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Some visual stimuli are consistently better remembered than others across individuals, due to variations in memorability (the stimulus-intrinsic property that determines ease of encoding into visual long-term memory (VLTM)). However, it remains unclear what cognitive processes give rise to this mnemonic benefit. One possibility is that this benefit is imbued within the capacity-limited bottleneck of VLTM encoding, namely visual working memory (VWM). More precisely, memorable stimuli may be preferentially encoded into VLTM because fewer cognitive resources are required to store them in VWM (efficiency hypothesis). Alternatively, memorable stimuli may be more competitive in obtaining cognitive resources than forgettable stimuli, leading to more successful storage in VWM (competitiveness hypothesis). Additionally, the memorability benefit might emerge post-VWM, specifically, if memorable stimuli are less prone to be forgotten (i.e., are "stickier") than forgettable stimuli after they pass through the encoding bottleneck (stickiness hypothesis). To test this, we conducted two experiments to examine how memorability benefits emerge by manipulating the stimulus memorability, set size, and degree of competition among stimuli as participants encoded them in the context of a working memory task. Subsequently, their memory for the encoded stimuli was tested in a VLTM task. In the VWM task, performance was better for memorable stimuli compared to forgettable stimuli, supporting the efficiency hypothesis. In addition, we found that when in direct competition, memorable stimuli were also better at attracting limited VWM resources than forgettable stimuli, supporting the competitiveness hypothesis. However, only the efficiency advantage translated to a performance benefit in VLTM. Lastly, we found that memorable stimuli were less likely to be forgotten after they passed through the encoding bottleneck imposed by VWM, supporting the "stickiness" hypothesis. Thus, our results demonstrate that the memorability benefit develops across multiple cognitive processes.
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Memória de Longo Prazo , Memória de Curto Prazo , Humanos , Rememoração Mental , Percepção VisualRESUMO
The transformation to health and readiness for individuals and organizations, while structured in common strategies, metrics, and process improvement frameworks used throughout healthcare, will not be achieved or sustained without a shift in mindset.
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Atenção à Saúde , Modelo de Crenças de Saúde , Humanos , OrganizaçõesRESUMO
Implementation of the Generic Drug User Fee Amendments (GDUFA I) as part of the Food and Drug Administration Safety and Innovation Act of 2012 (Generic Drug User Fee Amendments. https://www.fda.gov/industry/fda-user-fee-programs/generic-drug-user-fee-amendments) successfully allowed the U.S. Food and Drug Administration (FDA) to modernize review of Abbreviated New Drug Applications (ANDAs) with goal dates. The goal of this study was to assess the success of GDUFA I in decreasing ANDA time to approval and the number of review cycles across the five fiscal years of GDUFA I. Results of this study underscore FDA's continuous progress within its generic drug program and highlight the ongoing collaborative communication process between FDA and ANDA applicants that must continue for the timely approval of high-quality, safe, and effective generic drugs for the American public.
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Aprovação de Drogas , Medicamentos Genéricos , Estados Unidos , United States Food and Drug AdministrationRESUMO
BACKGROUND: Immunotherapeutic regulation of the tumor microenvironment in prostate cancer patients is not understood. Most antibody immunotherapies have not succeeded in prostate cancer. We showed previously that high-risk PCa patients have a higher density of tumor infiltrating B-cells in prostatectomy specimens. In mouse models, anti-CD20 antibody ablation of B-cells delayed PCa regrowth post-treatment. We sought to determine whether neoadjuvant anti-CD20 immunotherapy with rituximab could reduce CD20+ B cell infiltration of prostate tumors in patients. METHODS: An open label, single arm clinical trial enrolled eight high-risk PCa patients to receive one cycle of neoadjuvant rituximab prior to prostatectomy. Eleven clinical specimens with similar characteristics were selected as controls. Treated and control samples were concurrently stained for CD20 and digitally scanned in a blinded fashion. A new method of digital image quantification of lymphocytes was applied to prostatectomy sections of treated and control cases. CD20 density was quantified by a deconvolution algorithm in pathologist-marked tumor and adjacent regions. Statistical significance was assessed by one sided Welch's t-test, at 0.05 level using a gatekeeper strategy. Secondary outcomes included CD3+ T-cell and PD-L1 densities. RESULTS: Mean CD20 density in the tumor regions of the treated group was significantly lower than the control group (p = 0.02). Mean CD3 density in the tumors was significantly decreased in the treated group (p = 0.01). CD20, CD3 and PD-L1 staining primarily occurred in tertiary lymphoid structures (TLS). Neoadjuvant rituximab was well-tolerated and decreased B-cell and T-cell density within high-risk PCa tumors compared to controls. CONCLUSIONS: This is the first study to treat patients prior to surgical prostate removal with an immunotherapy that targets B-cells. Rituximab treatment reduced tumor infiltrating B and T-cell density especially in TLSs, thus, demonstrating inter-dependence between B- and T-cells in prostate cancer and that Rituximab can modify the immune environment in prostate tumors. Future studies will determine who may benefit from using rituximab to improve their immune response against prostate cancer. Trial registration NCT01804712, March 5th, 2013 https://clinicaltrials.gov/ct2/show/NCT01804712?cond=NCT01804712&draw=2&rank=1.
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Terapia Neoadjuvante , Neoplasias da Próstata , Animais , Antígeno B7-H1 , Humanos , Linfócitos do Interstício Tumoral , Masculino , Camundongos , Prostatectomia , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/cirurgia , Rituximab/uso terapêutico , Linfócitos T , Microambiente TumoralRESUMO
Implementation of the first Generic Drug User Fee Amendments of 2012 (GDUFA I) provided funding to the US Food and Drug Administration (FDA) for modernizing review of the FDA/CDER Generic Drug Program. Under GDUFA I, FDA agreed to reduce the backlog of pending generic Abbreviated New Drug Applications (ANDAs), improve the efficiency of generic drug review, and reduce the number of review cycles with the goal of reducing overall time to approval. This study presents a preliminary analysis of initial filing and regulatory first actions on ANDAs during GDUFA I cohort year 3 (CY3) and cohort year 4 (CY4). It highlights initial successes and areas of improvement in the ANDA review process for both FDA and ANDA applicants to improve the efficiency of providing the public with high-quality, affordable generic drugs.
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Aprovação de Drogas/legislação & jurisprudência , Legislação de Medicamentos/organização & administração , Benchmarking , Aprovação de Drogas/organização & administração , Medicamentos Genéricos , Aplicação de Novas Drogas em Teste , Fatores de Tempo , Estados Unidos , United States Food and Drug AdministrationRESUMO
Background: Cohorts of bottlenose (Tursiops truncatus) dolphins are at significant risk for nephrolithiasis development. However, effective surgical treatment has been limited due to absence of literature and also familiarity by both veterinarians and urologists. Recently a joint veterinarian and urology team were called to treat local bottlenose dolphins in San Diego, CA, and they performed several cases. The fund of knowledge from these cases is presented for future providers who may be asked to surgically treat these animals. Case Presentation: Two surgical kidney stone cases were performed by a joint veterinarian and physician team. An effective ureteroscopic stone removal was performed on a 39-year-old female bottlenose dolphin with 9.7 mm distal ureteral calculus. The second case involved laparoscopic ureterolithotomy on a 31-year-old male bottlenose dolphin with a 6-mm right distal ureteral calculus that previously failed retrograde ureteroscopic removal. The stone was not effectively removed laparoscopically as well due to failure to progress associated with operative machinery malfunction. The dolphin was ultimately euthanized. Conclusion: Despite suboptimal outcome in one case, extremely valuable lessons were learned during both cases. We present our surgical experiences, as well as pertinent anatomical differences, in these animals with the hope that this discussion will facilitate future surgical kidney stone treatment of dolphins.
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INTRODUCTION: To compare surgical complications and tyrosine kinase inhibitor (TKI)-toxicities in patients who underwent primary cytoreductive nephrectomy (CN) followed by adjuvant TKI therapy versus those who underwent neoadjuvant TKI therapy prior to planned CN for metastatic renal cell carcinoma (mRCC). MATERIALS AND METHODS: Two-center retrospective analysis. Sixty-one mRCC patients underwent TKI therapy with sunitinib between July 2007 to January 2014. Patients were divided into three groups: primary CN followed by adjuvant TKI (n = 27, Group 1), neoadjuvant TKI prior to CN (n = 21, Group 2), and primary TKI alone (no surgery, n = 13, Group 3). Primary outcome was frequency and severity of surgical complications (Clavien). Secondary outcome was frequency and severity of TKI-related toxicities (NIH Common Toxicity Criteria). Multivariable analysis was carried out for factors associated with complications. RESULTS: There were no significant differences in demographics, ECOG status, and median number TKI cycles (p = 0.337). Mean tumor size (cm) was larger in Group 3 (12.8) than Group 2 (8.9) and Group 1 (9.3), p = 0.014. TKI-related toxicities occurred in 100%, 90.5%, and 88.9% in Group 3, Group 2, and Group 1 (p = 0.469). There was no difference in incidence of high grade (p = 0.967) and low grade (p = 0.380) TKI-toxicities. Overall surgical complication rate was similar between Group 2 (47.6%) and Group 1 (33.3%), p = 0.380. Group 2 had more high grade surgical complications (28.6%) than Group 1 (0%), p = 0.004. Multivariable analysis demonstrated increasing age was independently associated with development of surgical complications (HR 1.059, p = 0.040). CONCLUSION: Patients receiving neoadjuvant TKI therapy prior to CN experienced more high grade surgical complications than patients who underwent primary CN. Potential for increased high grade surgical complications requires further investigation and may impact pretreatment counseling.
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Antineoplásicos/uso terapêutico , Carcinoma de Células Renais/terapia , Neoplasias Renais/terapia , Nefrectomia/métodos , Carcinoma de Células Renais/diagnóstico , Carcinoma de Células Renais/secundário , Quimioterapia Adjuvante , Intervalo Livre de Doença , Feminino , Humanos , Neoplasias Renais/mortalidade , Neoplasias Renais/patologia , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Taxa de Sobrevida/tendências , Resultado do Tratamento , Estados Unidos/epidemiologiaRESUMO
INTRODUCTION: To investigate association of C-reactive protein (CRP), a marker of systemic inflammation, with renal functional decline patients undergoing partial nephrectomy (PN) for renal mass. MATERIALS AND METHODS: Retrospective study of patients who underwent PN between February 2006-March 2011, with ≥ 6 months follow up. Data was analyzed between two groups: CRP increase ≥ 0.5 mg/L from 6 months postoperative ('CRP rise,' CRPR), versus no CRP increase = 0.5 ('CRP stable,' CRPS). Primary outcome was change in estimated glomerular filtration rate (ΔeGFR, mL/min/1.73 m²), with de novo postoperative stage III chronic kidney disease (stage III-CKD, eGFR < 60 mL/min/1.73 m²) being secondary. Multivariable analysis (MVA) was conducted to identify risk factors for development of de novo stage III-CKD. RESULTS: A total of 243 patients (206 CRPS/37 CRPR) were analyzed. Demographics and R.E.N.A.L. nephrometry scores were similar. CRPR had significantly higher median ΔeGFR (-13.7 versus -32.0 mL/min/1.73 m², p < 0.001) and de novo stage III-CKD at last follow up (43.2% vs. 3.7%, p < 0.001). Median time to CRP rise was 10 (IQR 6.5-12) months. Median time from CRP rise to de novo stage III-CKD was 9 (IQR 7.5-11) months. MVA found RENAL score (OR 1.89, p = 0.001), hypertension (OR 4.75, p = 0.016), and CRP rise (OR 55.76, p < 0.001) were associated with de novo stage III-CKD. Sensitivity of CRP increase ≥ 0.5 for predicting CKD was 69.6%, specificity 93.3%, positive predictive value 55.2%, and negative predictive value 96.3%. CONCLUSION: Rise in CRP postoperatively is independently associated with renal functional decline after PN and may be useful in identifying patients to evaluate for renoprotective strategies. Further studies are requisite to clarify etiology of this association.
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Proteína C-Reativa/metabolismo , Neoplasias Renais/cirurgia , Nefrectomia/efeitos adversos , Insuficiência Renal Crônica/sangue , Adulto , Idoso , Feminino , Seguimentos , Taxa de Filtração Glomerular , Humanos , Masculino , Pessoa de Meia-Idade , Nefrectomia/métodos , Valor Preditivo dos Testes , Insuficiência Renal Crônica/etiologia , Insuficiência Renal Crônica/fisiopatologia , Fatores de Risco , Fatores de TempoRESUMO
To determine the effect of bipolar cooled radiofrequency ablation (BCRF) on bone and tumour in a lapine pathologic femoral model. Under institutional approval, twelve New Zealand white rabbits received a single femoral injection of VX2 carcinoma cells (day 0). The rabbit femora, (n = 24), were block-randomized into four experimental groups: tumour-bearing radiofrequency ablation (RFA) treated, healthy bone RFA treated, tumour-bearing shams and healthy bone shams (n = 6 per group). 15 min of thermally regulated (65 °C) BCRF was applied at day 14. Pre- and post-treatment MR imaging was performed and repeated at day 28 prior to euthanasia. Histologic evaluation was used to determine treatment effect on tumour and bone tissue. A thirteenth injected rabbit served as a histologic control (no BCRF electrode placement). Large volumes (12.9 ± 5.5 cm(3)) of thermal ablation were achieved. An eight-fold reduction in tumour growth resulted in RFA treated animals compared to tumour-bearing sham controls (p < 0.001). Osteolysis was controlled in the tumour-treated group. Therapeutic effects were best imaged using MR contrast-enhanced SPoiled Gradient Recalled (SPGR) sequences. Osteoclasts and osteoblasts were observed to be sensitive to BCRF but osteocytes were more resilient. A small number of tumour cells within BCRF treated regions appeared viable post treatment. New bone formation was stimulated in the periphery of the targeted BCRF treatment zone. Structurally large VX2 tumour volumes within bone were successfully ablated with BCRF, stimulating new bone formation in the treatment periphery, although viable appearing osteocytes and tumour cells were observed in some treated regions.
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Ablação por Cateter/métodos , Modelos Animais de Doenças , Neoplasias Femorais/cirurgia , Animais , Temperatura Baixa , Neoplasias Femorais/patologia , Imageamento por Ressonância Magnética , Osteoblastos/patologia , Osteoclastos/patologia , Osteogênese , Osteólise , CoelhosRESUMO
The pathophysiology of nephrolithiasis is multifactorial. Obesity, diabetes mellitus and hypertension are implicated in its formation. Dyslipidemia (DLD) recently has received attention as well. Congruent with a vascular etiology in stone formation, DLD theoretically would predispose patients to nephrolithiasis. We investigated a possible association of DLD with nephrolithiasis. A random cohort of 60,000 patients was established by collecting the first 5,000 patient charts per month in the year 2000. After excluding pediatric patients, a retrospective study was performed by reviewing age, sex, comorbidities, and last patient follow-up. Median lipid laboratory levels also were reviewed. Descriptive statistics were performed as well as Cox proportional-hazards regression analysis, and univariate and multivariate analyses. 52,184 (22,717 women/29,467 men) patient charts were reviewed. The average age was 31.0 ± 15.2 years. On univariate analysis, DLD was associated with nephrolithiasis with a hazard ratio (HR) of 2.2 [Confidence Interval (CI), 1.9-2.5; p < 0.001] and on multivariate analysis HR = 1.2 (1.0-1.5; p = 0.033). Low-density lipoprotein and triglycerides had no association with stone disease. Patients with high-density lipoprotein (HDL) values <45 for men and <60 for women had an HR of 1.4 (1.1-1.7, 95% CI, p = 0.003) on univariate analysis and on multivariate analysis; HR = 1.27 (1.03-1.56; p = 0.024) for nephrolithiasis. DLD was associated with an increased risk of stone disease though the only specific lipid panel associated with lower nephrolithiasis was HDL. Clinicians should consider obtaining lipid levels with the intent that treatment could potentially not only mitigate atherosclerotic disease but also decrease nephrolithiasis risk.
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Dislipidemias/complicações , Nefrolitíase/etiologia , Adulto , Feminino , Humanos , Lipoproteínas HDL/sangue , Masculino , Pessoa de Meia-Idade , Modelos de Riscos Proporcionais , Estudos Retrospectivos , RiscoRESUMO
INTRODUCTION: Prostate cancer bone metastasis occurs in 50-90% of men with advanced disease for which there is no cure. Bone metastasis leads to debilitating fractures and severe bone pain. It is associated with therapy resistance and rapid decline. Androgen deprivation therapy (ADT) is standard of care for advanced prostate cancer, however, bone metastatic prostate cancer (PCa) often becomes resistant to ADT. There are few pre-clinical models to understand the interaction between the bone microenvironment and prostate cancer. Here we report the castrate resistant growth in the bone niche of PCSD1, a patient-derived intra-femoral xenograft model of prostate bone metastatic cancer treated with the anti-androgen, bicalutamide. METHODS: PCSD1 bone-niche model was derived from a human prostate cancer femoral metastasis resected during hemiarthroplasty and serially transplanted into Rag2(-/-); γ c(-/-) mice intra-femorally (IF) or sub-cutaneously (SC). At 5 weeks post-transplantation mice received bicalutamide or vehicle control for 18 days. Tumor growth of PCSD1 was measured with calipers. PSA expression in PCSD1 xenograft tumors was determined using quantitative RT-PCR and immunohistochemistry. Expression of AR and PSMA, were also determined with qPCR. RESULTS: PCSD1 xenograft tumor growth capacity was 24 fold greater in the bone (intra-femoral, IF) than in the soft tissue (sub-cutaneous, SC) microenvironment. Treatment with the anti-androgen, bicalutamide, inhibited tumor growth in the sub-cutaneous transplantation site. However, bicalutamide was ineffective in suppressing PCSD1 tumor growth in the bone-niche. Nevertheless, bicalutamide treatment of intra-femoral tumors significantly reduced PSA expression (p < = 0.008) and increased AR (p < = 0.032) relative to control. CONCLUSIONS: PCSD1 tumors were castrate resistant when growing in the bone-niche compared to soft tissue. Bicalutamide had little effect on reducing tumor burden in the bone yet still decreased tumor PSA expression and increased AR expression, thus, this model closely recapitulated castrate-resistant, human prostate cancer bone metastatic disease. PCSD1 is a new primary prostate cancer bone metastasis-derived xenograft model to study bone metastatic disease and for pre-clinical drug development of novel therapies for inhibiting therapy resistant prostate cancer growth in the bone-niche.
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Neoplasias Ósseas/secundário , Modelos Animais de Doenças , Orquiectomia , Neoplasias da Próstata/patologia , Antagonistas de Androgênios/uso terapêutico , Anilidas/uso terapêutico , Animais , Neoplasias Ósseas/tratamento farmacológico , Neoplasias Ósseas/patologia , Xenoenxertos , Humanos , Masculino , Camundongos , Nitrilas/uso terapêutico , Neoplasias da Próstata/tratamento farmacológico , Compostos de Tosil/uso terapêuticoRESUMO
PURPOSE: Infection after transrectal prostate biopsy has become an increasing concern due to fluoroquinolone resistant bacteria. We determined whether colonization identified by rectal culture can identify men at high risk for post-transrectal prostate biopsy infection. MATERIALS AND METHODS: Six institutions provided retrospective data through a standardized, web based data entry form on patients undergoing transrectal prostate biopsy who had rectal culture performed. The primary outcome was any post-transrectal prostate biopsy infection and the secondary outcome was hospital admission 30 days after transrectal prostate biopsy. We used chi-square and logistic regression statistical analysis. RESULTS: A total of 2,673 men underwent rectal culture before transrectal prostate biopsy from January 1, 2007 to September 12, 2013. The prevalence of fluoroquinolone resistance was 20.5% (549 of 2,673). Fluoroquinolone resistant positive rectal cultures were associated with post-biopsy infection (6.6% vs 1.6%, p <0.001) and hospitalization (4.4% vs 0.9%, p <0.001). Fluoroquinolone resistant positive rectal culture increased the risk of infection (OR 3.98, 95% CI 2.37-6.71, p <0.001) and subsequent hospital admission (OR 4.77, 95% CI 2.50-9.10, p <0.001). If men only received fluoroquinolone prophylaxis, the infection and hospitalization proportion increased to 8.2% (28 of 343) and 6.1% (21 of 343), with OR 4.77 (95% CI 2.50-9.10, p <0.001) and 5.67 (95% CI 3.00-10.90, p <0.001), respectively. The most common fluoroquinolone resistant bacteria isolates were Escherichia coli (83.7%). Limitations include the retrospective study design, nonstandardized culture and interpretation of resistance methods. CONCLUSIONS: Colonization of fluoroquinolone resistant organisms in the rectum identifies men at high risk for infection and subsequent hospitalization from prostate biopsy, especially in those with fluoroquinolone prophylaxis only.
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Antibacterianos/farmacologia , Farmacorresistência Bacteriana , Fluoroquinolonas/farmacologia , Complicações Pós-Operatórias/microbiologia , Próstata/patologia , Reto/microbiologia , Idoso , Infecções Bacterianas/epidemiologia , Biópsia/efeitos adversos , Biópsia/métodos , Humanos , Masculino , Pessoa de Meia-Idade , Complicações Pós-Operatórias/epidemiologia , Estudos Retrospectivos , Medição de RiscoRESUMO
The novel androgen, dimethandrolone (DMA) has both androgenic and progestational activities, properties that may maximize gonadotropin suppression. We assessed the pharmacokinetics of dimethandrolone undecanoate (DMAU), an orally bioavailable, longer acting ester of DMA, for male contraceptive development. Our objective was to examine the safety and pharmacokinetics of single, escalating doses of DMAU (powder in capsule formulation) administered orally with or without food in healthy men. We conducted a randomized, double-blind Phase 1 study. For each dose of DMAU (25-800 mg), 10 male volunteers received DMAU and two received placebo at two academic medical centres. DMAU was administered both fasting and after a high-fat meal (200-800 mg doses). Serial serum samples were collected over 24 h following each dose. DMAU was well tolerated without significant effects on vital signs, safety laboratory tests or electrocardiograms. When administered while fasting, serum DMA (active compound) was detectable in only 4/10 participants after the 800 mg dose. When administered with a 50% fat meal, serum DMA was detectable in all participants given 200 mg DMAU and showed a dose-incremental increase up to 800 mg, with peak levels 4-8 h after taking the dose. Serum gonadotropins and sex hormone concentrations were significantly suppressed 12 h after DMAU administration with food at doses above 200 mg. This first-in-man study demonstrated that a single, oral dose of DMAU up to 800 mg is safe. A high-fat meal markedly improved DMAU/DMA pharmacokinetics.
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Anticoncepcionais Masculinos/farmacocinética , Nandrolona/análogos & derivados , Administração Oral , Adolescente , Adulto , Gorduras na Dieta/administração & dosagem , Método Duplo-Cego , Jejum , Alimentos , Gonadotropinas/sangue , Humanos , Masculino , Pessoa de Meia-Idade , Nandrolona/sangue , Nandrolona/farmacocinéticaRESUMO
INTRODUCTION: Renal functional decline after partial nephrectomy (PN) may be related to a variety of nonmodifiable and modifiable factors, including ischemia time (IT) and modality. We sought to determine the impact of these factors on renal functional degeneration after PN. MATERIALS AND METHODS: Multicenter retrospective analysis (n = 347) was performed, identifying patients who underwent open PN using warm, cold, and non-ischemic techniques. Primary outcome was development of de novo chronic kidney disease (CKD), (estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73 m2), at 1 year follow up. Univariate and multivariable analysis (MVA) were performed examining factors associated with ischemia technique and the development of de novo CKD. RESULTS: Median follow up 34.7 months. Two hundred and forty-one patients underwent warm ischemic, 31 cold ischemic, and 75 clampless PN. Patient characteristics were similar between groups. Clampless group had lower mean RENAL scores (6.4) than cold (7.9, p = 0.005) and warm (7, p = 0.037) ischemia groups. Cold ischemia cohort had longer median IT than the warm cohort (50min versus 25 min, p = 0.001). There were no significant differences in proportion of patients developing de novo CKD (warm 14.9%, cold 15%, clampless 8.7%, p = 0.422). MVA demonstrated that neither ischemic modality nor IT ≥ 30 minutes was associated with development of de novo CKD, while RENAL scores of increasing complexity (RENAL score 7-9 OR 4.32, p = 0.003; RENAL score ≥ 10 OR 15.42, p < 0.001) were independently associated with de novo CKD. CONCLUSIONS: Increasing tumor complexity, as indicated by the RENAL score, was an overriding determinant of post PN renal functional outcome. Prospective investigation is requisite to elucidate risk and protective factors for renal functional degeneration after PN.
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Isquemia Fria/efeitos adversos , Neoplasias Renais/cirurgia , Nefrectomia/efeitos adversos , Insuficiência Renal Crônica/etiologia , Isquemia Quente/efeitos adversos , Adulto , Idoso , Feminino , Seguimentos , Taxa de Filtração Glomerular , Humanos , Rim/fisiopatologia , Neoplasias Renais/patologia , Masculino , Pessoa de Meia-Idade , Nefrectomia/métodos , Insuficiência Renal Crônica/fisiopatologia , Estudos Retrospectivos , Fatores de TempoRESUMO
BACKGROUND: The presence of increased B-cell tumor infiltrating lymphocytes (TILs) was seen in mouse prostate cancer (PCa) but has not been fully documented in human PCa. We, therefore, investigated the density of infiltrating B cells within human PCa utilizing a quantitative computational method. METHODS: Archived radical prostatectomy specimens from 53 patients with known clinical outcome and D'Amico risk category were obtained and immunohistochemically (IHC) stained for the B cell marker, CD20. Slides were reviewed by a genitourinary pathologist who manually delineated the tumoral regions of PCa. Slides were digitally scanned and a computer algorithm quantified the area of CD20 stained B-cells as a measure of B cell density within the outlined regions of prostate cancer (intra-tumoral region), versus extra-tumoral prostate tissue. Correlations were analyzed between B-cell density and demographic and clinical variables, including D'Amico risk groups and disease recurrence. RESULTS: For the entire cohort, the mean intra-tumoral B cell density was higher (3.22 SE = 0.29) than in the extra-tumoral region of each prostatectomy section (2.24, SE = 0.19) (paired t test; P < 0.001). When analyzed according to D'Amico risk group, the intra-tumoral B cell infiltration in low risk (0.0377 vs. 0.0246; p = 0.151) and intermediate risk (0.0260 vs. 0.0214; p = 0.579) patient prostatectomy specimens did not show significantly more B-cells within the PCa tumor. However, patient specimens from the high-risk group (0.0301 vs. 0.0197; p < 0.001) and from those who eventually had PCa recurrence or progression (0.0343 vs. 0.0246; p = 0.019) did show significantly more intra-tumoral CD20+ B-cell staining. Extent of B-cell infiltration in the prostatectomy specimens did not correlate with any other clinical parameters. CONCLUSIONS: Our study shows that higher B-cell infiltration was present within the intra-tumoral PCa regions compared to the extra-tumoral benign prostate tissue regions in prostatectomy sections. For this study we developed a new method to measure B-cells using computer-assisted digitized image analysis. Accurate, consistent quantitation of B-cells in prostatectomy specimens is essential for future clinical trials evaluating the effect of B cell ablating antibodies. The interaction of B-cells and PCa may serve as the basis for new therapeutic targets.
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Linfócitos B/imunologia , Linfócitos B/patologia , Linfócitos do Interstício Tumoral/imunologia , Linfócitos do Interstício Tumoral/patologia , Neoplasias da Próstata/imunologia , Neoplasias da Próstata/patologia , Animais , Antígenos CD20/metabolismo , Contagem de Células , Demografia , Humanos , Processamento de Imagem Assistida por Computador , Imuno-Histoquímica , Masculino , Camundongos , Pessoa de Meia-Idade , Prostatectomia , Neoplasias da Próstata/cirurgia , Resultado do TratamentoRESUMO
BACKGROUND CONTEXT: Cancer spread to the spine affects bone stability and can lead to pathologic fracture and neurologic impairment. Radiofrequency ablation (RFA) recently has gained popularity in treating skeletal tumors. Conventional RFA devices use a monopolar design, which limits the ability to comprehensively treat large tumors in bony tissues and may pose risks to adjacent critical normal neurologic tissues when applied to vertebrae. New bipolar-cooled radiofrequency (BCRF) may generate larger controlled lesions without the same degree of risk to adjacent structures. PURPOSE: The purpose of this study was to evaluate the feasibility, efficacy, and safety of RFA with the use of a new bone-specific, BCRF probe in a porcine vertebral model and to evaluate the ability of magnetic resonance (MR) imaging to represent histologic outcomes of RFA treatment. STUDY DESIGN: Basic science: preclinical in vivo study. METHODS: RFA was evaluated in three noncontiguous lumbar vertebrae in six Yorkshire pigs (25-30 kg). Via a transpedicular approach for probe placement, two vertebrae received BCRF treatment and one vertebrae served as a sham control. MR imaging and neurological assessments were conducted pre- and posttreatment as well as immediately before animal sacrifice (n=3 at day 0, n=3 at day 14). MR ablation zones were compared with hematoxylin and eosin-stained histological sections. RESULTS: With BCRF, large reproducible zones of ablation were achieved, confined within the vertebrae, without damage to adjacent tissues or the spinal cord. All animals demonstrated normal consistent neurologic behavior pre- and posttreatment. External tissue temperatures around targeted vertebrae were not increased. MR imaging after 14 days was more effective in demonstrating ablation effects than images on day 0, with radiologic findings most apparent on T2-weighted sequences. Histologic analysis of samples corresponded well to the zones of ablation observed on MR images (R=0.9, p<.01). CONCLUSIONS: The study demonstrated feasibility, safety, and effectiveness of BCRF ablation of vertebral bone. This motivates ongoing preclinical evaluation in diseased models to further explore the potential for its use in clinical treatment of metastatic vertebrae.
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Ablação por Cateter/instrumentação , Desenho de Equipamento , Neoplasias da Coluna Vertebral/cirurgia , Animais , Ablação por Cateter/efeitos adversos , Ablação por Cateter/normas , Modelos Animais de Doenças , Estudos de Viabilidade , Vértebras Lombares/patologia , Vértebras Lombares/cirurgia , Distribuição Aleatória , Neoplasias da Coluna Vertebral/secundário , SuínosRESUMO
Minimal incision laparoscopy-assisted open pyeloplasty (MILAP) incorporates elements of open pyeloplasty (OP) and single incision laparoscopy to improve technical ease and cosmetic outcomes. Six MILAP procedures were performed using a single transumbilical incision through which the ureteropelvic junction (UPJ) is mobilized with standard laparoscopic instrumentation. The UPJ is brought extracorporeally through a 1-cm flank incision, and a traditional Anderson-Hynes open pyeloplasty is performed. Compared with OP, perioperative outcomes were similar. Follow-up renal scans all showed improvement of obstruction. A 1-cm flank incision is the only obvious scar.
Assuntos
Pelve Renal/cirurgia , Laparoscopia/métodos , Procedimentos Cirúrgicos Urológicos/métodos , Adolescente , Perda Sanguínea Cirúrgica , Criança , Pré-Escolar , Cicatriz/prevenção & controle , Estudos de Coortes , Feminino , Seguimentos , Humanos , Lactente , Laparoscópios , Tempo de Internação , Masculino , Microdissecção/métodos , Duração da Cirurgia , Medição de Risco , Fatores de Tempo , Resultado do TratamentoRESUMO
OBJECTIVES: To determine whether early initiation of clean intermittent catheterization is associated with increased renal preservation in children with spinal dysraphism based on dimercaptosuccinic acid (DMSA) renal scans. METHODS: A retrospective review was performed of 100 patients from a pediatric spinal defects clinic from June 2007 to October 2011 who were followed with routine studies including DMSA scans, voiding cystourethrograms, renal/bladder ultrasounds, and urodynamics. DMSA scans were reviewed for evidence of renal cortical loss as defined by presence of scarring or difference in differential function greater than 15%. Multivariate analysis was performed for risk factors for upper tract damage. RESULTS: Renal cortical loss on DMSA scan was found in 43/100 (43%) of patients. CIC was started at birth in 17/100 (17%) of patients with the rest starting at a median age of 5 years (IQR 3-9). Upon multivariate regression analysis, age at DMSA scan (OR 1.21; 95% CI 1.08-1.36), history of VUR (OR 8.64; 95% CI 2.52-29.57), history of hydronephrosis (OR 3.44; 95% CI 1.12-10.5), and CIC from birth (OR 9.26; 95% CI 1.99-43.18) were statistically significant predictors of kidney damage. CONCLUSION: Early initiation of CIC may not reduce the incidence of DMSA abnormalities in pediatric patients with spinal dysraphism.
Assuntos
Cateterismo Uretral Intermitente/métodos , Insuficiência Renal/prevenção & controle , Insuficiência Renal/terapia , Disrafismo Espinal/complicações , Succímero , Adolescente , Criança , Pré-Escolar , Cicatriz/patologia , Estudos de Coortes , Intervalos de Confiança , Cistoscopia/métodos , Feminino , Seguimentos , Humanos , Testes de Função Renal , Masculino , Análise Multivariada , Intensificação de Imagem Radiográfica , Análise de Regressão , Insuficiência Renal/diagnóstico por imagem , Insuficiência Renal/etiologia , Estudos Retrospectivos , Medição de Risco , Prevenção Secundária/métodos , Índice de Gravidade de Doença , Disrafismo Espinal/diagnóstico , Estatísticas não Paramétricas , Fatores de Tempo , Tomografia Computadorizada por Raios X/métodos , Resultado do Tratamento , Urodinâmica , Urografia/métodosRESUMO
OBJECTIVE: To describe a laparoscopic-assisted modification to the traditional open retroperitoneal lymph node dissection (RPLND) to significantly shorten incision length and decrease morbidity of the laparotomy. METHODS: We describe 3 patients who underwent primary RPLND using the laparoscopic-assisted cord excision for stage I nonseminomatous germ cell testicular tumors. Spermatic cord excision is performed laparoscopically, and a standard nerve-sparing bilateral template RPLND is then performed through a supraumbilical incision. Operative time, intraoperative estimated blood loss, number of lymph nodes resected, complications, length of hospital stay, and follow-up were determined. RESULTS: All patients were clinical stage 1 (T1-2, Nx, M0 S0). The primary testicular tumor size was 2.2-5.5 cm with embryonal components, and all had negative results on abdominal and chest computed tomography imaging. Mean estimated blood loss was 267 mL (range, 100-500), operating room time was 293 minutes (range, 254-306), and all patients were discharged on postoperative day 5. There were no complications noted. Node counts were 22-33. The median length of follow-up was 20 months with no recurrence. CONCLUSION: Laparoscopic removal of the spermatic cord during open RPLND is a simple modification to the standard technique that reduces incision size without compromising the quality of open RPLND.