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BACKGROUND: Tinnitus is burdensome to many patients. Sound amplification and masking therapy has been useful for some patients. METHOD: Retrospective chart review of patients treated for tinnitus at a single academic medical center over a 12-month period. Information on treatment course and outcomes was collected and analyzed. Statistical comparisons were made using a t-test for paired means. RESULTS: In 2021, 141 patients were evaluated for tinnitus sound amplification and masking therapy at our medical center. Average age at presentation was 55.2. Average onset was 6-7 years before presentation. Tinnitus perception was decreased in patients who received a trial of amplification and masking therapy, from 9.2 out of 20 at baseline to 6.1 with amplification and 3.2 with amplification and masking at the initial visit. The difference in each of these values is statistically significant. Nine patients recorded a Tinnitus Handicap Index (THI), which measures tinnitus burden, before and after being treated with amplification and masking therapy. These nine patients saw a decrease in THI from 39.6/100 to 19.1/100, which was also statistically significant. LIMITATIONS: This study has several limitations. Our data are from a single clinic over one year with limited follow up information, and it is a retrospective study. CONCLUSION: Our data showed benefit in sound amplification and masking therapy for the treatment of tinnitus. Patients treated with amplification and masking therapy showed a statistically significant decrease in perception of their tinnitus during their in-office demonstration. Long term data are still needed. Our data contribute to the broader discussion on the proper treatment course of tinnitus and the most effective measures.
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Acúfeno , Humanos , Estudios Retrospectivos , Acúfeno/terapia , Centros Médicos Académicos , Instituciones de Atención Ambulatoria , Resultado del TratamientoRESUMEN
PURPOSE: Existing prognostic biomarkers are inadequate for stratifying breast cancer patients with the highest risk of tumor progression at the time of diagnosis. Here, we demonstrate that the small GTPase Ran has predictive value for breast cancer (BC) patients as a whole, and for specific BC subtypes. PATIENTS AND METHODS: Ran expression was quantified by immunohistochemistry in 263 patients with primary breast cancer diagnosed at the Breast Unit, Royal Liverpool Hospital. Additionally as an independent validation, we also analyzed the mRNA expressions of Ran, ER, PR, and Cerb-2, the triple-negative endocrine receptors, and their associations with patient survival in a combined patient cohorts of multiple public datasets (n = 1079). We analyzed the data with Spearman's rank correlation and Kaplan-Meier plots coupled with Wilcoxon-Gehan tests, respectively. All statistical tests were two-sided. RESULTS: Ran nuclear, cytoplasmic, and total staining are substantially associated with poor survival, independent of conventional prognostic markers such as estrogen receptor (ER), human epidermal growth factor receptor 2 (HER2), and lymph node status. According to the datasets, Ran was significantly correlated with distant metastasis-free survival (DMFS) and relapse-free survival (RFS). CONCLUSION: We found that Ran expression is a unique predictive biomarker for patient survival, metastasis, and tumor relapse. This biomarker could be used for diagnostic purposes, using formalin-fixed, paraffin-embedded tumor biopsy samples from breast cancer patients in the early stages.
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Neoplasias de la Mama , Femenino , Humanos , Biomarcadores de Tumor/genética , Neoplasias de la Mama/diagnóstico , Neoplasias de la Mama/genética , Neoplasias de la Mama/metabolismo , Supervivencia sin Enfermedad , Recurrencia Local de Neoplasia , Pronóstico , Receptores de Progesterona/genéticaRESUMEN
Most patients who die of cancer do so from its metastasis to other organs. The calcium-binding protein S100A4 can induce cell migration/invasion and metastasis in experimental animals and is overexpressed in most human metastatic cancers. Here, we report that a novel inhibitor of S100A4 can specifically block its increase in cell migration in rat (IC50, 46 µM) and human (56 µM) triple negative breast cancer (TNBC) cells without affecting Western-blotted levels of S100A4. The moderately-weak S100A4-inhibitory compound, US-10113 has been chemically attached to thalidomide to stimulate the proteasomal machinery of a cell. This proteolysis targeting chimera (PROTAC) RGC specifically eliminates S100A4 in the rat (IC50, 8 nM) and human TNBC (IC50, 3.2 nM) cell lines with a near 20,000-fold increase in efficiency over US-10113 at inhibiting cell migration (IC50, 1.6 nM and 3.5 nM, respectively). Knockdown of S100A4 in human TNBC cells abolishes this effect. When PROTAC RGC is injected with mouse TNBC cells into syngeneic Balb/c mice, the incidence of experimental lung metastases or local primary tumour invasion and spontaneous lung metastasis is reduced in the 10-100 nM concentration range (Fisher's Exact test, p ≤ 0.024). In conclusion, we have established proof of principle that destructive targeting of S100A4 provides the first realistic chemotherapeutic approach to selectively inhibiting metastasis.
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Proteína de Unión al Calcio S100A4 , Neoplasias de la Mama Triple Negativas , Animales , Humanos , Ratones , Ratas , Línea Celular Tumoral , Movimiento Celular , Invasividad Neoplásica , Metástasis de la Neoplasia , Proteína de Unión al Calcio S100A4/farmacología , Neoplasias de la Mama Triple Negativas/tratamiento farmacológico , Neoplasias de la Mama Triple Negativas/metabolismo , Quimera Dirigida a la Proteólisis/metabolismo , Quimera Dirigida a la Proteólisis/farmacologíaRESUMEN
BACKGROUND: The impact of preprocedure imaging on the safety and effectiveness of left atrial appendage occlusion (LAAO) remains unclear. OBJECTIVES: This study sought to determine the rates of use of preprocedure computed tomography (CT)/cardiac magnetic resonance (CMR) and its association with safety and effectiveness of LAAO procedures. METHODS: The National Cardiovascular Data Registry LAAO Registry was used to evaluate patients who underwent attempted LAAO with the WATCHMAN and WATCHMAN FLX devices between January 1, 2016, and June 30, 2021. Safety and effectiveness of LAAO procedures was compared by use vs nonuse of preprocedural CT/CMR. Outcomes of interest included implantation success (deployment and release of device), device success (device released with peridevice leak <5 mm), and procedure success (device released with peridevice leak <5 mm and no in-hospital major adverse events [MAE]). Multivariable logistic regression was used to assess the relationship between preprocedure imaging and outcomes. RESULTS: Preprocedure CT/CMR was used for 18.2% (n = 20,851) of the 114,384 procedures in this study. CT/CMR use was more common among government and university hospitals and hospitals in the Midwest and South; it was less common among patients with uncontrolled hypertension, with abnormal renal function, and without prior thromboembolism. Overall rates of implantation success, device success, and procedure success were 93.4%, 91.2%, and 89.4%, respectively. Preprocedure CT/CMR was independently associated with an increased likelihood of implantation success (OR: 1.08; 95% CI: 1.00-1.17), device success (OR: 1.10; 95% CI: 1.04-1.16), and procedural success (OR: 1.07; 95% CI: 1.02-1.13). MAE were uncommon (2.3%) and not associated with use of preprocedure CT/CMR (OR: 1.02; 95% CI: 0.92-1.12). CONCLUSIONS: Preprocedure CT/CMR was associated with an increased likelihood of successful LAAO implantation; however, the magnitude of benefit appears small and it was not associated with MAE.
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Apéndice Atrial , Hipertensión , Humanos , Apéndice Atrial/diagnóstico por imagen , Resultado del Tratamiento , Tomografía Computarizada por Rayos X , Sistema de RegistrosRESUMEN
RAS-related nuclear protein(RAN) is a nuclear shuttle and normally regulates events in the cell cycle. When overexpressed in cultured cells, it causes increases in cell migration/invasion in vitro and its overexpression is associated with early breast cancer patient deaths in vivo. However, the underlying mechanism is unknown. The effect of RAN overexpression on potential targets MMP2, ATF3, CXCR3 was investigated by Real-Time PCR/Western blots in the triple receptor negative breast cancer(TRNBC) cell line MDA-MB231 and consequent biological effects were measured by cell adhesion, cell migration and cell invasion assays. Results showed that knockdown of RAN lead to a reduction of MMP2 and its potential regulators ATF3 and CXCR3. Moreover, knockdown of ATF3 or CXCR3 downregulated MMP2 without affecting RAN, indicating that RAN regulates MMP2 through ATF3 and CXCR3. Knockdown of RAN and MMP2 reduced cell adhesion, cell migration and cell growth in agar, whilst overexpression of MMP2 reversed the knockdown of RAN. Furthermore, immunohistochemical staining for RAN and MMP2 are positively associated with each other in the same tumour and separately with patient survival times in breast cancer specimens, suggesting that a high level of RAN may be a pre-requisite for MMP2 overexpression and metastasis. Moreover, positive immunohistochemical staining for both RAN and MMP-2 reduces further patient survival times over that for either protein separately. Our results suggest that MMP2 expression can stratify progression of breast cancers with a high and low incidence of RAN, both RAN and MMP2 in combination can be used for a more accurate patient prognosis. SIMPLE SUMMARY: Ran is an important regulator of normal cell growth and behaviour. We have established in cell line models of breast cancer (BC) a molecular pathway between RAN and its protein-degrading effector MMP-2 and properties related to metastasis in culture. Using immunohistochemistry (IHC) staining of primary BCs, we have shown that RAN and MMP-2 are on their own significantly associated with patient demise from metastatic BC. Moreover, when staining for MMP-2 is added to that for RAN in the primary tumours, there is a significant decrease in patient survival time over that for either protein alone. Thus a combination of staining for RAN and MMP2 is an excellent marker for poor prognosis in breast cancer.
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Neoplasias de la Mama , Metaloproteinasa 2 de la Matriz , Neoplasias de la Mama Triple Negativas , Proteína de Unión al GTP ran , Femenino , Humanos , Neoplasias de la Mama/patología , Línea Celular Tumoral , Movimiento Celular , Regulación Neoplásica de la Expresión Génica , Guanosina Trifosfato , Metaloproteinasa 2 de la Matriz/metabolismo , Invasividad Neoplásica , Proteína de Unión al GTP ran/genética , Proteína de Unión al GTP ran/metabolismo , Neoplasias de la Mama Triple Negativas/patologíaRESUMEN
Atrial cardiomyopathy has been recognized as having important consequences for cardiac performance and clinical outcomes. The pathophysiological role of the left atrial (LA) appendage and the effect of percutaneous left atrial appendage occlusion (LAAO) upon LA mechanics is incompletely understood. We evaluated if changes in LA stiffness due to endocardial LAAO can be detected by LA pressure-volume (PV) analysis and whether stiffness parameters are associated with baseline characteristics. Patients undergoing percutaneous endocardial LAAO (n = 25) were studied using a novel PV analysis using near-simultaneous three-dimensional LA volume measurements by transesophageal echocardiography (TEE) and direct invasive LA pressure measurements. LA stiffness (dP/dV, change in pressure with change in volume) was calculated before and after LAAO. Overall LA stiffness significantly increased after LAAO compared with baseline (median, 0.41-0.64 mmHg/mL; P ⪠0.001). LA body stiffness after LAAO correlated with baseline LA appendage size by indexed maximum depth (Spearman's rank correlation coefficient Rs = 0.61; P < 0.01). LA stiffness change showed an even stronger correlation with baseline LA appendage size by indexed maximum depth (Rs = 0.70; P < 0.001). We found that overall LA stiffness increases after endocardial LAAO. Baseline LA appendage size correlates with the magnitude of increase and LA body stiffness. These findings document alteration of LA mechanics after endocardial LAAO and suggest that the LA appendage modulates overall LA compliance.NEW & NOTEWORTHY Our study documents a correlation of LA appendage remodeling with the degree of chronically abnormal LA body stiffness. In addition, we found that LA appendage size was the baseline parameter that best correlated with the magnitude of a further increase in overall LA stiffness after appendage occlusion. These findings offer insights about the LA appendage and LA mechanics that are relevant to patients at risk for adverse atrial remodeling, especially candidates for LA appendage occlusion.
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Apéndice Atrial , Fibrilación Atrial , Accidente Cerebrovascular , Enfermedades Vasculares , Apéndice Atrial/diagnóstico por imagen , Fibrilación Atrial/diagnóstico por imagen , Fibrilación Atrial/etiología , Cateterismo Cardíaco , Ecocardiografía Transesofágica/métodos , Humanos , Accidente Cerebrovascular/etiología , Resultado del TratamientoRESUMEN
BACKGROUND: Pivotal trials of percutaneous left atrial appendage occlusion (LAAO) used specific postprocedure treatment protocols. OBJECTIVES: This study sought to evaluate patterns of postprocedure care after LAAO with the Watchman device in clinical practice and compare the risk of adverse events for different discharge antithrombotic strategies. METHODS: We evaluated patients in the LAAO Registry of the National Cardiovascular Data Registry who underwent LAAO with the Watchman device between 2016 and 2018. We assessed adherence to the full postprocedure trial protocol including standardized follow-up, imaging, and antithrombotic agents and then evaluated the most commonly used antithrombotic strategies and compared the rates and risk of adverse events at 45 days and 6 months by means of multivariable COX frailty regression. RESULTS: Among 31,994 patients undergoing successful LAAO, only 12.2% received the full postprocedure treatment protocol studied in pivotal trials; the most common protocol deviations were with discharge antithrombotic medications. The most common discharge medication strategies were warfarin and aspirin (36.9%), direct oral anticoagulant (DOAC) and aspirin (20.8%), warfarin only (13.5%), DOAC only (12.3%), and dual antiplatelet therapy (5.0%). In multivariable Cox frailty regression, the adjusted risk of any adverse event through the 45-day follow-up visit were significantly lower for discharge on warfarin alone (HR: 0.692; 95% CI: 0.569-0.841) and DOAC alone (HR: 0.731; 95% CI: 0.574-0.930) compared with warfarin and aspirin. Warfarin alone retained lower risk at the 6-month follow-up. CONCLUSIONS: In contemporary U.S. practice, practitioners rarely used the full U.S. Food and Drug Administration-approved postprocedure treatment protocols studied in pivotal trials of the Watchman device. Discharge after implantation on warfarin or DOAC without concomitant aspirin was associated with lower risk of adverse outcomes.
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Apéndice Atrial , Fibrilación Atrial , Fragilidad , Accidente Cerebrovascular , Anticoagulantes/uso terapéutico , Aspirina/uso terapéutico , Apéndice Atrial/cirugía , Fibrilación Atrial/complicaciones , Fibrilación Atrial/tratamiento farmacológico , Fibrilación Atrial/cirugía , Fibrinolíticos/uso terapéutico , Fragilidad/complicaciones , Humanos , Accidente Cerebrovascular/epidemiología , Accidente Cerebrovascular/etiología , Accidente Cerebrovascular/prevención & control , Resultado del Tratamiento , Warfarina/uso terapéuticoRESUMEN
This article examines the genesis, development and implementation of an interdisciplinary university cross-school research group (three individual schools) at Federation University in Australia. This CSRG is a consequence of both local and national calls for interdisciplinarity in university research and a direct response to the revised Strategic Goals and Policy document at Federation University. Using a conceptual framework based on a treatise by Jürgen Habermas (The theory of communicative action, Beacon Press, 1987) incorporating three socio-political levels (Lifeworld, Steering Media and Systems), we examined the ideals, processes and challenges in setting up an interdisciplinary research group within a traditional disciplinary-based university environment. Drawing on multiple data sets composed of member survey responses and interviews, email communication, online meetings, policy documents and co-leader feedback, we identified key resonant themes focussing on academic aspiration and motivation, the role of policy and practice, influence of grants and grant development across schools, mentoring and publishing. Using Habermas' conceptual framework and his overarching notion of Lifeworld with qualitative methods of data analysis, this article explores establishment of the CSRG, deeper academic aspirations and engagement for interdisciplinarity informing the group's formation and effectiveness of the processes used in this specific case. The impact on systems and policy is addressed together with the processes adopted to bring about interdisciplinary university collaboration. Evaluating the formation of the CSRG, the authors found that researchers placed a high value on opportunities to creatively collaborate in a cross-school and interdisciplinary environment, whereas obtaining grants and publishing research were seen by staff as indirect and less immediate benefits of collaboration. This article contributes to the growing body of research on interdisciplinary collaboration by applying a distinct theoretical and analytical framework to emphasise the potential of grassroots collaboration and the role of power and influence on research within universities.
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BACKGROUND: Implantable cardioverter-defibrillators (ICDs) are recommended for patients with cardiac sarcoidosis (CS) with an indication for pacing, prior ventricular arrhythmias, cardiac arrest, or left ventricular ejection fraction <35%, but data on outcomes are limited. METHODS: Using data from the National Cardiovascular Data Registry ICD Registry between April 1, 2010 and December 31, 2015, we evaluated a propensity matched cohort of CS patients implanted with ICDs versus non-ischemic cardiomyopathies (NICM). We compared mortality using Kaplan-Meier survival curves and Cox proportional hazards models. RESULTS: We identified 1,638 patients with CS and 8,190 propensity matched patients with NICM. The rate of death at 1 and 2 years was similar in patients with CS and patients with NICM (5.2% vs 5.4%, P = 0.75 and 9.0% vs 9.3%, P = 0.72, respectively). After adjusting for other covariates, patients with CS had similar mortality at 2 years after ICD implantations compared with NICM patients (RR 1.03, 95% CI 0.87-1.23). Among patients with CS, multivariable logistic regression identified 6 factors significantly associated with increased 2-year mortality: presence of heart failure (HR 1.92, 95% CI 1.44-3.22), New York Heart Association (NYHA) Class III heart failure (HR 1.68, 95% CI 1.16-2.45), NYHA Class IV heart failure (HR 3.08, 95% CI 1.49-6.39), atrial fibrillation/flutter (HR 1.66, 95% CI 1.17-2.35), chronic lung disease (HR 1.64, 95% CI 1.17-2.29), creatinine >2.0 mg/dL (HR 4.07, 95% CI 2.63-6.30), and paced rhythm (HR 2.66, 95% CI 1.07-6.59). CONCLUSION: Mortality following ICD implantation was similar in CS patients compared with propensity matched NICM patients. Presence of heart failure, NYHA class, atrial fibrillation/flutter, chronic lung disease, renal dysfunction, and paced rhythm at time of implantation were all predictors of increased 2-year mortality among CS patients with ICDs.
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Fibrilación Atrial , Desfibriladores Implantables , Insuficiencia Cardíaca , Miocarditis , Sarcoidosis , Muerte Súbita Cardíaca/epidemiología , Muerte Súbita Cardíaca/etiología , Muerte Súbita Cardíaca/prevención & control , Insuficiencia Cardíaca/terapia , Humanos , Estudios Retrospectivos , Factores de Riesgo , Sarcoidosis/complicaciones , Volumen Sistólico , Función Ventricular IzquierdaRESUMEN
PURPOSE: Brain metastases (BM) are an increasing clinical problem. This study aimed to assess paired primary breast cancers (BC) and BM for aberrations within TP53, PIK3CA, ESR1, ERBB2 and AKT utilising the MassARRAY® UltraSEEK® technology (Agena Bioscience, San Diego, USA). METHODS: DNA isolated from 32 paired primary BCs and BMs was screened using the custom UltraSEEK® Breast Cancer Panel. Data acquisition and analysis was performed by the Agena Bioscience Typer software v4.0.26.74. RESULTS: Mutations were identified in 91% primary BCs and 88% BM cases. TP53, AKT1, ESR1, PIK3CA and ERBB2 genes were mutated in 68.8%, 37.5%, 31.3%, 28.1% and 3.1% respectively of primary BCs and in 59.4%, 37.5%, 28.1%, 28.1% and 3.1% respectively of BMs. Differences in the mutations within the 5 genes between BC and paired BM were identified in 62.5% of paired cases. In primary BCs, ER-positive/HER2-negative cases harboured the most mutations (70%), followed by ER-positive/HER2-positive (15%) and triple-negatives (13.4%), whereas in BMs, the highest number of mutations was observed in triple-negative (52.5%), followed by ER-positive/HER2-negative (35.6%) and ER-negative/HER2-positive (12%). There was a significant association between the number of mutations in the primary BC and breast-to-brain metastasis-free survival (p = 0.0001) but not with overall survival (p = 0.056). CONCLUSION: These data demonstrate the discordancy between primary BC and BM, as well as the presence of clinically important, actionable mutations in BCBM. The UltraSEEK® Breast Cancer Panel provides a tool for BCBM that can be utilised to direct more tailored treatment decisions and for clinical studies investigating targeted agents.
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Neoplasias Encefálicas , Neoplasias de la Mama , Biomarcadores de Tumor/genética , Neoplasias Encefálicas/genética , Mama , Neoplasias de la Mama/genética , Femenino , Genómica , Humanos , Mutación , Receptor ErbB-2/genéticaRESUMEN
A 62-year-old woman with human T-lymphotropic virus type 1 cell lymphoma developed heart failure after mogamulizumab, an immunotherapy agent. Clinical presentation and cardiac magnetic resonance imaging were consistent with myocarditis, and a recurrence of heart failure occurred after rechallenge with the therapy. (Level of Difficulty: Advanced.).
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BACKGROUND: Immune checkpoint inhibitors (ICIs) are highly effective in treating cancer; however, cardiotoxicity can occur, including myocarditis. Cardiac magnetic resonance (CMR) imaging is useful for evaluation of myocarditis, although it has not been well studied in ICI cardiotoxicity. METHODS: We identified patients referred for CMR evaluation of ICI cardiotoxicity from September 2015 through September 2019. We assessed structural and functional parameters, feature tracking (FT) left ventricular and atrial strain, T2- weighted ratios and quantitative late gadolinium enhancement (LGE). We also applied the Updated Lake Louise Criteria for diagnosis of myocarditis. RESULTS: Of the 20 patients referred, the median left ventricular ejection fraction (LVEF) was 52.5% ± 19.1 and 50% had a normal LVEF (≥53%). FT strain analysis revealed an average abnormal global longitudinal strain (GLS) of -9.8%± 4.2%. In patients with a normal LVEF, the average GLS remained depressed at -12.3%± 2.4%. In all patients, GLS demonstrated a significant negative correlation with LVEF (rs = -0.64, p 0.002). Sixteen patients (80%) had presence of LGE (14 non-ischemic pattern and 2 ischemic). Percent LGE did not correlate with any CMR parameters and notably did not correlate with LVEF (rs = -0.29, p = 0.22) or GLS (rs = 0.10, p = 0.67), highlighting the value of tissue characterization beyond functional assessment. Nine patients (45%) met full Updated Lake Louise Criteria and 85% met at least one criterion, suggestive of myocarditis in the correct clinical context. Thirteen patients (65%) were treated for ICI-associated myocarditis and, of these, 54% (n = 7) had recovery of LVEF to normal. There was no correlation between LVEF (p = 0.47), GLS (0.89), or % LGE (0.15) and recovery of LVEF with treatment. CONCLUSION: In patients with suspected ICI cardiotoxicity, CMR is an important diagnostic tool, even in the absence of overt left ventricular dysfunction, as abnormalities in left ventricular strain, T2 signal and LGE can identifying disease.
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Cardiotoxicidad/diagnóstico por imagen , Inhibidores de Puntos de Control Inmunológico/efectos adversos , Miocarditis/diagnóstico por imagen , Disfunción Ventricular Izquierda/diagnóstico por imagen , Anciano , Cardiotoxicidad/complicaciones , Cardiotoxicidad/diagnóstico , Medios de Contraste , Edema/diagnóstico por imagen , Femenino , Fibrosis/diagnóstico por imagen , Gadolinio , Humanos , Inflamación/diagnóstico por imagen , Imagen por Resonancia Magnética , Imagen por Resonancia Cinemagnética , Masculino , Persona de Mediana Edad , Miocarditis/complicaciones , Miocarditis/patología , Disfunción Ventricular Izquierda/complicaciones , Disfunción Ventricular Izquierda/fisiopatología , Función Ventricular IzquierdaRESUMEN
Study objectives: Mogamulizumab is an important treatment for T-cell leukemia and lymphoma. Adverse cardiovascular events (ACE) after mogamulizumab therapy have not been investigated. The aim of the study is to investigate ACE occurrence after mogamulizumab therapy. Methods: The International World Health Organization database, VigiBase, was analyzed from January 2013 to August 2019 for all adverse events, including ACE, that occurred after mogamulizumab treatment. ACE was defined as: cardiac death, myocardial infarction, heart failure, myocarditis, arrhythmia, vasculitis, thrombosis, palpitations and new hypertension. Results: ACE after mogamulizumab therapy affected 28 out of 650 unique patients (4.3%). Heart failure (42.8%) and ventricular arrhythmias (17.85%) were most common. ACE accounted for 10% of all fatal adverse outcomes, and 25% of all ACE were fatal. Time to fatal outcome was significantly shorter for patients with ACE compared to non-cardiovascular events, with a mean of 7.7 days (SD 6.91) vs 73 days (SD 90.7), p = 0.017, respectively. There was an increased total number of adverse cardiovascular events in patients greater than 65 and in Asian countries. Conclusions: Cardiovascular toxicity with mogamulizumab is a possible early occurring adverse outcome associated with high mortality.
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Background Outcomes data in patients with cardiac amyloidosis after implantable cardioverter-defibrillator (ICD) implantation are limited. We compared outcomes of patients with ICDs implanted for cardiac amyloidosis versus nonischemic cardiomyopathies (NICMs) and evaluated factors associated with mortality among patients with cardiac amyloidosis. Methods and Results Using National Cardiovascular Data Registry's ICD Registry data between April 1, 2010 and December 31, 2015, we created a 1:5 propensity-matched cohort of patients implanted with ICDs with cardiac amyloidosis and NICM. We compared mortality between those with cardiac amyloidosis and matched patients with NICM using Kaplan-Meier survival curves and Cox proportional hazards models. We also evaluated risk factors associated with 1-year mortality in patients with cardiac amyloidosis using multivariable Cox proportional hazards regression models. Among 472 patients with cardiac amyloidosis and 2360 patients with propensity-matched NICMs, 1-year mortality was significantly higher in patients with cardiac amyloidosis compared with patients with NICMs (26.9% versus 11.3%, P<0.001). After adjustment for covariates, cardiac amyloidosis was associated with a significantly higher risk of all-cause mortality (hazard ratio [HR], 1.80; 95% CI, 1.56-2.08). In a multivariable analysis of patients with cardiac amyloidosis, several factors were significantly associated with mortality: syncope (HR, 1.78; 95% CI, 1.22-2.59), ventricular tachycardia (HR, 1.65; 95% CI, 1.15-2.38), cerebrovascular disease (HR, 2.03; 95% CI, 1.28-3.23), diabetes mellitus (HR, 1.55; 95% CI, 1.05-2.27), creatinine = 1.6 to 2.5 g/dL (HR, 1.99; 95% CI, 1.32-3.02), and creatinine >2.5 (HR, 4.34; 95% CI, 2.72-6.93). Conclusions Mortality after ICD implantation is significantly higher in patients with cardiac amyloidosis than in patients with propensity-matched NICMs. Factors associated with death among patients with cardiac amyloidosis include prior syncope, ventricular tachycardia, cerebrovascular disease, diabetes mellitus, and impaired renal function.
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Amiloidosis/mortalidad , Cardiomiopatías/mortalidad , Desfibriladores Implantables/efectos adversos , Implantación de Prótesis/mortalidad , Anciano , Estudios de Casos y Controles , Femenino , Humanos , Masculino , Persona de Mediana Edad , Sistema de Registros , Estudios RetrospectivosRESUMEN
Data is lacking on the contemporary risk of death and readmission following implantable cardioverter-defibrillator (ICD) implantation in patients with non-ischemic cardiomyopathies (NICM) compared with ischemic cardiomyopathies (ICM) in a large nationally representative cohort. We performed a retrospective cohort study using the National Cardiovascular Data Registry ICD Registry linked with Medicare claims from April 1, 2010 to December 31, 2013. We established a cohort of NICM and ICM patients with a left ventricular ejection fraction ≤35% who received a de novo, primary prevention ICD. We compared mortality and readmission using Kaplan-Meier curves and Cox proportional hazard regressions models. We also evaluated temporal trends in mortality. In 31,044 NICM and 68,458 ICM patients with a median follow up of 2.4 years, 1-year mortality was significantly higher in ICM patients (12.3%) compared with NICM (7.9%, p < 0.001). The higher mortality in ICM patients remained significant after adjustment for covariates (hazard ratio [HR] 1.40; 95% confidence interval [CI] 1.36 to 1.45), and was consistent in subgroup analyses. These findings were consistent across the duration of the study. ICM patients were also significantly more likely to be readmitted for all causes (adjusted HR 1.15, CI 1.12 to 1.18) and for heart failure (adjusted HR 1.25, CI 1.21 to 1.31). In conclusion, the risks of mortality and hospital readmission after primary prevention ICD implantation were significantly higher in patients with ICM compared with NICM which was consistent across all patient subgroups tested and over the duration of the study.
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Cardiomiopatías/etiología , Cardiomiopatías/mortalidad , Desfibriladores Implantables , Isquemia Miocárdica/complicaciones , Isquemia Miocárdica/mortalidad , Readmisión del Paciente , Anciano , Cardiomiopatías/terapia , Femenino , Humanos , Masculino , Persona de Mediana Edad , Isquemia Miocárdica/terapia , Sistema de Registros , Estudios Retrospectivos , Tasa de Supervivencia , Estados UnidosRESUMEN
Breast cancer brain metastasis (BCBM) is an area of unmet clinical need. MicroRNAs (miRNAs) have been linked to the metastatic process in breast cancer (BC). In this study, we aim to determine differentially-expressed miRNAs utilising primary BCs that did not relapse (BCNR, n = 12), primaries that relapsed (BCR) and their paired (n = 40 pairs) brain metastases (BM) using the NanoString™ nCounter™ miRNA Expression Assays. Significance analysis of microarrays identified 58 and 11 differentially-expressed miRNAs between BCNR vs BCR and BCR vs BM respectively and pathway analysis revealed enrichment for genes involved in invasion and metastasis. Four miRNAs, miR-132-3p, miR-199a-5p, miR-150-5p and miR-155-5p, were differentially-expressed within both cohorts (BCNR-BCR, BCR-BM) and receiver-operating characteristic curve analysis (p = 0.00137) and Kaplan-Meier survival method (p = 0.0029, brain metastasis-free survival; p = 0.0007, overall survival) demonstrated their potential use as prognostic markers. Ingenuity pathway enrichment linked them to the MET oncogene, and the cMET protein was overexpressed in the BCR (p < 0.0001) and BM (p = 0.0008) cases, compared to the BCNRs. The 4-miRNAs panel identified in this study could be potentially used to distinguish BC patients with an increased risk of developing BCBM and provide potential novel therapeutic targets, whereas cMET-targeting warrants further investigation in the treatment of BCBM.
Asunto(s)
Neoplasias Encefálicas/genética , Neoplasias Encefálicas/mortalidad , Neoplasias de la Mama/mortalidad , Regulación Neoplásica de la Expresión Génica , MicroARNs/genética , Biomarcadores de Tumor/genética , Neoplasias Encefálicas/secundario , Neoplasias de la Mama/genética , Neoplasias de la Mama/patología , Femenino , Perfilación de la Expresión Génica , Humanos , Estimación de Kaplan-Meier , Invasividad Neoplásica , Recurrencia Local de Neoplasia , Distribución Normal , Análisis de Secuencia por Matrices de Oligonucleótidos , Análisis de Componente Principal , Pronóstico , Curva ROC , Riesgo , Resultado del TratamientoRESUMEN
Previous study has suggested that the FABP5-PPARγ-signalling transduction pathway gradually replaces the androgen receptor activated pathway in promoting malignant progression of castration-resistant prostate cancer (CRPC) cells. To interfere with this newly discovered FABP5-related signalling pathway, we have produced a highly efficient recombinant FABP5 inhibitor, named dmrFABP5. Treatment with dmrFABP5 significantly supressed the proliferation, migration, invasion and colony formation of the highly malignant prostate cancer cells PC3-M in vitro. To test dmrFABP5's suppressive effect in CRPC, the human PC3-M cells were implanted orthotopically into the prostate gland of immunosuppressed mice to produce tumours. These mice were then treated with dmrFABP5 and produced a highly significant reduction of 100% in metastatic rate and a highly significant reduction of 13-fold in the average size of primary tumours. Immunocytochemial staining showed that the staining intensity of dmrFABP5 treated tumours was reduced by 67%. When tested in vitro, dmrFABP5 suppressed the cancer cells by blocking fatty acid stimulation of PPARγ, and thereby prevented it activating down-stream cancer-promoting or inhibiting cancer-suppressing genes. Our results show that the FABP5 inhibitor dmrFABP5 is a novel molecule for treatment of experimental CRPC and its inhibitory effect is much greater than that produced by SB-FI-26 reported in our previous work.
RESUMEN
Brain metastases are common and are usually detected by MRI. Diffusion tensor imaging (DTI) is a derivative MRI technique that can detect disruption of white matter tracts in the brain. We have matched preoperative DTI with image-guided sampling of the brain-tumor interface in 26 patients during resection of a brain metastasis and assessed mean diffusivity and fractional anisotropy (FA). The tissue samples were analyzed for vascularity, inflammatory cell infiltration, growth pattern, and tumor expression of proteins associated with growth or local invasion such as Ki67, S100A4, and MMP2, 9, and 13. A lower FA in the peritumoral region indicated more white matter tract disruption and independently predicted longer overall survival times (HR for death = 0.21; 95% confidence interval, 0.06-0.82; P = 0.024). Of all the biological markers studied, only increased density of CD3+ lymphocytes in the same region correlated with decreased FA (Mann-Whitney U, P = 0.037) as well as confounding completely the effect of FA on multivariate survival analyses. We conclude that the T-cell response to brain metastases is not a surrogate of local tumor invasion, primary cancer type, or aggressive phenotype and is associated with patient survival time regardless of these biological factors. Furthermore, it can be assayed by DTI, potentially offering a quick, noninvasive, clinically available method to detect an active immune microenvironment and, in principle, to measure susceptibility to immunotherapy.Significance: These findings show that white matter tract integrity is degraded in areas where T-cell infiltration is highest, providing a noninvasive method to identify immunologically active microenvironments in secondary brain tumors. Cancer Res; 78(3); 610-6. ©2017 AACR.