RESUMO
Penile prosthesis implantation is the definitive treatment for refractory erectile dysfunction, yet exposure to this procedure during training of urology residents is often limited. To assess the effects of resident participation in penile prosthesis surgery, we compared surgical outcomes in a retrospective case series of 253 penile prosthesis surgeries by a single surgeon at the same institution between 2017 and 2020 with the assistance of either a registered nurse first assistant (RNFA) or a resident. Pertinent patient characteristics and surgical complications including device complications, surgical site infection, postoperative bleeding, iatrogenic injury, cardiovascular events, pulmonary events, and urinary retention were documented. Measured outcomes included operative time, Emergency Room (ER) visits, unplanned postoperative visits, pain medication refills, and surgical complications. Compared to RFNAs, resident-assisted penile prosthesis surgery was associated with significant increase in mean operative time (71.4 min vs. 87.9 min, p < 0.01) and postoperative ER visits (3.0% vs. 10.6%, p = 0.03) but not surgical complications (19.7% vs. 20.8%, OR 1.03, 95% CI [0.46 -2.30]) or other measured outcomes. Compared to a dedicated RFNA, Resident assistance increased operative time by approximately 17 min, but did not increase post-operative surgical complications, supporting the notion that resident assistance in these procedures may be appropriate as an integral part of training.
Assuntos
Disfunção Erétil , Implante Peniano , Prótese de Pênis , Masculino , Humanos , Implante Peniano/métodos , Disfunção Erétil/cirurgia , Prótese de Pênis/efeitos adversos , Estudos Retrospectivos , Resultado do Tratamento , Satisfação do PacienteRESUMO
AIMS: To determine whether phosphodiesterase inhibitors (PDEi) or α-antagonists (AA) were associated with differences in region of interest (ROI) characteristics or prostate cancer detection on fusion biopsy (FB). MATERIALS AND METHODS: Records from 847 consecutive patients undergoing FB at three separate institutions over a period of 2 years were retrospectively reviewed. Associations between medication use, Prostate Imaging Reporting & Data System (PIRADS) scores, and ROI locations were assessed with ordinal logistic regression. Associations with lesion size and International Society of Urologic Pathology (ISUP) grade group (GG) on biopsy were tested using multivariate regression. RESULTS: Medication use included PDEi in 14.2% and AA in 23.0%. PDEi use was associated with 19.3% smaller lesion diameter (-2.8 mm; CI from -4.8 to -0.7; p < 0.01) and lower PIRADS scores on MRI (OR 0.60; CI 0.40 - 1.00; p = 0.05). AA use was associated with higher PIRADS scores (OR 1.43; CI 0.97 - 2.11; p = 0.06), fewer positive fusion-directed biopsy cores (-28.6%, CI from -57.9 to 0.01%, p = 0.05), and downgrading on final pathology (-19%; CI from -40 to 2%; p = 0.06). CONCLUSION: For PIRADS scores ≥ 3, PDEi use is associated with smaller ROI and lower PIRADS scores, while AA use is associated with higher PIRADS scores. Neither medication was associated with differences in biopsy GG. Prospective studies are needed to investigate the discordance between multi-parametric magnetic resonance imaging (mpMRI) results and oncologic outcomes associated with PDEi and AA use.
Assuntos
Inibidores de Fosfodiesterase , Próstata , Neoplasias da Próstata , Humanos , Biópsia Guiada por Imagem/métodos , Imageamento por Ressonância Magnética/métodos , Masculino , Inibidores de Fosfodiesterase/efeitos adversos , Próstata/diagnóstico por imagem , Próstata/efeitos dos fármacos , Próstata/patologia , Neoplasias da Próstata/diagnóstico por imagem , Neoplasias da Próstata/tratamento farmacológico , Estudos RetrospectivosRESUMO
BACKGROUND: The challenge of managing non-muscle-invasive bladder cancer (NMIBC) is its high recurrence rate. Clinical investigations have begun to explore the role of androgen suppression as an adjunct to bladder cancer (BC) treatment. OBJECTIVE: To examine the effect of androgen suppression therapy (AST) on recurrence and progression rate of risk-stratified NMIBC. DESIGN, SETTING, AND PARTICIPANTS: Male patients with NMIBC were identified retrospectively from a US institutional database between 2001 and 2017. AST included 5α-reductase inhibitor, gonadotropin-releasing hormone agonist, and antiandrogen. Patients who were exposed to AST prior to documented recurrence/progression were included in the treatment arm. BC was risk stratified to investigate the differential response to AST. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Hazard ratios (HRs) for NMIBC recurrence and progression were estimated using Cox proportional hazards multivariate regression models with stepwise method. Recurrence-free survival (RFS) and progression-free survival (PFS) were compared between groups with and without AST. RESULTS AND LIMITATIONS: We identified a total of 274 males with a median follow-up period of 3.1 yr (interquartile range [IQR] 1.5-5.2). Thirty-six patients were exposed to AST with a median duration of 1.7 yr (IQR 0.7-2.6). AST was associated with a lower risk of recurrence (HR 0.53, 95% confidence interval 0.30-0.88) as well as improved RFS (p = 0.014). However, no significant reduction of progression or improvement of PFS (p = 0.23) was found with AST. After risk stratification, all five patients who progressed in the AST cohort had high-risk disease on initial transurethral resection (TUR), whereas no patients with low/intermediate-risk disease progressed on AST. Limitations of the study include nonstandardized initiation of AST in relation to initial TUR, lack of androgen level quantification, and small sample size in the treatment arm. CONCLUSIONS: In this retrospective, single-institution study, AST was associated with a lower risk of recurrence in NMIBC. No significant association between AST and progression was found. Further investigation is warranted to define the role of AST as an adjunctive therapy for NMIBC. PATIENT SUMMARY: Non-muscle-invasive bladder cancer is a highly recurrent disease that often requires patients to undergo repeated surgical treatments. This single-institution report suggests that medical suppression of androgen may be a potential preventive therapy to reduce recurrence in certain patients.
Assuntos
Antagonistas de Androgênios/uso terapêutico , Colestenona 5 alfa-Redutase/uso terapêutico , Recidiva Local de Neoplasia , Neoplasias da Bexiga Urinária/tratamento farmacológico , Idoso , Idoso de 80 Anos ou mais , Androgênios , Humanos , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/tratamento farmacológico , Recidiva Local de Neoplasia/epidemiologia , Recidiva Local de Neoplasia/patologia , Receptores LHRH , Estudos Retrospectivos , Estados Unidos/epidemiologia , Neoplasias da Bexiga Urinária/epidemiologia , Neoplasias da Bexiga Urinária/patologiaRESUMO
PURPOSE: The main purpose of this study was to investigate refractive errors in children with unilateral and bilateral retinoblastoma (RB). METHODS: An institutional review board-approved consecutive retrospective cohort study was undertaken. Subjects underwent examination under general anesthesia as part of their RB follow-up, which included evaluation by a single pediatric ophthalmologist. Cycloplegic retinoscopy was performed and keratometry data assessed with a handheld Retinomax K Plus 3 keratorefractometer (Righton Ophthalmic Instruments). RESULTS: The study included 61 eyes of 37 subjects, with 18 (49%) males and 19 females. Seventeen eyes (28%) had hyperopia with spherical equivalent ≥3 D. Refractive astigmatism ≥1.5 D was present in 32% of all eyes. Nine (38%) subjects had anisometropia ≥2 D. Fifteen (63%) subjects had anisometropia ≥1 D. CONCLUSION: This study reports the high proportion of amblyogenic refractive risk factors in children with RB, both in RB-affected eyes and contralateral normal eyes.
RESUMO
Patients with cytokine receptor-like factor 2 rearranged (CRLF2-re) subgroup Philadelphia chromosome-like B-cell acute lymphoblastic leukemia (Ph-like B-ALL) have a high relapse rate and poor clinical outcomes. CRFL2-re Ph-like B-ALL is characterized by heightened activation of multiple signaling pathways, including the JAK/STAT and PI3K/AKT/mTOR pathways. We hypothesized that the combined inhibition by JAK2 and mTOR inhibitors would induce an additive antileukemia effect in CRLF2-re Ph-like B-ALL. In this study, we tested the antileukemia efficacy of the type I JAK inhibitor ruxolitinib and type II JAK inhibitor NVP-BBT594 (hereafter abbreviated BBT594) [1] alone and combined with allosteric mTOR inhibitor rapamycin and a second generation ATP-competitive mTOR kinase inhibitor AZD2014. We found that BBT594/AZD2014 combination produced robust anti-leukemic effects in Ph-like cell lines in vitro and in patient-derived xenograft (PDX) cells cultured ex vivo. JAK2/mTOR inhibition arrested the cell cycle and reduced cell survival to a greater extent in Ph-like B-ALL cells with CRLF2-re and JAK2 mutation. Synergistic cell killing was associated with the greater inhibition of JAK2 phosphorylation by BBT594 than by ruxolitinib and the greater inhibition of AKT and 4E-BP1 phosphorylation by AZD2014 than by rapamycin. In vivo, BBT594/AZD2014 co-treatment was most efficacious in reducing spleen size in three Ph-like PDX models, and markedly depleted bone marrow and spleen ALL cells in an ATF7IP-JAK2 fusion PDX. In summary, combined inhibition of JAK/STAT and mTOR pathways by next-generation inhibitors had promising antileukemia efficacy in preclinical models of CRFL2-re Ph-like B-ALL.
Assuntos
Glomerulonefrite Membranoproliferativa/diagnóstico , Glomerulonefrite Membranoproliferativa/etiologia , Linfoma de Células T Periférico/complicações , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Biomarcadores , Biópsia , Medula Óssea/patologia , Glomerulonefrite Membranoproliferativa/terapia , Humanos , Biópsia Guiada por Imagem , Testes de Função Renal , Linfoma de Células T Periférico/diagnóstico , Linfoma de Células T Periférico/tratamento farmacológico , Linfoma de Células T Periférico/genética , Masculino , Pessoa de Meia-Idade , Tomografia Computadorizada por Raios XRESUMO
More than 90% of drugs with preclinical activity fail in human trials, largely due to insufficient efficacy. We hypothesized that adequately powered trials of patient-derived xenografts (PDX) in mice could efficiently define therapeutic activity across heterogeneous tumors. To address this hypothesis, we established a large, publicly available repository of well-characterized leukemia and lymphoma PDXs that undergo orthotopic engraftment, called the Public Repository of Xenografts (PRoXe). PRoXe includes all de-identified information relevant to the primary specimens and the PDXs derived from them. Using this repository, we demonstrate that large studies of acute leukemia PDXs that mimic human randomized clinical trials can characterize drug efficacy and generate transcriptional, functional, and proteomic biomarkers in both treatment-naive and relapsed/refractory disease.
Assuntos
Xenoenxertos , Leucemia/patologia , Linfoma/patologia , Bancos de Tecidos , Ensaios Antitumorais Modelo de Xenoenxerto , Animais , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Biomarcadores Tumorais , Linhagem da Célula , Feminino , Perfilação da Expressão Gênica , Genes p53 , Humanos , Internet , Isoquinolinas/farmacologia , Isoquinolinas/uso terapêutico , Leucemia/metabolismo , Leucemia Experimental/tratamento farmacológico , Linfoma/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos NOD , Terapia de Alvo Molecular , Proteínas de Neoplasias/antagonistas & inibidores , Transplante de Neoplasias , Fenótipo , Piperazinas/farmacologia , Piperazinas/uso terapêutico , Leucemia-Linfoma Linfoblástico de Células Precursoras B/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras B/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras B/patologia , Proteoma , Proteínas Proto-Oncogênicas c-mdm2/antagonistas & inibidores , Distribuição Aleatória , Ensaios Clínicos Controlados Aleatórios como Assunto/métodos , Projetos de Pesquisa , TranscriptomaRESUMO
A variety of cancers depend on JAK2 signaling, including the high-risk subset of B cell acute lymphoblastic leukemias (B-ALLs) with CRLF2 rearrangements. Type I JAK2 inhibitors induce paradoxical JAK2 hyperphosphorylation in these leukemias and have limited activity. To improve the efficacy of JAK2 inhibition in B-ALL, we developed the type II inhibitor CHZ868, which stabilizes JAK2 in an inactive conformation. CHZ868 potently suppressed the growth of CRLF2-rearranged human B-ALL cells, abrogated JAK2 signaling, and improved survival in mice with human or murine B-ALL. CHZ868 and dexamethasone synergistically induced apoptosis in JAK2-dependent B-ALLs and further improved in vivo survival compared to CHZ868 alone. These data support the testing of type II JAK2 inhibition in patients with JAK2-dependent leukemias and other disorders.
Assuntos
Aminopiridinas/administração & dosagem , Antineoplásicos/administração & dosagem , Benzimidazóis/administração & dosagem , Dexametasona/administração & dosagem , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Janus Quinase 2/antagonistas & inibidores , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Inibidores de Proteínas Quinases/administração & dosagem , Aminopiridinas/farmacologia , Animais , Antineoplásicos/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Apoptose , Benzimidazóis/farmacologia , Linhagem Celular Tumoral , Citoproteção/efeitos dos fármacos , Sinergismo Farmacológico , Humanos , Janus Quinase 2/química , Janus Quinase 2/genética , Camundongos , Mutação , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Inibidores de Proteínas Quinases/farmacologia , Transdução de Sinais/efeitos dos fármacos , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Activating mutations in genes encoding G protein α (Gα) subunits occur in 4-5% of all human cancers, but oncogenic alterations in Gß subunits have not been defined. Here we demonstrate that recurrent mutations in the Gß proteins GNB1 and GNB2 confer cytokine-independent growth and activate canonical G protein signaling. Multiple mutations in GNB1 affect the protein interface that binds Gα subunits as well as downstream effectors and disrupt Gα interactions with the Gßγ dimer. Different mutations in Gß proteins clustered partly on the basis of lineage; for example, all 11 GNB1 K57 mutations were in myeloid neoplasms, and seven of eight GNB1 I80 mutations were in B cell neoplasms. Expression of patient-derived GNB1 variants in Cdkn2a-deficient mouse bone marrow followed by transplantation resulted in either myeloid or B cell malignancies. In vivo treatment with the dual PI3K-mTOR inhibitor BEZ235 suppressed GNB1-induced signaling and markedly increased survival. In several human tumors, mutations in the gene encoding GNB1 co-occurred with oncogenic kinase alterations, including the BCR-ABL fusion protein, the V617F substitution in JAK2 and the V600K substitution in BRAF. Coexpression of patient-derived GNB1 variants with these mutant kinases resulted in inhibitor resistance in each context. Thus, GNB1 and GNB2 alterations confer transformed and resistance phenotypes across a range of human tumors and may be targetable with inhibitors of G protein signaling.
Assuntos
Transformação Celular Neoplásica/genética , Resistencia a Medicamentos Antineoplásicos/genética , Subunidades beta da Proteína de Ligação ao GTP/genética , Proteínas de Ligação ao GTP/genética , Linfoma de Células B/genética , Animais , Linhagem Celular Tumoral , Proteínas de Fusão bcr-abl/antagonistas & inibidores , Proteínas de Fusão bcr-abl/genética , Subunidades beta da Proteína de Ligação ao GTP/metabolismo , Proteínas de Ligação ao GTP/metabolismo , Regulação Neoplásica da Expressão Gênica , Humanos , Janus Quinase 2/biossíntese , Linfoma de Células B/tratamento farmacológico , Linfoma de Células B/patologia , Camundongos , Mutação , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Proto-Oncogênicas c-akt/biossíntese , Proteínas Proto-Oncogênicas c-akt/genéticaRESUMO
Down syndrome confers a 20-fold increased risk of B cell acute lymphoblastic leukemia (B-ALL), and polysomy 21 is the most frequent somatic aneuploidy among all B-ALLs. Yet the mechanistic links between chromosome 21 triplication and B-ALL remain undefined. Here we show that germline triplication of only 31 genes orthologous to human chromosome 21q22 confers mouse progenitor B cell self renewal in vitro, maturation defects in vivo and B-ALL with either the BCR-ABL fusion protein or CRLF2 with activated JAK2. Chromosome 21q22 triplication suppresses histone H3 Lys27 trimethylation (H3K27me3) in progenitor B cells and B-ALLs, and 'bivalent' genes with both H3K27me3 and H3K4me3 at their promoters in wild-type progenitor B cells are preferentially overexpressed in triplicated cells. Human B-ALLs with polysomy 21 are distinguished by their overexpression of genes marked with H3K27me3 in multiple cell types. Overexpression of HMGN1, a nucleosome remodeling protein encoded on chromosome 21q22 (refs. 3,4,5), suppresses H3K27me3 and promotes both B cell proliferation in vitro and B-ALL in vivo.