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BACKGROUND: Patritumab deruxtecan (HER3-DXd) is a human epidermal growth factor receptor 3 (HER3)-directed antibody-drug conjugate composed of a fully human anti-HER3 monoclonal antibody (patritumab) covalently linked to a topoisomerase I inhibitor payload via a stable, tumor-selective, tetrapeptide-based cleavable linker. TOT-HER3 is a window-of-opportunity study designed to assess the biological activity, measured by CelTIL score [= -0.8 × tumor cellularity (in %) + 1.3 × tumor-infiltrating lymphocytes (TILs) (in %)], and clinical activity of HER3-DXd during short-term (21 days) pre-operative treatment in patients with primary operable HER2-negative early breast cancer. PATIENTS AND METHODS: Patients with previously untreated hormone receptor-positive/HER2-negative tumors were allocated to one of four cohorts according to baseline ERBB3 messenger RNA expression. All patients received one dose of HER3-DXd 6.4 mg/kg. The primary objective was to evaluate change from baseline in CelTIL score. RESULTS: Seventy-seven patients were evaluated for efficacy. A significant change in CelTIL score was observed, with a median increase from baseline of 3.5 (interquartile range, -3.8 to 12.7; P = 0.003). Among patients assessable for clinical response (n = 62), an overall response rate of 45% was observed (tumor measurement by caliper), with a trend toward an increase in CelTIL score among responders compared with non-responders (mean difference, +11.9 versus +1.9). Change in CelTIL score was independent of baseline ERBB3 messenger RNA and HER3 protein levels. Genomic changes occurred, including switching toward a less proliferative tumor phenotype based on PAM50 subtypes, suppression of cell proliferation genes, and induction of genes associated with immunity. Treatment-emergent adverse events were observed in 96% of patients (14% grade ≥3); most common were nausea, fatigue, alopecia, diarrhea, vomiting, abdominal pain, and neutrophil count decrease. CONCLUSIONS: A single dose of HER3-DXd was associated with clinical response, increased immune infiltration, suppression of proliferation in hormone receptor-positive/HER2-negative early breast cancer, and a tolerable safety profile consistent with previously reported results. These findings support further study of HER3-DXd in early breast cancer.
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Neoplasias da Mama , Humanos , Feminino , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Receptor ErbB-2/metabolismo , Camptotecina/uso terapêutico , Trastuzumab/uso terapêuticoRESUMO
BACKGROUND: The HER2DX genomic test predicts pathological complete response (pCR) and survival outcome in early-stage HER2-positive (HER2+) breast cancer. Here, we evaluated the association of HER2DX scores with (i) pCR according to hormone receptor status and various treatment regimens, and (ii) survival outcome according to pCR status. MATERIALS AND METHODS: Seven neoadjuvant cohorts with HER2DX and clinical individual patient data were evaluated (DAPHNe, GOM-HGUGM-2018-05, CALGB-40601, ISPY-2, BiOnHER, NEOHER and PAMELA). All patients were treated with neoadjuvant trastuzumab (n = 765) in combination with pertuzumab (n = 328), lapatinib (n = 187) or without a second anti-HER2 drug (n = 250). Event-free survival (EFS) and overall survival (OS) outcomes were available in a combined series of 268 patients (i.e. NEOHER and PAMELA) with a pCR (n = 118) and without a pCR (n = 150). Cox models were adjusted to evaluate whether HER2DX can identify patients with low or high risk beyond pCR status. RESULTS: HER2DX pCR score was significantly associated with pCR in all patients [odds ratio (OR) per 10-unit increase = 1.59, 95% confidence interval 1.43-1.77; area under the ROC curve = 0.75], with or without dual HER2 blockade. A statistically significant increase in pCR rate due to dual HER2 blockade over trastuzumab-only was observed in HER2DX pCR-high tumors treated with chemotherapy (OR = 2.36 (1.09-5.42). A statistically significant increase in pCR rate due to multi-agent chemotherapy over a single taxane was observed in HER2DX pCR-medium tumors treated with dual HER2 blockade (OR = 3.11, 1.54-6.49). The pCR rates in HER2DX pCR-low tumors were ≤30.0% regardless of treatment administered. After adjusting by pCR status, patients identified as HER2DX low-risk had better EFS (P < 0.001) and OS (P = 0.006) compared with patients with HER2DX high-risk. CONCLUSIONS: HER2DX pCR score and risk score might help identify ideal candidates to receive neoadjuvant dual HER2 blockade in combination with a single taxane in early-stage HER2+ breast cancer.
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Neoplasias da Mama , Humanos , Feminino , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Receptor ErbB-2/genética , Resultado do Tratamento , Trastuzumab , Taxoides , Terapia Neoadjuvante/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversosRESUMO
BACKGROUND: In human epidermal growth factor receptor 2 (HER2+) breast cancers, neoadjuvant trials of chemotherapy plus anti-HER2 treatment consistently showed lower pathologic complete response (pCR) rates in hormone receptor (HR) positive versus negative tumors. The PerELISA study was aimed to evaluate the efficacy of a de-escalated, chemotherapy-free neoadjuvant regimen in HR+/HER2+ breast cancer patients selected on the basis of Ki67 inhibition after 2-week letrozole. PATIENTS AND METHODS: PerELISA is a phase II, multicentric study for postmenopausal patients with HR+/HER2+ operable breast cancer. Patients received 2-week letrozole, and then underwent re-biopsy for Ki67 evaluation. Patients classified as molecular responders (Ki67 relative reduction >20% from baseline) continued letrozole and started trastuzumab-pertuzumab for five cycles. Patients classified as molecular non-responders started weekly paclitaxel for 13 weeks combined with trastuzumab-pertuzumab. Primary aim was breast and axillary pCR. According to a two-stage Simon's design, to reject the null hypothesis, at least 8/43 pCR had to be documented. RESULTS: Sixty-four patients were enrolled, 44 were classified as molecular responders. All these patients completed the assigned treatment with letrozole-trastuzumab-pertuzumab and underwent surgery. A pCR was observed in 9/44 cases (20.5%, 95% confidence interval 11.1% to 34.5%). Among molecular non-responders, 16/17 completed treatment and underwent surgery, with pCR observed in 81.3% of the cases. PAM50 intrinsic subtype was significantly associated with Ki67 response and pCR. Among molecular responders, the pCR rate was significantly higher in HER2-enriched than in other subtypes (45.5% versus 13.8%, P = 0.042). CONCLUSIONS: The primary end point of the study was met, by reaching the pre-specified pCRs. In patients selected using Ki67 reduction after short-term letrozole exposure, a meaningful pCR rate can be achieved without chemotherapy. PAM50 intrinsic subtyping further refines our ability to identify a subset of patients for whom chemotherapy might be spared. EUDRACT NUMBER: 2013-002662-40. CLINICALTRIALS.GOV IDENTIFIER: NCT02411344.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Antígeno Ki-67/metabolismo , Receptor ErbB-2/metabolismo , Receptores de Estrogênio/metabolismo , Receptores de Progesterona/metabolismo , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais Humanizados/administração & dosagem , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Neoplasias da Mama/cirurgia , Carcinoma Ductal de Mama/tratamento farmacológico , Carcinoma Ductal de Mama/metabolismo , Carcinoma Ductal de Mama/patologia , Carcinoma Ductal de Mama/cirurgia , Carcinoma Lobular/tratamento farmacológico , Carcinoma Lobular/metabolismo , Carcinoma Lobular/patologia , Carcinoma Lobular/cirurgia , Relação Dose-Resposta a Droga , Feminino , Seguimentos , Humanos , Letrozol/administração & dosagem , Pessoa de Meia-Idade , Terapia Neoadjuvante , Invasividade Neoplásica , Prognóstico , Indução de Remissão , Trastuzumab/administração & dosagemRESUMO
Background: The presence of stromal tumor-infiltrating lymphocytes (TILs) is associated with increased pathologic complete response (pCR) and improved outcomes in HER2-positive early-breast cancer (BC) treated with anti-HER2-based chemotherapy. In the absence of chemotherapy, the association of TILs with pCR following anti-HER2 therapy-only is largely unknown. Patients and methods: The PAMELA neoadjuvant trial treated 151 women with HER2-positive BC with lapatinib and trastuzumab [and hormonal therapy if hormone receptor (HR)-positive] for 18 weeks. Percentage of TILs and tumor cellularity were determined at baseline (N = 148) and at day 15 (D15) of treatment (N = 134). Associations of TILs and tumor cellularity with pCR in the breast were evaluated. A combined score based on tumor cellularity and TILs (CelTIL) measured at D15 was derived in PAMELA, and validated in D15 samples from 65 patients with HER2-positive disease recruited in the LPT109096 neoadjuvant trial, where anti-HER2 therapy-only was administer for 2 weeks, then standard chemotherapy was added for 24 weeks. Results: In PAMELA, baseline and D15 TILs were significantly associated with pCR in univariate analysis. In multivariable analysis, D15 TILs, but not baseline TILs, were significantly associated with pCR. At D15, TILs and tumor cellularity were found independently associated with pCR. A combined score (CelTIL) taking into account both variables was derived. CelTIL at D15 as a continuous variable was significantly associated with pCR, and patients with CelTIL-low and CelTIL-high scores had a pCR rate of 0% and 33%, respectively. In LPT109096, CelTIL at D15 was found associated with pCR both as a continuous variable and as group categories using a pre-defined cut-off (75.0% versus 33.3%). Conclusions: On-treatment TILs, but not baseline TILs, are independently associated with response following anti-HER2 therapy-only. A combined score of TILs and tumor cellularity measured at D15 provides independent predictive information upon completion of neoadjuvant anti-HER2-based therapy. Clinical trial number: NCT01973660.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/imunologia , Linfócitos do Interstício Tumoral/imunologia , Modelos Biológicos , Receptor ErbB-2/antagonistas & inibidores , Idoso , Neoplasias da Mama/enzimologia , Neoplasias da Mama/patologia , Ensaios Clínicos Fase II como Assunto , Feminino , Humanos , Lapatinib/administração & dosagem , Linfócitos do Interstício Tumoral/patologia , Pessoa de Meia-Idade , Modelos Estatísticos , Estudos Multicêntricos como Assunto , Terapia Neoadjuvante , Valor Preditivo dos Testes , Ensaios Clínicos Controlados Aleatórios como Assunto , Receptor ErbB-2/metabolismo , Trastuzumab/administração & dosagem , Resultado do TratamentoRESUMO
Background: We hypothesized that the abundance of PD1 mRNA in tumor samples might explain the differences in overall response rates (ORR) observed following anti-PD1 monotherapy across cancer types. Patients and methods: RNASeqv2 data from 10 078 tumor samples representing 34 different cancer types was analyzed from TCGA. Eighteen immune-related gene signatures and 547 immune-related genes, including PD1, were explored. Correlations between each gene/signature and ORRs reported in the literature following anti-PD1 monotherapy were calculated. To translate the in silico findings to the clinical setting, we analyzed the expression of PD1 mRNA using the nCounter platform in 773 formalin-fixed paraffin embedded (FFPE) tumor samples across 17 cancer types. To test the direct relationship between PD1 mRNA, PDL1 immunohistochemistry (IHC), stromal tumor-infiltrating lymphocytes (sTILs) and ORR, we evaluated an independent FFPE-based dataset of 117 patients with advanced disease treated with anti-PD1 monotherapy. Results: In pan-cancer TCGA, PD1 mRNA expression was found strongly correlated (r > 0.80) with CD8 T-cell genes and signatures and the proportion of PD1 mRNA-high tumors (80th percentile) within a given cancer type was variable (0%-84%). Strikingly, the PD1-high proportions across cancer types were found strongly correlated (r = 0.91) with the ORR following anti-PD1 monotherapy reported in the literature. Lower correlations were found with other immune-related genes/signatures, including PDL1. Using the same population-based cutoff (80th percentile), similar proportions of PD1-high disease in a given cancer type were identified in our in-house 773 tumor dataset as compared with TCGA. Finally, the pre-established PD1 mRNA FFPE-based cutoff was found significantly associated with anti-PD1 response in 117 patients with advanced disease (PD1-high 51.5%, PD1-intermediate 26.6% and PD1-low 15.0%; odds ratio between PD1-high and PD1-intermediate/low = 8.31; P < 0.001). In this same dataset, PDL1 tumor expression by IHC or percentage of sTILs was not found associated with response. Conclusions: Our study provides a clinically applicable assay that links PD1 mRNA abundance, activated CD8 T-cells and anti-PD1 efficacy.
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Antineoplásicos Imunológicos/uso terapêutico , Linfócitos T CD8-Positivos/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Linfócitos do Interstício Tumoral/efeitos dos fármacos , Neoplasias/metabolismo , Receptor de Morte Celular Programada 1/metabolismo , RNA Mensageiro/metabolismo , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Linfócitos T CD8-Positivos/imunologia , Estudos de Coortes , Feminino , Seguimentos , Humanos , Linfócitos do Interstício Tumoral/imunologia , Masculino , Pessoa de Meia-Idade , Neoplasias/tratamento farmacológico , Neoplasias/imunologia , Neoplasias/patologia , Prognóstico , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Receptor de Morte Celular Programada 1/genética , RNA Mensageiro/genética , Taxa de SobrevidaRESUMO
BACKGROUND: Currently, imaging technologies that can accurately assess or provide surrogate markers of the human cutaneous microvessel network are limited. Dynamic optical coherence tomography (D-OCT) allows the detection of blood flow in vivo and visualization of the skin microvasculature. However, image processing is necessary to correct images, filter artifacts, and exclude irrelevant signals. The objective of this study was to develop a novel image processing workflow to enhance the technical capabilities of D-OCT. MATERIALS AND METHODS: Single-center, vehicle-controlled study including healthy volunteers aged 18-50 years. A capsaicin solution was applied topically on the subject's forearm to induce local inflammation. Measurements of capsaicin-induced increase in dermal blood flow, within the region of interest, were performed by laser Doppler imaging (LDI) (reference method) and D-OCT. RESULTS: Sixteen subjects were enrolled. A good correlation was shown between D-OCT and LDI, using the image processing workflow. Therefore, D-OCT offers an easy-to-use alternative to LDI, with good repeatability, new robust morphological features (dermal-epidermal junction localization), and quantification of the distribution of vessel size and changes in this distribution induced by capsaicin. The visualization of the vessel network was improved through bloc filtering and artifact removal. Moreover, the assessment of vessel size distribution allows a fine analysis of the vascular patterns. CONCLUSION: The newly developed image processing workflow enhances the technical capabilities of D-OCT for the accurate detection and characterization of microcirculation in the skin. A direct clinical application of this image processing workflow is the quantification of the effect of topical treatment on skin vascularization.
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Microvasos/diagnóstico por imagem , Pele/diagnóstico por imagem , Fluxo de Trabalho , Administração Cutânea , Adolescente , Adulto , Capsaicina/farmacologia , Humanos , Processamento de Imagem Assistida por Computador , Fluxometria por Laser-Doppler , Microcirculação/efeitos dos fármacos , Microvasos/efeitos dos fármacos , Pessoa de Meia-Idade , Fármacos do Sistema Sensorial/farmacologia , Pele/irrigação sanguínea , Pele/efeitos dos fármacos , Tomografia de Coerência Óptica , Adulto JovemRESUMO
BACKGROUND: The HER2DX risk-score has undergone rigorous validation in prior investigations involving patients with early-stage human epidermal growth factor receptor 2 (HER2)-positive (HER2+) breast cancer. In this study, we present the outcomes of the HER2DX risk-score within the most recent release of the Sweden Cancerome Analysis Network-Breast (SCAN-B) HER2+ cohort. This updated examination benefits from a larger patient sample, an extended follow-up duration, and detailed treatment information. MATERIALS AND METHODS: Clinical and RNAseq data from the SCAN-B dataset were retrieved from Gene Expression Omnibus (GSE81538). Among the 6600 patients, 819 had HER2+ breast cancer, with 757 individuals with research-based HER2DX risk-scores and corresponding survival outcomes. The HER2DX risk-score was evaluated (i) as a continuous variable and (ii) using predefined cut-offs. The primary endpoint for this study was overall survival (OS). The Kaplan-Meier method and Cox models were used to estimate OS and a multistate model with four states was fitted to better characterize patients' follow-up. RESULTS: The median follow-up time was 7.5 years (n = 757). The most common systemic therapy was chemotherapy with trastuzumab (82.0%) and most tumors were classified as T1-T2 (97.1%). The HER2DX risk-score as a continuous variable was significantly associated with OS after adjustment for clinical variables and treatment regimen [hazard ratios (HR) per 10-unit increment = 1.31, 95% confidence interval (CI) 1.13-1.51, P < 0.001] as well as within predefined risk groups (high versus low; HR = 2.57, 95% CI 1.36-4.85, P < 0.001). Patients classified as HER2DX high-risk also had higher risk of (i) breast cancer recurrence and (ii) death without previous recurrence. Within the subgroup of HER2+ T1N0 tumors (n = 297), those classified as high-risk demonstrated inferior OS compared to low-risk tumors (7-year OS 77.8% versus 96.8%, P < 0.001). The HER2DX mRNA ERBB2 score was associated with clinical HER2 status (area under the receiver operating characteristic curve = 0.91). CONCLUSIONS: In patients with early-stage HER2+ breast cancer, HER2DX risk-score provides prognostic information beyond clinicopathological variables, including treatment regimen with or without trastuzumab.
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Neoplasias da Mama , Humanos , Feminino , Neoplasias da Mama/tratamento farmacológico , Prognóstico , Suécia/epidemiologia , Recidiva Local de Neoplasia/tratamento farmacológico , Trastuzumab/farmacologia , Trastuzumab/uso terapêuticoRESUMO
BACKGROUND: The characterization and comparison of gene expression and intrinsic subtype (IS) changes induced by neoadjuvant chemotherapy (NACT) and endocrine therapy in hormone receptor-positive (HR+)/human epidermal growth factor receptor 2 (HER2)-low versus HR+/HER2-0 breast cancer (BC) has not been conducted so far. Most evidence on the association of HER2 status with pathologic responses and prognosis in HR+/HER2-negative BC is controversial and restricted to NACT-treated disease. Similarly, a temporal heterogeneity in HER2 status has been described only with NACT. METHODS: We retrospectively recruited a consecutive cohort of 186 patients with stage I-IIIB HR+/HER2-negative BC treated with neoadjuvant therapy (NAT). Available diagnostic biopsies and surgical samples were characterized for main pathological features, PAM50 IS and ROR-P score, and gene expression. Associations with pathologic complete response, residual cancer burden-0/I, event-free survival (EFS) and overall survival (OS) based on HER2 status were assessed. Pre/post pathologic/molecular changes were analyzed in matched samples. RESULTS: The HER2-low (62.9%) and HER2-0 (37.1%) cohorts did not differ significantly in main baseline features, treatments administered, breast-conserving surgery, pathologic complete response and residual cancer burden-0/I rates, EFS, and OS. NAT induced, regardless of HER2 status, a significant reduction of estrogen receptor/progesterone receptor and Ki67 levels, a down-regulation of PAM50 proliferation- and luminal-related genes/signatures, an up-regulation of selected immune genes, and a shift towards less aggressive IS and lower ROR-P. Moreover, 25% of HER2-0 changed to HER2-low and 34% HER2-low became HER2-0. HER2 shifts were significant after NACT (P < 0.001), not neoadjuvant endocrine therapy (P = 0.063), with consistent ERBB2 mRNA level dynamics. HER2 changes were not associated with EFS/OS. CONCLUSIONS: HER2-low and HER2-0 status change after NAT in â¼30% of cases, mostly after NACT. Targeted adjuvant strategies should be investigated accordingly. Molecular downstaging with current chemo/endocrine agents and immunotherapy should not rely on HER2 immunohistochemical levels in HR+/HER2-negative BC. Instead, HER2-low-targeted approaches should be explored to pursue more effective and/or less toxic dimensional downstaging.
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Neoplasias da Mama , Terapia Neoadjuvante , Receptor ErbB-2 , Humanos , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Neoplasias da Mama/metabolismo , Feminino , Terapia Neoadjuvante/métodos , Receptor ErbB-2/metabolismo , Pessoa de Meia-Idade , Estudos Retrospectivos , Adulto , Idoso , Receptores de Estrogênio/metabolismo , Receptores de Progesterona/metabolismo , Prognóstico , Biomarcadores Tumorais/metabolismo , Antineoplásicos Hormonais/uso terapêutico , Antineoplásicos Hormonais/farmacologiaRESUMO
BACKGROUND: In hormone receptor-positive (HoR+) breast cancer (BC), gene expression analysis identifies luminal A (LumA), luminal B (LumB), human epidermal growth factor receptor 2 (HER2)-enriched (HER2-E), basal-like (BL) intrinsic subtypes and a normal-like group. This classification has an established prognostic value in early-stage HoR+ BC. Here, we carried out a trial-level meta-analysis to determine the prognostic ability of subtypes in metastatic BC (MBC). MATERIALS AND METHODS: We systematically reviewed all the available prospective phase II/III trials in HoR+ MBC where subtype was assessed. The primary endpoint was progression-free survival (PFS)/time to progression (TTP) of the LumA subtype compared to non-LumA. Secondary endpoints were PFS/TTP of each individual subtype, according to treatment, menopausal and HER2 status and overall survival (OS). The random-effect model was applied, and heterogeneity assessed through Cochran's Q and I2. Threshold for significance was set at P < 0.05. The study was registered in PROSPERO (ID: CRD42021255769). RESULTS: Seven studies were included (2536 patients). Non-LumA represented 55.2% and was associated with worse PFS/TTP than LumA [hazard ratio (HR) 1.77, P < 0.001, I2 = 61%], independently of clinical HER2 status [Psubgroup difference (Psub) = 0.16], systemic treatment (Psub = 0.96) and menopausal status (Psub = 0.12). Non-LumA tumors also showed worse OS (HR 2.00, P < 0.001, I2 = 65%), with significantly different outcomes for LumB (PFS/TTP HR 1.46; OS HR 1.41), HER2-E (PFS/TTP HR 2.39; OS HR 2.08) and BL (PFS/TTP HR 2.67; OS HR 3.26), separately (PFS/TTP Psub = 0.01; OS Psub = 0.005). Sensitivity analyses supported the main result. No publication bias was observed. CONCLUSIONS: In HoR+ MBC, non-LumA disease is associated with poorer PFS/TTP and OS than LumA, independently of HER2, treatment and menopausal status. Future trials in HoR+ MBC should consider this clinically relevant biological classification.
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Antineoplásicos , Neoplasias da Mama , Humanos , Feminino , Neoplasias da Mama/tratamento farmacológico , Prognóstico , Estudos Prospectivos , Antineoplásicos/uso terapêutico , Modelos de Riscos ProporcionaisRESUMO
OBJECTIVES: The aim of this article is to review the current state of immediate implants, with their pros and contras, and the clinical indications and contraindications. MATERIAL AND METHODS: An exhaustive literature search has been carried out in the COCHRANE library and MEDLINE electronic databases from 2004 to November 2009. Randomized clinical trials and clinical trials focused on single implants placed in fresh extraction sockets were included and compared. A meta-analysis could not be performed due to heterogeneity of the data. RESULTS: Twenty studies out of 135 articles from the initial search were finally included, which summed up a total of 1139 immediate implants with at least a 12-month follow-up. Our results have been compared with other current available papers in the literature reviewed that obtained similar outcomes. DISCUSSION: Immediate implants have predictable results with several advantages over delayed implant placement. However, technical complications have been described regarding this technique. Also, biomaterials may be needed when the jumping distance is greater than 1mm or any bone defect is present. CONCLUSIONS: Few studies report on success rates rather than survival rates in the literature reviewed. Short-term clinical results were described and results were comparable to those obtained with delayed implant placement. Further long-term, randomized clinical trials are needed to give scientific evidence on the benefits of immediate implants over delayed implant placement.
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Implantação Dentária/métodos , Extração Dentária , Humanos , Fatores de TempoRESUMO
Despite their recognised role in HER2-positive (HER2+) breast cancer (BC), the composition, localisation and functional orientation of immune cells within tumour microenvironment, as well as its dynamics during anti-HER2 treatment, is largely unknown. We here investigate changes in tumour-immune contexture, as assessed by stromal tumour-infiltrating lymphocytes (sTILs) and by multiplexed spatial cellular phenotyping, during treatment with lapatinib-trastuzumab in HER2+ BC patients (PAMELA trial). Moreover, we evaluate the relationship of tumour-immune contexture with hormone receptor status, intrinsic subtype and immune-related gene expression. sTIL levels increase after 2 weeks of HER2 blockade in HR-negative disease and HER2-enriched subtype. This is linked to a concomitant increase in cell density of all four immune subpopulations (CD3+, CD4+, CD8+, Foxp3+). Moreover, immune contexture analysis showed that immune cells spatially interacting with tumour cells have the strongest association with response to anti-HER2 treatment. Subsequently, sTILs consistently decrease at the surgery in patients achieving pathologic complete response, whereas most residual tumours at surgery remain inflamed, possibly reflecting a progressive loss of function of T cells. Understanding the features of the resulting tumour immunosuppressive microenvironment has crucial implications for the design of new strategies to de-escalate or escalate systemic therapy in early-stage HER2+ BC.
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Lithium was tested on an animal model of a brain cholinergic excitotoxic lesion. Male Wistar rats received unilaterally 50 nmol ibotenic acid in the nucleus basalis magnocellularis. Some were treated intraperitoneally with LiCl from two days before to six days after lesioning. Such treated rats showed less deficits than untreated lesioned animals on passive avoidance, ambulatory behaviour and choline acetyltransferase activity in the lesioned cortex. Lithium protection against excitatory amino acid neurotoxicity is suggested.
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Comportamento Animal/efeitos dos fármacos , Agonistas de Aminoácidos Excitatórios/toxicidade , Ácido Ibotênico/antagonistas & inibidores , Lítio/farmacologia , Sistema Nervoso Parassimpático/fisiologia , Prosencéfalo/fisiologia , Animais , Aprendizagem da Esquiva/efeitos dos fármacos , Gânglios da Base/efeitos dos fármacos , Gânglios da Base/metabolismo , Gânglios da Base/fisiologia , Colina O-Acetiltransferase/antagonistas & inibidores , Ácido Ibotênico/toxicidade , Masculino , Atividade Motora/efeitos dos fármacos , Sistema Nervoso Parassimpático/efeitos dos fármacos , Sistema Nervoso Parassimpático/metabolismo , Prosencéfalo/efeitos dos fármacos , Prosencéfalo/metabolismo , Ratos , Ratos WistarRESUMO
We have studied 48 rheumatoid arthritis (RA) patients treated with nonsteroidal antiinflammatory drugs (NSAIDs), except salicylates, in 31 of whom parenteral gold was associated as therapeutic agent. In order to assess initial tubular involvement, the activities of some urinary enzymes were measured: N-acetylglucosaminidase (NAG, EC 3.2.1.30), microsomal amino-peptidase (MAP, EC 3.4.11.2) and gamma-glutamyltransferase (GGT; EC 2.3.2.2). Results were compared with a control group of 51 subjects of similar age, with no rheumatic symptoms and normal renal function. Both groups of patients (31 with gold therapy and 17 without) showed a significantly increased activity of NAG in urine, but the increase was greater in those treated with gold. MAP and GGT were not elevated significantly in either group. There was no correlation, however, between the increase of NAG and the cumulative dose of gold. NAG, MAP and GGT activities in serum yielded no relevant information. All the usual tests of renal function were also normal. Determination of NAG in urine may be regarded as a sensitive test, capable of detecting selective involvement of renal tubular cells, whose final diagnostic and prognostic significance merits further evaluation.
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Artrite Reumatoide/urina , Enzimas/urina , Ouro/efeitos adversos , Acetilglucosaminidase/sangue , Acetilglucosaminidase/urina , Adulto , Idoso , Aminopeptidases/sangue , Aminopeptidases/urina , Artrite Reumatoide/tratamento farmacológico , Enzimas/sangue , Feminino , Ouro/uso terapêutico , Humanos , Masculino , Pessoa de Meia-Idade , gama-Glutamiltransferase/sangue , gama-Glutamiltransferase/urinaRESUMO
PURPOSES: To address prostate cancer (PCa) detection with respect to the number of biopsy sessions performed, to identify risk factors for detection after a negative biopsy, and to analyze the clinical characteristics of the detected tumors. SCOPE: Only biopsied men (sextant) were included. A total of 1011 biopsy sessions were carried out in 770 men; 172 underwent a second prostate biopsy and 51 a third biopsy. During the first biopsy round, 111 cancers were found (14.4%), 27 in the second (15.7%), and five during the third round (9.8%), P=0.156. Only high-grade PIN or atypia were identified as independent predictors or PCa detection in subsequent biopsies (P=0.008). A nonsignificant increase of clinically localized tumors, and a decrease of metastatic and poorly differentiated cases were found when more biopsy sessions were needed for detection. CONCLUSIONS: A nonsignificant trend to lower cancer detection rates and less clinical relevance of the tumors detected can be observed when more biopsy rounds are needed for detection.
Assuntos
Próstata/patologia , Neoplasias da Próstata/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Biópsia , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias da Próstata/diagnósticoRESUMO
Following a brief introduction on the history and generic codification of the different cardiac stimulation methods available, the implantation techniques are described and the requisites, such as human resources, their qualifications and the materials required, which are essential in the organization of a Pacemaker Unit are discussed. The current indications for permanent cardiac stimulation are reported and are classified by sections in tales following the 1998 norms of the ACC/AHA. In another section, the indications in special situations such as hypertrophic or dilated cardiomyopathy are described. Stimulation frequency modulation with the incorporation of biodetectors in modern pacemakers or in the probes are commented upon as is atriosynchronic ventricular stimulation with a single electrode (VDD). The recent automatisms which have been implemented in the current pacemakers are discussed and the most adequate selection of the stimulation mode for each patient is analyzed and demonstrated in a table which may be easily interpreted. On establishing the recommendable protocol for undertaking the follow up of the patient with a pacemaker, the criteria accepted as replacement indicators are discussed. In a brief section some legal aspects (drivers license, informed consent) are commented upon and the possible sources of interference with the function of the system implanted, whether medical or environmental or laboral, have been analyzed more in depth. The chapter ends with a brief discussion on the survival of patients with pacemakers.
Assuntos
Marca-Passo Artificial , Adolescente , Adulto , Criança , Competência Clínica , Campos Eletromagnéticos , Seguimentos , Cardiopatias/terapia , Humanos , Desenho de Prótese , Taxa de SobrevidaRESUMO
To study the characteristics of our outpatient clinic patients presenting with chronic cough as the sole symptom of bronchial asthma, and to evaluate the bronchial hyperreactivity of such patients in comparison with that of classic asthmatic patients with normal spirometry. For 3 years we studied 193 consecutive patients with chronic cough as the sole symptom, using the study protocol specified in the section on patients and methods. Sixty-three patients were diagnosed of bronchial asthma. Bronchial hyperreactivity was considered to be the cause of coughing based on reversibility testing or a positive methacholine test, along with response to specific antiasthmatic therapy. Forty-six (73%) of the 63 patients had unproductive cough and 28 (44%) coughed mainly at night. In 14 (22%) symptoms began with an upper respiratory tract infection. Wheezing could be heard in only 4 (6%). Diagnosis was based on reversibility in 11 (17%) and methacholine testing in 52 (83%). Mean PC20 was higher in patients diagnosed of variant cough. Unlike classic asthma, persistent and usually unproductive cough caused by asthma has few or no accompanying symptoms. The diagnostic yield of methacholine testing is high in such patients.
Assuntos
Asma/diagnóstico , Tosse/etiologia , Adolescente , Adulto , Idoso , Asma/complicações , Asma/fisiopatologia , Tosse/fisiopatologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , EspirometriaRESUMO
The authors report a case with a double mitral orifice associated with a single auricle; it was operated on successfully. It was unnecessary to carry out any surgical procedure on the mitral valve itself, as it was functioning normally. A review of the literature follows.
Assuntos
Comunicação Interatrial/cirurgia , Valva Mitral/anatomia & histologia , Criança , Técnicas de Diagnóstico por Cirurgia , Feminino , Comunicação Interatrial/diagnóstico , Comunicação Interatrial/embriologia , Humanos , Métodos , PrognósticoRESUMO
INTRODUCTION: Infection continues to be a cause of concern in neonatal units. The high cost of the body surface cultures used to study infection and their limited utility is controversial. MATERIAL AND METHODS: The medical records of newborns admitted for suspected infection in 1999 were retrospectively reviewed. Request criteria, cost, and the clinical utility of body surface cultures were analyzed. RESULTS: In 1999, body surface cultures were requested in 204 newborns admitted to hospital (70 % of all admitted newborns). Of these, six were diagnosed with bacteremia (6.23/1000; 95 % CI: 5.9-6.5). The most frequently isolated microorganisms were Escherichia coli and Streptococcus agalactiae. The total cost of body surface cultures was 6,510.95 euros (1,083,331 pesetas). In 25 % of cases the results of cultures influenced clinical decision making. The cost necessary to obtain clinical repercussion in a patient was 191.50 euros (31,863 pesetas). Requesting two body surface cultures only (otic and umbilical) halved the cost without diminishing their clinical utility. CONCLUSIONS: A considerable percentage of newborns admitted to hospital present suspected infection requiring microbiological studies. Although the cost of body surface cultures is high, the results of these cultures influence diagnostic and therapeutic decisions in a quarter of patients. We do not believe that eliminating the use of these cultures would be beneficial. However, their cost can be reduced by carefully selecting request criteria and by limiting cultures to two samples (otic and umbilical).
Assuntos
Infecções/microbiologia , Técnicas Bacteriológicas/economia , Análise Custo-Benefício , Feminino , Humanos , Recém-Nascido , Unidades de Terapia Intensiva Neonatal , Masculino , Estudos RetrospectivosRESUMO
OBJETIVO: Mostrar los hallazgos imagenológicos en la resonancia magnética (RM) de la sinovitis vellonodular pigmentada (SVP) y el tumor de células gigantes de la vaina sinovial (TCGVS), dado que son entidades que representan un diverso grupo de alteraciones en la proliferación de la sinovial. MATERIALES Y MÉTODOS: Entre mayo de 2011 y junio de 2013, se estudiaron en nuestra institución 25 casos con diagnóstico histológico de proliferación de la sinovial. Se destacaron los distintos tipos de presentación en imágenes a través de una RM 1.5 Tesla. Los resultados fueron analizados y comparados con la literatura. RESULTADOS: La RM mostró características similares para esta patología en todos los pacientes. No obstante, se distinguieron 4 patrones principales de presentación, dependiendo de la morfología, la localización de la lesión y las características radiológicas diferenciales. Estos fueron: como dominante, el tumor de células gigantes de la vaina sinovial (n = 10), todos de localización extraarticular; la sinovitis vellonodular pigmentada de localización bursal (n = 2); la sinovitis vellonodular pigmentada de forma intraarticular focal (n = 5); y la sinovitis vellonodular pigmentada difusa (n = 8). CONCLUSIÓN: La sinovitis vellonodular pigmentada y el tumor de células gigantes de la vaina sinovial se consideran entidades similares desde el punto de vista anatomopatológico. La RM fue de gran utilidad para objetivar tanto las características radiológicas comunes como las diferenciales. Estas últimas, junto con la localización, nos permitieron clasificar 4 patrones de presentación. Su reconocimiento posibilita un adecuado seguimiento de la patología y un óptimo manejo terapéutico.
PURPOSE: To show the resonance magnetic imaging (MRI) findings of pigmented villonodular synovitis (PVNS) and giant cell tumor of the tendon sheath (PVNTS), entities with similar histology but differences in clinical and some radiological manifestations. MATERIALS AND METHODS: We studied 25 cases with histologically benign synovial proliferation in intra and extraarticular location of the extremities. It highlighted with a 1.5T MRI unit the different types of images presentation. The results were analyzed and compared with the literature. RESULTS: MRI displayed very specific imaging features in all patients. However, we were able to distinguish 4 main patterns of presentation depending on the morphology, location of the lesion and radiological differential. These were: as dominant presentation, pigmented villonodular synovitis localized form (n=10); pigmented villonodular synovitis bursal form (n=2); pigmented villonodular synovitis focal (n =5); and pigmented villonodular synovitis diffuse (n = 8). CONCLUSION: Both pigmented villonodular synovitis as well as giant cell tumor of the tendon sheath are considered similar from the point of view of the histological findings. MRI was useful to objectify both radiological features in common, such as the differential, which along with the location, allow us to classify patterns into 4 individual presentations. This recognition involves adequate radiological evaluation and is important for optimal management.