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1.
Front Oncol ; 11: 774088, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34858854

RESUMO

Breast cancer (BC) categorized as human epidermal growth factor receptor 2 (HER2) borderline [2+ by immunohistochemistry (IHC 2+)] presents challenges for the testing, frequently obscured by intratumoral heterogeneity (ITH). This leads to difficulties in therapy decisions. We aimed to establish prognostic models of overall survival (OS) of these patients, which take into account spatial aspects of ITH and tumor microenvironment by using hexagonal tiling analytics of digital image analysis (DIA). In particular, we assessed the prognostic value of Immunogradient indicators at the tumor-stroma interface zone (IZ) as a feature of antitumor immune response. Surgical excision samples stained for estrogen receptor (ER), progesterone receptor (PR), Ki67, HER2, and CD8 from 275 patients with HER2 IHC 2+ invasive ductal BC were used in the study. DIA outputs were subsampled by HexT for ITH quantification and tumor microenvironment extraction for Immunogradient indicators. Multiple Cox regression revealed HER2 membrane completeness (HER2 MC) (HR: 0.18, p = 0.0007), its spatial entropy (HR: 0.37, p = 0.0341), and ER contrast (HR: 0.21, p = 0.0449) as independent predictors of better OS, with worse OS predicted by pT status (HR: 6.04, p = 0.0014) in the HER2 non-amplified patients. In the HER2-amplified patients, HER2 MC contrast (HR: 0.35, p = 0.0367) and CEP17 copy number (HR: 0.19, p = 0.0035) were independent predictors of better OS along with worse OS predicted by pN status (HR: 4.75, p = 0.0018). In the non-amplified tumors, three Immunogradient indicators provided the independent prognostic value: CD8 density in the tumor aspect of the IZ and CD8 center of mass were associated with better OS (HR: 0.23, p = 0.0079 and 0.14, p = 0.0014, respectively), and CD8 density variance along the tumor edge predicted worse OS (HR: 9.45, p = 0.0002). Combining these three computational indicators of the CD8 cell spatial distribution within the tumor microenvironment augmented prognostic stratification of the patients. In the HER2-amplified group, CD8 cell density in the tumor aspect of the IZ was the only independent immune response feature to predict better OS (HR: 0.22, p = 0.0047). In conclusion, we present novel prognostic models, based on computational ITH and Immunogradient indicators of the IHC biomarkers, in HER2 IHC 2+ BC patients.

2.
Healthcare (Basel) ; 9(11)2021 Nov 09.
Artigo em Inglês | MEDLINE | ID: mdl-34828568

RESUMO

The pandemic spread of the COVID-19 virus significantly affected daily life, but the highest pressure was piled on the health care system. Our aim was to evaluate an impact of COVID-19 pandemic management measures on cancer services at the National Cancer Institute (NCI) of Lithuania. We assessed the time period from 1 February 2020 to 31 December 2020 and compared it to the same period of 2019. Data for our analysis were extracted from the NCI Hospital Information System (HIS) and the National Health Insurance Fund (NHIF). Contingency table analysis and ANOVA were performed. The COVID-19 pandemic negatively affected the cancer services provided by NCI. Reductions in diagnostic radiology (-16%) and endoscopy (-29%) procedures were accompanied by a decreased number of patients with ongoing medical (-30%), radiation (-6%) or surgical (-10%) treatment. The changes in the number of newly diagnosed cancer patients were dependent on tumor type and disease stage, showing a rise in advanced disease at diagnosis already during the early period of the first lockdown. The extent of out-patient consultations (-14%) and disease follow-up visits (-16%) was also affected by the pandemic, and only referrals to psychological/psychiatric counselling were increased. Additionally, the COVID-19 pandemic had an impact on the structure of cancer services by fostering the application of modified systemic anticancer therapy or hypofractionated radiotherapy. The most dramatic drop occurred in the number of patients participating in cancer prevention programs; the loss was 25% for colon cancer and 62% for breast cancer screening. Marked restriction in access to preventive cancer screening and overall reduction of the whole spectrum of cancer services may negatively affect cancer survival measures in the nearest future.

3.
Ann Surg Oncol ; 2021 Oct 13.
Artigo em Inglês | MEDLINE | ID: mdl-34647202

RESUMO

INTRODUCTION: Recent data suggest that margins ≥2 mm after breast-conserving surgery may improve local control in invasive breast cancer (BC). By allowing large resection volumes, oncoplastic breast-conserving surgery (OBCII; Clough level II/Tübingen 5-6) may achieve better local control than conventional breast conserving surgery (BCS; Tübingen 1-2) or oncoplastic breast conservation with low resection volumes (OBCI; Clough level I/Tübingen 3-4). METHODS: Data from consecutive high-risk BC patients treated in 15 centers from the Oncoplastic Breast Consortium (OPBC) network, between January 2010 and December 2013, were retrospectively reviewed. RESULTS: A total of 3,177 women were included, 30% of whom were treated with OBC (OBCI n = 663; OBCII n = 297). The BCS/OBCI group had significantly smaller tumors and smaller resection margins compared with OBCII (pT1: 50% vs. 37%, p = 0.002; proportion with margin <1 mm: 17% vs. 6%, p < 0.001). There were significantly more re-excisions due to R1 ("ink on tumor") in the BCS/OBCI compared with the OBCII group (11% vs. 7%, p = 0.049). Univariate and multivariable regression analysis adjusted for tumor biology, tumor size, radiotherapy, and systemic treatment demonstrated no differences in local, regional, or distant recurrence-free or overall survival between the two groups. CONCLUSIONS: Large resection volumes in oncoplastic surgery increases the distance from cancer cells to the margin of the specimen and reduces reexcision rates significantly. With OBCII larger tumors are resected with similar local, regional and distant recurrence-free as well as overall survival rates as BCS/OBCI.

5.
Breast ; 60: 98-110, 2021 Sep 08.
Artigo em Inglês | MEDLINE | ID: mdl-34555676

RESUMO

AIM: We developed tailored axillary surgery (TAS) to reduce the axillary tumor volume in patients with clinically node-positive breast cancer to the point where radiotherapy can control it. The aim of this study was to quantify the extent of tumor load reduction achieved by TAS. METHODS: International multicenter prospective study embedded in a randomized trial. TAS is a novel pragmatic concept for axillary surgery de-escalation that combines palpation-guided removal of suspicious nodes with the sentinel procedure and, optionally, imaging-guided localization. Pre-specified study endpoints quantified surgical extent and reduction of tumor load. RESULTS: A total of 296 patients were included at 28 sites in four European countries, 125 (42.2%) of whom underwent neoadjuvant chemotherapy (NACT) and 71 (24.0%) achieved nodal pathologic complete response. Axillary metastases were detectable only by imaging in 145 (49.0%) patients. They were palpable in 151 (51.0%) patients, of whom 63 underwent NACT and 21 had residual palpable disease after NACT. TAS removed the biopsied and clipped node in 279 (94.3%) patients. In 225 patients with nodal disease at the time of surgery, TAS removed a median of five (IQR 3-7) nodes, two (IQR 1-4) of which were positive. Of these 225 patients, 100 underwent ALND after TAS, which removed a median of 14 (IQR 10-17) additional nodes and revealed additional positive nodes in 70/100 (70%) of patients. False-negative rate of TAS in patients who underwent subsequent ALND was 2.6%. CONCLUSIONS: TAS selectively reduced the tumor load in the axilla and remained much less radical than ALND.

6.
Eur J Breast Health ; 17(2): 188-196, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33870120

RESUMO

Objective: In early 2020, the spread of coronavirus disease-2019 (COVID-19) led the World Health Organization to declare this disease a pandemic. Initial epidemiological data showed that patients with cancer were at high risk of developing severe forms of COVID-19. National scientific societies published recommendations modifying the patients' breast cancer (BC) management to preserve, in theory, quality oncologic care, avoiding the increased risk of contamination. The Senology International Society (SIS) decided to take an inventory of the actions taken worldwide. This study investigates COVID-19-related changes concerning BC management and analyzes the will to maintain them after the pandemic, evaluating their oncological safety consequences. Materials and Methods: SIS network members participated in an online survey using a questionnaire (Microsoft® Forms) from June 15th to July 31st, 2020. Results: Forty-five responses from 24 countries showed that screening programs had been suspended (68%); magnetic resonance imagines were postponed (73%); telemedicine was preferred when possible (71%). Surgeries were postponed: reconstructive (77%), for benign diseases (84%), and in patients with significant comorbidities (66%). Chemotherapy and radiotherapy protocols had been adapted in 28% of patients in both. Exception for telemedicine (34%), these changes in practice should not be continued. Conclusion: The SIS survey showed significant changes in BC's diagnosis and treatment during the first wave of the COVID-19 pandemic, but most of these changes should not be maintained. Indeed, women have fewer severe forms of COVID-19 and are less likely to die than men. The risk of dying from COVID-19 is more related to the presence of comorbidities and age than to BC. Stopping screening and delaying treatment leads to more advanced stages of BC. Only women aged over 65 with BC under treatment and comorbidities require adaptation of their cancer management.

7.
Sci Rep ; 11(1): 6556, 2021 03 22.
Artigo em Inglês | MEDLINE | ID: mdl-33753859

RESUMO

Hyperactivation of ABC transporter ABCB1 and induction of epithelial-mesenchymal transition (EMT) are the most common mechanism of acquired cancer chemoresistance. This study describes possible mechanisms, that might contribute to upregulation of ABCB1 and synergistically boost the acquisition of doxorubicin (DOX) resistance in breast cancer MX-1 cell line. DOX resistance in MX-1 cell line was induced by a stepwise increase of drug concentration or by pretreatment of cells with an ABCB1 transporter activator tetraphenylphosphonium (TPP+) followed by DOX exposure. Transcriptome analysis of derived cells was performed by human gene expression microarrays and by quantitative PCR. Genetic and epigenetic mechanisms of ABCB1 regulation were evaluated by pyrosequencing and gene copy number variation analysis. Gradual activation of canonical EMT transcription factors with later activation of ABCB1 at the transcript level was observed in DOX-only treated cells, while TPP+ exposure induced considerable activation of ABCB1 at both, mRNA and protein level. The changes in ABCB1 mRNA and protein level were related to the promoter DNA hypomethylation and the increase in gene copy number. ABCB1-active cells were highly resistant to DOX and showed morphological and molecular features of EMT. The study suggests that nongenotoxic ABCB1 inducer can possibly accelerate development of DOX resistance.


Assuntos
Antineoplásicos/farmacologia , Doxorrubicina/farmacologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Oniocompostos/farmacologia , Compostos Organofosforados/farmacologia , Subfamília B de Transportador de Cassetes de Ligação de ATP/agonistas , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Biologia Computacional/métodos , Metilação de DNA , Resistencia a Medicamentos Antineoplásicos/genética , Epigênese Genética/efeitos dos fármacos , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Transição Epitelial-Mesenquimal/genética , Feminino , Dosagem de Genes , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Humanos , Modelos Biológicos , Transcriptoma
8.
Front Oncol ; 10: 950, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32612954

RESUMO

Immunohistochemistry (IHC) for ER, PR, HER2, and Ki67 is used to predict outcome and therapy response in breast cancer patients. The current IHC assessment, visual or digital, is based mostly on global biomarker expression levels in the tissue sample. In our study, we explored the prognostic value of digital image analysis of conventional breast cancer IHC biomarkers supplemented with their intratumoral heterogeneity and tissue immune response indicators. Surgically excised tumor samples from 101 female patients with hormone receptor-positive breast cancer (HRBC) were stained for ER, PR, HER2, Ki67, SATB1, CD8, and scanned at 20x. Digital image analysis was performed using the HALO™ platform. Subsequently, hexagonal tiling was used to compute intratumoral heterogeneity indicators for ER, PR and Ki67 expression. Multiple Cox regression analysis revealed three independent predictors of the patient's overall survival: Haralick's texture entropy of PR (HR = 0.19, p = 0.0005), Ki67 Ashman's D bimodality (HR = 3.0, p = 0.01), and CD8+SATB1+ cell density in tumor tissue (HR = 0.32, p = 0.02). Remarkably, the PR and Ki67 intratumoral heterogeneity indicators were prognostically more informative than the rates of their expression. In particular, a distinct non-linear relationship between the rate of PR expression and its intratumoral heterogeneity was observed and revealed a non-linear prognostic effect of PR expression. The independent prognostic significance of CD8+SATB1+ cells infiltrating the tumor could indicate their role in anti-tumor immunity. In conclusion, we suggest that prognostic modeling, based entirely on the computational image-based IHC biomarkers, is possible in HRBC patients. The intratumoral heterogeneity and immune response indicators outperformed both conventional breast cancer IHC and clinicopathological variables while markedly increasing the power of the model.

9.
Am J Pathol ; 190(6): 1309-1322, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32194048

RESUMO

The distribution of tumor-infiltrating lymphocytes (TILs) within the tumor microenvironment provides strong prognostic value, which is increasingly important with the arrival of new immunotherapy modalities. Both visual and image analysis-based assays are developed to assess the immune contexture of the tumors. We propose an automated method based on grid subsampling of microscopy image analysis data to extract the tumor-stroma interface zone (IZ) of controlled width. The IZ is a ranking of tissue areas by their distance to the tumor edge, which is determined by a set of explicit rules. TIL density profiles across the IZ are used to compute a set of novel immunogradient indicators that reflect TIL gradient towards the tumor. We applied this method on CD8 immunohistochemistry images of surgically excised hormone receptor-positive breast and colorectal cancers to predict overall patient survival. In both cohorts, the immunogradient indicators enabled strong and independent prognostic stratification, outperforming clinical and pathologic variables. Patients with breast cancer with low immunogradient levels had a prominent decrease in survival probability 5 years after surgery. Our study provides proof of concept that data-driven, automated, operator-independent IZ sampling enables spatial immune response measurement in the tumor-host interaction frontline for prediction of disease outcomes.


Assuntos
Neoplasias da Mama/patologia , Linfócitos T CD8-Positivos/imunologia , Neoplasias Colorretais/patologia , Linfócitos do Interstício Tumoral/imunologia , Microambiente Tumoral/imunologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias da Mama/imunologia , Neoplasias Colorretais/imunologia , Feminino , Humanos , Imuno-Histoquímica , Masculino , Pessoa de Meia-Idade , Prognóstico
10.
Medicina (Kaunas) ; 56(2)2020 Feb 11.
Artigo em Inglês | MEDLINE | ID: mdl-32054000

RESUMO

BACKGROUND AND OBJECTIVES: The purpose of this study is to evaluate the level of oxidative stress before and after breast cancer surgery. MATERIALS AND METHODS: Malondialdehyde (MDA) level was tested using a thiobarbituric acid (TBA) assay based on the release of a color complex due to TBA reaction with MDA. The glutathione S-transferase (GST) activity was evaluated by enzymatic conjugation of reduced glutathione (GSH) with 1-chloro-2,4-dinitrobenzene. The level of total glutathione (reduced GSH and oxidized GSSG) was detected using a recycling system by 5,5-dithiobis(2-nitrobenzoic acid). The levels of the indices were determined in the serum of 52 patients before surgery, two hours and five days after surgery, and in 42 healthy women. RESULTS: In the patients over 50 years old the level of MDA was higher after surgery in comparison with before surgery, and GST activity was lower in comparison with the control. The GSH + GSSG level in both ages groups after surgery was lower than in the control. Significant differences of MDA level were detected in patients with stage III after surgery compared to the control. The level of GSH + GSSG was significantly lower in the patients with I-III stages compared to the control. CONCLUSION: The most expressed changes demonstrate the significance of MDA as a marker to evaluate oxidative stress in breast cancer patients. The degree of oxidative stress depends on the patient's age and stage of disease.


Assuntos
Antioxidantes/análise , Neoplasias da Mama/sangue , Oxidantes/sangue , Período Pós-Operatório , Período Pré-Operatório , Adulto , Feminino , Glutationa Transferase/análise , Glutationa Transferase/sangue , Humanos , Malondialdeído/análise , Malondialdeído/sangue , Pessoa de Meia-Idade , Estresse Oxidativo , Tiobarbitúricos/análise , Tiobarbitúricos/sangue
11.
J Cancer Res Ther ; 14(Supplement): S1091-S1097, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30539851

RESUMO

Introduction: There is mounting evidence that the time of breast cancer diagnosis and the start of treatment can improve survival rates. The aim of this study was to test the relationship between the season of breast cancer diagnosis and the survival of women patients receiving standard surgery treatment with radiotherapy. Materials and Methods: The nonmetastatic breast cancer patients (n = 991) were followed from the date of diagnosis until death. Cox proportional hazards models were used to calculate multivariate hazard ratios (HRs) for all-cause mortality. HRs and 95% confidence intervals (CIs) were estimated in models adjusted for clinicopathologic and treatment factors. Results: After adjusting for independent prognostic variables, we found that patients diagnosed in summer and autumn had a 40% reduced risk for 0-3-year mortality when compared to those diagnosed in spring. Among women aged <50 years, HRs comparing autumn with spring diagnosis categories were 0.53 (95% CI: 0.31-0.91) for 0-5-years and 0.68 (95% CI: 0.46-0.89) for 5-10-years after diagnosis. Diagnosis in autumn was associated with improving survival in younger patients treated with adjuvant chemotherapy (HR = 0.61, 95% CI: 0.39-0.96, P = 0.003). Conclusions: The diagnosis in summer and autumn was associated with a better overall prognosis. The effect of season of diagnosis on survival rate was most pronounced in the young age patients receiving chemotherapy.


Assuntos
Neoplasias da Mama/mortalidade , Sobreviventes de Câncer/estatística & dados numéricos , Modelos Biológicos , Estações do Ano , Fatores Etários , Antineoplásicos/uso terapêutico , Neoplasias da Mama/diagnóstico , Neoplasias da Mama/terapia , Quimioterapia Adjuvante/métodos , Estudos de Coortes , Feminino , Humanos , Estimativa de Kaplan-Meier , Lituânia/epidemiologia , Pessoa de Meia-Idade , Prognóstico , Modelos de Riscos Proporcionais , Taxa de Sobrevida/tendências
12.
J BUON ; 23(2): 290-295, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29745067

RESUMO

Breast cancer is the most frequently diagnosed cancer in females. Triple negative breast cancer (TNBC) is a molecular subtype of breast cancer which has a high mortality rate because of aggressive proliferation, quick occurrence of metastasis, and lack of effective treatment. New data show evidence that the type of anaesthesia can affect breast cancer recurrence and long-term outcome. Because TNBC lacks targets for modern specific therapy, a perioperative period could be the field of investigations for the long-term outcomes in TNBC influence. We reviewed the literature on research focusing on the influence of anaesthetics to oxidative stress, inflammation, molecular regulators, and TNBC oncological outcomes.


Assuntos
Anestesia/efeitos adversos , Inflamação/tratamento farmacológico , Recidiva Local de Neoplasia/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/cirurgia , Biomarcadores Tumorais/genética , Feminino , Humanos , Inflamação/induzido quimicamente , Inflamação/genética , Inflamação/patologia , Metástase Linfática , Recidiva Local de Neoplasia/induzido quimicamente , Recidiva Local de Neoplasia/genética , Estresse Oxidativo/efeitos dos fármacos , Estresse Oxidativo/genética , Período Perioperatório , Propofol/efeitos adversos , Propofol/uso terapêutico , Sevoflurano/efeitos adversos , Sevoflurano/uso terapêutico , Resultado do Tratamento , Neoplasias de Mama Triplo Negativas/classificação , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/genética
13.
Int J Gynecol Cancer ; 27(2): 258-266, 2017 02.
Artigo em Inglês | MEDLINE | ID: mdl-27870712

RESUMO

OBJECTIVE: Advanced/metastatic or recurrent endometrial cancer has a poor prognosis. Malignant endometrial tissue has high steroid sulphatase (STS) activity. The aim of this study was to evaluate STS as a therapeutic target in patients with endometrial cancer. METHODS: This was a phase 2, multicenter, international, open-label, randomized (1:1), 2-arm study of the STS inhibitor oral irosustat 40 mg/d versus oral megestrol acetate 160 mg/d in women with advanced/metastatic or recurrent estrogen receptor-positive endometrial cancer. The primary end point was the proportion of patients without progression or death 6 months after start of treatment. Secondary end points included progression-free survival, time to progression, overall survival, and safety. RESULTS: Seventy-one patients were treated (36 with irosustat, 35 with megestrol acetate). The study was prematurely stopped after futility analysis. Overall, 36.1% and 54.1% of patients receiving irosustat or megestrol acetate had not progressed or died at 6 months, respectively. There were no statistically significant differences between irosustat and megestrol acetate in response and overall survival rates. Irosustat patients had a median progression-free survival of 16 weeks (90% confidence interval, 9.0-31.4) versus 40 weeks (90% confidence interval, 16.3-64.0) in megestrol acetate patients. Treatment-related adverse events occurred in 20 (55.6%) and 13 (37.1%) patients receiving irosustat or megestrol, respectively. Most adverse events in both groups were grade 1 or 2. CONCLUSIONS: Although irosustat monotherapy did not attain a level of activity sufficient for further development in patients with advanced/recurrent endometrial cancer, this study confirms the activity of hormonal treatment (megestrol acetate) for this indication.


Assuntos
Antineoplásicos Hormonais/uso terapêutico , Neoplasias do Endométrio/tratamento farmacológico , Acetato de Megestrol/uso terapêutico , Ácidos Sulfônicos/uso terapêutico , Idoso , Antineoplásicos Hormonais/efeitos adversos , Intervalo Livre de Doença , Neoplasias do Endométrio/metabolismo , Neoplasias do Endométrio/patologia , Feminino , Humanos , Acetato de Megestrol/efeitos adversos , Recidiva Local de Neoplasia/tratamento farmacológico , Recidiva Local de Neoplasia/metabolismo , Recidiva Local de Neoplasia/patologia , Receptores de Estrogênio/metabolismo , Ácidos Sulfônicos/efeitos adversos
14.
Oncotarget ; 6(38): 41134-45, 2015 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-26512778

RESUMO

Biological diversity of breast cancer presents challenges for personalized therapy and necessitates multiparametric approaches to understand and manage the disease. Multiple protein biomarkers tested by immunohistochemistry (IHC), followed by digital image analysis and multivariate statistics of the data, have been shown to be effective in exploring latent profiles of tumor tissue immunophenotype. In this study, based on tissue microarrays of 107 patients with hormone receptor (HR) positive invasive ductal breast carcinoma, we investigated the prognostic value of the integrated immunophenotype to predict overall survival (OS) of the patients. A set of 10 IHC markers (ER, PR, HER2, Ki67, AR, BCL2, HIF-1α, SATB1, p53, and p16) was used. The main factor of the variance was characterized by opposite loadings of ER/PR/AR/BCL2 and Ki67/HIF-1α; it was associated with histological grade but did not predict OS. The second factor was driven by SATB1 expression along with moderate positive HIF-1α and weak negative Ki67 loadings. Importantly, this factor did not correlate with any clinicopathologic parameters, but was an independent predictor of better OS. Ki67 and SATB1 did not reach statistical significance as single predictors; however, high Ki67/SATB1 ratio was an independent predictor of worse OS. In addition, our data indicate potential double prognostic meaning of HIF-1α expression in breast cancer and necessitate focused studies, taking into account the immunophenotype interactions and tissue heterogeneity aspects.


Assuntos
Biomarcadores Tumorais/metabolismo , Neoplasias da Mama/metabolismo , Carcinoma Ductal de Mama/metabolismo , Antígeno Ki-67/metabolismo , Proteínas de Ligação à Região de Interação com a Matriz/metabolismo , Receptores de Esteroides/metabolismo , Neoplasias da Mama/diagnóstico , Neoplasias da Mama/radioterapia , Carcinoma Ductal de Mama/diagnóstico , Carcinoma Ductal de Mama/radioterapia , Feminino , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Imuno-Histoquímica , Estimativa de Kaplan-Meier , Pessoa de Meia-Idade , Invasividade Neoplásica , Avaliação de Resultados em Cuidados de Saúde/métodos , Avaliação de Resultados em Cuidados de Saúde/estatística & dados numéricos , Prognóstico , Modelos de Riscos Proporcionais , Estudos Prospectivos , Análise de Sobrevida
15.
Lung Cancer ; 90(2): 326-33, 2015 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-26319316

RESUMO

OBJECTIVES: Tangible clinical benefit is achieved in only a relatively small proportion of extensive-stage small cell lung cancer (SCLC) patients receiving current treatment strategies. Therefore, a more personalized use of current and novel treatment approaches is of critical importance. Individualized therapy relies on the identification of specific biomarkers predictive of response to a particular type of cancer treatment. Immune-related parameters emerge as powerful biomarkers among a variety of predictors of clinical response to various types of cancer treatment. PATIENTS AND METHODS: Using multicolor flow cytometry, we evaluated a predictive value of CD8(high)CD57(+) T-cell population and its immunosuppressive (FOXP3(+), NKG2A(+)) and cytotoxic (Perforin(+)) subsets in the peripheral blood of extensive-stage SCLC patients (n=82) treated with either chemotherapy-alone (n=24), or chemoradiation therapy (n=42), or receiving best supportive care (n=16). RESULTS: The low level (<20%) of CD8(high)CD57(+) T cells within the peripheral blood CD8(+) T-cell population and the low level (<3%) of the immunosuppressive FOXP3-positive subset within the CD8(high)CD57(+) T-cell population were independent predictors of a better response to treatment with chemoradiation therapy, but not with chemotherapy alone or best supportive care. Importantly there was no significant survival difference between SCLC patients who were: (i) treated with chemoradiation, but had an unfavourable immune profile (≥20% of CD8(high)CD57(+) T cells and ≥3% of its FOXP3-positive subset), (ii) treated with chemotherapy alone, or (iii) received best supportive care. CONCLUSIONS: We show that only a combination of chemotherapy with radiation therapy offered a considerable survival benefit that was confined to a subset of extensive-stage SCLC patients with a favourable predictive immune profile in the peripheral blood.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/terapia , Carcinoma de Pequenas Células do Pulmão/imunologia , Carcinoma de Pequenas Células do Pulmão/terapia , Adulto , Idoso , Idoso de 80 Anos ou mais , Quimiorradioterapia/métodos , Feminino , Citometria de Fluxo/métodos , Humanos , Masculino , Pessoa de Meia-Idade
16.
Vaccine ; 32(32): 4015-24, 2014 Jul 07.
Artigo em Inglês | MEDLINE | ID: mdl-24837511

RESUMO

Accumulation of firm evidence that clinically apparent cancer develops only when malignant cells manage to escape immunosurveillance led to the introduction of tumor immunotherapy strategies aiming to reprogramm the cancer-dysbalanced antitumor immunity and restore its capacity to control tumor growth. There are several immunotherapeutical strategies, among which specific active immunotherapy or therapeutic cancer vaccination is one of the most promising. It targets dendritic cells (DCs) which have a unique ability of inducing naive and central memory T cell-mediated immune response in the most efficient manner. DCs can be therapeutically targeted either in vivo/in situ or by ex vivo manipulations followed by their re-injection back into the same patient. The majority of current DC targeting strategies are based on autologous or allogeneic tumor-associated antigens (TAAs) which possess various degrees of inherent tolerogenic potential. Therefore still limited efficacy of various tumor immunotherapy approaches may be attributed, among various other mechanisms, to the insufficient immunogenicity of self-protein-derived TAAs. Based on such an idea, the use of homologous xenogeneic antigens, derived from different species was suggested to overcome the natural immune tolerance to self TAAs. Xenoantigens are supposed to differ sufficiently from self antigens to a degree that renders them immunogenic, but at the same time preserves an optimal homology range with self proteins still allowing xenoantigens to induce cross-reactive T cells. Here we discuss the concept of xenogeneic vaccination, describe the cons and pros of autologous/allogeneic versus xenogeneic therapeutic cancer vaccines, present the results of various pre-clinical and several clinical studies and highlight the future perspectives of integrating xenovaccination into rapidly developing tumor immunotherapy regimens.


Assuntos
Antígenos Heterófilos/administração & dosagem , Vacinas Anticâncer/imunologia , Tolerância Imunológica , Imunoterapia Ativa/métodos , Neoplasias/terapia , Animais , Antígenos de Neoplasias/imunologia , Células Dendríticas/imunologia , Humanos , Linfócitos T/imunologia
17.
Crit Rev Immunol ; 33(6): 489-547, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-24266347

RESUMO

Dendritic cells (DCs) are the most potent professional antigen-presenting cells, capable of initiating proper adaptive immune responses. Although tumor-infiltrating DCs are able to recognize cancer cells and uptake tumor antigens, they often have impaired functions because of the immunosuppressive tumor milieu. Therefore, DCs are targeted by therapeutic means either in vivo or ex vivo to facilitate tumor antigen presentation to T cells and induce or promote efficient antitumor immune responses in cancer patients. This immunotherapeutical approach is defined as specific active tumor immunotherapy or therapeutic cancer vaccination. In this review we briefly discuss general aspects of DC biology, followed by a thorough description of the current knowledge and optimization trends of DC vaccine production ex vivo, including various approaches for the induction of proper DC maturation and efficient loading with tumor antigens. We also discuss critical clinical aspects of DC vaccine application in cancer patients, including protocols of administration (routes and regimens), individualization of tumor immunotherapy, prediction and proper evaluation of immune and clinical responses to immunotherapy, and the critical role of combining tumor immunotherapy with other cancer treatment strategies to achieve maximal therapeutic effects.


Assuntos
Vacinas Anticâncer , Células Dendríticas/imunologia , Imunoterapia/métodos , Animais , Apresentação do Antígeno , Antígenos de Neoplasias/imunologia , Ensaios Clínicos como Assunto , Células Dendríticas/transplante , Humanos
18.
Medicina (Kaunas) ; 49(2): 78-83, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23888343

RESUMO

BACKGROUND AND OBJECTIVE: Breast cancer is the leading cause of death from cancer among women worldwide. The aberrant promoter methylation of tumor suppressor genes is a typical epigenetic alteration for breast cancer and can be detected in early carcinogenesis. High-throughput and cost-effective methods are needed for the early and sensitive detection of epigenetic changes in clinical material. The main purpose of our study was to optimize a high-resolution melting (HRM) assay for the reliable and quantitative assessment of RASSF1 gene methylation, which is considered one of the earliest epigenetic alterations in breast cancer. MATERIAL AND METHODS: A total of 76 breast carcinomas and 10 noncancerous breast tissues were studied by means of HRM and compared with the results obtained by means of quantitative methylation-specific polymerase chain reaction (QMSP) and methylation-specific polymerase chain reaction (MSP). RESULTS: Both quantitative methods, HRM and QMSP, showed a similar specificity and sensitivity for the detection of RASSF1 methylation in breast cancer (about 80% and 70%, respectively). In breast cancer, the mean methylation intensity of RASSF1 was 42.5% and 48.6% according to HRM and QMSP, respectively. Both methods detected low levels of methylation (less than 5%) in noncancerous breast tissues. In comparison with quantitative methods, MSP showed a lower sensitivity (70%), but a higher specificity (80%) for the detection of RASSF1 methylation in breast cancer. CONCLUSIONS: HRM is as a simple, cost-effective method for the reliable high-throughput quantification of DNA methylation in clinical material.


Assuntos
Neoplasias da Mama/genética , Metilação de DNA , Reação em Cadeia da Polimerase/métodos , Proteínas Supressoras de Tumor/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Pessoa de Meia-Idade , Desnaturação de Ácido Nucleico , Temperatura de Transição
19.
J Radiat Res ; 54(5): 872-9, 2013 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-23397075

RESUMO

We retrospectively evaluated the risk of second malignancies among 832 patients with inner or central breast cancer treated with conventional external beam schedule (CRT group), or neutron brachytherapy using Californium-252 (²5²Cf) sources and hypofractionated external beam radiotherapy (HRTC group), between 1987 and 1996 at the Institute of Oncology, Vilnius University. Patients were observed until the occurrences of death or development of a second malignancy, or until 31 December 2009, whichever was earlier. Median follow-up time was 10.4 years (range, 1.2-24.1 years). Risk of second primary cancers was quantified using standardized incidence ratios (SIRs). Cox proportional hazards regression models were used to estimate hazard ratios (HRs). There was a significant increase in the risk of second primary cancers compared with the general population (SIR 1.3, 95% CI 1.1-1.5). The observed number of second primary cancers was also higher than expected for breast (SIR 1.8, 95% CI 1.3-2.4) and lung cancer (SIR 3.8, 95% CI 2.0-6.7). For second breast cancer, no raised relative risk was observed during the period ≥10 or more years after radiotherapy. Compared with the CRT group, HRTC patients had a not statistically significant higher risk of breast cancer. Increased relative risks were observed specifically for age at initial diagnosis of <50 years (HR 2.9, 95% CI 1.6-5.2) and for obesity (HR 2.8, 95% CI 1.1-7.2).


Assuntos
Braquiterapia/mortalidade , Neoplasias da Mama/mortalidade , Neoplasias da Mama/radioterapia , Califórnio/uso terapêutico , Neoplasias Induzidas por Radiação/mortalidade , Segunda Neoplasia Primária/mortalidade , Radioterapia Conformacional/mortalidade , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Coortes , Terapia Combinada/mortalidade , Comorbidade , Feminino , Humanos , Incidência , Lituânia/epidemiologia , Pessoa de Meia-Idade , Nêutrons , Compostos Radiofarmacêuticos/uso terapêutico , Estudos Retrospectivos , Fatores de Risco , Taxa de Sobrevida , Resultado do Tratamento
20.
Diagn Pathol ; 7: 27, 2012 Mar 16.
Artigo em Inglês | MEDLINE | ID: mdl-22424533

RESUMO

BACKGROUND: Molecular studies of breast cancer revealed biological heterogeneity of the disease and opened new perspectives for personalized therapy. While multiple gene expression-based systems have been developed, current clinical practice is largely based upon conventional clinical and pathologic criteria. This gap may be filled by development of combined multi-IHC indices to characterize biological and clinical behaviour of the tumours. Digital image analysis (DA) with multivariate statistics of the data opens new opportunities in this field. METHODS: Tissue microarrays of 109 patients with breast ductal carcinoma were stained for a set of 10 IHC markers (ER, PR, HER2, Ki67, AR, BCL2, HIF-1α, SATB1, p53, and p16). Aperio imaging platform with the Genie, Nuclear and Membrane algorithms were used for the DA. Factor analysis of the DA data was performed in the whole group and hormone receptor (HR) positive subgroup of the patients (n = 85). RESULTS: Major factor potentially reflecting aggressive disease behaviour (i-Grade) was extracted, characterized by opposite loadings of ER/PR/AR/BCL2 and Ki67/HIF-1α. The i-Grade factor scores revealed bimodal distribution and were strongly associated with higher Nottingham histological grade (G) and more aggressive intrinsic subtypes. In HR-positive tumours, the aggressiveness of the tumour was best defined by positive Ki67 and negative ER loadings. High Ki67/ER factor scores were strongly associated with the higher G and Luminal B types, but also were detected in a set of G1 and Luminal A cases, potentially indicating high risk patients in these categories. Inverse relation between HER2 and PR expression was found in the HR-positive tumours pointing at differential information conveyed by the ER and PR expression. SATB1 along with HIF-1α reflected the second major factor of variation in our patients; in the HR-positive group they were inversely associated with the HR and BCL2 expression and represented the major factor of variation. Finally, we confirmed high expression levels of p16 in Triple-negative tumours. CONCLUSION: Factor analysis of multiple IHC biomarkers measured by automated DA is an efficient exploratory tool clarifying complex interdependencies in the breast ductal carcinoma IHC profiles and informative value of single IHC markers. Integrated IHC indices may provide additional risk stratifications for the currently used grading systems and prove to be useful in clinical outcome studies. VIRTUAL SLIDES: The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/1512077125668949.


Assuntos
Biomarcadores Tumorais/análise , Neoplasias da Mama/patologia , Carcinoma Ductal de Mama/patologia , Interpretação de Imagem Assistida por Computador/métodos , Algoritmos , Neoplasias da Mama/metabolismo , Carcinoma Ductal de Mama/metabolismo , Análise Fatorial , Feminino , Humanos , Imuno-Histoquímica , Pessoa de Meia-Idade , Gradação de Tumores , Estadiamento de Neoplasias , Análise Serial de Tecidos
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