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1.
Eur J Cancer ; 163: 35-43, 2022 Jan 12.
Artigo em Inglês | MEDLINE | ID: mdl-35032815

RESUMO

BACKGROUND: Low human epidermal growth factor receptor 2 (HER2) expression is emerging as an actionable biomarker for the treatment of breast cancer (BC) with novel anti-HER2 drugs. However, the evolution of this biomarker during the course of disease is still poorly characterised, and controversial data exist on its prognostic implications. METHODS: We reviewed data of patients with HER2-negative BC according to the latest ASCO/CAP guidelines referred between January 2014 and December 2020. We grouped patients based on the immunohistochemistry (IHC) expression of HER2, HER2-zero (IHC 0) and HER2-low subgroup (IHC 1+ or 2+/ISH-negative) and evaluated the evolution of HER2 expression between the primary tumour and the first biopsy collected in the advanced setting. Disease-free survival, overall survival and progression-free survival were compared between patients with HER2-zero and HER2-low expression on the primary tumour. RESULTS: 232 patients were included in the analysis. Among the overall population, there was a relevant discordance in HER2 expression between the primary tumour and the matched biopsy (K = 0.33, 95%CI 0.21-0.44): 44% of the HER2-zero primary tumour showed an increased HER2 score on biopsy, and 22% of the HER2-low primary tumours turned into HER2-IHC 0. The findings in the sub-populations of hormone-receptors positive (K = 0.32, 95%CI 0.19-0.45) and triple-negative tumours (K = 0.18, 95%CI -0.09-0.46) were consistent with the primary analysis. No difference in survival outcomes was observed between HER2-low and HER2-zero primary tumours. CONCLUSIONS: HER2-low expression is dynamic in BC and may be enriched in the advanced-stage setting. No prognostic significance was demonstrated for HER2-low expression.

2.
J Immunother Cancer ; 10(1)2022 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-35022192

RESUMO

The landscape in immuno-oncology (I-O) has undergone profound changes since its early beginnings up through the rapid advances happening today. The current drug development pipeline consists of thousands of potential I-O therapies and therapy combinations, many of which are being evaluated in clinical trials. The efficient and successful development of these assets requires the investment in and utilization of appropriate tools and technologies that can facilitate the rapid transitions from preclinical evaluation through clinical development. These tools include (i) appropriate preclinical models, (ii) biomarkers of pharmacodynamic, predictive and monitoring utility, and (iii) evolving clinical trial designs that allow rapid and efficient evaluation during the development process. This article provides an overview of how novel discoveries and insights into each of these three areas have the potential to further address the clinical management needs for patients with cancer.

3.
JAMA Oncol ; 2022 Jan 13.
Artigo em Inglês | MEDLINE | ID: mdl-35024766

RESUMO

Importance: Metastatic breast cancer (MBC) has traditionally been considered incurable. Accordingly, current treatment algorithms are aimed at maintaining quality of life and improving overall survival, rather than at complete eradication of the disease. Attempts to achieve cure with high-dose chemotherapy were conducted in the 1990s, with no observed long-term benefit compared with conventional chemotherapy. Nonetheless, Erb-B2 receptor tyrosine kinase 2 (ERBB2, formerly HER2)-targeted biologic treatments, developed in the past 2 decades, are currently challenging this paradigm. Indeed, a fraction of patients with ERBB2-positive MBC achieve long-lasting responses to chemotherapy and ERBB2-blockade, resembling a cure. In this setting, the challenge of identifying the optimal curable population has emerged, including identifying populations in whom treatment escalation strategies may be beneficial, while avoiding overtreatment in patients with incurable disease. Observations: A number of clinical and pathologic features allow physicians to identify patients with ERBB2-positive MBC who are more likely to experience a long-lasting response to chemotherapy and ERBB2-blockade. Long-term responders tend to be de novo metastatic, have a reduced disease burden, and tend to show deep responses to systemic treatment. In pathologic terms, features associated with long-term response are high ERBB2 expression, lack of detrimental genomic aberrations, and antitumor immune activation. This population of patients may potentially derive benefit from a tailored escalation of frontline treatment with novel anti-ERBB2 drugs, such as trastuzumab deruxtecan, tucatinib, or margetuximab. Additional recent therapeutic and diagnostic advancements could further aid in the path toward a cure for ERBB2-positive MBC. Conclusions and Relevance: Careful implementation of novel diagnostic and treatment tools could potentially expand the population of patients with ERBB2-positive MBC experiencing long-lasting disease response. Trials are in preparation to confirm this paradigm, and hopefully lead to a new era of precision therapy for breast cancer.

4.
Eur Heart J ; 2021 Dec 14.
Artigo em Inglês | MEDLINE | ID: mdl-34904661

RESUMO

The discipline of Cardio-Oncology has seen tremendous growth over the past decade. It is devoted to the cardiovascular (CV) care of the cancer patient, especially to the mitigation and management of CV complications or toxicities of cancer therapies, which can have profound implications on prognosis. To that effect, many studies have assessed CV toxicities in patients undergoing various types of cancer therapies; however, direct comparisons have proven difficult due to lack of uniformity in CV toxicity endpoints. Similarly, in clinical practice, there can be substantial differences in the understanding of what constitutes CV toxicity, which can lead to significant variation in patient management and outcomes. This document addresses these issues and provides consensus definitions for the most commonly reported CV toxicities, including cardiomyopathy/heart failure and myocarditis, vascular toxicity, and hypertension, as well as arrhythmias and QTc prolongation. The current document reflects a harmonizing review of the current landscape in CV toxicities and the definitions used to define these. This consensus effort aims to provide a structure for definitions of CV toxicity in the clinic and for future research. It will be important to link the definitions outlined herein to outcomes in clinical practice and CV endpoints in clinical trials. It should facilitate communication across various disciplines to improve clinical outcomes for cancer patients with CV diseases.

5.
Cancer Treat Rev ; 103: 102324, 2021 Dec 16.
Artigo em Inglês | MEDLINE | ID: mdl-34953200

RESUMO

Brain metastases (BMs) are an important source of morbidity and mortality in patients with metastatic breast cancer (BC). As survival of patients with advanced BC considerably improved thanks to research advancements and new therapeutic approaches, the apparent incidence of BMs is increasing. Local interventions, in the form of either surgical resection or radiation therapy, remain the mainstay in the management of BMs. Systemic treatments are typically used to complement local strategies to further improve and maintain control of central nervous system (CNS) disease. Although high-level evidence data about the impact of the blood-brain barrier (BBB), as well as the efficacy of anti-cancer agents on BMs and differentials between the systemic compartment and CNS are still scant, our understanding of the activity of systemic treatments with impact on BMs is rapidly evolving. Novel anti-HER2 agents, such as tucatinib, ado-trastuzumab emtansine, trastuzumab deruxtecan and neratinib, have shown intracranial efficacy. Current research efforts are ongoing not only to clarify the activity of existing treatments on the CNS, as well as to develop new drugs and innovative multi-modality approaches. This review will encompass the current treatment landscape of BMs arising from BC, with a focus on recent advancements in the field and investigational approaches.

6.
Expert Rev Anticancer Ther ; : 1-13, 2021 Dec 28.
Artigo em Inglês | MEDLINE | ID: mdl-34919490

RESUMO

INTRODUCTION: The addition of immune checkpoint inhibitors (ICIs) to frontline chemotherapy has improved survival for patients with advanced triple-negative breast cancer (TNBC) expressing programmed death-ligand 1 (PD-L1). Nonetheless, most patients develop resistance, with outcomes remaining poor for this population. Moreover, unsatisfactory activity has been observed with ICIs in PD-L1-negative TNBC and in other breast cancer (BC) subtypes, warranting a deeper understanding of resistance to ICIs in BC. AREAS COVERED: We discuss the immune landscape of distinct BC subtypes, review the clinical activity of immunotherapy in BC, and highlight strategies under development to overcome resistance to ICIs. EXPERT OPINION: Activity and resistance to ICIs in BC are strongly related to the intrinsic immunophenotype of the tumor tissue. Several promising biomarkers reflecting the immunological state of BC are emerging, with only PD-L1 expression currently adopted into clinical practice. However, limitations make of PD-L1 a sub-optimal biomarker for patient selection, which require efforts to integrate this marker with other immunological features. Concomitantly, a wide variety of drug combinations designed to overcome immune-resistance are being evaluated, with some encouraging signals observed in early-phase trials. Combination strategies tailored to patient and tumor immunophenotype may allow to overcome resistance and fully exploit the potential of ICIs.

8.
Chirurgia (Bucur) ; 116(500): S97-S104, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34967317

RESUMO

Ductal carcinoma in situ (DCIS) is a noninvasive breast cancer (BC), whose diagnosis significatively increased with the diffusion of BC screening programs. DCIS actually represents roughly 20% of new BC diagnoses (1). About 70% of DCIS shows positivity for hormone receptor (HR), while HER2 is overexpressed in 25-30% of the cases (2,3). Concerning the systemic approach, the only one that should be considered for HR-positive DCIS is adjuvant endocrine therapy (ET), according to NCCN guidelines (4). In fact, the excellent prognosis of this neoplasm does not justify the utilization of more aggressive treatment strategies, such as HER2- directed therapies or chemotherapy. Here we discuss the results of the most important clinical trials enrolling DCIS patients in the adjuvant and in the preoperative setting; in addition, we report the chemoprevention studies utilizing ET which demonstrated a reduction of the risk of DCIS development. On balance, the choice to undertake or not an adjuvant ET, which is often burdened by adverse events that could impact on the quality of life of the patients and on their adherence to the therapy, should be discussed with the patient, taking into account that no survival advantage has been demonstrated so far.


Assuntos
Neoplasias da Mama , Carcinoma Ductal de Mama , Carcinoma Intraductal não Infiltrante , Mama , Neoplasias da Mama/diagnóstico , Neoplasias da Mama/tratamento farmacológico , Carcinoma Intraductal não Infiltrante/terapia , Feminino , Humanos , Qualidade de Vida , Resultado do Tratamento
10.
Eur J Cancer ; 2021 Nov 22.
Artigo em Inglês | MEDLINE | ID: mdl-34823982

RESUMO

The ability to exploit the immune system as a weapon against cancer has revolutionised the treatment of cancer patients, especially through immune checkpoint inhibitors (ICIs). However, ICIs demonstrated a modest benefit in treating breast cancer (BC), with the exception of certain subsets of triple-negative BCs. An immune-suppressive tumour microenvironment (TME), typically present in BC, is an important factor in the poor response to immunotherapy. After almost two decades of poor clinical trial results, cancer vaccines (CVs), an active immunotherapy, have come back in the spotlight because of some technological advancements, ultimately boosted by coronavirus disease 2019 pandemic. In particular, neoantigens are emerging as the preferred targets for CVs, with gene-based and viral vector-based platforms in development. Moreover, lipid nanoparticles proved to be immunogenic and efficient delivery vehicles. Past clinical trials investigating CVs focused especially on the metastatic disease, where the TME is more likely compromised by inhibitory mechanisms. In this sense, favouring the use of CVs as monotherapy in premalignant or in the adjuvant setting and establishing combination treatments (i.e. CV plus ICI) in late-stage disease are promising strategies. This review provides a full overview of the past and current breast cancer vaccine landscape.

11.
J Immunother Cancer ; 9(11)2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34824159

RESUMO

BACKGROUND: Natural killer (NK) cells require a functional lytic granule machinery to mediate effective antitumor responses. Evading the lytic cargo deployed at the immune synapse (IS) could be a critical step for cancer progression through yet unidentified mechanisms. METHODS: NK cell antibody-dependent cellular cytotoxicity (ADCC) is a major determinant of the clinical efficacy of some therapeutic antibodies including the anti-HER2 Trastuzumab. Thus, we screened sera of Trastuzumab-resistant HER2 +patients with breast cancer for molecules that could inhibit NK cell ADCC. We validated our findings in vitro using cytotoxicity assays and confocal imaging of the lytic granule machinery and in vivo using syngeneic and xenograft murine models. RESULTS: We found that sera from Trastuzumab-refractory patients could inhibit healthy NK cell ADCC in vitro. These sera contained high levels of the inflammatory protein chitinase 3-like 1 (CHI3L1) compared with sera from responders and healthy controls. We demonstrate that recombinant CHI3L1 inhibits both ADCC and innate NK cell cytotoxicity. Mechanistically, CHI3L1 prevents the correct polarization of the microtubule-organizing center along with the lytic granules to the IS by hindering the receptor of advanced glycation end-products and its downstream JNK signaling. In vivo, CHI3L1 administration drastically impairs the control of NK cell-sensitive tumors, while CHI3L1 blockade synergizes with ADCC to cure mice with HER2 +xenografts. CONCLUSION: Our work highlights a new paradigm of tumor immune escape mediated by CHI3L1 which acts on the cytotoxic machinery and prevents granule polarization. Targeting CHI3L1 could mitigate immune escape and potentiate antibody and cell-based immunotherapies.

12.
Cancers (Basel) ; 13(22)2021 Nov 20.
Artigo em Inglês | MEDLINE | ID: mdl-34830983

RESUMO

Pivotal trials of COVID-19 vaccines did not include cancer patients, with questions remaining about their safety and efficacy in this population. Patients enrolled in early-phase clinical trials receive novel treatments with unknown efficacy and safety profiles. Studies on the safety of COVID-19 vaccines in these patients are urgently required. This is a retrospective, real-world, cohort study of patients receiving anticancer treatments and COVID-19 vaccines between 1 February and 25 June 2021 at the Division of New Drugs Development for Innovative Therapies of the European Institute of Oncology. One hundred thirteen patients were enrolled, 40 in early-phase clinical trials, and 20 under novel immunotherapy agents. Nearly three-quarters of the patients experienced at least one adverse event (AE) after the first dose (1D) (74.3%) and second dose (2D) (72.6%). Most of the AEs were local (67.3% 1D and 61.9% after 2D), while 31.8% (1D) and 38.1% (2D) of the patients had systemic AEs. No AEs above grade 2 were observed. Therefore, COVID-19 vaccines appear to be safe in patients enrolled in early-phase clinical trials, including patients receiving novel immunotherapy compounds. All cancer patients should be prioritized for COVID-19 vaccination, regardless of ongoing treatments or enrollment in early-phase trials.

13.
Expert Opin Ther Targets ; : 1-20, 2021 Nov 25.
Artigo em Inglês | MEDLINE | ID: mdl-34763593

RESUMO

INTRODUCTION: To overcome mechanisms of primary and secondary resistance to the anti-tumor immune response, novel targets such as ICOS, LAG3, and TIM3 are currently being explored at preclinical and early-phase clinical levels. AREAS COVERED: This article examines the landscape of the immune therapeutics investigated in early-phase clinical trials for TNBC. Preclinical rationale is provided for each immune target, predominant expression, and function. Clinical implications and preliminary available trial results are discussed and finally, we reflect on aspects of future expectations and challenges in this field. EXPERT OPINION: Several immune strategies have been investigated in TNBC, including co-inhibitory molecules beyond PD1-PD-L1 axis, co-stimulatory checkpoints, cancer vaccines, adoptive cell transfer, combination therapies, as well as different routes of administration. Most of approaches showed signs of anti-cancer activity and a good safety profile in early-phase clinical trials. Since IO provided benefit only to a small subgroup of TNBC patients so far, identifying predictive biomarkers is a priority to refine patient-selection. Data from ongoing clinical trials, with the gradually improving interpretation of the breast tumor immune environment, will hopefully refine the role of new immune targets for the treatment of TNBC.

14.
CA Cancer J Clin ; 2021 Nov 12.
Artigo em Inglês | MEDLINE | ID: mdl-34767258

RESUMO

As distinct cancer biomarkers have been discovered in recent years, a need to reclassify tumors by more than their histology has been proposed, and therapies are now tailored to treat cancers based on specific molecular aberrations and immunologic markers. In fact, multiple histology-agnostic therapies are currently adopted in clinical practice for treating patients regardless of their tumor site of origin. In parallel with this new model for drug development, in the past few years, several novel antibody-drug conjugates (ADCs) have been approved to treat solid tumors, benefiting from engineering improvements in the conjugation process and the introduction of novel linkers and payloads. With the recognition that numerous surface targets are expressed across various cancer histologies, alongside the remarkable activity of modern ADCs, this drug class has been increasingly evaluated as suitable for a histology-agnostic expansion of indication. For illustration, the anti-HER2 ADC trastuzumab deruxtecan has demonstrated compelling activity in HER2-overexpressing breast, gastric, colorectal, and lung cancer. Examples of additional novel and potentially histology-agnostic ADC targets include trophoblast cell-surface antigen 2 (Trop-2) and nectin-4, among others. In the current review article, the authors summarize the current approvals of ADCs by the US Food and Drug Administration focusing on solid tumors and discuss the challenges and opportunities posed by the multihistological expansion of ADCs.

15.
Cancers (Basel) ; 13(21)2021 Oct 28.
Artigo em Inglês | MEDLINE | ID: mdl-34771579

RESUMO

Cutaneous metastases (CMs) account for 2% of all skin malignancies, and nearly 70% of CMs in women originate from breast cancer (BC). CMs are usually associated with poor prognosis, are difficult to treat, and can pose diagnostic problems, such as in histopathological diagnosis when occurring long after development of the primary tumor. In addition, the molecular differences between the primary tumors and their CMs, and between CMs and metastases in other organs, are not well defined. Here, we review the main clinical, pathological, and molecular characteristics of breast cancer CMs. Identifying molecular markers in primary BC that predict CM and can be used to determine the molecular differences between primary tumors and their metastases is of great interest for the design of new therapeutic approaches.

16.
Eur J Surg Oncol ; 2021 Nov 09.
Artigo em Inglês | MEDLINE | ID: mdl-34772587

RESUMO

Ductal carcinoma in situ (DCIS) is a non-obligate precursor of invasive breast cancer. It accounts for 25% of all breast cancers diagnosed, as a result of the expansion of breast cancer screening and is associated with a high survival rate. DCIS is particularly clinically challenging, due to its heterogeneous pathological and biological traits and its management is continually evolving towards more personalized and less aggressive therapies. This article suggests evidence-based guidelines for proper DCIS clinical management, which should be discussed within a multidisciplinary team in order to propose the most suitable approach in clinical practice, taking into account recent scientific studies. Here we include updated multidisciplinary treatment protocols and techniques in accordance with the most recent contributions published on this topic in the peer-reviewed medical literature, and we outline future perspectives.

17.
Cancer Discov ; 11(11): 2677-2678, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34725088

RESUMO

Comprehensive genomic and transcriptomic analysis for guiding therapeutic decisions provide the basis of precision cancer medicine. In this issue of Cancer Discovery, continued progress in this field is demonstrated by two large collaborative studies: Horak and colleagues in the MASTER trial for patients with rare cancers and Van Tilburg and colleagues in the INFORM registry in pediatric tumors.See related article by van Tilburg et al., p. 2764.See related article by Horak et al., p. 2780.

18.
Clin Cancer Res ; 2021 Oct 06.
Artigo em Inglês | MEDLINE | ID: mdl-34615718

RESUMO

PURPOSE: To assess the safety and tolerability of BMS-986148, a mesothelin-directed antibody-drug conjugate (ADC) ± nivolumab, in patients with selected tumors. PATIENTS AND METHODS: In an international phase I/IIa study [NCT02341625 (CA008-002)], patients received BMS-986148 monotherapy (0.1-1.6 mg/kg intravenously (i.v.) every 3 weeks or 0.4 or 0.6 mg/kg i.v. once weekly; n = 96) or BMS-986148 0.8 mg/kg + nivolumab 360 mg i.v. every 3 weeks (n = 30). The primary endpoint was safety and tolerability. RESULTS: In CA008-002, the most common (≥ 10%) treatment-related adverse events (TRAEs) included increased aspartate aminotransferase, alanine aminotransferase, and alkaline phosphatase. Grade 3/4 TRAEs occurred in 42 patients (49%) receiving BMS-986148 every 3 weeks monotherapy, three (25%) receiving BMS-986148 once-weekly monotherapy, and 10 (33%) receiving BMS-986148 + nivolumab every 3 weeks. Overall, 17 of 126 patients (13%) discontinued because of a TRAE. The MTD of BMS-986148 was 1.2 mg/kg i.v. every 3 weeks. The safety profile of BMS-986148 + nivolumab was similar to that of BMS-986148 monotherapy (0.8 mg/kg). Active ADC exposures increased in a dose-proportional manner with both dosing regimens (every 3 weeks and once weekly). Preliminary clinical activity was observed with BMS-986148 ± nivolumab. No association between mesothelin expression and response was detected. CONCLUSIONS: BMS-986148 ± nivolumab demonstrated a clinically manageable safety profile and preliminary evidence of clinical activity, supporting additional studies combining directed cytotoxic therapies with checkpoint inhibitors as potential multimodal therapeutic strategies in patients with advanced solid tumors.

19.
Lancet Oncol ; 22(11): 1632-1642, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34653370

RESUMO

BACKGROUND: In some countries, breast cancer age-standardised mortality rates have decreased by 2-4% per year since the 1990s, but others have yet to achieve this outcome. In this study, we aimed to characterise the associations between national health system characteristics and breast cancer age-standardised mortality rate, and the degree of breast cancer downstaging correlating with national age-standardised mortality rate reductions. METHODS: In this population-based study, national age-standardised mortality rate estimates for women aged 69 years or younger obtained from GLOBOCAN 2020 were correlated with a broad panel of standardised national health system data as reported in the WHO Cancer Country Profiles 2020. These health system characteristics include health expenditure, the Universal Health Coverage Service Coverage Index (UHC Index), dedicated funding for early detection programmes, breast cancer early detection guidelines, referral systems, cancer plans, number of dedicated public and private cancer centres per 10 000 patients with cancer, and pathology services. We tested for differences between continuous variables using the non-parametric Kruskal-Wallis test, and for categorical variables using the Pearson χ2 test. Simple and multiple linear regression analyses were fitted to identify associations between health system characteristics and age-standardised breast cancer mortality rates. Data on TNM stage at diagnosis were obtained from national or subnational cancer registries, supplemented by a literature review of PubMed from 2010 to 2020. Mortality trends from 1950 to 2016 were assessed using the WHO Cancer Mortality Database. The threshold for significance was set at a p value of 0·05 or less. FINDINGS: 148 countries had complete health system data. The following variables were significantly higher in high-income countries than in low-income countries in unadjusted analyses: health expenditure (p=0·0002), UHC Index (p<0·0001), dedicated funding for early detection programmes (p=0·0020), breast cancer early detection guidelines (p<0·0001), breast cancer referral systems (p=0·0030), national cancer plans (p=0·014), cervical cancer early detection programmes (p=0·0010), number of dedicated public (p<0·0001) and private (p=0·027) cancer centres per 10 000 patients with cancer, and pathology services (p<0·0001). In adjusted multivariable regression analyses in 141 countries, two health system characteristics were significantly associated with lower age-standardised mortality rates: higher UHC Index levels (ß=-0·12, 95% CI -0·16 to -0·08) and increasing numbers of public cancer centres (ß=-0·23, -0·36 to -0·10). These findings indicate that each unit increase in the UHC Index was associated with a 0·12-unit decline in age-standardised mortality rates, and each additional public cancer centre per 10 000 patients with cancer was associated with a 0·23-unit decline in age-standardised mortality rate. Among 35 countries with available breast cancer TNM staging data, all 20 that achieved sustained mean reductions in age-standardised mortality rate of 2% or more per year for at least 3 consecutive years since 1990 had at least 60% of patients with invasive breast cancer presenting as stage I or II disease. Some countries achieved this reduction without most women having access to population-based mammographic screening. INTERPRETATION: Countries with low breast cancer mortality rates are characterised by increased levels of coverage of essential health services and higher numbers of public cancer centres. Among countries achieving sustained mortality reductions, the majority of breast cancers are diagnosed at an early stage, reinforcing the value of clinical early diagnosis programmes for improving breast cancer outcomes. FUNDING: None.


Assuntos
Neoplasias da Mama/diagnóstico , Neoplasias da Mama/mortalidade , Programas Nacionais de Saúde/estatística & dados numéricos , Neoplasias da Mama/patologia , Institutos de Câncer/estatística & dados numéricos , Detecção Precoce de Câncer/estatística & dados numéricos , Feminino , Saúde Global/estatística & dados numéricos , Gastos em Saúde/estatística & dados numéricos , Humanos , Modelos Lineares , Estadiamento de Neoplasias/estatística & dados numéricos , Encaminhamento e Consulta/estatística & dados numéricos , Sistema de Registros/estatística & dados numéricos , Estatísticas não Paramétricas , Cobertura Universal do Seguro de Saúde/estatística & dados numéricos , Neoplasias do Colo do Útero/diagnóstico
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