoma wild type, control (scrambled), ABCA1 Knockout ( ABCA1 KO) and ABCA1 chemically inactivated cells were used to study the impact of ABCA1 activity on human melanoma metastasis processes. RESULTS: The immunohistochemical analysis of clinical samples showed that high level of ABCA1 transporter in human melanoma is associated with a poor prognosis. Depletion or inhibition ofABCA1 impacts invasion capacities of aggressive melanoma cells. Loss of ABCA1 activity partially prevented cellular motility by affecting active focal adhesions formation via blocking clustering of phosphorylated focal adhesion kinases and active integrin ß3. Moreover, ABCA1 activity regulated the lateral organization of the plasma membrane in melanoma cells. Disrupting this organization, by increasing the content of cholesterol, also blocked active focal adhesion formation. CONCLUSION: Human melanoma cells reorganize their plasma membrane cholesterol content and organization via ABCA1 activity to promote motility processes and aggressiveness potential. Therefore, ABCA1 may contribute to tumor progression and poor prognosis, suggesting ABCA1 to be a potential metastatic marker in melanoma.
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Humanos , Melanoma , Análisis por Conglomerados , Membrana Celular , Transportador 1 de Casete de Unión a ATPRESUMEN
Alpha-enolase (ENO1) is a glycolytic metalloenzyme, and its overexpression occurs in numerous cancers, contributing to cancer cell survival, proliferation, and maintenance of the Warburg effect. Patients with an overexpression of ENO1 have a poor prognosis. The aim of the present study was to investigate the prognostic significance of ENO1 in surgical resections from 112 melanoma patients and to assess its expression and enzymatic activity in normoxia and hypoxia in several melanoma cell lines. Overexpression of ENO1 in tumor cells from patients was correlated with unfavorable prognosticators such as Breslow thickness, Clark level, mitotic activity, and the presence of ulceration. The expression of ENO1 also positively correlated with a greater thickness of the neoplastic infiltrate and a worse long-term prognosis for patients with cutaneous melanoma. We report significantly higher expression of ENO1 in melanoma cell lines in comparison to normal melanocytes. To conclude, our in vitro and clinical models showed that overexpression of ENO1 promotes invasiveness of melanoma cells and correlates with aggressive clinical behavior. These observations open the way to further search of a potential prognostic and therapeutic target in cutaneous melanoma.
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The association of immune markers and clinicopathologic features and patient outcome has not been extensively studied in Merkel cell carcinoma (MCC). We correlated tumoral PD-L1 and IDO1 expression, and intratumoral CD8+ and FoxP3+ lymphocytes count with clinicopathologic variables, Merkel cell polyomavirus (MCPyV) status, and patient outcomes in a series of 132 MCC. By univariate analyses, tumoral PD-L1 expression >1% and combined tumoral PD-L1 >1% and high intratumoral FoxP3+ lymphocyte count correlated with improved overall survival (OS) (p = 0.016, 0.0072), MCC-specific survival (MSS) (p = 0.019, 0.017), and progression-free survival (PFS) (p = 0.043, 0.004, respectively). High intratumoral CD8+ and FoxP3+ lymphocyte count correlated with longer MSS (p = 0.036) and improved PFS (p = 0.047), respectively. Ulceration correlated with worse OS and worse MSS. Age, male gender, and higher stage (3 and 4) significantly correlated with worse survival. MCPyV positivity correlated with immune response. By multivariate analyses, only ulceration and age remained as independent predictors of worse OS; gender and stage remained for shorter PFS. Tumoral PD-L1 expression and increased density of intratumoral CD8+ lymphocytes and FoxP+ lymphocytes may represent favorable prognosticators in a subset of MCCs. Tumoral PD-L1 expression correlated with intratumoral CD8+ and FoxP3+ lymphocytes, which is supportive of an adaptive immune response.
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Antígeno B7-H1/biosíntesis , Linfocitos T CD8-positivos/inmunología , Carcinoma de Células de Merkel/mortalidad , Indolamina-Pirrol 2,3,-Dioxigenasa/biosíntesis , Linfocitos Infiltrantes de Tumor/inmunología , Proteínas de Neoplasias/biosíntesis , Neoplasias Cutáneas/mortalidad , Subgrupos de Linfocitos T/inmunología , Inmunidad Adaptativa , Factores de Edad , Anciano , Anciano de 80 o más Años , Biomarcadores de Tumor , Linfocitos T CD8-positivos/química , Carcinoma de Células de Merkel/química , Carcinoma de Células de Merkel/inmunología , Carcinoma de Células de Merkel/virología , Femenino , Factores de Transcripción Forkhead/análisis , Neoplasias de Cabeza y Cuello/química , Neoplasias de Cabeza y Cuello/inmunología , Neoplasias de Cabeza y Cuello/mortalidad , Neoplasias de Cabeza y Cuello/virología , Humanos , Estimación de Kaplan-Meier , Recuento de Linfocitos , Masculino , Poliomavirus de Células de Merkel/aislamiento & purificación , Persona de Mediana Edad , Análisis Multivariante , Estadificación de Neoplasias , Neoplasias Primarias Secundarias/química , Neoplasias Primarias Secundarias/inmunología , Neoplasias Primarias Secundarias/mortalidad , Neoplasias Primarias Secundarias/virología , Pronóstico , Supervivencia sin Progresión , Modelos de Riesgos Proporcionales , Factores Sexuales , Neoplasias Cutáneas/química , Neoplasias Cutáneas/inmunología , Neoplasias Cutáneas/virología , Úlcera Cutánea/etiología , Infecciones Tumorales por VirusRESUMEN
BACKGROUND: Merkel cell carcinomas of unknown primary (MCC-UPs) are defined as deep-seated tumors without an associated cutaneous tumor. Although the distinction has important clinical implications, it remains unclear whether these tumors represent primary tumors of lymph nodes or metastatic cutaneous primaries. METHODS: We compared the immunohistochemical profiles of four groups of MCCs (Merkel cell polyomavirus (MCPyV)-positive UP, MCPyV-negative UP, MCPyV-positive known primary (KP), and MCPyV-negative KP) using B-cell and pre-B-cell markers, cell cycle regulating proteins, follicular stem cell markers, and immune markers, and performed next generation and Sanger sequencing. RESULTS: Virus-positive and virus-negative MCC-UPs exhibited an immunoprofile similar to virus-positive and virus-negative primary cutaneous MCCs, respectively. MCC-UP tumors (both virus-positive and -negative) were immunogenic with similar or even higher tumoral PD-L1 expression and intratumoral CD8 and FoxP3 infiltrates in comparison to MCPyV-positive cutaneous tumors. In addition, similar to primary cutaneous MCCs, MCPyV-negative MCC-UPs exhibited UV signatures and frequent high tumor mutational burdens, whereas few molecular alterations were noted in MCPyV-positive MCC-UPs. CONCLUSIONS: Our results showed distinct UV-signatures in MCPyV-negative tumors and high immunogenicity in MCPyV-positive tumors. Although additional studies are warranted for the MCPyV-positive cases, our findings are supportive of a cutaneous metastatic origin for MCPyV-negative MCC-UP tumors.
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(1) Background: Poly(ADP-ribose) polymerase 1) (PARP1) is a pleiotropic enzyme involved in several cellular processes, e.g., DNA damage repair, regulation of mitosis, and immune response. Little is known about the role of PARP1 in melanoma development and progression. We aimed to investigate the prognostic significance of PARP1 expression in cutaneous melanoma through evaluation of mRNA and protein levels of PARP1 in normal melanocytes and melanoma cell lines, as well as in patients' tissue material from surgical resections. (2) Methods: An in vitro model was based on two types of normal human melanocytes (HEMn-DP and HEMn-LP) and four melanoma cell lines (A375, WM1341D, Hs294T, and WM9). PARP1 mRNA gene expression was estimated using real-time polymerase chain reaction (RT-PCR), whereas the protein level of PARP1 was evaluated by fluorescence confocal microscopy and then confirmed by Western Blotting analysis. The expression of PARP1 was also assessed by immunohistochemistry in formalin-fixed paraffin-embedded tissues of 128 primary cutaneous melanoma patients and correlated with follow-up and clinicopathologic features. (3) Results: The in vitro study showed that melanoma cells exhibited significantly higher PARP1 expression at mRNA and protein levels than normal melanocytes. High PARP1 expression was also associated with the invasiveness of tumor cells. Elevated nuclear PARP1 expression in patients without nodal metastases strongly correlated with significantly shorter disease-free survival (p = 0.0015) and revealed a trend with shorter cancer-specific overall survival (p = 0.05). High PARP1 immunoreactivity in the lymph node-negative group of patients was significantly associated with higher Breslow tumor thickness, presence of ulceration, and a higher mitotic index (p = 0.0016, p = 0.023, and p < 0.001, respectively). In patients with nodal metastases, high PARP1 expression significantly correlated with the presence of microsatellitosis (p = 0.034), but we did not confirm the prognostic significance of PARP1 expression in these patients. In the entire analyzed group of patients (with and without nodal metastases at the time of diagnosis), PARP1 expression was associated with a high mitotic index (p = 0.001) and the presence of ulceration (p = 0.036). Moreover, in patients with elevated PARP1 expression, melanoma was more frequently located in the skin of the head and neck region (p = 0.015). In multivariate analysis, high PARP1 expression was an independent unfavorable prognosticator in lymph node-negative cutaneous melanoma patients. (4) Conclusions: In vitro molecular biology approaches demonstrated enhanced PARP1 expression in cutaneous melanoma. These results were confirmed by the immunohistochemical study with clinical parameter analysis, which showed that a high level of PARP1 correlated with unfavorable clinical outcome. These observations raise the potential role of PARP1 inhibitor-based therapy in cutaneous melanoma.
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Melanoma/genética , Poli(ADP-Ribosa) Polimerasa-1/uso terapéutico , Neoplasias Cutáneas/genética , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Masculino , Melanoma/patología , Persona de Mediana Edad , Fenotipo , Poli(ADP-Ribosa) Polimerasa-1/farmacología , Pronóstico , Neoplasias Cutáneas/patología , Adulto Joven , Melanoma Cutáneo MalignoAsunto(s)
Carcinoma de Células de Merkel/mortalidad , Núcleo Celular/patología , Infecciones por Polyomavirus/diagnóstico , Neoplasias Cutáneas/mortalidad , Piel/patología , Carcinoma de Células de Merkel/diagnóstico , Carcinoma de Células de Merkel/terapia , Carcinoma de Células de Merkel/virología , Quimioterapia Adyuvante/estadística & datos numéricos , Humanos , Estimación de Kaplan-Meier , Poliomavirus de Células de Merkel/aislamiento & purificación , Infecciones por Polyomavirus/mortalidad , Infecciones por Polyomavirus/patología , Infecciones por Polyomavirus/virología , Pronóstico , Piel/citología , Piel/virología , Neoplasias Cutáneas/diagnóstico , Neoplasias Cutáneas/terapia , Neoplasias Cutáneas/virologíaRESUMEN
The most common cause of mortality due to malignant neoplasms in the general population around the world is lung cancer. In the last 10 years, there has been an enormous improvement in the treatment of this disease, mainly due to the immunotherapy that activates the immune system to fight cancer. Patients with metastatic non-small cell lung cancer are a special group of patients requiring not only cancer treatment but also considerable support in the treatment of cancer-related problems, as well as comorbidities. Early palliative care is important in this area. In addition, there is certain evidence that medicines most commonly administered in palliative care may lower the efficacy of immunotherapy. The present review article compares information on the prolonging of life after early hospice care, which has become the foundation of current standards of management in patients with metastatic lung cancer, and reports of decreased efficacy of the immunotherapy due to the administration of major palliative care medications.
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BACKGROUND: RhoA and its downstream effectors Rho-associated coiled-coil kinases (ROCK) 1 and 2 are central controllers of cytoskeleton dynamics, and therefore influence cell shape, adhesion and migration. Since modulation of these processes holds promise for an effective anticancer strategy, effects of ROCK inhibition have been evaluated in a number of malignancies. MATERIALS AND METHODS: Using immunohistochemistry, ROCK1 and ROCK2 expression was semi-quantitatively assessed in 129 patient-derived primary melanomas. RESULTS: There was a striking predilection for low melanocytic expression of both kinases in thick, ulcerated and mitogenic tumors, as well as in nodular histological type. ROCK1 and -2 expression in tumor-infiltrating lymphocytes (TILs) was preferentially down-regulated in advanced and aggressive tumors. Moreover, diminished ROCK2 reactivity in melanoma cells and TILs was associated with shorter melanoma-specific and recurrence-free survival. CONCLUSION: This is the first analysis of ROCK1 and -2 protein expression in clinical melanoma samples and the results indicated the suppression of ROCK signaling in melanocytes of aggressive and late-stage tumors. Functional models that more accurately represent the clinical setting are necessary to dissect the role of ROCK1 and -2 in melanoma. Additionally, our study indicates that ROCK activity in TILs may be involved in the pathogenesis of cancer, and thus merits further investigations.
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Melanoma/genética , Neoplasias Cutáneas/genética , Quinasas Asociadas a rho/genética , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Proliferación Celular/genética , Supervivencia sin Enfermedad , Femenino , Regulación Neoplásica de la Expresión Génica/genética , Humanos , Estimación de Kaplan-Meier , Linfocitos Infiltrantes de Tumor/metabolismo , Linfocitos Infiltrantes de Tumor/patología , Masculino , Melanocitos/metabolismo , Melanocitos/patología , Melanoma/epidemiología , Melanoma/patología , Persona de Mediana Edad , Estadificación de Neoplasias , Transducción de Señal/genética , Neoplasias Cutáneas/epidemiología , Neoplasias Cutáneas/patología , Adulto JovenRESUMEN
OBJECTIVES: Merkel cell carcinoma is a rare but very aggressive cutaneous tumor. We evaluated the prognostic potential of B-cell markers (terminal deoxynucleotidyl transferase [TdT], PAX5, CD117), follicular stem cell markers (CK15, CK19), p63, p53, RB, and Merkel cell polyomavirus (MCPyV; CM2B4) in 136 primary cutaneous Merkel cell carcinomas. METHODS: Clinical, histopathologic, and immunohistochemical analyses were performed. The results were correlated with patient outcomes by Fisher exact test, log-rank tests, and Cox multivariate models. RESULTS: By Fisher exact test, although TdT significantly correlated with both lack of progression (P = .0087) and alive status (P = .0056), MCPyV status correlated only with alive status (P = .031). In univariate analyses, TdT, MCPyV, and RB significantly correlated with improved overall survival, whereas p63 and CK15 correlated with worse overall survival. However, in multivariate analyses, only TdT expression remained as an independent predictor of improved overall survival, Merkel cell carcinoma-specific survival, and progression-free survival. By linear regression analyses, significant correlations between MCPyV vs TdT, PAX5, and CD117 were observed. CONCLUSIONS: TdT expression is a potential marker of better survival in Merkel cell carcinoma. Expression of B-cell markers is associated with MCPyV, suggesting that clonal viral integration might play a role in the expression of these markers.
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Biomarcadores de Tumor/análisis , Carcinoma de Células de Merkel , ADN Nucleotidilexotransferasa/análisis , Infecciones por Polyomavirus/complicaciones , Neoplasias Cutáneas , Anciano , Anciano de 80 o más Años , Linfocitos B/inmunología , Carcinoma de Células de Merkel/inmunología , Carcinoma de Células de Merkel/mortalidad , Carcinoma de Células de Merkel/virología , Femenino , Humanos , Estimación de Kaplan-Meier , Masculino , Poliomavirus de Células de Merkel , Persona de Mediana Edad , Infecciones por Polyomavirus/mortalidad , Neoplasias Cutáneas/inmunología , Neoplasias Cutáneas/mortalidad , Neoplasias Cutáneas/virología , Infecciones Tumorales por Virus/inmunología , Infecciones Tumorales por Virus/mortalidad , Infecciones Tumorales por Virus/virologíaRESUMEN
RhoA GTPase is physiologically involved in the formation of stress fibers, cellular contractility and polarity, maintenance of cell cycle and transcriptional control. During tumorigenesis, it plays roles in cancer cell proliferation, apoptosis, adhesion, invasion and metastasis. While RhoA seems to act as a tumor promotor in most malignancies, data regarding its function in skin melanoma are fragmentary and conflicting. We aimed to clarify the clinical significance of RhoA expression in melanoma by immunohistochemical evaluation of 134 primary tumors and subsequent statistical analysis with clinicopathological profiles of patients. Increased RhoA expression was associated with thinner tumors, higher grade of tumor-infiltrating lymphocytes and lack of disease recurrence. Moreover, we observed a trend towards higher RhoA expression in cases without concurrent metastases. Recurrence-free survival and melanoma-specific survival of patients with high RhoA-expressing tumors were significantly prolonged. Multivariable regression model adjusting for melanoma thickness and status of regional lymph nodes confirmed independent prognostic value of RhoA immunoreactivity. In summary, we found associations between RhoA expression and histopathological phenotype of primary tumors as well as patient survival which suggest a suppressive role of RhoA in skin melanoma.
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Overexpression of SMAD7-a hallmark inhibitor of transforming growth factor ß (TGFß) signaling-has been documented and related with adverse prognosis in a number of epithelial malignancies, suggesting that it may be responsible for resistance to TGFß-induced growth arrest of cancer cells. The involvement of SMAD7 in development and progression of malignant melanoma is unclear, and its expression has not been characterized so far at the protein level in clinical melanoma tissue samples. We evaluated SMAD7 expression in 205 skin melanoma primary tumors by immunohistochemistry and correlated the findings with clinicopathological profiles of patients. Melanocytic SMAD7 was evidenced in 204 cases, and the expression pattern was predominantly nuclear. High expression of SMAD7 was positively associated with several features of tumor aggressiveness, for example, presence of ulceration (P < 0.001), higher tumor thickness (P < 0.001), and mitotic rate (P < 0.001), but not presence of regional or distant metastases. Moreover, high SMAD7 expression independently predicted unfavorable outcome: melanoma-specific survival (hazard ratioâ¯=â¯3.16, P < 0.001) and recurrence-free survival (hazard ratio = 2.88, P < 0.001). Taken together, our results underline the importance of TGFß signaling in cancer and define SMAD7 as a marker of aggressive tumor behavior and adverse clinical outcomes in melanoma patients.
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Melanoma/mortalidad , Neoplasias Cutáneas/mortalidad , Proteína smad7/fisiología , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Inmunohistoquímica , Masculino , Melanocitos/química , Melanoma/química , Melanoma/patología , Persona de Mediana Edad , Transducción de Señal/fisiología , Neoplasias Cutáneas/química , Neoplasias Cutáneas/patología , Proteína smad7/análisis , Factor de Crecimiento Transformador beta/fisiología , Adulto JovenRESUMEN
Cutaneous melanoma is an aggressive cancer and its onset and growth are associated, through direct and indirect interactions, with the cancer microenvironment. The microenvironment comprises a dynamic complex of numerous types of cells (due to histogenesis) that constantly interact with each other through multiple cytokines and signaling proteins. Macrophages are one of the most thoroughly studied pleiotropic cells of the immune system. One of their major cytophysiological functions is their involvement in phagocytosis. Previous studies examining the microenvironment of melanomas and tumor-associated macrophages have revealed that they are involved in all stages of melanomagenesis. In the case of cancer initiation, they form an inflammatory microenvironment and then suppress the anticancer activity of the immune system, stimulate angiogenesis, enhance migration and invasion of the cancer cells, and ultimately contribute to the metastatic process. The present review provides a detailed overview on the function of macrophages in the melanoma microenvironment.
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AIM: To investigate secreted protein acidic and rich in cystein (SPARC) and neural cadherin (NCAD), which are associated with epithelial-mesenchymal transition in primary skin melanoma and nodal metastases and their prognostic impact in melanoma patients. METHODS: Expression of proteins was assessed by immunochemistry in archival paraffin samples from 103 primary melanoma tumors and 16 nodal metastases. RESULTS: Increased expression of SPARC and NCAD in primary skin melanoma was associated with decreased overall survival, adverse clinicopathological features and particularly with microsatellitosis (SPARC) and ulceration (NCAD). In univariate Cox regression analysis, both biomarkers were significantly associated with the risk of death; the multivariate Cox regression analysis identified no significance. CONCLUSION: The most important result of our study was that we confirmed the strict correlation between SPARC and NCAD expression and clinicopathological parameters related with melanoma progression, which is a specific clinical equivalent of the molecular mechanisms of epithelial-mesenchymal transition process and confirms its key role in the disease outcome.
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Biomarcadores de Tumor/metabolismo , Melanoma/patología , Neoplasias Cutáneas/patología , Adulto , Anciano , Cadherinas/metabolismo , Progresión de la Enfermedad , Transición Epitelial-Mesenquimal , Femenino , Humanos , Inmunohistoquímica , Estimación de Kaplan-Meier , Metástasis Linfática , Masculino , Melanoma/diagnóstico , Melanoma/mortalidad , Persona de Mediana Edad , Osteonectina/metabolismo , Pronóstico , Modelos de Riesgos Proporcionales , Neoplasias Cutáneas/diagnóstico , Neoplasias Cutáneas/mortalidadRESUMEN
The presence of ulceration has been considered as one of the most important primary tumor characteristics of cutaneous malignant melanoma (CMM) for predicting patient outcome. Yet recently, scientific attention has been drawn towards another microscopic feature of primary tumors, the mitotic rate (MR). The present study aimed to examine the relationship between the presence of ulceration and the mitotic rate and clinicopathological characteristics and melanoma patient survival, and to discuss the results in the context of AJCC melanoma staging recommendations. Tissue samples were obtained from 104 patients treated for CMM. In classical H&E staining, the mitotic rate and the presence of ulceration were evaluated. Non-mitogenic tumors were defined as having 0 mitoses/mm2, low mitogenic potential, 1-2 mitoses/mm2 and highly mitogenic tumors, ≥3 mitoses/mm2. In the entire group of 104 patients, a high mitotic rate (hMR) and ulceration were highly negative prognostic factors, and indicated considerably shorter overall survival, cancer-specific overall survival and disease-free survival. Notably, hMR appeared to have a statistically significant negative impact on survival in early melanomas in both the pT1 (P=0.001) and pT2 subgroups (P=0.006). KaplanMeier analysis of the remaining subsets (pT3 and pT4) did not reveal any important differences in the 5-year survival with regard to MR values. The presence of ulceration also had a prognostic significance for early melanomas, but only for pT1 tumors (P=0.05). Multivariate analysis confirmed that hMR was strongly associated with an unfavorable prognosis. Ulceration had no prognostic significance in the Cox proportional hazards model. Considering the biology of melanoma, hMR seems to be a more reliable parameter than the presence of ulceration. The value of MR categorizes melanomas into tumors with low or high proliferative potential, thus giving direct information concerning their capacity to infiltrate deeper layers of the dermis and, potentially, to generate regional lymph node and distant metastases.
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Melanoma/genética , Índice Mitótico , Pronóstico , Neoplasias Cutáneas/genética , Adulto , Anciano , Supervivencia sin Enfermedad , Femenino , Humanos , Estimación de Kaplan-Meier , Masculino , Melanoma/epidemiología , Melanoma/patología , Persona de Mediana Edad , Mitosis , Estadificación de Neoplasias , Modelos de Riesgos Proporcionales , Neoplasias Cutáneas/epidemiología , Neoplasias Cutáneas/patología , Melanoma Cutáneo MalignoRESUMEN
Epithelial-mesenchymal transition (EMT) is a biological process that drives polarized, immotile epithelial cells to undergo multiple biochemical changes to acquire a mesenchymal cell phenotype. The characteristic features of EMT are cell apolarity, loss of cellular adhesion, reduced expression of E-cadherin and increased migratory capacity, as well as invasiveness. EMT is a physiological process that is essential for normal embryonic development. Additionally, abnormal activation of EMT contributes to some human pathologies such as tissue fibrosis, cancer cell invasion and metastasis. In both situations, the basic molecular mechanisms are similar, but lead to different effects depending on cell type and biological conditions of the environment. TGF-ß is a multifunctional cytokine that controls proliferation, differentiation and other functions in many cell types. It has been found that neoplastic development converts TGF-ß into an oncogenic cytokine. It activates various molecular processes, which are engaged in EMT initiation. All that makes TGF-ß a key regulator of EMT.
Asunto(s)
Transición Epitelial-Mesenquimal/fisiología , Neoplasias/patología , Neoplasias/fisiopatología , Lesiones Precancerosas/patología , Lesiones Precancerosas/fisiopatología , Factor de Crecimiento Transformador beta/metabolismo , Animales , Cadherinas/metabolismo , Adhesión Celular , Diferenciación Celular , Progresión de la Enfermedad , Humanos , Células Madre Mesenquimatosas/metabolismo , Células Madre Mesenquimatosas/patología , Invasividad Neoplásica , Metástasis de la Neoplasia/patología , Metástasis de la Neoplasia/fisiopatología , Transducción de SeñalRESUMEN
BACKGROUND/AIMS: To assess the incidence and risk of urinary complications after anterior rectal cancer resection with regard to the surgical device used for total mesorectal excision (TME). METHODOLOGY: During the years 2004-2009 we operated 374 rectal cancer patients with TME and the intent of autonomic nerves sparing intent. Seventeen patients underwent mesorectal dissection with ultrasound scalpel (US). They were compared to the control series of 35 cases selected from the patients for whom electrocautery was used. Selection was done in the manner to eliminate any other significant differences between groups. RESULTS: Intraoperative complications, postoperative mortality, anastomotic leakage and infectious complications did not occur. Urinary bladder disturbances developed in US group in 1 patient (6%) while in 12 patients (34%) in EC group (p<0.05). In US group the character of complication was transient stress incontinence with symptoms being significantly reduced during six postoperative months. In EC group two patients had dysuria, two nycturia, one had both. Stress incontinence occurred in six patients, complete incontinence requiring catheterization in one. CONCLUSIONS: When compared to EC, TME with US is related to lower risk of urinary complications and facilitates autonomic nerve preservation due to minimized thermal lateral tissue damage.