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BACKGROUND: Published studies have demonstrated inconclusive relationships between serum lipid levels and mortality after cancer. METHODS: The primary objective was to evaluate the relationship between fasting lipid levels and mortality after cancer. Data were obtained on baseline lipids and outcomes after cancer from 1263 postmenopausal women diagnosed with 13 obesity-related cancers who were part of the Women's Health Initiative (WHI) lipid biomarkers cohort. Obesity-related cancers included incident invasive cancers of the breast, colorectum, endometrium, esophagus (adenocarcinoma), kidney, liver, gallbladder, pancreas, ovaries, small intestine, thyroid, stomach, as well as multiple myeloma. Baseline lipid measurements included high-density lipoprotein (HDL)-cholesterol, low-density lipoprotein (LDL)-cholesterol, and non-HDL-cholesterol. Outcomes were all cause, cancer-specific, and CVD mortality. Multivariable Cox proportional hazards models were used to measure associations between lipid levels and mortality (all cause, cancer, and CVD) after a cancer diagnosis, with lipids analyzed as continuous variables. RESULTS: Among women with obesity-related cancer, there were 707 deaths, of which 379 (54%) were due to cancer and 113 (16%) were due to CVD. Mean time from blood draw to cancer diagnosis was 5.1 years (range: 0.05-10 years). LDL-C values above the 95th percentile were associated with higher risk of all-cause mortality (p < 0.001), and cancer-specific mortality (p < 0.001), but not mortality due to CVD. Non-HDL-C values above the 65th percentile were associated with higher risk of all-cause mortality (p = 0.01) and mortality due to CVD (p = 0.003), but not cancer-specific mortality (p = 0.37). HDL-C values above the 95th percentile were associated with lower all-cause mortality (p = 0.002), and above the 65th percentile with lower cancer-specific mortality (p = 0.003), but no significant relationship with mortality due to CVD was observed. CONCLUSIONS: The relationship between pre-diagnosis fasting lipid levels and mortality after cancer diagnosis is complex. These results suggest that improved lipid control through lifestyle and anti-lipid medications could have a meaningful impact on outcomes after cancer.
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Doenças Cardiovasculares , Mieloma Múltiplo , Feminino , Humanos , Doenças Cardiovasculares/diagnóstico , Doenças Cardiovasculares/etiologia , Fatores de Risco , Saúde da Mulher , Obesidade/complicações , Biomarcadores , Colesterol , Mieloma Múltiplo/complicações , HDL-ColesterolRESUMO
Purpose: The objective of this study was to assess the association between the Oncotype DX Genomic Prostate Score (GPS) assay and long-term outcomes in men with localized prostate cancer (PCa) after radiation therapy (RT). We hypothesized that the GPS assay is prognostic for biochemical failure (BCF), along with distant metastasis (DM) and PCa-specific mortality in patients with PCa receiving RT. Methods and Materials: We retrospectively studied men with localized PCa treated with definitive RT at Georgia Urology from 2010 to 2016. The primary objective was to assess the association between GPS results and time to BCF per the Phoenix criteria; we also assessed time to DM and PCa-specific mortality. We used Cox proportional hazards regression models for all analyses, with clinicopathologic covariates determined a priori for multivariable modeling. Results: A total of 450 patients (median age, 65 years; 35% Black) met eligibility criteria. There was a strong univariable association between GPS result and time to BCF (hazard ratio [HR] per 20-unit increase = 3.08; 95% confidence interval [CI], 2.11-4.46; P < .001), which persisted after adjusting for clinicopathologic characteristics in multivariable analyses. We also observed this association for time to DM (HR = 5.19; 95% CI, 3.06-8.77; P < .001) and PCa-specific mortality (HR = 13.07; 95% CI, 4.42-49.39; P < .001). Race was not a predictor of time to BCF or DM, and the GPS assay was strongly prognostic for all endpoints in Black and White patients. Conclusions: In a community-based cohort, the GPS assay was strongly prognostic for time to BCF as well as long-term outcomes in men treated with RT for localized PCa.
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Richter's Transformation (RT) is a poorly understood and fatal progression of chronic lymphocytic leukemia (CLL) manifesting histologically as diffuse large B-cell lymphoma. Protein arginine methyltransferase 5 (PRMT5) is implicated in lymphomagenesis, but its role in CLL or RT progression is unknown. We demonstrate herein that tumors uniformly overexpress PRMT5 in patients with progression to RT. Furthermore, mice with B-specific overexpression of hPRMT5 develop a B-lymphoid expansion with increased risk of death, and Eµ-PRMT5/TCL1 double transgenic mice develop a highly aggressive disease with transformation that histologically resembles RT; where large-scale transcriptional profiling identifies oncogenic pathways mediating PRMT5-driven disease progression. Lastly, we report the development of a SAM-competitive PRMT5 inhibitor, PRT382, with exclusive selectivity and optimal in vitro and in vivo activity compared to available PRMT5 inhibitors. Taken together, the discovery that PRMT5 drives oncogenic pathways promoting RT provides a compelling rationale for clinical investigation of PRMT5 inhibitors such as PRT382 in aggressive CLL/RT cases.
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Leucemia Linfocítica Crônica de Células B , Linfoma Difuso de Grandes Células B , Animais , Camundongos , Leucemia Linfocítica Crônica de Células B/genética , Leucemia Linfocítica Crônica de Células B/patologia , Linfoma Difuso de Grandes Células B/patologiaRESUMO
The validated 17-gene Oncotype DX Genomic Prostate Score® (GPS™) assay risk-stratifies prostate-cancer patients with localized disease. The assay has primarily been utilized in lower risk patients deciding between active surveillance versus definitive therapy. In this retrospective cohort study, we analyze the association of the GPS result with time to biochemical recurrence post-prostatectomy in patients with National Comprehensive Cancer Network® (NCCN) intermediate and higher risk prostate cancer. The 141 patients included in the study were from the NorthShore University HealthSystem diagnosed 2014-2019 with NCCN intermediate (n = 109) or higher risk (n = 32) prostate cancer, treated with radical prostatectomy 2015-2019. The association of GPS result with time to biochemical recurrence was evaluated using univariable and multivariable Cox proportional hazards models in 120 patients with unfavorable intermediate or higher risk. Median (interquartile range) follow-up time was 28 (20 to 38) months. The GPS result was significantly associated with time to biochemical recurrence as both a continuous and dichotomous variable in univariable (hazard ratio [HR] per 20 GPS units 2.36, 95% CI 1.45-3.80, p < 0.001; HR for GPS result 41-100 vs 0-40 3.28, 95% CI 1.61-7.19, p < 0.001) and in multivariable models accounting for NCCN risk group (HR per 20 GPS units 2.14, 95% CI 1.31-3.46, p = 0.003; HR for GPS result 41-100 vs 0-40 3.00, 95% CI 1.43-6.72, p = 0.003) or biopsy Gleason Score and diagnostic PSA or PSA density. These results indicate that the GPS assay was a strong predictor of biochemical recurrence after radical prostatectomy in this unfavorable intermediate and higher risk prostate cancer patient population.
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Próstata , Neoplasias da Próstata , Genômica , Humanos , Masculino , Gradação de Tumores , Recidiva Local de Neoplasia/patologia , Próstata/patologia , Próstata/cirurgia , Antígeno Prostático Específico , Prostatectomia/efeitos adversos , Neoplasias da Próstata/diagnóstico , Neoplasias da Próstata/genética , Neoplasias da Próstata/cirurgia , Estudos Retrospectivos , Medição de Risco/métodosRESUMO
Using a genome-wide CRISPR screen, we identified CDK9, DHODH, and PRMT5 as synthetic lethal partners with gilteritinib treatment in fms-like tyrosine kinase 3 (FLT3)-internal tandem duplication (ITD) acute myeloid leukemia (AML) and genetically and pharmacologically validated their roles in gilteritinib sensitivity. The presence of FLT3-ITD is associated with an increase in anaerobic glycolysis, rendering leukemia cells highly sensitive to inhibition of glycolysis. Supportive of this, our data show the enrichment of single guide RNAs targeting 28 glycolysis-related genes upon gilteritinib treatment, suggesting that switching from glycolysis to oxidative phosphorylation (OXPHOS) may represent a metabolic adaption of AML in gilteritinib resistance. CDK9i/FLT3i, DHODHi/FLT3i, and PRMT5i/FLT3i pairs mechanistically converge on OXPHOS and purine biosynthesis blockade, implying that targeting the metabolic functions of these three genes and/or proteins may represent attractive strategies to sensitize AML to gilteritinib treatment. Our findings provide the basis for maximizing therapeutic impact of FLT3-ITD inhibitors and a rationale for a clinical trial of these novel combinations.
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PURPOSE: We investigated the association of coffee and caffeine with breast cancer (BCa) risk, overall and by ER/PR status. We also examined potential interactions of coffee and caffeine with postmenopausal hormone use. METHODS: Our study included 77,688 postmenopausal participants from the Women's Health Initiative observational study cohort without a history of any cancer at baseline (except non-melanoma skin) and with valid Food Frequency Questionnaire data and complete data on dietary caffeine. Regular coffee (none, 1, 2-3, 4-5, and ≥ 6 cups/day) and caffeine (tertiles) were assessed at baseline. Information on BCa risk factors was collected at baseline. The associations were examined using survival analysis, accounting for death as a competing risk. RESULTS: The median follow-up time for our cohort was 18.3 years. During the follow-up, 5005 women developed invasive breast cancer. In multivariable analysis, coffee was not associated with the overall invasive BCa risk. Higher caffeine intake was mildly associated with increased BCa risk (2nd vs. 1st tertile SHR = 1.10, 95% CI 1.03-1.18, 3rd vs. 1st tertile SHR-1.05, 95% CI 0.98-1.13, overall p = 0.03). We found no interaction of coffee/caffeine with postmenopausal hormone use (p interaction = 0.44 and 0.42, respectively). In the exploratory analysis by ER/PR status, we found a positive association of caffeine with ER+ /PR+ BCa (2nd vs. 1st tertile SHR = 1.17, 95% CI 1.07-1.28, 3rd vs. 1st tertile SHR = 1.13, 95% CI 1.03-1.24, overall p = 0.002); no associations were observed for ER-/PR- tumors. Coffee was not associated with the risk of ER+ /PR+ or ER-/PR- tumors. CONCLUSION: We found no associations of coffee with BCa risk, overall and for ER/PR-defined tumor subtypes. The higher caffeine consumption was mildly and positively associated with the overall BCa risk and with ER+ /PR+ tumors.
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Neoplasias da Mama , Neoplasias da Mama/epidemiologia , Cafeína/efeitos adversos , Feminino , Hormônios , Humanos , Pós-Menopausa , Fatores de RiscoRESUMO
Rare, recurrent balanced translocations occur in a variety of cancers but are often not functionally interrogated. Balanced translocations with the immunoglobulin heavy chain locus (IGH; 14q32) in chronic lymphocytic leukemia (CLL) are infrequent but have led to the discovery of pathogenic genes including CCND1, BCL2, and BCL3. Following identification of a t(X;14)(q28;q32) translocation that placed the mature T cell proliferation 1 gene (MTCP1) adjacent to the immunoglobulin locus in a CLL patient, we hypothesized that this gene may have previously unrecognized importance. Indeed, here we report overexpression of human MTCP1 restricted to the B cell compartment in mice produces a clonal CD5+/CD19+ leukemia recapitulating the major characteristics of human CLL and demonstrates favorable response to therapeutic intervention with ibrutinib. We reinforce the importance of genetic interrogation of rare, recurrent balanced translocations to identify cancer driving genes via the story of MTCP1 as a contributor to CLL pathogenesis.
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Leucemia Linfocítica Crônica de Células B/genética , Leucemia Linfocítica Crônica de Células B/metabolismo , Proteínas Proto-Oncogênicas/genética , Proteínas Proto-Oncogênicas/metabolismo , Translocação Genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Proteína 3 do Linfoma de Células B , Ciclina D1 , Feminino , Regulação da Expressão Gênica , Genes de Cadeia Pesada de Imunoglobulina , Humanos , Cadeias Pesadas de Imunoglobulinas/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Pessoa de Meia-Idade , Oncogenes/genética , Proteínas Proto-Oncogênicas c-bcl-2RESUMO
KPT-9274 is a phase 1 first-in-class dual PAK4/NAMPT inhibitor for solid tumor and non-Hodgkin's lymphoma. It demonstrates pre-clinical efficacy toward a broad spectrum of acute myeloid leukemia (AML) subtypes by inhibiting NAMPT-dependent NAD+ production. NAMPT is the rate-limiting enzyme in the salvage metabolic pathway leading to NAD+ generation. Tumor cells which are deficient in de novo pathway enzyme NAPRT1 are addicted to NAMPT. In clinical trials, treatment with NAMPT inhibitors resulted in dose-limiting toxicities. In order to dissect the mechanism of toxicity, mice were treated with KPT-9274 and resulting toxicities were characterized histopathologically and biochemically. KPT-9274 treatment caused gender-dependent stomach and kidney injuries and anemia. Female mice treated with KPT-9274 had EPO deficiency and associated impaired erythropoiesis. KPT-9274 treatment suppressed SIRT3 expression and concomitantly upregulated acetyl-manganese superoxide dismutase (MnSOD) in IMCD3 cells, providing a mechanistic basis for observed kidney toxicity. Importantly, niacin supplementation mitigated KPT-9274-caused kidney injury and EPO deficiency without affecting its efficacy. Altogether, our study delineated the mechanism of KPT-9274-mediated toxicity and sheds light onto developing strategies to improve the tolerability of this important anti-AML inhibitor.
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Acrilamidas/efeitos adversos , Aminopiridinas/efeitos adversos , Anemia/induzido quimicamente , Antineoplásicos/efeitos adversos , Nefropatias/induzido quimicamente , Nicotinamida Fosforribosiltransferase/antagonistas & inibidores , Acetilação/efeitos dos fármacos , Anemia/etiologia , Anemia/metabolismo , Anemia/patologia , Animais , Eritropoese/efeitos dos fármacos , Feminino , Humanos , Nefropatias/etiologia , Nefropatias/metabolismo , Nefropatias/patologia , Masculino , Camundongos , Nicotinamida Fosforribosiltransferase/metabolismo , Fatores Sexuais , Sirtuína 3/metabolismo , Superóxido Dismutase/metabolismoRESUMO
PURPOSE: Nicotinamide phosphoribosyltransferase (NAMPT) inhibitors (NAMPTi) are currently in development, but may be limited as single-agent therapy due to compound-specific toxicity and cancer metabolic plasticity allowing resistance development. To potentially lower the doses of NAMPTis required for therapeutic benefit against acute myeloid leukemia (AML), we performed a genome-wide CRISPRi screen to identify rational disease-specific partners for a novel NAMPTi, KPT-9274. EXPERIMENTAL DESIGN: Cell lines and primary cells were analyzed for cell viability, self-renewal, and responses at RNA and protein levels with loss-of-function approaches and pharmacologic treatments. In vivo efficacy of combination therapy was evaluated with a xenograft model. RESULTS: We identified two histone deacetylases (HDAC), HDAC8 and SIRT6, whose knockout conferred synthetic lethality with KPT-9274 in AML. Furthermore, HDAC8-specific inhibitor, PCI-34051, or clinical class I HDAC inhibitor, AR-42, in combination with KPT-9274, synergistically decreased the survival of AML cells in a dose-dependent manner. AR-42/KPT-9274 cotreatment attenuated colony-forming potentials of patient cells while sparing healthy hematopoietic cells. Importantly, combined therapy demonstrated promising in vivo efficacy compared with KPT-9274 or AR-42 monotherapy. Mechanistically, genetic inhibition of SIRT6 potentiated the effect of KPT-9274 on PARP-1 suppression by abolishing mono-ADP ribosylation. AR-42/KPT-9274 cotreatment resulted in synergistic attenuation of homologous recombination and nonhomologous end joining pathways in cell lines and leukemia-initiating cells. CONCLUSIONS: Our findings provide evidence that HDAC8 inhibition- or shSIRT6-induced DNA repair deficiencies are potently synergistic with NAMPT targeting, with minimal toxicity toward normal cells, providing a rationale for a novel-novel combination-based treatment for AML.
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Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Citocinas/antagonistas & inibidores , Leucemia Mieloide Aguda/tratamento farmacológico , Nicotinamida Fosforribosiltransferase/antagonistas & inibidores , Proteínas Repressoras/antagonistas & inibidores , Sirtuínas/antagonistas & inibidores , Acrilamidas/farmacologia , Acrilamidas/uso terapêutico , Aminopiridinas/farmacologia , Aminopiridinas/uso terapêutico , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Linhagem Celular Tumoral , Dano ao DNA , Reparo do DNA por Junção de Extremidades/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/genética , Técnicas de Inativação de Genes , Histona Desacetilases/genética , Histona Desacetilases/metabolismo , Humanos , Ácidos Hidroxâmicos/farmacologia , Ácidos Hidroxâmicos/uso terapêutico , Indóis/farmacologia , Indóis/uso terapêutico , Leucemia Mieloide Aguda/patologia , Masculino , Camundongos , Fenilbutiratos/farmacologia , Fenilbutiratos/uso terapêutico , Reparo de DNA por Recombinação/efeitos dos fármacos , Proteínas Repressoras/genética , Proteínas Repressoras/metabolismo , Sirtuínas/genética , Sirtuínas/metabolismo , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
B-cell receptor (BCR) antagonists such as the BTK inhibitor ibrutinib have proven to effectively target chronic lymphocytic leukemia (CLL) tumor cells, leading to impressive response rates in these patients. However patients do still relapse on ibrutinib, and the progressive disease is often quite aggressive requiring immediate treatment. Several strategies are being pursued to treat patients who relapse on ibrutinib therapy. As the most common form of relapse is the development of a mutant form of BTK which limits ibrutinib binding, agents which lead to degradation of the BTK protein are a promising strategy. Our study explores the efficacy of the Hsp90 inhibitor, SNX-5422, in CLL. The SNX Hsp90 inhibitor was effective in primary CLL cells, as well as B-cell lines expressing either BTK wild type or C481 mutant BTK, which has been identified as the primary resistance mechanism to ibrutinib in CLL patients. Furthermore the combination of SNX-5422 and ibrutinib provided a remarkable in vivo survival benefit in the Eµ-TCL1 mouse model of CLL compared to the vehicle or single agent groups (51 day median survival in the vehicle and ibrutinib groups versus 100 day median survival in the combination). We report here preclinical data suggesting that the Hsp90 inhibitor SNX-5422, which has been pursued in clinical trials in both solid tumor and hematological malignancies, is a potential therapy for ibrutinib resistant CLL.
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Adenina/análogos & derivados , Antineoplásicos/uso terapêutico , Benzamidas/uso terapêutico , Glicina/uso terapêutico , Proteínas de Choque Térmico HSP90/antagonistas & inibidores , Indazóis/uso terapêutico , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Piperidinas/uso terapêutico , Adenina/farmacologia , Adenina/uso terapêutico , Animais , Antineoplásicos/farmacologia , Benzamidas/farmacologia , Linhagem Celular Tumoral , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Glicina/farmacologia , Humanos , Indazóis/farmacologia , Leucemia Linfocítica Crônica de Células B/patologia , Camundongos , Piperidinas/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêuticoRESUMO
BACKGROUND: Exportin 1 (XPO1/CRM1) is a key mediator of nuclear export with relevance to multiple cancers, including chronic lymphocytic leukemia (CLL). Whole exome sequencing has identified hot-spot somatic XPO1 point mutations which we found to disrupt highly conserved biophysical interactions in the NES-binding groove, conferring novel cargo-binding abilities and forcing cellular mis-localization of critical regulators. However, the pathogenic role played by change-in-function XPO1 mutations in CLL is not fully understood. METHODS: We performed a large, multi-center retrospective analysis of CLL cases (N = 1286) to correlate nonsynonymous mutations in XPO1 (predominantly E571K or E571G; n = 72) with genetic and epigenetic features contributing to the overall outcomes in these patients. We then established a mouse model with over-expression of wildtype (wt) or mutant (E571K or E571G) XPO1 restricted to the B cell compartment (Eµ-XPO1). Eµ-XPO1 mice were then crossed with the Eµ-TCL1 CLL mouse model. Lastly, we determined crystal structures of XPO1 (wt or E571K) bound to several selective inhibitors of nuclear export (SINE) molecules (KPT-185, KPT-330/Selinexor, and KPT-8602/Eltanexor). RESULTS: We report that nonsynonymous mutations in XPO1 associate with high risk genetic and epigenetic features and accelerated CLL progression. Using the newly-generated Eµ-XPO1 mouse model, we found that constitutive B-cell over-expression of wt or mutant XPO1 could affect development of a CLL-like disease in aged mice. Furthermore, concurrent B-cell expression of XPO1 with E571K or E571G mutations and TCL1 accelerated the rate of leukemogenesis relative to that of Eµ-TCL1 mice. Lastly, crystal structures of E571 or E571K-XPO1 bound to SINEs, including Selinexor, are highly similar, suggesting that the activity of this class of compounds will not be affected by XPO1 mutations at E571 in patients with CLL. CONCLUSIONS: These findings indicate that mutations in XPO1 at E571 can drive leukemogenesis by priming the pre-neoplastic lymphocytes for acquisition of additional genetic and epigenetic abnormalities that collectively result in neoplastic transformation.
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Regulação Leucêmica da Expressão Gênica , Carioferinas/genética , Leucemia Linfocítica Crônica de Células B/genética , Mutação , Receptores Citoplasmáticos e Nucleares/genética , Animais , Epigênese Genética , Feminino , Humanos , Masculino , Camundongos Endogâmicos C57BL , Modelos Moleculares , Estudos Retrospectivos , Transcriptoma , Proteína Exportina 1RESUMO
PURPOSE: Assess time to hemodynamic stability (HDS) in obese patients with septic shock who received <30 vs. ≥30 ml/kg of initial fluid resuscitation based on actual body weight (ABW). MATERIALS AND METHODS: Multicenter, retrospective, cohort analysis of 322 patients. RESULTS: Overall 216 (67%) patients received <30 ml/kg of initial fluid resuscitation. Initial fluid received was lower in the <30 ml/kg vs. ≥30 ml/kg group (16 vs. 37 ml/kg). The ≥30 ml/kg group had shorter time to HDS (multivariable p = 0.038) and lower riskof in-hospital death (multivariable p = 0.038). An exploratory subgroup analysis (n = 227) was performed, classifying patients by dosing strategy [ABW, adjusted body weight (AdjBW), ideal body weight (IBW)] based on fluid received at 3 h divided by 30 ml/kg. ABW dosed patients had a shorter time to HDS (multivariable p = 0.013) and lower risk of in-hospital death (multivariable p = 0.008) vs. IBW. Similar outcomes were observed between ABW vs. AdjBW. CONCLUSIONS: Obese patients given ≥30 ml/kg based on ABW had a shorter time to HDS and a lower risk of in-hospital death. Exploratory results suggest improved outcomes resuscitating by ABW vs. IBW; ABW showed no strong benefit over AdjBW. Further prospective studies are needed to confirm the optimal fluid dosing in obese patients.
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Choque Séptico , Hidratação , Hemodinâmica , Mortalidade Hospitalar , Humanos , Obesidade/complicações , Obesidade/terapia , Ressuscitação , Estudos Retrospectivos , Choque Séptico/terapiaRESUMO
OBJECTIVE: To report and compare presentation and management of Fournier's Gangrene (FG) in female vs male patients at a single tertiary care center. METHODS: Patient demographics, clinical characteristics, treatments and outcomes were summarized and compared between males and females who were treated for FG from 2011 to 2018 at a single institution. RESULTS: Of the 143 patients treated for FG at our institution, 33 (23%) were female. Female patients were predominantly white (82%), with a median (IQR) age of 55 (46, 59). Median female boby mass index (BMI) was 42.1 (32, 50.4). Female patients' wound cultures were polymicrobial mix of gram positive and gram negative organisms. Median number of debridements for females was 2 (1,3). The most common anatomic region of gangrene involvement in females was labia (76%) followed by perineum (55%) and gluteus/buttocks (42%). Mortality rate during initial admission was 6% for females. Female patients had a higher median BMI than males (42.1 vs 33.7 respectively; P = .003). FG severity index, length of hospital stay, number of debridements, and wound cultures were comparable to males. The surgical team managing initial debridements differed with females managed primarily by general surgery and males primarily by urology. Mortality rate was comparable to men (6% vs 7%, P >.05). CONCLUSION: Female patients with FG have greater BMI but similar clinical presentation, microbiologic characteristics and mortality rate compared to men. Urologists have little involvement during initial management for females at our institution.
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Desbridamento , Gangrena de Fournier/microbiologia , Gangrena de Fournier/cirurgia , Índice de Massa Corporal , Nádegas/patologia , Nádegas/cirurgia , Feminino , Gangrena de Fournier/mortalidade , Humanos , Masculino , Pessoa de Meia-Idade , Períneo/patologia , Períneo/cirurgia , Estudos Retrospectivos , Centros de Atenção Terciária , Vulva/patologia , Vulva/cirurgiaRESUMO
Acute myeloid leukemia (AML) is a heterogeneous and complex disease, and treatments for this disease have not been curative for the majority of patients. In younger patients, internal tandem duplication of FLT3 (FLT3-ITD) is a common mutation for which two inhibitors (midostaurin and gilteritinib) with varied potency and specificity for FLT3 are clinically approved. However, the high rate of relapse or failed initial response of AML patients suggests that the addition of a second targeted therapy may be necessary to improve efficacy. Using an unbiased large-scale CRISPR screen, we genetically identified BCL2 knockout as having synergistic effects with an approved FLT3 inhibitor. Here, we provide supportive studies that validate the therapeutic potential of the combination of FLT3 inhibitors with venetoclax in vitro and in vivo against multiple models of FLT3-ITD-driven AML. Our unbiased approach provides genetic validation for co-targeting FLT3 and BCL2 and repurposes CRISPR screening data, utilizing the genome-wide scope toward mechanistic understanding.
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Leucemia Mieloide Aguda/terapia , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Proto-Oncogênicas c-bcl-2/genética , Tirosina Quinase 3 Semelhante a fms/antagonistas & inibidores , Compostos de Anilina/uso terapêutico , Animais , Antineoplásicos/uso terapêutico , Compostos Bicíclicos Heterocíclicos com Pontes/uso terapêutico , Sistemas CRISPR-Cas , Linhagem Celular Tumoral , Feminino , Técnicas de Inativação de Genes , Terapia Genética , Humanos , Leucemia Mieloide Aguda/genética , Camundongos SCID , Pirazinas/uso terapêutico , Estaurosporina/análogos & derivados , Estaurosporina/uso terapêutico , Sulfonamidas/uso terapêuticoRESUMO
Acute myeloid leukemia (AML) is a hematopoietic stem-cell-derived leukemia with often successive derived driver mutations. Late onset acquisition of internal tandem duplication in FLT3 (FLT3-ITD) at a high variant allele frequency often contributes to full transformation to a highly proliferative, rapidly progressive disease with poor outcome. The FLT3-ITD mutation is targetable with approved FLT3 small molecule inhibitors, including midostaurin and gilteritinib. However, outside of patients receiving allogeneic transplant, most patients fail to respond or relapse, suggesting alternative approaches of therapy will be required. We employed genome-wide pooled CRISPR knockout screening as a method for large-scale identification of targets whose knockout produces a phenotypic effect that enhances the antitumor properties of FLT3 inhibitors. Among the candidate targets we identified the effect of XPO1 knockout to be synergistic with midostaurin treatment. Next, we validated the genetic finding with pharmacologic combination of the slowly reversible XPO1 inhibitor selinexor with midostaurin and gilteritinib in FLT3-ITD AML cell lines and primary patient samples. Lastly, we demonstrated improved survival with either combination therapy compared to its monotherapy components in an aggressive AML murine model, supporting further evaluation and rapid clinical translation of this combination strategy.
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BACKGROUND: Acute myeloid leukemia (AML) is the most common type of adult leukemia. Several studies have demonstrated that oncogenesis in AML is enhanced by kinase signaling pathways such as Src family kinases (SFK) including Src and Lyn, spleen tyrosine kinase (SYK), and bruton's tyrosine kinase (BTK). Recently, the multi-kinase inhibitor ArQule 531 (ARQ 531) has demonstrated potent inhibition of SFK and BTK that translated to improved pre-clinical in vivo activity as compared with the irreversible BTK inhibitor ibrutinib in chronic lymphocytic leukemia (CLL) models. Given the superior activity of ARQ 531 in CLL, and recognition that this molecule has a broad kinase inhibition profile, we pursued its application in pre-clinical models of AML. METHODS: The potency of ARQ 531 was examined in vitro using FLT3 wild type and mutated (ITD) AML cell lines and primary samples. The modulation of pro-survival kinases following ARQ 531 treatment was determined using AML cell lines. The effect of SYK expression on ARQ 531 potency was evaluated using a SYK overexpressing cell line (Ba/F3 murine cells) constitutively expressing FLT3-ITD. Finally, the in vivo activity of ARQ 531 was evaluated using MOLM-13 disseminated xenograft model. RESULTS: Our data demonstrate that ARQ 531 treatment has anti-proliferative activity in vitro and impairs colony formation in AML cell lines and primary AML cells independent of the presence of a FLT3 ITD mutation. We demonstrate decreased phosphorylation of oncogenic kinases targeted by ARQ 531, including SFK (Tyr416), BTK, and fms-related tyrosine kinase 3 (FLT3), ultimately leading to changes in down-stream targets including SYK, STAT5a, and ERK1/2. Based upon in vitro drug synergy data, we examined ARQ 531 in the MOLM-13 AML xenograft model alone and in combination with venetoclax. Despite ARQ 531 having a less favorable pharmacokinetics profile in rodents, we demonstrate modest single agent in vivo activity and synergy with venetoclax. CONCLUSIONS: Our data support consideration of the application of ARQ 531 in combination trials for AML targeting higher drug concentrations in vivo.
Assuntos
Antineoplásicos/uso terapêutico , Leucemia Mieloide Aguda/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Tirosina Quinases/antagonistas & inibidores , Animais , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Humanos , Leucemia Mieloide Aguda/metabolismo , Leucemia Mieloide Aguda/patologia , Camundongos , Inibidores de Proteínas Quinases/farmacologia , Proteínas Tirosina Quinases/metabolismoRESUMO
OBJECTIVES: Lung cancer is the leading cause of cancer mortality in both men and women in the United States. COPD is associated with lung cancer independently of cigarette smoking, but remains understudied in women. Utilizing data from the Women's Health Initiative Observational Study (WHI-OS), this report investigates the association between COPD and development of lung cancer, with a focus on ethnicity and cancer subtype. MATERIALS AND METHODS: The WHI-OS, part of the larger Women's Health Initiative (WHI), is comprised of postmenopausal women between ages 50 and 79 years old at enrollment. Self-administered questionnaires were utilized to gather baseline demographic, socioeconomic, and behavioral information from participants. For this analysis, COPD status was determined at study entry (baseline) and on annual survey (incident). Information on the primary outcome of interest, diagnosis of lung cancer, was also collected annually. RESULTS AND CONCLUSION: Of the 92,789 women examined, 1,536 developed lung cancer. Overall, women with COPD were 1.64 times more likely to develop lung cancer than those without COPD, after adjusting for smoking status and intensity, ethnicity, education, body mass index, and income (HRâ¯=â¯1.64, 95 % CI: 1.43, 1.89). The relationship between COPD and lung cancer was not found to be significantly different between ethnic groups (p-valueâ¯=â¯0.697). The associations between COPD and lung cancer was similar across subtypes (HR range 1.31-2.16), after adjusting for smoking status and intensity. COPD increases risk of lung cancer in women, thus they may benefit from more intensive surveillance compared to similar women without COPD.
Assuntos
Neoplasias Pulmonares/epidemiologia , Pós-Menopausa , Doença Pulmonar Obstrutiva Crônica/fisiopatologia , Saúde da Mulher , Idoso , Feminino , Humanos , Incidência , Pessoa de Meia-Idade , Prognóstico , Fatores de Risco , Inquéritos e Questionários , Estados Unidos/epidemiologiaRESUMO
INTRODUCTION: Uric acid (UA) nephrolithiasis represents 10% of kidney stones in the US with low urine pH and high saturation of UA as the main risk factors for stone development. Dissolution therapy for UA kidney stones via urinary alkalization has been described as a treatment option. We present our experience in treating UA nephrolithiasis with medical dissolution therapy. METHODS: A retrospective review was performed of UA stone patients referred for surgery but treated with dissolution therapy between July 2007 and July 2016. Patients were identified using ICD-9 codes. Patients were treated with potassium citrate alone or in combination with allopurinol. Serial imaging and urine pH were obtained at follow-up. Demographics, aggregate stone size, time to stone clearance, urine pH (office dip), and complications were recorded. RESULTS OBTAINED: Twenty-four patients (14 men and 10 women) were identified that started medical dissolution therapy for UA nephrolithiasis after initial referral for surgical management. Three patients (13%) did not tolerate the initiation of dissolution therapy and discontinued this treatment. Of the 21 patients that were maintained on dissolution therapy, 14 patients (67%) showed complete resolution of nephrolithiasis and 7 patients (33%) showed partial reduction. Patients with partial response had a mean reduction in stone burden of 68%. There were 3 recorded complications (UTI, GI upset with therapy, and throat irritation) and 4 recorded stone recurrences among these 21 patients. CONCLUSION: Based on our study population, medical dissolution therapy is a well-tolerated, non-invasive option for UA nephrolithiasis.
Assuntos
Alopurinol/uso terapêutico , Nefrolitíase/tratamento farmacológico , Citrato de Potássio/uso terapêutico , Ácido Úrico , Adulto , Idoso , Feminino , Humanos , Cálculos Renais/química , Cálculos Renais/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Ácido Úrico/análiseRESUMO
Treatment options for acute myeloid leukemia (AML) remain extremely limited and associated with significant toxicity. Nicotinamide phosphoribosyltransferase (NAMPT) is involved in the generation of NAD+ and a potential therapeutic target in AML. We evaluated the effect of KPT-9274, a p21-activated kinase 4/NAMPT inhibitor that possesses a unique NAMPT-binding profile based on in silico modeling compared with earlier compounds pursued against this target. KPT-9274 elicited loss of mitochondrial respiration and glycolysis and induced apoptosis in AML subtypes independent of mutations and genomic abnormalities. These actions occurred mainly through the depletion of NAD+, whereas genetic knockdown of p21-activated kinase 4 did not induce cytotoxicity in AML cell lines or influence the cytotoxic effect of KPT-9274. KPT-9274 exposure reduced colony formation, increased blast differentiation, and diminished the frequency of leukemia-initiating cells from primary AML samples; KPT-9274 was minimally cytotoxic toward normal hematopoietic or immune cells. In addition, KPT-9274 improved overall survival in vivo in 2 different mouse models of AML and reduced tumor development in a patient-derived xenograft model of AML. Overall, KPT-9274 exhibited broad preclinical activity across a variety of AML subtypes and warrants further investigation as a potential therapeutic agent for AML.