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OPINION STATEMENT: In the past, the standard of care for treatment of BM was whole brain radiation therapy (WBRT), stereotactic radiosurgery (SRS), and surgery. There has been a greater role for medical therapies in the last two decades due to the discovery of driver mutations and corresponding targeted therapies. These innovations have dramatically altered the approach to treating these patients. Some of the important mutations include epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK) mutations in small cell lung cancer, human epidermal growth factor receptor (HER2) mutation in breast cancer, and BRAF mutation in melanoma. Disease-specific graded prognostic assessments have identified prognostic factors for each of the major tumor types associated with BM. These reflect the increased treatment sensitivity of these tumors to specific agents. Furthermore, there is a difference in the genetic makeup of BM compared to their primary tumor. Genomic studies of BM patients comparing somatic point mutations and copy number variations with their primary tumor have demonstrated that while both the primary tumor and BM share a number of common mutations, BM can often develop distinct mutations. Therefore, there is a need to individualize systemic therapies in BM. Several organizations including the Food and Drug Administration and the American Society of Clinical Oncology now emphasize the inclusion of BM patients in various phases of clinical drug development.
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Antineoplásicos/uso terapêutico , Neoplasias Encefálicas/secundário , Neoplasias Encefálicas/terapia , Neoplasias da Mama/terapia , Terapia de Alvo Molecular , Radiocirurgia , Neoplasias Encefálicas/mortalidade , Neoplasias da Mama/mortalidade , Neoplasias da Mama/patologia , Ensaios Clínicos Fase III como Assunto , Terapia Combinada , Irradiação Craniana , Receptores ErbB , Feminino , Humanos , Mutação , Receptor ErbB-2/antagonistas & inibidores , Resultado do TratamentoRESUMO
Using structure based drug design (SBDD), a novel class of potent coagulation Factor IXa (FIXa) inhibitors was designed and synthesized. High selectivity over FXa inhibition was achieved. Selected compounds demonstrated oral bioavailability in rat IV/PO pharmacokinetic (PK) studies. Finally, the pharmacodynamics (PD) of this class of molecules was evaluated in Thrombin Generation Assay (TGA) in Corn Trypsin Inhibitor (CTI) citrated human plasma and demonstrated characteristics of a FIXa inhibitor.
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Aminas/farmacologia , Inibidores Enzimáticos/farmacologia , Fator IXa/antagonistas & inibidores , Administração Oral , Aminas/síntese química , Aminas/química , Animais , Disponibilidade Biológica , Cristalografia por Raios X , Relação Dose-Resposta a Droga , Desenho de Fármacos , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Fator IXa/metabolismo , Humanos , Modelos Moleculares , Estrutura Molecular , Ratos , Relação Estrutura-AtividadeRESUMO
Using structure based drug design, a novel class of potent coagulation factor IXa (FIXa) inhibitors was designed and synthesized. High selectivity over FXa inhibition was achieved. Selected compounds were evaluated in rat IV/PO pharmacokinetic (PK) studies and demonstrated desirable oral PK profiles. Finally, the pharmacodynamics (PD) of this class of molecules were evaluated in thrombin generation assay (TGA) in Corn Trypsin Inhibitor (CTI) citrated human plasma and demonstrated characteristics of a FIXa inhibitor.
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Desenho de Fármacos , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Fator IXa/antagonistas & inibidores , Compostos Heterocíclicos com 3 Anéis/química , Compostos Heterocíclicos com 3 Anéis/farmacologia , Administração Oral , Animais , Cristalografia por Raios X , Ativação Enzimática/efeitos dos fármacos , Inibidores Enzimáticos/química , Compostos Heterocíclicos com 3 Anéis/síntese química , Humanos , Estrutura Molecular , RatosRESUMO
Neuromedin U (NMU) is an endogenous peptide implicated in the regulation of feeding, energy homeostasis, and glycemic control, which is being considered for the therapy of obesity and diabetes. A key liability of NMU as a therapeutic is its very short half-life in vivo. We show here that conjugation of NMU to human serum albumin (HSA) yields a compound with long circulatory half-life, which maintains full potency at both the peripheral and central NMU receptors. Initial attempts to conjugate NMU via the prevalent strategy of reacting a maleimide derivative of the peptide with the free thiol of Cys34 of HSA met with limited success, because the resulting conjugate was unstable in vivo. Use of a haloacetyl derivative of the peptide led instead to the formation of a metabolically stable conjugate. HSA-NMU displayed long-lasting, potent anorectic, and glucose-normalizing activity. When compared side by side with a previously described PEG conjugate, HSA-NMU proved superior on a molar basis. Collectively, our results reinforce the notion that NMU-based therapeutics are promising candidates for the treatment of obesity and diabetes.
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Fármacos Antiobesidade/síntese química , Hipoglicemiantes/síntese química , Neuropeptídeos/síntese química , Neuropeptídeos/farmacologia , Polietilenoglicóis/farmacologia , Albumina Sérica/síntese química , Animais , Fármacos Antiobesidade/farmacocinética , Fármacos Antiobesidade/farmacologia , Glicemia , Linhagem Celular , Avaliação Pré-Clínica de Medicamentos , Humanos , Hipoglicemiantes/farmacocinética , Hipoglicemiantes/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Neuropeptídeos/farmacocinética , Polietilenoglicóis/farmacocinética , Receptores de Neurotransmissores/agonistas , Albumina Sérica/farmacocinética , Albumina Sérica/farmacologia , Albumina Sérica Humana , Redução de Peso/efeitos dos fármacosRESUMO
OBJECTIVE: To investigate whether Heartfulness meditation practice, compared to Gratitude practice, leads to measurable changes in mental wellbeing among healthcare providers across the US. METHOD: Participants were randomly assigned to one of the following 6-week interventions: the trainer-guided virtual Heartfulness meditation program or the podcast-based self-guided gratitude practice group. The Professional Quality of Life Scale-5 (ProQOL-5) was used to determine Compassion Satisfaction (CS) and risk for Burnout (BO) and secondary traumatic stress (STS). The Utrecht Work Engagement Scale (UWES) was used to assess vigor, dedication, and absorption at work. Outcomes were collected at baseline and the end of the study period. Qualitative questions regarding the experience of learning and practicing were also offered at the end of the six weeks. RESULTS: The majority of participants were nurses (50%), followed by allied healthcare professionals (37%) and physicians (13%) (N = 83). There was a general trend towards increases in CS in the Heartfulness group compared to the gratitude group. However, this was not statistically significant. Strong evidence suggests there was a significant improvement in BO for the Heartfulness group between Week 0 and Week 6 (p = 0.002), as well as STS (p = 0.0004) and vigor (p = 0.0392). Qualitative data analysis revealed that the subjects in the Heartfulness arm reported improved sleep and decreased reactivity to stress. Subjects in the gratitude arm reported improved mood and favorable results using gratitude practices at home with family members. CONCLUSION: In our study, Heartfulness meditation practice was associated with a significant improvement in burnout and vigor at work, with a trend towards compassion satisfaction after six weeks compared with gratitude practices. Qualitative analysis indicates the benefits of both Heartfulness and Gratitude practices. Further randomized trials with a larger sample size are needed to explore these science-based practices for the wellbeing of healthcare workers.
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Esgotamento Profissional , Pessoal de Saúde , Meditação , Humanos , Meditação/psicologia , Meditação/métodos , Feminino , Masculino , Adulto , Pessoal de Saúde/psicologia , Esgotamento Profissional/psicologia , Esgotamento Profissional/prevenção & controle , Pessoa de Meia-Idade , Qualidade de Vida , Engajamento no Trabalho , Empatia , Satisfação no EmpregoRESUMO
PURPOSE: The majority of patients with metastatic prostate cancer who receive androgen-deprivation therapy and androgen receptor (AR) signaling inhibitors (ARSI) progress. Activation of the glucocorticoid receptor (GR) is associated with ARSI resistance. This single-arm phase I trial assessed safety and pharmacokinetic (PK) feasibility of a combined AR antagonist (enzalutamide) and selective GR modulator (relacorilant) in patients with metastatic castration-resistant prostate cancer (mCRPC). PATIENTS AND METHODS: This was a phase I trial (NCT03674814) of relacorilant and enzalutamide in patients with refractory mCRPC enrolled using a 6+3 design. The enzalutamide dose was kept constant at 120 mg/d with escalating doses of relacorilant based on safety and PK measures in cohorts of ≥6 patients. The primary objective was safety and establishment of pharmacologically active doses. Secondary objectives were related to antitumor activity. RESULTS: Thirty-five patients with mCRPC were enrolled. Twenty-three were accrued across three dose cohorts in the dose-escalation phase, and 12 enrolled at the recommended phase II dose. The combination was generally well tolerated, safe, and achieved desirable enzalutamide PK. RP2D of 120 + 150 mg/d, respectively, was established. Median time on study was 2.2 months with four patients remaining on study for longer than 11 months. Four of 12 evaluable patients had a prostate-specific antigen (PSA) partial response. CONCLUSIONS: This is the first prospective trial combining an AR antagonist and a nonsteroidal selective GR modulator. The combination was safe and well tolerated with PSA response and prolonged disease control observed in a limited subset of patients. Further prospective trials are justified to evaluate efficacy and identify predictive biomarkers of response.
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Protocolos de Quimioterapia Combinada Antineoplásica , Benzamidas , Nitrilas , Feniltioidantoína , Neoplasias de Próstata Resistentes à Castração , Receptores de Glucocorticoides , Humanos , Masculino , Feniltioidantoína/administração & dosagem , Feniltioidantoína/efeitos adversos , Feniltioidantoína/uso terapêutico , Feniltioidantoína/farmacocinética , Benzamidas/administração & dosagem , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Neoplasias de Próstata Resistentes à Castração/patologia , Nitrilas/administração & dosagem , Idoso , Pessoa de Meia-Idade , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Idoso de 80 Anos ou mais , Metástase Neoplásica , Antagonistas de Receptores de Andrógenos/uso terapêutico , Antagonistas de Receptores de Andrógenos/administração & dosagem , Antagonistas de Receptores de Andrógenos/farmacocinética , Antagonistas de Receptores de Andrógenos/efeitos adversos , Receptores Androgênicos/metabolismo , Resultado do TratamentoRESUMO
Immune-based therapies induce durable remissions in subsets of patients across multiple malignancies. However, there is limited efficacy of immunotherapy in metastatic castrate-resistant prostate cancer (mCRPC), manifested by an enrichment of immunosuppressive (M2) tumor- associated macrophages (TAM) in the tumor immune microenvironment (TME). Therefore, therapeutic strategies to overcome TAM-mediated immunosuppression are critically needed in mCRPC. Here we discovered that NLR family pyrin domain containing 3 (NLRP3), an innate immune sensing protein, is highly expressed in TAM from metastatic PC patients treated with standard-of-care androgen deprivation therapy (ADT). Importantly, ex vivo studies revealed that androgen receptor (AR) blockade in TAM upregulates NLRP3 expression, but not inflammasome activity, and concurrent AR blockade/NLRP3 agonist (NLRP3a) treatment promotes cancer cell phagocytosis by immunosuppressive M2 TAM. In contrast, NLRP3a monotherapy was sufficient to enhance phagocytosis of cancer cells in anti-tumor (M1) TAM, which exhibit high de novo NLRP3 expression. Critically, combinatorial treatment with ADT/NLRP3a in a murine model of advanced PC resulted in significant tumor control, with tumor clearance in 55% of mice via TAM phagocytosis. Collectively, our results demonstrate NLRP3 as an AR-regulated "macrophage phagocytic checkpoint", inducibly expressed in TAM by ADT and activated by NLRP3a treatment, the combination resulting in TAM-mediated phagocytosis and tumor control.
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Streptococcus mutans develops competence for genetic transformation in response to regulatory circuits that sense at least two peptide pheromones. One peptide, known as CSP, is sensed by a two-component signal transduction system through a membrane receptor, ComD. The other, derived from the primary translation product ComS, is thought to be sensed by an intracellular receptor, ComR, after uptake by oligopeptide permease. To allow study of this process in a medium that does not itself contain peptides, development of competence was examined in the chemically defined medium (CDM) described by van de Rijn and Kessler (Infect. Immun. 27:444, 1980). We confirmed a previous report that in this medium comS mutants of strain UA159 respond to a synthetic peptide comprising the seven C-terminal residues of ComS (ComS(11-17)) by increasing expression of the alternative sigma factor SigX, which in turn allows expression of competence effector genes. This response provided the basis for a bioassay for the ComS pheromone in the 100 to 1,000 nM range. It was further observed that comS(+) (but not comS mutant) cultures developed a high level of competence in the late log and transition phases of growth in this CDM without the introduction of any synthetic stimulatory peptide. This endogenous competence development was accompanied by extracellular release of one or more signals that complemented a comS mutation at levels equivalent to 1 µM synthetic ComS(11-17).
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Meios de Cultura/química , Competência de Transformação por DNA , Streptococcus mutans/genética , Transformação Genética , Proteínas de Bactérias/metabolismo , Regulação Bacteriana da Expressão Gênica , Feromônios/metabolismo , Transdução de Sinais , Streptococcus mutans/crescimento & desenvolvimento , Streptococcus mutans/fisiologiaRESUMO
Neuromedin U (NMU) is an endogenous peptide, whose role in the regulation of feeding and energy homeostasis is well documented. Two NMU receptors have been identified: NMUR1, expressed primarily in the periphery, and NMUR2, expressed predominantly in the brain. We recently demonstrated that acute peripheral administration of NMU exerts potent but acute anorectic activity and can improve glucose homeostasis, with both actions mediated by NMUR1. Here, we describe the development of a metabolically stable analog of NMU, based on derivatization of the native peptide with high molecular weight poly(ethylene) glycol (PEG) ('PEGylation'). PEG size, site of attachment, and conjugation chemistry were optimized, to yield an analog which displays robust and long-lasting anorectic activity and significant glucose-lowering activity in vivo. Studies in NMU receptor-deficient mice showed that PEG-NMU displays an expanded pharmacological profile, with the ability to engage NMUR2 in addition to NMUR1. In light of these data, PEGylated derivatives of NMU represent promising candidates for the treatment of obesity and diabetes.
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Diabetes Mellitus Experimental/tratamento farmacológico , Neuropeptídeos/farmacologia , Obesidade/tratamento farmacológico , Polietilenoglicóis/química , Receptores de Neurotransmissores/agonistas , Animais , Relação Dose-Resposta a Droga , Teste de Tolerância a Glucose , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Neuropeptídeos/administração & dosagem , Neuropeptídeos/síntese química , Polietilenoglicóis/administração & dosagem , Polietilenoglicóis/síntese química , Polietilenoglicóis/farmacologia , Receptores de Neurotransmissores/deficiência , Relação Estrutura-AtividadeRESUMO
Cryptosporidium is an obligate enteric protozoan parasite commonly associated with severe symptoms such as profound diarrhea and dehydration in the immunocompromised, particularly those living with HIV/AIDS. In the immunocompetent, Cryptosporidiosis is self-limited, and characterized by mild non-bloody diarrhea with associated nausea and vomiting. We present an unusual case of presumed Cryptosporidium colitis, in an immunocompetent host, characterized by anorexia and pneumoperitoneum.
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Serious neurologic complications from coronavirus disease 2019 (COVID-19) vaccination are rare, and only a few cases of Guillain-Barré syndrome (GBS) have been reported after COVID-19 vaccination. We present the first reported case of the facial diplegia variant of GBS after recent COVID-19 vaccination in a pregnant woman. The 30-year-old patient was 27 weeks pregnant at the time she was diagnosed with the facial diplegia variant of GBS. Her symptoms began two weeks after she received the Ad26.COV2.S COVID-19 vaccine. A thorough evaluation for GBS was done, including a lumbar puncture that demonstrated elevated cerebrospinal fluid (CSF) protein and nerve conduction study (NCS) that found evidence of a diffuse sensorimotor demyelinating polyneuropathy. Nasal swab testing for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was negative on two occasions five days apart. All other diagnostic testing was unremarkable or nonexplanatory of the patient's clinical presentation. She was started on intravenous immunoglobulin (IVIG) and had significantly improved dysphasia, dysarthria, and facial strength. The patient recovered to baseline four weeks after presentation.
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BACKGROUND: Immunotherapy combinations including ipilimumab and nivolumab are now the standard of care for untreated metastatic renal cell carcinoma (mRCC). Biomarkers of response are lacking to predict patients who will have a favorable or unfavorable response to immunotherapy. This study aimed to use the OmniSeq transcriptome-based platform to develop biomarkers of response to immunotherapy. METHODS: Two cohorts of patients were retrospectively collected. These included an investigational cohort of patients with mRCC treated with immune checkpoint inhibitor therapy from five institutions, and a subsequent validation cohort of patients with mRCC treated with combination ipilimumab and nivolumab from two institutions (Duke Cancer Institute and Cleveland Clinic Taussig Cancer Center). Tissue-based RNA sequencing was performed using the OmniSeq Immune Report Card on banked specimens to identify gene signatures and immune checkpoints associated with differential clinical outcomes. A 5-gene expression panel was developed based on the investigational cohort and was subsequently evaluated in the validation cohort. Clinical outcomes including progression-free survival (PFS) and overall survival (OS) were extracted by retrospective chart review. Objective response rate (ORR) was assessed by Response Evaluation Criteria in Solid Tumors (RECIST) V.1.1. RESULTS: The initial investigation cohort identified 86 patients with mRCC who received nivolumab (80%, 69/86), ipilimumab/nivolumab (14%, 12/86), or pembrolizumab (6%, 5/86). A gene expression score was created using the top five genes found in responders versus non-responders (FOXP3, CCR4, KLRK1, ITK, TIGIT). The ORR in patients with high gene expression (GEhigh) on the 5-gene panel was 29% (14/48), compared with low gene expression (GElow) 3% (1/38, χ2 p=0.001). The validation cohort was comprised of 62 patients who received ipilimumab/nivolumab. There was no difference between GEhigh and GElow in terms of ORR (44% vs 38.5%), PFS (HR 1.5, 95% CI 0.58 to 3.89), or OS (HR 0.96, 95% CI 0.51 to 1.83). Similarly, no differences in ORR, PFS or OS were observed when patients were stratified by tumor mutational burden (high=top 20%), PD-L1 (programmed death-ligand 1) expression by immunohistochemistry or RNA expression, or CTLA-4 (cytotoxic T-lymphocytes-associated protein 4) RNA expression. The International Metastatic RCC Database Consortium (IMDC) risk score was prognostic for OS but not PFS. CONCLUSION: A 5-gene panel that was associated with improved ORR in a predominantly nivolumab monotherapy population of patients with mRCC was not predictive for radiographic response, PFS, or OS among patients with mRCC treated with ipilimumab and nivolumab.
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Carcinoma de Células Renais , Neoplasias Renais , Humanos , Antígeno B7-H1/uso terapêutico , Carcinoma de Células Renais/tratamento farmacológico , Carcinoma de Células Renais/genética , Carcinoma de Células Renais/patologia , Antígeno CTLA-4/uso terapêutico , Fatores de Transcrição Forkhead , Inibidores de Checkpoint Imunológico/farmacologia , Inibidores de Checkpoint Imunológico/uso terapêutico , Ipilimumab/farmacologia , Ipilimumab/uso terapêutico , Neoplasias Renais/patologia , Nivolumabe/farmacologia , Nivolumabe/uso terapêutico , Estudos Retrospectivos , Microambiente TumoralRESUMO
Stress and lack of quality sleep affect a large portion of the population around the globe, and the COVID-19 pandemic has genuinely brought attention to these problems. This study aimed to investigate whether using a virtual heart-based meditation program is associated with improved stress levels and quality of sleep among participants from the general population during the COVID-19 pandemic. We recruited 63 participants to receive an 8-week virtually conducted Heartfulness meditation program in a prospective pre-post single-arm intervention study from September 28 to November 22 2020. Perceived Stress Scale (PSS) and Pittsburgh Sleep Quality Index (PSQI) scores were collected at baseline, at 4 weeks, and 8 weeks. Of the 63 participants enrolled in the study, 36 (57%) completed an 8-week Heartfulness meditation program. There was a significant decrease in PSS (mean difference of 6.68 with 95% C.I. 4.89-8.47, p < 0.0001) and in PSQI (mean difference of 2.05 with 95% C.I. 1.03-3.07, p < 0.0001) between week zero and week eight, regardless of Health Care Professional status. The qualitative thematic analysis strongly supported the survey results. A significant reduction in perceived stress score and improvement in sleep quality index was noted at the end of a virtual Heartfulness meditation program. Moreover, Heartfulness meditation practice may help cultivate the quality of empathy, acceptance, and individual peace. We conclude that the effects of virtually accessible Heartfulness meditation practice need to be explored further in larger studies.
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COVID-19 , Meditação , Humanos , Pandemias , Estudos Prospectivos , SARS-CoV-2 , Sono , Estresse Psicológico/prevenção & controleRESUMO
Statin therapy is a widely prescribed medication class for hypercholesterolemia. In statin-induced autoimmune myopathy, genetically predisposed and at-risk patients can develop antibodies against hydroxy-3-methylglutaryl-CoA reductase (HMGCR), the key enzyme in the production of cholesterol. As a result, an autoimmune reaction causing weakness, myalgia, with possible severe rhabdomyolysis, renal failure, and myonecrosis also can occur. A 73-year-old female presented to clinic with myalgia and fatigue. She was on atorvastatin 20 mg/day for over 1 year, which she stopped 1 week prior to her initial presentation. Patient did experience rhabdomyolysis as well as a transaminitis. She underwent an autoimmune workup which was positive for HMG-CoA reductase antibodies. Patient was initially treated on a prednisone taper, starting dose 50 mg/day. Without remission of symptoms, methotrexate 15 mg/week was initiated.
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Doenças Autoimunes , Inibidores de Hidroximetilglutaril-CoA Redutases , Doenças Musculares , Miosite , Idoso , Autoanticorpos , Doenças Autoimunes/induzido quimicamente , Doenças Autoimunes/tratamento farmacológico , Feminino , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/efeitos adversos , Doenças Musculares/induzido quimicamenteRESUMO
Chronic Inflammatory Demyelinating Polyneuropathy (CIDP) is a relapsing-remitting or progressive inflammatory neuropathy, which can present in a multitude of phenotypes. It can be a challenging condition to diagnose and requires thorough clinical evaluation and electrodiagnostic testing. With the outbreak of coronavirus disease in 2019 (COVID-19), large portions of the medical field converted to telemedicine to facilitate patient visits. We report a case of a 50-year-old female who was seen via video visit during the COVID-19 pandemic who was later diagnosed with CIDP and treated with intravenous immunoglobulins with improvement in clinical examination and electrodiagnostic testing. This case highlights the limitations of performing the neuromuscular examination via telemedicine.
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Huggins and Hodges demonstrated the therapeutic effect of gonadal testosterone deprivation in the 1940s and therefore firmly established the concept that prostate cancer is a highly androgen-dependent disease. Since that time, hormonal therapy has undergone iterative advancement, from the types of gonadal testosterone deprivation to modalities that block the generation of adrenal and other extragonadal androgens, to those that directly bind and inhibit the androgen receptor (AR). The clinical states of prostate cancer are the product of a superimposition of these therapies with nonmetastatic advanced prostate cancer, as well as frankly metastatic disease. Today's standard of care for advanced prostate cancer includes gonadotropin-releasing hormone agonists (e.g., leuprolide), second-generation nonsteroidal AR antagonists (enzalutamide, apalutamide, and darolutamide) and the androgen biosynthesis inhibitor abiraterone. The purpose of this review is to provide an assessment of hormonal therapies for the various clinical states of prostate cancer. The advancement of today's standard of care will require an accounting of an individual's androgen physiology that also has recently recognized germline determinants of peripheral androgen metabolism, which include HSD3B1 inheritance.
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Neoplasias de Próstata Resistentes à Castração , Neoplasias da Próstata , Antagonistas de Androgênios/uso terapêutico , Antagonistas de Receptores de Andrógenos/uso terapêutico , Androgênios/uso terapêutico , Humanos , Masculino , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/metabolismo , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Neoplasias de Próstata Resistentes à Castração/patologia , Receptores Androgênicos/uso terapêutico , Testosterona/uso terapêuticoRESUMO
Coronavirus disease 2019 (COVID-19) is associated with multiple neurological complications including Guillain-Barre syndrome (GBS). While there are reports of COVID-19 -related GBS cases, much remain unknown. We report two cases of GBS-associated COVID-19, which started about eight weeks after the initial COVID-19 infection. Such a long duration between infection and symptom onset of GBS is unusual for post-infectious GBS. Moreover, severely ill patients with COVID-19 may have prolonged hospital stay leading to critical illness myoneuropathy. Diagnosing superimposed GBS can be challenging in such cases. Clinical suspicion, nerve conduction studies with electromyography, and cerebrospinal fluid analysis can help in making the correct diagnosis. Both presented cases responded to intravenous immunoglobulin therapy.
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BACKGROUND: Bone metastases (BM) in renal cell carcinoma (RCC) patients are associated with poor outcomes. There are limited published data on outcomes in these patients with immunotherapy agents. We present a multi-institutional, retrospective analysis of metastatic RCC patients with BM treated with ipilimumab and nivolumab (I + N). OBJECTIVE: Patient, tumor, and treatment-related variables were retrospectively collected from electronic medical records of patients with a histologically confirmed diagnosis of RCC and at least one radiographically confirmed BM prior to initiation of I + N. Best objective response was assessed by clinical chart review, imaging reports, and treating physician evaluation; progression-free survival (PFS) and overall survival (OS) were recorded as of 31 December 2020. Descriptive statistics were used to summarize patient characteristics and BM-related variables. Kaplan-Meier method and Mantel-Haenszel log-rank test were used to compare survival among groups. Cox regression univariable and multivariable models were used to correlate patient- and treatment-related variables to outcomes. RESULTS: Eighty patients with RCC and BM treated with I + N were identified. Patients were predominantly male and Caucasian presenting primarily with IMDC intermediate or poor-risk clear-cell RCC. Best response to I + N was progressive disease (46%), stable disease (28%), partial response (21%), and not evaluable (5%). Median PFS was 6.1 months (95% CI 3.8-8.9 months) with the majority of patients (65%) discontinuing I + N due to disease progression. Median OS was 25.6 months (95% CI 14.9-NA) with median follow-up of 25.2 months. A multivariable regression model for PFS showed several variables to be significantly associated with worse PFS including female gender [p = 0.02; hazard ratio (HR) 2.16; 95% CI 1.14-4.12], metastases to other sites (p = 0.006; HR 2.12; 95% CI 1.24-3.62) and presence of BM to ribs (p = 0.0007; HR 2.61; 95% CI 1.50-4.52). A multivariable Cox model of OS showed no prior radiation therapy to BM (p = 0.02; HR 2.17; 95% CI 1.13-4.17) and presence of liver metastases (p = 0.0006; HR 3.19; 95% CI 1.65-6.19) to be significantly associated with worse OS. CONCLUSION: RCC patients with ≥ 1 BM who received I + N therapy had a relatively low response rate, PFS, and OS. Strategies to improve outcomes in this subset of patients are needed.
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Carcinoma de Células Renais , Neoplasias Renais , Carcinoma de Células Renais/tratamento farmacológico , Feminino , Humanos , Ipilimumab/uso terapêutico , Neoplasias Renais/tratamento farmacológico , Masculino , Nivolumabe/farmacologia , Nivolumabe/uso terapêutico , Estudos RetrospectivosRESUMO
The combination of ipilimumab plus nivolumab (I+N) has greatly improved outcomes in patients with intermediate or poor-risk untreated metastatic renal cell carcinoma (mRCC). However, little is known about the outcomes of patients with brain metastasis (BrM) treated with I+N. A search was performed to retrospectively identify all patients with mRCC treated with I+N in the Duke Cancer Institute and the Cleveland Clinic Taussig Cancer Center, followed by a chart review. Patients were included if they had BrM at the time of I+N initiation. Cohort characteristics are summarized with descriptive statistics. Kaplan-Meier method was used to estimate overall survival (OS) and global, intracranial, and extracranial progression-free survival (PFS) for the cohort and log rank test was used to compare OS and PFS between patient groups. Radiographic response was categorized by RECIST. Fisher's exact test was used to correlate patient factors with radiographic response. From October 2017 to December 2020, 19 patients with BrM received I+N for mRCC with a median follow-up time of 27.1 months (range 15.0-35.6). By International Metastatic RCC Database Consortium (IMDC) risk criteria, 16% had favorable, 58% had intermediate, and 26% had poor-risk disease. 68% were systemic therapy naïve, and 77% of patients had clear cell histology. 95% had received local CNS directed therapy with surgery, radiotherapy, or both. The objective response rate was 44% (0% complete response) with three of six patients treated in the second line or greater setting experiencing a partial response. The median PFS was 7.6 months (95% CI 5.6 to 14.9). The median extracranial PFS was 8.5 months (95% CI 5.6 to 19.7), and median intracranial PFS was 14.7 months (95% CI 7.2 to not reached). No variables assessed were significantly associated with radiographic response (gender, IMDC risk, presence of bone metastasis, line of therapy, or presence of immune related adverse events). In our retrospective cohort of patients with mRCC with BrM, I+N, in combination with CNS-directed local therapy, appears to have clinical efficacy as previously described with responses seen beyond the first-line setting. Further investigation is warranted in this population given exclusion from prior clinical trials.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Encefálicas/secundário , Carcinoma de Células Renais/tratamento farmacológico , Ipilimumab/uso terapêutico , Neoplasias Renais/tratamento farmacológico , Nivolumabe/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Feminino , Humanos , Ipilimumab/farmacologia , Masculino , Metástase Neoplásica , Nivolumabe/farmacologia , Resultado do TratamentoRESUMO
Sickle cell disease (SCD) is associated with hemolysis, vascular inflammation, and organ damage. Affected patients experience chronic painful vaso-occlusive events requiring hospitalization. Hypoxia-induced polymerization of sickle hemoglobin S (HbS) contributes to sickling of red blood cells (RBCs) and disease pathophysiology. Dilution of HbS with nonsickling hemoglobin or hemoglobin with increased oxygen affinity, such as fetal hemoglobin or HbS bound to aromatic aldehydes, is clinically beneficial in decreasing polymerization. We investigated a novel alternate approach to modify HbS and decrease polymerization by inhibiting methionine aminopeptidase 2 (MetAP2), which cleaves the initiator methionine (iMet) from Val1 of α-globin and ßS-globin. Kinetic studies with MetAP2 show that ßS-globin is a fivefold better substrate than α-globin. Knockdown of MetAP2 in human umbilical cord blood-derived erythroid progenitor 2 cells shows more extensive modification of α-globin than ß-globin, consistent with kinetic data. Treatment of human erythroid cells in vitro or Townes SCD mice in vivo with selective MetAP2 inhibitors extensively modifies both globins with N-terminal iMet and acetylated iMet. HbS modification by MetAP2 inhibition increases oxygen affinity, as measured by decreased oxygen tension at which hemoglobin is 50% saturated. Acetyl-iMet modification on ßS-globin delays HbS polymerization under hypoxia. MetAP2 inhibitor-treated Townes mice reach 50% total HbS modification, significantly increasing the affinity of RBCs for oxygen, increasing whole blood single-cell RBC oxygen saturation, and decreasing fractional flow velocity losses in blood rheology under decreased oxygen pressures. Crystal structures of modified HbS variants show stabilization of the nonpolymerizing high O2-affinity R2 state, explaining modified HbS antisickling activity. Further study of MetAP2 inhibition as a potential therapeutic target for SCD is warranted.