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Background: Systemic inflammatory markers draw great interest as potential blood-based prognostic factors in several oncological settings. Objectives: The aim of this study is to evaluate whether neutrophil-to-lymphocyte ratio (NLR) and pan-immune-inflammation value (PIV) predict nodal pathologic complete response (pCR) after neoadjuvant chemotherapy (NAC) in node-positive (cN+) breast cancer (BC) patients. Design: Clinically, cN+ BC patients undergoing NAC followed by breast and axillary surgery were enrolled in a multicentric study from 11 Breast Units. Methods: Pretreatment blood counts were collected for the analysis and used to calculate NLR and PIV. Logistic regression analyses were performed to evaluate independent predictors of nodal pCR. Results: A total of 1274 cN+ BC patients were included. Nodal pCR was achieved in 586 (46%) patients. At multivariate analysis, low NLR [odds ratio (OR) = 0.71; 95% CI, 0.51-0.98; p = 0.04] and low PIV (OR = 0.63; 95% CI, 0.44-0.90; p = 0.01) were independently predictive of increased likelihood of nodal pCR. A sub-analysis on cN1 patients (n = 1075) confirmed the statistical significance of these variables. PIV was significantly associated with axillary pCR in estrogen receptor (ER)-/human epidermal growth factor receptor 2 (HER2)+ (OR = 0.31; 95% CI, 0.12-0.83; p = 0.02) and ER-/HER2- (OR = 0.41; 95% CI, 0.17-0.97; p = 0.04) BC patients. Conclusion: This study found that low NLR and PIV levels predict axillary pCR in patients with BC undergoing NAC. Registration: Eudract number NCT05798806.
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Identification of reliable and accessible biomarkers to characterize ischemic stroke patients' prognosis remains a clinical challenge. Neurofilament light chain (NfL) and glial fibrillary acidic protein (GFAP) are markers of brain injury, detectable in blood by high-sensitive technologies. Our aim was to measure serum NfL and GFAP after stroke, and to evaluate their correlation with functional outcome and the scores in rehabilitation scales at 3-month follow-up. Stroke patients were prospectively enrolled in a longitudinal observational study within 24 hours from symptom onset (D1) and monitored after 7 (D7), 30 ± 3 (M1) and 90 ± 5 (M3) days. At each time-point serum NfL and GFAP levels were measured by Single Molecule Array and correlated with National Institute of Health Stroke Scale (NIHSS), modified Rankin scale (mRS), Trunk Control Test (TCT), Functional Ambulation Classification (FAC) and Functional Independence Measure (FIM) scores. Serum NfL and GFAP showed different temporal profiles: NfL increased after stroke with a peak value at D7; GFAP showed an earlier peak at D1. NfL and GFAP concentrations correlated with clinical/rehabilitation outcomes both longitudinally and prospectively. Multivariate analysis revealed that NfL-D7 and GFAP-D1 were independent predictors of 3-month NIHSS, TCT, FAC and FIM scores, with NfL being the biomarker with the best predictive performance.
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Accidente Cerebrovascular Isquémico , Accidente Cerebrovascular , Humanos , Proteína Ácida Fibrilar de la Glía , Filamentos Intermedios , BiomarcadoresRESUMEN
Despite the remarkable improvements achieved in the management of metastatic melanoma, there are still unmet clinical needs. A considerable fraction of patients does not respond to immune and/or targeted therapies owing to primary and acquired resistance, high-grade immune-related adverse events, and a lack of alternative treatment options. To design effective combination therapies, we set up a functional ex vivo preclinical assay on the basis of a drop-out genetic screen in metastatic melanoma patient-derived xenografts. We showed that this approach can be used to isolate actionable vulnerabilities predictive of drug efficacy. In particular, we highlighted that the dual targeting of AURKA and MAPK/extracellular signal-regulated kinase kinase employing the combination of alisertib and trametinib is highly effective in a cohort of metastatic melanoma patient-derived xenografts, both ex vivo and in vivo. Alisertib and trametinib combination therapy outperforms standard-of-care therapy in both BRAF-mutant patient-derived xenografts and targeted therapy-resistant models. Furthermore, alisertib and trametinib treatment modulates several critical cancer pathways, including an early metabolic reprogramming that leads to the transcriptional upregulation of the fatty acid oxidation pathway. This acquired trait unveiled an additional point of intervention for pharmacological targeting, and indeed, the triple combination of alisertib and trametinib with the fatty acid oxidation inhibitor etomoxir proved to be further beneficial, inducing tumor regression and remarkably prolonging the overall survival of the mice.
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Aurora Quinasa A , Melanoma , Humanos , Ratones , Animales , Aurora Quinasa A/genética , Inhibidores de Proteínas Quinasas/farmacología , Inhibidores de Proteínas Quinasas/uso terapéutico , Melanoma/tratamiento farmacológico , Melanoma/genética , Pirimidinonas/uso terapéutico , Quinasas de Proteína Quinasa Activadas por Mitógenos , Ácidos Grasos , Proteínas Proto-Oncogénicas B-raf/genética , MutaciónRESUMEN
Deubiquitinating enzymes are key regulators of the ubiquitin-proteasome system and cell cycle, and their dysfunction leads to tumorigenesis. Our in vivo drop-out screens in patient-derived xenograft models identify USP7 as a regulator of melanoma. We show that USP7 downregulation induces cellular senescence, arresting melanoma growth in vivo and proliferation in vitro in BRAF- and NRAS-mutant melanoma. We provide a comprehensive understanding of targets and networks affected by USP7 depletion by performing a global transcriptomic and proteomics analysis. We show that RRM2 is a USP7 target and is regulated by USP7 during S phase of the cell cycle. Ectopic expression of RRM2 in USP7-depleted cells rescues the senescent phenotype. Pharmacological inhibition of USP7 by P5091 phenocopies the shUSP7-induced senescent phenotype. We show that the bifunctional histone deacetylase (HDAC)/LSD1 inhibitor domatinostat has an additive antitumor effect, eliminating P5091-induced senescent cells, paving the way to a therapeutic combination for individuals with melanoma.
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Inhibidores de Histona Desacetilasas , Melanoma , Línea Celular Tumoral , Inhibidores de Histona Desacetilasas/farmacología , Histona Desacetilasas , Histona Demetilasas/genética , Humanos , Melanoma/patología , Complejo de la Endopetidasa Proteasomal , Proteínas Proto-Oncogénicas B-raf/genética , Tiofenos , Peptidasa Específica de Ubiquitina 7/metabolismo , UbiquitinasRESUMEN
Comprehensive genomic studies have delineated key driver mutations linked to disease progression for most cancers. However, corresponding transcriptional changes remain largely elusive because of the bias associated with cross-study analysis. Here, we overcome these hurdles and generate a comprehensive prostate cancer transcriptome atlas that describes the roadmap to tumor progression in a qualitative and quantitative manner. Most cancers follow a uniform trajectory characterized by upregulation of polycomb-repressive-complex-2, G2-M checkpoints, and M2 macrophage polarization. Using patient-derived xenograft models, we functionally validate our observations and add single-cell resolution. Thereby, we show that tumor progression occurs through transcriptional adaption rather than a selection of pre-existing cancer cell clusters. Moreover, we determine at the single-cell level how inhibition of EZH2 - the top upregulated gene along the trajectory - reverts tumor progression and macrophage polarization. Finally, a user-friendly web-resource is provided enabling the investigation of dynamic transcriptional perturbations linked to disease progression.
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Proteína Potenciadora del Homólogo Zeste 2/genética , Proteínas de Neoplasias/genética , Neoplasias de la Próstata/genética , Transcriptoma , Animales , Atlas como Asunto , Línea Celular Tumoral , Progresión de la Enfermedad , Proteína Potenciadora del Homólogo Zeste 2/metabolismo , Puntos de Control de la Fase G2 del Ciclo Celular/genética , Perfilación de la Expresión Génica , Regulación Neoplásica de la Expresión Génica , Xenoinjertos , Humanos , Macrófagos/metabolismo , Macrófagos/patología , Masculino , Ratones , Proteínas de Neoplasias/metabolismo , Complejo Represivo Polycomb 2/genética , Complejo Represivo Polycomb 2/metabolismo , Análisis de Componente Principal , Próstata/metabolismo , Próstata/patología , Neoplasias de la Próstata/metabolismo , Neoplasias de la Próstata/patología , Transducción de Señal , Análisis de la Célula IndividualRESUMEN
The microbiota comprises the microorganisms that live in close contact with the host, with mutual benefit for both counterparts. The contribution of the gut microbiota to the emergence of castration-resistant prostate cancer (CRPC) has not yet been addressed. We found that androgen deprivation in mice and humans promotes the expansion of defined commensal microbiota that contributes to the onset of castration resistance in mice. Specifically, the intestinal microbial community in mice and patients with CRPC was enriched for species capable of converting androgen precursors into active androgens. Ablation of the gut microbiota by antibiotic therapy delayed the emergence of castration resistance even in immunodeficient mice. Fecal microbiota transplantation (FMT) from CRPC mice and patients rendered mice harboring prostate cancer resistant to castration. In contrast, tumor growth was controlled by FMT from hormone-sensitive prostate cancer patients and Prevotella stercorea administration. These results reveal that the commensal gut microbiota contributes to endocrine resistance in CRPC by providing an alternative source of androgens.
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Andrógenos/biosíntesis , Bacterias/metabolismo , Microbioma Gastrointestinal/fisiología , Interacciones Microbiota-Huesped , Neoplasias de la Próstata Resistentes a la Castración/metabolismo , Neoplasias de la Próstata Resistentes a la Castración/microbiología , Anciano , Anciano de 80 o más Años , Antagonistas de Andrógenos/uso terapéutico , Animales , Antibacterianos/farmacología , Bacterias/efectos de los fármacos , Bacterias/genética , Línea Celular Tumoral , Trasplante de Microbiota Fecal , Microbioma Gastrointestinal/efectos de los fármacos , Microbioma Gastrointestinal/genética , Humanos , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Endogámicos NOD , Ratones SCID , Persona de Mediana Edad , Neoplasias Experimentales , Prevotella/metabolismo , Neoplasias de la Próstata Resistentes a la Castración/tratamiento farmacológico , Simbiosis , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Transition from proliferative-to-invasive phenotypes promotes metastasis and therapy resistance in melanoma. Reversion of the invasive phenotype, however, is challenged by the poor understanding of mechanisms underlying its maintenance. Here, we report that the lncRNA TINCR is down-regulated in metastatic melanoma and its silencing increases the expression levels of invasive markers, in vitro migration, in vivo tumor growth, and resistance to BRAF and MEK inhibitors. The critical mediator is ATF4, a central player of the integrated stress response (ISR), which is activated in TINCR-depleted cells in the absence of starvation and eIF2α phosphorylation. TINCR depletion increases global protein synthesis and induces translational reprogramming, leading to increased translation of mRNAs encoding ATF4 and other ISR proteins. Strikingly, re-expression of TINCR in metastatic melanoma suppresses the invasive phenotype, reduces numbers of tumor-initiating cells and metastasis formation, and increases drug sensitivity. Mechanistically, TINCR interacts with mRNAs associated with the invasive phenotype, including ATF4, preventing their binding to ribosomes. Thus, TINCR is a suppressor of the melanoma invasive phenotype, which functions in nutrient-rich conditions by repressing translation of selected ISR RNAs.
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Melanoma , Preparaciones Farmacéuticas , ARN Largo no Codificante , Factor de Transcripción Activador 4/genética , Factor de Transcripción Activador 4/metabolismo , Línea Celular Tumoral , Humanos , Melanoma/genética , Fosforilación , ARN Largo no Codificante/genética , ARN Largo no Codificante/metabolismo , ARN Mensajero/metabolismoRESUMEN
Driver genes with a mutually exclusive mutation pattern across tumor genomes are thought to have overlapping roles in tumorigenesis. In contrast, we show here that mutually exclusive prostate cancer driver alterations involving the ERG transcription factor and the ubiquitin ligase adaptor SPOP are synthetic sick. At the molecular level, the incompatible cancer pathways are driven by opposing functions in SPOP. ERG upregulates wild type SPOP to dampen androgen receptor (AR) signaling and sustain ERG activity through degradation of the bromodomain histone reader ZMYND11. Conversely, SPOP-mutant tumors stabilize ZMYND11 to repress ERG-function and enable oncogenic androgen receptor signaling. This dichotomy regulates the response to therapeutic interventions in the AR pathway. While mutant SPOP renders tumor cells susceptible to androgen deprivation therapies, ERG promotes sensitivity to high-dose androgen therapy and pharmacological inhibition of wild type SPOP. More generally, these results define a distinct class of antagonistic cancer drivers and a blueprint toward their therapeutic exploitation.
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Proteínas Nucleares/metabolismo , Proteínas Oncogénicas/metabolismo , Neoplasias de la Próstata/metabolismo , Proteínas Represoras/metabolismo , Regulador Transcripcional ERG/metabolismo , Complejos de Ubiquitina-Proteína Ligasa/metabolismo , Animales , Biomarcadores de Tumor/metabolismo , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , Línea Celular Tumoral , Proteínas Co-Represoras/genética , Proteínas Co-Represoras/metabolismo , Proteínas de Unión al ADN/genética , Proteínas de Unión al ADN/metabolismo , Células HEK293 , Humanos , Inmunohistoquímica , Inmunoprecipitación , Masculino , Ratones , Ratones Desnudos , Mutación/genética , Proteínas Nucleares/genética , Proteínas Oncogénicas/genética , Neoplasias de la Próstata/genética , Unión Proteica , Proteómica , Receptores Androgénicos/metabolismo , Proteínas Represoras/genética , Transducción de Señal/fisiología , Regulador Transcripcional ERG/genética , Complejos de Ubiquitina-Proteína Ligasa/genéticaRESUMEN
Extracellular vesicles (EVs) are relevant means for transferring signals across cells and facilitate propagation of oncogenic stimuli promoting disease evolution and metastatic spread in cancer patients. Here, we investigated the release of miR-424 in circulating small EVs or exosomes from prostate cancer patients and assessed the functional implications in multiple experimental models. We found higher frequency of circulating miR-424 positive EVs in patients with metastatic prostate cancer compared to patients with primary tumors and BPH. Release of miR-424 in small EVs was enhanced in cell lines (LNCaPabl), transgenic mice (Pb-Cre4;Ptenflox/flox;Rosa26ERG/ERG) and patient-derived xenograft (PDX) models of aggressive disease. EVs containing miR-424 promoted stem-like traits and tumor-initiating properties in normal prostate epithelial cells while enhanced tumorigenesis in transformed prostate epithelial cells. Intravenous administration of miR-424 positive EVs to mice, mimicking blood circulation, promoted miR-424 transfer and tumor growth in xenograft models. Circulating miR-424 positive EVs from patients with aggressive primary and metastatic tumors induced stem-like features when supplemented to prostate epithelial cells. This study establishes that EVs-mediated transfer of miR-424 across heterogeneous cell populations is an important mechanism of tumor self-sustenance, disease recurrence and progression. These findings might indicate novel approaches for the management and therapy of prostate cancer.
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Transformación Celular Neoplásica/genética , Micropartículas Derivadas de Células/metabolismo , Vesículas Extracelulares/metabolismo , MicroARNs/metabolismo , Neoplasias de la Próstata , Animales , Línea Celular Tumoral , Transformación Celular Neoplásica/metabolismo , Micropartículas Derivadas de Células/genética , Vesículas Extracelulares/genética , Humanos , Masculino , Ratones , Ratones Endogámicos NOD , Ratones SCID , Ratones Transgénicos , MicroARNs/genética , Modelos Teóricos , Invasividad Neoplásica , Neoplasias de la Próstata/genética , Neoplasias de la Próstata/metabolismo , Neoplasias de la Próstata/patologíaRESUMEN
The aim of this study was to provide an innovative nomogram to predict the risk of >2 positive nodes in patients fulfilling the Z0011 criteria with 1-2 sentinel lymph nodes (SLNs) only retrieved.From 2007 to 2017, at the Breast Unit of ICS Maugeri Hospital 271 patients with 1-2 macrometastatic SLNs, fulfilling the Z0011 criteria, underwent axillary dissection and were retrospectively reviewed.A mean of 1.5 SLNs per patient were identified and retrieved. One hundred eighty-seven (69.0%) had 1-2 positive nodes, and 84 (31.0%) had >2 metastatic nodes. Independent predictors of axillary status were: positive SLNs/retrieved SLNs ratio (odds ratio [OR] 10.95, Pâ=â.001), extranodal extension (OR 5.51, Pâ=â.0002), and multifocal disease (OR 2.9, Pâ=â.003). A nomogram based on these variables was constructed (area under curve after bootstrapâ=â0.74).The proposed nomogram might select those patients fulfilling the Z0011 criteria, with 1-2 SLNs harvested, in whom a high axillary tumor burden is expected, aiding to guide adjuvant treatments.
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Neoplasias de la Mama/patología , Neoplasias Primarias Múltiples/patología , Nomogramas , Ganglio Linfático Centinela/patología , Anciano , Antineoplásicos Hormonales/uso terapéutico , Área Bajo la Curva , Axila , Neoplasias de la Mama/terapia , Quimioterapia Adyuvante , Femenino , Humanos , Metástasis Linfática , Mastectomía Segmentaria , Persona de Mediana Edad , Estadificación de Neoplasias , Radioterapia Adyuvante , Carga TumoralRESUMEN
BACKGROUND: Development of metastases and drug resistance are still a challenge for a successful systemic treatment in breast cancer (BC) patients. One of the mechanisms that confer metastatic properties to the cell relies in the epithelial-to-mesenchymal transition (EMT). Moreover, both EMT and metastasis are partly modulated through epigenetic mechanisms, by repression or induction of specific related genes. METHODS: We applied shRNAs and drug targeting approaches in BC cell lines and metastatic patient-derived xenograft (PDX) models to inhibit WDR5, the core subunit of histone H3 K4 methyltransferase complexes, and evaluate its role in metastasis regulation. RESULT: We report that WDR5 is crucial in regulating tumorigenesis and metastasis spreading during BC progression. In particular, WDR5 loss reduces the metastatic properties of the cells by reverting the mesenchymal phenotype of triple negative- and luminal B-derived cells, thus inducing an epithelial trait. We also suggest that this regulation is mediated by TGFß1, implying a prominent role of WDR5 in driving EMT through TGFß1 activation. Moreover, such EMT reversion can be induced by drug targeting of WDR5 as well, leading to BC cell sensitization to chemotherapy and enhancement of paclitaxel-dependent effects. CONCLUSIONS: We suggest that WDR5 inhibition could be a promising pharmacologic approach to reduce cell migration, revert EMT, and block metastasis formation in BC, thus overcoming resistance to standard treatments.
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Neoplasias de la Mama/genética , Neoplasias de la Mama/patología , Transición Epitelial-Mesenquimal/genética , Péptidos y Proteínas de Señalización Intracelular/genética , Fenotipo , Animales , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/metabolismo , Línea Celular Tumoral , Proliferación Celular , Modelos Animales de Enfermedad , Progresión de la Enfermedad , Transición Epitelial-Mesenquimal/efectos de los fármacos , Femenino , Regulación Leucémica de la Expresión Génica , Xenoinjertos , Humanos , Péptidos y Proteínas de Señalización Intracelular/antagonistas & inhibidores , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Ratones , Ratones Transgénicos , Modelos Biológicos , Metástasis de la Neoplasia , Estadificación de Neoplasias , Interferencia de ARN , ARN Interferente Pequeño/genética , Transducción de Señal , Transcripción Genética , Factor de Crecimiento Transformador beta1/metabolismoRESUMEN
BACKGROUND: The oncologic benefit of upfront re-excision of involved margins after breast-conserving surgery in the context of current multimodal clinical management of breast cancer is unclear. The aim of the present study was to assess the 5-years locoregional recurrence (LRR)-free and distant metastases (DM)-free survival probabilities in patients not undergoing re-excision of positive margins after lumpectomy for breast cancer. METHODS: A cohort of 104 patients with positive margins not undergoing re-excision was matched by propensity score with a cohort of 2006 control patients with clear margins after breast-conserving surgery, treated between 2008 and 2018. A multivariate survival analysis was performed accounting for all variables related to LRR and DM, including adjuvant treatments. RESULTS: After adjusting for potential confounders, avoiding to re-excise a positive margin after lumpectomy had no effect on 5-years LRR-free survival probability (HR 0.98, 95%CI 0.36-2.67, pâ¯=â¯0.96) or 5-years DM-free survival probability (HR 0.37, 95%CI 0.08-1.61, pâ¯=â¯0.18). No correlation was found between occurrence of LRR and number of involved margins (HR 1.28, 95%CI 0.10-12.4, Log-rank pâ¯=â¯0.83), or extension of infiltrating disease (HR 1.21, 95%CI 0.20-7.40, Log-rank pâ¯=â¯0.83), but a trend toward higher LRR probability was found for invasive ductal (HR 6.92, 95%CI 0.7-68.8, Log-rank pâ¯=â¯0.10) and invasive lobular cancer (HR 12.95, 95%CI 0.79-213.6, Log-rank pâ¯=â¯0.07) on positive margins. CONCLUSIONS: In the era of multimodal treatment of breast cancer and accurate strategies to reduce the probability of residual disease in the post-lumpectomy cavity, re-excision of positive margins might be omitted in selected patients with low-risk breast cancers.
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Neoplasias de la Mama/mortalidad , Carcinoma Ductal de Mama/mortalidad , Carcinoma Intraductal no Infiltrante/mortalidad , Carcinoma Lobular/mortalidad , Márgenes de Escisión , Mastectomía Segmentaria/mortalidad , Recurrencia Local de Neoplasia/mortalidad , Neoplasias de la Mama/patología , Neoplasias de la Mama/cirugía , Carcinoma Ductal de Mama/secundario , Carcinoma Ductal de Mama/cirugía , Carcinoma Intraductal no Infiltrante/secundario , Carcinoma Intraductal no Infiltrante/cirugía , Carcinoma Lobular/secundario , Carcinoma Lobular/cirugía , Femenino , Estudios de Seguimiento , Humanos , Metástasis Linfática , Persona de Mediana Edad , Invasividad Neoplásica , Recurrencia Local de Neoplasia/patología , Recurrencia Local de Neoplasia/cirugía , Pronóstico , Estudios Prospectivos , Reoperación , Estudios Retrospectivos , Tasa de SupervivenciaRESUMEN
Obtaining a tailored breast resection is challenging in microcalcifications detected on screening mammography, and an accurate localization is required. The aim of this study was to compare the efficacy of radio-guided localization (ROLL) versus ultrasound localization of a titanium clip with collagen (TCC) in terms of clear margins, re-intervention rates, excess of resected breast tissue, and operative times in pure malignant microcalcifications detected on screening mammography. Two hundred and twenty-one consecutive patients with malignant microcalcifications detected on screening mammography from a tertiary breast unit were reviewed: 177 patients were localized by TCC and 44 patients by stereotactic ROLL. A propensity score-matched analysis was performed, followed by a logistic regression model, to avoid selection bias. Adequacy of resection was expressed as the calculated resection ratio considering lesion size. No differences were found in clear margins with ROLL versus TCC (77.3% vs 81.8%, adjusted OR 2, P = 0.27). Re-operation rates were similar, being 11.3% with ROLL and 7.4% with TCC (P = 0.627). Mean resection volume was 46.2 cm3 with ROLL versus 54.2 cm3 with TCC (P = 0.222). Adjusted mean calculated resection ratio was 1.8 with ROLL and 2.1 with TCC (P = 0.38). Surgery time was longer with TCC compared to ROLL (69.6 vs 52.7 minutes, P < 0.0001). ROLL and TCC are equally effective to excise malignant microcalcifications with clear margins, providing similar re-intervention rates and resection volumes.
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Neoplasias de la Mama/cirugía , Calcinosis/cirugía , Mastectomía Segmentaria/métodos , Neoplasias de la Mama/diagnóstico por imagen , Neoplasias de la Mama/patología , Calcinosis/diagnóstico por imagen , Calcinosis/patología , Femenino , Humanos , Márgenes de Escisión , Radiografía Intervencional/métodos , Cintigrafía/métodos , Resultado del Tratamiento , Ultrasonografía , Ultrasonografía Mamaria/métodosRESUMEN
INTRODUCTION: Autologous fat transfer (AFT) is widely adopted for breast reconstruction, but its long-term oncologic safety is still not clearly established. The aim of the present study was to compare the 10-year loco-regional recurrence (LRR)-free and distant metastases (DM)-free survival probabilities in AFT vs. control patients, also evaluating the impact of AFT in different intrinsic molecular subtypes of breast cancer. MATERIALS AND METHODS: 464 AFT patients were exactly matched with a cohort of 3100 control patients treated between 2007 and 2017. A multivariate survival analysis was performed accounting for all variables related to LRR and DM, including adjuvant/neoadjuvant treatments. End-points were analyzed both overall and in each molecular subtype. RESULTS: LRR occurred in 6.4% of AFT and in 5.0% of control patients (pâ¯=â¯0.42), while DM were observed respectively in 7.7% and 5.4% of cases (pâ¯=â¯0.20). AFT showed no effect on the 10-year LRR-free survival probability (adjusted HR 0.87, 95%CI 0.43-1.76, pâ¯=â¯0.69) or the 10-year DM-free survival probability (adjusted HR 0.82, 95%CI 0.43-1.57, pâ¯=â¯0.55). Luminal A patients treated by AFT showed a decreased LRR-free survival probability (HR 2.38, 95%CI 0.91-6.17, Log-Rank pâ¯=â¯0.07), which was significantly lower than controls after 80 months (Log-Rank pâ¯=â¯0.02). No differences in the 10-year event-free survival probability were found in Luminal B, HER2-positive or triple-negative patients. CONCLUSION: AFT does not increase breast cancer recurrence, with the possible exception of late LRRs for Luminal A patients, but further clinical and preclinical data are required to better clarify this data. The use of AFT should not be discouraged.
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Tejido Adiposo/trasplante , Neoplasias de la Mama/cirugía , Mamoplastia/métodos , Recurrencia Local de Neoplasia/epidemiología , Neoplasias de la Mama/mortalidad , Supervivencia sin Enfermedad , Femenino , Estudios de Seguimiento , Humanos , Incidencia , Italia/epidemiología , Mastectomía , Estudios Retrospectivos , Tasa de Supervivencia/tendencias , Factores de Tiempo , Trasplante Autólogo , Resultado del TratamientoRESUMEN
BACKGROUND AND OBJECTIVES: An accurate localization is mandatory to tailor breast lumpectomy in nonpalpable cancers. The aim of this study was to compare radio-guided localization (ROLL) vs ultrasound localization of a titanium clip with collagen (TCC) in nonpalpable mass-like breast cancers. METHODS: Two hundred seventy-three consecutive patients were reviewed: 64 patients were localized by TCC and 209 patients by ROLL. Propensity score-matched analysis was performed. Margin status and reintervention rates were compared. Adequacy of resection was expressed as the calculated resection ratio (CRR) considering lesion size. Loco-regional and distant recurrence rates were assessed with ROLL vs TCC. RESULTS: No differences were found with ROLL vs TCC in clear margins (90.6% vs 89.1%; odds ratio, 0.74; P = 0.64) or reoperations (6.7% vs 1.6%; P = 0.529). ROLL allowed more tailored resections compared with TCC (adjusted CRR, 1.7 vs 2.7; P = 0.0008), particularly in lesions with associated extensive intraductal component (CRR, 3.0 vs 4.5; P = 0.017). Loco-regional recurrence occurred in 1.9% of ROLL patients vs 3.2% of TCC cases (P = 0.628). CONCLUSIONS: ROLL and TCC are equally effective to excise nonpalpable mass-like breast cancers with clear margins, providing similar loco-regional control. However, ROLL allows more tailored breast resections, particularly in lesions with the associated extensive intraductal component.
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Neoplasias de la Mama/diagnóstico por imagen , Neoplasias de la Mama/cirugía , Mastectomía Segmentaria/métodos , Anciano , Femenino , Humanos , Metástasis Linfática , Márgenes de Escisión , Persona de Mediana Edad , Puntaje de Propensión , Cintigrafía/métodos , Estudios Retrospectivos , Instrumentos Quirúrgicos , Titanio , Ultrasonografía Mamaria/métodosRESUMEN
MOTIVATION: Acute myeloid leukemia (AML) is one of the most common hematological malignancies, characterized by high relapse and mortality rates. The inherent intra-tumor heterogeneity in AML is thought to play an important role in disease recurrence and resistance to chemotherapy. Although experimental protocols for cell proliferation studies are well established and widespread, they are not easily applicable to in vivo contexts, and the analysis of related time-series data is often complex to achieve. To overcome these limitations, model-driven approaches can be exploited to investigate different aspects of cell population dynamics. RESULTS: In this work, we present ProCell, a novel modeling and simulation framework to investigate cell proliferation dynamics that, differently from other approaches, takes into account the inherent stochasticity of cell division events. We apply ProCell to compare different models of cell proliferation in AML, notably leveraging experimental data derived from human xenografts in mice. ProCell is coupled with Fuzzy Self-Tuning Particle Swarm Optimization, a swarm-intelligence settings-free algorithm used to automatically infer the models parameterizations. Our results provide new insights on the intricate organization of AML cells with highly heterogeneous proliferative potential, highlighting the important role played by quiescent cells and proliferating cells characterized by different rates of division in the progression and evolution of the disease, thus hinting at the necessity to further characterize tumor cell subpopulations. AVAILABILITY AND IMPLEMENTATION: The source code of ProCell and the experimental data used in this work are available under the GPL 2.0 license on GITHUB at the following URL: https://github.com/aresio/ProCell. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.
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Leucemia Mieloide Aguda , Animales , División Celular , Proliferación Celular , Xenoinjertos , Humanos , RatonesRESUMEN
BACKGROUND: Intraoperative radiotherapy (IORT) could be not-inferior to external beam radiotherapy (EBRT) in selected patients, but toxicities, self-perception of body image, quality of life, and resumption of work or daily activities have been poorly explored. The aim of the present study was to compare these outcomes between EBRT, IORT full-dose (IORT-f) and IORT boost (IORT-b). METHODS: 443 consecutive patients, candidates for breast-conserving surgery, were included: EBRT was performed in 220 patients (49.7%), IORT-f in 140 patients (31.6%), and IORT-b in 83 patients (18.7%). Radiotherapy-related toxicities were registered. Patients were evaluated at 6 months for Body Image after Breast Cancer Questionnaire (BIBCQ) to assess possible changes in self-perception of body image and limitations. A second questionnaire explored the impact of EBRT, IORT-f and IORT-b on resumption of work and normal daily activities. RESULTS: EBRT had a higher risk of breast fibrosis and retraction (OR 3.58, 95% CI 1.024-12.526, pâ¯=â¯0.046) and breast edema (OR 6, 95% CI 2.077-17.335, pâ¯=â¯0.001) compared to IORT-f, but a lower risk of seroma compared to IORT-b (OR 0.36, 95% CI 0.166-0.785, pâ¯=â¯0.01). The BIBCQ scores showed a better outcome in arm concerns with IORT-f (-3.3) vs. IORT-b (-1.3, pâ¯=â¯0.002) and EBRT (-1.7, pâ¯=â¯0.006), although biased by the lower rate in axillary dissections. Return to daily activities occurred after 70.6 days with EBRT vs. 41 days with IORT-f (pâ¯<â¯0.0001) and 53.3 days with IORT-b (pâ¯=â¯0.07), without any effect of age or axillary dissection. CONCLUSION: IORT could reduce adverse effects, allowing faster resumption of job and houseworks.
Asunto(s)
Neoplasias de la Mama/radioterapia , Cuidados Intraoperatorios/métodos , Mastectomía Segmentaria/métodos , Calidad de Vida , Reinserción al Trabajo , Anciano , Imagen Corporal/psicología , Neoplasias de la Mama/psicología , Neoplasias de la Mama/cirugía , Femenino , Humanos , Mastectomía Segmentaria/psicología , Persona de Mediana Edad , Periodo Posoperatorio , Dosificación Radioterapéutica , Radioterapia Adyuvante/métodos , Resultado del TratamientoRESUMEN
BACKGROUND: The equipment to detect indocyanine green (ICG) fluorescence for sentinel lymph node (SLN) biopsy in breast cancer is not widely accessible nor optimal. The fluorescence appears as a poorly defined white shine on a black background, and dimmed lighting is required. The aim of this study was to assess the feasibility, accuracy and healthcare costs of a novel approach for SLN biopsy by a video-assisted ICG-guided technique. METHODS: The technique for detecting SLN was radioisotope (RI) in 194 cases, video-assisted ICG-guided in 70 cases and a combined method in 71 cases. In the video-assisted ICG group, a full HD laparoscopic system equipped with xenon lamps was used for a laser-free detection of ICG within a colored and magnified high-resolution image. RESULTS: Detection of ICG fluorescence using a laparoscope with a near-infrared filter provided a highly defined and colored image during SLN biopsy. SLN was identified in 100% of patients in all groups. Multiple SLNs were identified in 0.5% of RI patients, in 12.9% of ICG patients and in 14.1% of ICG + RI patients (p < 0.0001). In ICG + RI group, 95.1% of lymph nodes were radioactive and 92.7% were fluorescent. Operative times and healthcare costs were equivalent between groups. CONCLUSIONS: Video-assisted ICG-guided technique is a feasible and surgeon-friendly method for SLN biopsy, with equivalent efficacy compared to RI, providing an accurate staging of the axilla.
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Neoplasias de la Mama/patología , Colorantes , Verde de Indocianina , Biopsia del Ganglio Linfático Centinela/métodos , Cirugía Asistida por Video/métodos , Anciano , Axila , Costos y Análisis de Costo , Estudios de Factibilidad , Femenino , Fluorescencia , Humanos , Ganglios Linfáticos/patología , Metástasis Linfática/diagnóstico , Persona de Mediana Edad , Estadificación de Neoplasias/métodos , Ganglio Linfático Centinela/patología , Biopsia del Ganglio Linfático Centinela/economía , Cirugía Asistida por Video/economíaRESUMEN
Sentinel lymph node biopsy for ductal carcinoma in situ (DCIS) of the breast is not standard of care. However, nodal involvement for DCIS patients is reported. Aim of our study was to identify preoperative features predictive of nodal involvement in DCIS patients. We have retrospectively reviewed 175 patients with a preoperative diagnosis of DCIS following a vacuum-assisted breast biopsy, and undergoing surgery with sentinel node biopsy. Variables distribution was compared between patients upstaged to invasive cancer at final pathology and patients with a confirmed DCIS, and between positive vs negative sentinel node patients. Univariate and multivariate analyses were performed for risk of a positive node. Lymph node biopsy was positive in 13 (7.4%) patients, with 8 (61.5%) macrometastases and 5 (38.5%) micrometastases. In these patients, Breast Imaging Reporting and Data System (BI-RADS) index >4 (OR 4.69, 95% CI 1.282-17.224, P = .02), lesion extension ≥20 mm (OR 4.25, 95% CI 1.255-14.447, P = .02), multifocal disease (OR 4.12, 95% CI 0.987-17.174, P = .05), comedo type (OR 3.54, 95% CI 1.044-11.969, P = .04), and upstaging (OR 4.56, 95% CI 1.080-19.249, P = .04) were all predictive of nodal involvement, although upstaging could not be predicted preoperatively. By multivariate analysis, the only independent factor predictive for positive sentinel node was multifocal disease (OR 5.14, 95% CI 1.015-26.066, P < .05). A preoperative diagnosis of DCIS, also including advanced biopsy systems such as vacuum-assisted breast biopsy, may be not always sufficient to exclude patients from sentinel node biopsy. DCIS patients with associated BI-RADS >4, lesion extension ≥20 mm, comedo type, and above all multifocal disease should be considered for axillary evaluation.