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2.
J Pain Symptom Manage ; 57(5): 923-932, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30708125

RESUMO

CONTEXT: Identifying factors that affect terminally ill patients' preferences for and actual place of death may assist patients to die wherever they wish. OBJECTIVE: The objective of this study was to investigate factors associated with preferred and actual place of death for cancer patients in Johannesburg, South Africa. METHODS: In a prospective cohort study at a tertiary hospital in Johannesburg, South Africa, adult patients with advanced cancer and their caregivers were enrolled from 2016 to 2018. Study nurses interviewed the patients at enrollment and conducted postmortem interviews with the caregivers. RESULTS: Of 324 patients enrolled, 191 died during follow-up. Preferred place of death was home for 127 (66.4%) and a facility for 64 (33.5%) patients; 91 (47.6%) patients died in their preferred setting, with a kappa value of congruence of 0.016 (95% CI = -0.107, 0.139). Factors associated with congruence were increasing age (odds ratio [OR]: 1.03, 95% CI: 1.00-1.05), use of morphine (OR: 1.87, 95% CI: 1.04-3.36), and wanting to die at home (OR: 0.44, 95% CI: 0.24-0.82). Dying at home was associated with increasing age (OR 1.03, 95% CI 1.00-1.05) and with the patient wishing to have family and/or friends present at death (OR 6.73, 95% CI 2.97-15.30). CONCLUSION: Most patients preferred to die at home, but most died in hospital and fewer than half died in their preferred setting. Further research on modifiable factors, such as effective communication, access to palliative care and morphine, may ensure that more cancer patients in South Africa die wherever they wish.

3.
Semin Oncol ; 2018 Oct 19.
Artigo em Inglês | MEDLINE | ID: mdl-30348533

RESUMO

INTRODUCTION: Neuroendocrine tumors (NETs) represent a small proportion of cancers, but are increasing in incidence due to incidental diagnosis. We examined NET incidence and survival over time in a population-based registry. MATERIALS/METHODS: We identified all NET cases diagnosed between 1995 and 2014 in the Surveillance, Epidemiology, and End Results database, November 2016 submission. We determined incidence rates and calculated overall and cancer-specific survival curves in different subgroups stratified by grade, stage, and age at diagnosis. RESULTS: We identified 85,133 patients with a diagnosis of NET between 1995 and 2014. Patients with grade 1, localized NETs had the best median overall survival (233 months, 95% confidence intervals [CI] not estimable) and 5-year cancer-specific survival (97.6%; 95% CI, 97.4%, 97.8%). The median overall survival decreased with age across the entire spectrum of ages, with patients >70 years having a particularly poor prognosis (28.0 months; 95% CI, 26.5, 29.5). Patients >70 years old often had distant (34.3%) or grade 3 disease (40.8%), but even elderly patients with lower grade and/or stage disease had worse median overall survival compared with younger subjects. CONCLUSIONS: Age appears to be associated with a worse prognosis independent of NET stage, and grade at the time of diagnosis. Patients with grade 1, localized NETs have an excellent long-term prognosis. Further research is warranted on reducing intensity of surveillance in these patients.

4.
Oncologist ; 2018 Oct 10.
Artigo em Inglês | MEDLINE | ID: mdl-30305414

RESUMO

Brain tumors comprise 2% of all cancers but are disproportionately responsible for cancer-related deaths. The 5-year survival rate of glioblastoma, the most common form of malignant brain tumor, is only 4.7%, and the overall 5-year survival rate for any brain tumor is 34.4%. In light of the generally poor clinical outcomes associated with these malignancies, there has been interest in the concept of brain tumor screening through magnetic resonance imaging. Here, we will provide a general overview of the screening principles and brain tumor epidemiology, then highlight the major studies examining brain tumor prevalence in asymptomatic populations in order to assess the potential benefits and drawbacks of screening for brain tumors. IMPLICATIONS FOR PRACTICE: Magnetic resonance imaging (MRI) screening in healthy asymptomatic adults can detect both early gliomas and other benign central nervous system abnormalities. Further research is needed to determine whether MRI will improve overall morbidity and mortality for the screened populations and make screening a worthwhile endeavor.

5.
Proc Natl Acad Sci U S A ; 115(34): E8007-E8016, 2018 08 21.
Artigo em Inglês | MEDLINE | ID: mdl-30072435

RESUMO

Isolated congenital asplenia (ICA) is the only known human developmental defect exclusively affecting a lymphoid organ. In 2013, we showed that private deleterious mutations in the protein-coding region of RPSA, encoding ribosomal protein SA, caused ICA by haploinsufficiency with complete penetrance. We reported seven heterozygous protein-coding mutations in 8 of the 23 kindreds studied, including 6 of the 8 multiplex kindreds. We have since enrolled 33 new kindreds, 5 of which are multiplex. We describe here 11 new heterozygous ICA-causing RPSA protein-coding mutations, and the first two mutations in the 5'-UTR of this gene, which disrupt mRNA splicing. Overall, 40 of the 73 ICA patients (55%) and 23 of the 56 kindreds (41%) carry mutations located in translated or untranslated exons of RPSA. Eleven of the 43 kindreds affected by sporadic disease (26%) carry RPSA mutations, whereas 12 of the 13 multiplex kindreds (92%) carry RPSA mutations. We also report that 6 of 18 (33%) protein-coding mutations and the two (100%) 5'-UTR mutations display incomplete penetrance. Three mutations were identified in two independent kindreds, due to a hotspot or a founder effect. Finally, RPSA ICA-causing mutations were demonstrated to be de novo in 7 of the 23 probands. Mutations in RPSA exons can affect the translated or untranslated regions and can underlie ICA with complete or incomplete penetrance.


Assuntos
Éxons , Síndromes de Imunodeficiência/genética , Mutação , Penetrância , Biossíntese de Proteínas/genética , Processamento de RNA/genética , Receptores de Laminina/genética , Proteínas Ribossômicas/genética , Baço/anormalidades , Regiões 5' não Traduzidas , Feminino , Efeito Fundador , Heterozigoto , Humanos , Síndromes de Imunodeficiência/metabolismo , Masculino , Receptores de Laminina/biossíntese , Proteínas Ribossômicas/biossíntese , Baço/metabolismo
6.
J Pain Symptom Manage ; 56(1): 98-106, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-29604380

RESUMO

CONTEXT: In sub-Saharan Africa, late diagnosis with cancer is common. Many dying patients rely on family members for care; little is known about the challenges African informal caregivers face. OBJECTIVES: To better understand the challenges of informal caregivers at the end of life in South Africa, both at home and in inpatient facilities. METHODS: We included advanced cancer patients and caregivers from a public hospital in Johannesburg, South Africa. Study nurses interviewed patients and caregivers about their experiences. Using univariate and multivariate analyses, we determined the factors associated with greater caregiver difficulty, focusing on patients dying at home vs. in inpatient facilities. RESULTS: Among 174 informal caregivers, 62 (36%) reported "a lot" of challenges. These caregivers struggled most with keeping the patient clean (16%) and with patient interactions (34%). Symptoms associated with greater difficulty included pain (odds ratio [OR] 2.4 [95% CI 1.2-4.7]), urinary incontinence (OR 2.3 [95% CI 1.1-4.9]), fecal incontinence (OR 2.4 [95% CI 1.0-5.7]), insomnia (OR 2.9 [95% CI 1.3-6.9]), fatigue (OR 6.3 [95% CI 1.8-21.6]), extremity weakness (OR 2.9 [95% CI 1.3-6.9]), shame (OR 4.2 [95% CI 1.5-12.0]), and sadness (OR 2.3 [95% CI 1.1-4.8]). Caregivers of patients dying at home reported the greatest difficulty with patients' physical symptoms; caregivers of those dying in facilities reported the greatest difficulty with emotional symptoms. CONCLUSION: Informal caregivers of patients dying at home reported challenges with practical functional care; this effect was reduced in the inpatient setting. Skills training for these caregivers could relieve some of this burden.

7.
J Clin Invest ; 126(10): 4030-4044, 2016 10 03.
Artigo em Inglês | MEDLINE | ID: mdl-27643438

RESUMO

In addition to the infectious consequences of immunodeficiency, patients with Wiskott-Aldrich syndrome (WAS) often suffer from poorly understood exaggerated immune responses that result in autoimmunity and elevated levels of serum IgE. Here, we have shown that WAS patients and mice deficient in WAS protein (WASP) frequently develop IgE-mediated reactions to common food allergens. WASP-deficient animals displayed an adjuvant-free IgE-sensitization to chow antigens that was most pronounced for wheat and soy and occurred under specific pathogen-free as well as germ-free housing conditions. Conditional deletion of Was in FOXP3+ Tregs resulted in more severe Th2-type intestinal inflammation than that observed in mice with global WASP deficiency, indicating that allergic responses to food allergens are dependent upon loss of WASP expression in this immune compartment. While WASP-deficient Tregs efficiently contained Th1- and Th17-type effector differentiation in vivo, they failed to restrain Th2 effector responses that drive allergic intestinal inflammation. Loss of WASP was phenotypically associated with increased GATA3 expression in effector memory FOXP3+ Tregs, but not in naive-like FOXP3+ Tregs, an effect that occurred independently of increased IL-4 signaling. Our results reveal a Treg-specific role for WASP that is required for prevention of Th2 effector cell differentiation and allergic sensitization to dietary antigens.


Assuntos
Hipersensibilidade Alimentar/metabolismo , Fatores de Transcrição Forkhead/fisiologia , Linfócitos T Reguladores/metabolismo , Células Th2/imunologia , Proteína da Síndrome de Wiskott-Aldrich/genética , Animais , Diferenciação Celular/imunologia , Feminino , Hipersensibilidade Alimentar/imunologia , Humanos , Imunoglobulina E/fisiologia , Masculino , Camundongos da Linhagem 129 , Camundongos Knockout , Mutação , Linfócitos T Reguladores/imunologia , Transcriptoma , Proteína da Síndrome de Wiskott-Aldrich/metabolismo
8.
J Allergy Clin Immunol ; 138(1): 187-99, 2016 07.
Artigo em Inglês | MEDLINE | ID: mdl-26948077

RESUMO

BACKGROUND: During IgE-mediated immediate hypersensitivity reactions, vascular endothelial cells permeabilize in response to mast cell mediators. We have demonstrated previously that patients and mice with signal transducer and activator of transcription 3 (STAT3) mutations (autosomal dominant hyper-IgE syndrome [AD-HIES]) are partially protected from anaphylaxis. OBJECTIVES: We sought to study the mechanism by which STAT3 contributes to anaphylaxis and determine whether small-molecule inhibition of STAT3 can prevent anaphylaxis. METHODS: Using unaffected and STAT3-inhibited or genetic loss-of-function samples, we performed histamine skin prick tests, investigated the contribution of STAT3 to animal models of anaphylaxis, and measured endothelial cell permeability, gene and protein expression, and histamine receptor-mediated signaling. RESULTS: Although mouse mast cell degranulation was minimally affected by STAT3 blockade, mast cell mediator-induced anaphylaxis was blunted in Stat3 mutant mice with AD-HIES and in wild-type mice subjected to small-molecule STAT3 inhibition. Histamine skin prick test responses were diminished in patients with AD-HIES. Human umbilical vein endothelial cells derived from patients with AD-HIES or treated with a STAT3 inhibitor did not signal properly through Src or cause appropriate dissolution of the adherens junctions made up of the proteins vascular endothelial-cadherin and ß-catenin. Furthermore, we found that diminished STAT3 target microRNA17-92 expression in human umbilical vein endothelial cells from patients with AD-HIES is associated with increased phosphatase and tensin homolog (PTEN) expression, which inhibits Src, and increased E2F transcription factor 1 expression, which regulates ß-catenin cellular dynamics. CONCLUSIONS: These data demonstrate that STAT3-dependent transcriptional activity regulates critical components for the architecture and functional dynamics of endothelial junctions, thus permitting vascular permeability.


Assuntos
Anafilaxia/imunologia , Anafilaxia/metabolismo , Permeabilidade Capilar/imunologia , Fator de Transcrição STAT3/metabolismo , Transdução de Sinais , Junções Aderentes/metabolismo , Anafilaxia/diagnóstico , Anafilaxia/genética , Animais , Permeabilidade Capilar/efeitos dos fármacos , Permeabilidade Capilar/genética , Degranulação Celular/efeitos dos fármacos , Degranulação Celular/imunologia , Citocinas/metabolismo , Modelos Animais de Doenças , Células Endoteliais da Veia Umbilical Humana , Humanos , Imunoglobulina E/imunologia , Mediadores da Inflamação/metabolismo , Mastócitos/metabolismo , Camundongos , Camundongos Knockout , Mutação , Receptores Histamínicos/imunologia , Receptores Histamínicos/metabolismo , Fator de Transcrição STAT3/antagonistas & inibidores , Fator de Transcrição STAT3/genética , Transdução de Sinais/efeitos dos fármacos , Testes Cutâneos , beta Catenina/metabolismo , Quinases da Família src/metabolismo
9.
Science ; 340(6135): 976-8, 2013 May 24.
Artigo em Inglês | MEDLINE | ID: mdl-23579497

RESUMO

Isolated congenital asplenia (ICA) is characterized by the absence of a spleen at birth in individuals with no other developmental defects. The patients are prone to life-threatening bacterial infections. The unbiased analysis of exomes revealed heterozygous mutations in RPSA in 18 patients from eight kindreds, corresponding to more than half the patients and over one-third of the kindreds studied. The clinical penetrance in these kindreds is complete. Expression studies indicated that the mutations carried by the patients-a nonsense mutation, a frameshift duplication, and five different missense mutations-cause autosomal dominant ICA by haploinsufficiency. RPSA encodes ribosomal protein SA, a component of the small subunit of the ribosome. This discovery establishes an essential role for RPSA in human spleen development.


Assuntos
Haploinsuficiência , Síndrome de Heterotaxia/genética , Receptores de Laminina/genética , Proteínas Ribossômicas/genética , Baço/anormalidades , Análise Mutacional de DNA , Loci Gênicos , Humanos , Mutação , Linhagem , Penetrância , Baço/crescimento & desenvolvimento
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