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The expression "lost at sea" means to be confused or perplexed. By extension, lost at SCLC references the current confusion about how to circumvent the chemoresistance, particularly platinum resistance, which so plagues the treatment of extensive-stage small cell lung cancer (ES-SCLC) that in 2012 the US National Cancer Institute (NCI) designated it a "recalcitrant cancer." Over a decade later, despite the approval of immune checkpoint inhibitors and the conditional approval of lurbinectedin, the prognosis for ES-SCLC, and especially platinum-resistant ES-SCLC, has scarcely improved. The focus of this review, which briefly summarizes current treatment options for ES-SCLC, is on five clinical-stage therapies with the potential to successfully reverse the platinum resistance that is perhaps the biggest obstacle to better clinical outcomes.
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AdAPT-001 is an investigational therapy consisting of a replicative type 5 adenovirus armed with a TGF-ß receptor-immunoglobulin Fc fusion trap, designed to neutralize isoforms 1 and 3 of the profibrotic and immunosuppressive cytokine, TGF-ß. In preclinical studies with an immunocompetent mouse model, AdAPT-001 eradicated directly treated 'cold' tumors as well as distant untreated tumors, and, from its induction of systemic CD8+ T cell-mediated antitumor immunity, protected the mice from rechallenge with tumor cells. AdAPT-001 also sensitized resistant tumors to checkpoint blockade. This manuscript describes the rationale and design of the first-in-human phase I, dose-escalation and dose-expansion study of AdAPT-001 alone and in combination with a checkpoint inhibitor in adults with treatment-refractory superficially accessible solid tumors.
The purpose of this study is to find out more about the experimental oncolytic virus called AdAPT-001 that has been designed to selectively eliminate cancer cells. The virus is also designed to make a particular protein called a TGF-ß trap, which neutralizes TGF-ß, an overproduced chemical in cancer cells that puts the immune system into a comatose state. This article discusses a clinical trial called BETA PRIME for patients with no other standard treatment options. The trial will explore different doses of AdAPT-001 both alone and in combination with an approved checkpoint inhibitor or another immunotherapy, which blocks the 'off' signal on immune cells, to determine the safest and best dose. Clinical Trial Registration: NCT04673942 (ClinicalTrials.gov).
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Neoplasias , Terapia Viral Oncolítica , Animais , Linhagem Celular Tumoral , Ensaios Clínicos Fase I como Assunto , Citocinas , Humanos , Imunoglobulinas , Imunoterapia , Camundongos , Neoplasias/tratamento farmacológico , Receptores de Fatores de Crescimento Transformadores beta , Fator de Crescimento Transformador betaRESUMO
RRx-001 is a small molecule NLRP3 inflammasome inhibitor with anti-CD47 and antiangiogenic/vascular normalization properties in a Phase 3 clinical trial that has been designated as a drug-device combination by the FDA. In the Phase 1 first-in-man dose escalation clinical trial, where RRx-001 was given by direct intravenous (IV) infusion, the main adverse event was a sterile painful infusion phlebitis (IP). Less pain was experienced when RRx-001 was infused at a slower rate over multiple hours which was impractical on an outpatient basis. In Phase 2, for reasons of convenience and safety, RRx-001 was co-administered with an aliquot of autologous blood from an ex-vivo device called the eLOOP on the premise that RRx-001 binds to hemoglobin on red blood cells (RBCs), making it unavailable to directly interact with venous nociceptors. Phlebitis has the potential to progress to deep venous thrombosis or septic thrombophlebitis or post-thrombotic syndrome in hypercoagulable and immunosuppressed cancer patients. In this 13-week toxicology study of once weekly IV RRx-001 administration to Wistar Han rats followed by a recovery period of 28 days. The main observed toxicity was a significant inflammatory response in the vein wall, consistent with superficial venous thrombosis observed in man. Due to this development, direct IV infusion of RRx-001 is relatively contraindicated in favor of co-administration with autologous blood.
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Inflamassomos , Flebite , Animais , Azetidinas , Hemoglobinas/metabolismo , Inflamação/induzido quimicamente , Proteína 3 que Contém Domínio de Pirina da Família NLR , Nitrocompostos , Ratos , Ratos WistarRESUMO
In medicine, inflammation is a fuzzy, overused word first coined by the Romans, the intended meaning and precise definition of which varies according to the person and the clinical context. It tends to carry a negative connotation as a response gone awry, like a raging, out-of-control wildfire that requires immediate control and containment lest it destroy all in its path; however, frequently overlooked or lost in the shuffle is the primordial importance of inflammation to health and survival. The precise definition of inflammation matters for several reasons, not least because of the over-liberal use of anti-inflammatory drugs to inhibit inflammation, which may, contrary to prevailing dogma that all inflammation is harmful, act counterproductively to prevent restitutio ad integrum. Using fire as a central analogy, this overview attempts to define inflammation, the better to determine how to manage it, i.e., whether to fan its flames, let it burn out, or suppress it entirely.
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Imunidade Inata , Inflamação , HumanosRESUMO
RRx-001 is a cysteine-directed anticancer alkylating agent with activity in a Phase II study in platinum refractory small cell lung cancer. Here, we describe the design of REPLATINUM, an open-label, Phase III trial. 120 patients with previously platinum-treated small cell lung cancer in third line will be randomized 1:1 to receive RRx-001 followed by four cycles of a platinum doublet, and then alternating cycles of RRx-001 and single agent platinum until progression versus four cycles of a platinum doublet. At radiologic progression on the platinum doublet, patients may cross over to the RRx-001 arm. Primary objective: to demonstrate superior progression-free survival in the RRx-001 population. Secondary objectives: to demonstrate superiority for overall survival and objective response rate. Clinical Trial registration: NCT03699956.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Pulmonares/tratamento farmacológico , Carcinoma de Pequenas Células do Pulmão/tratamento farmacológico , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Azetidinas/administração & dosagem , Carboplatina/administração & dosagem , Cisplatino/administração & dosagem , Etoposídeo/administração & dosagem , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Nitrocompostos/administração & dosagem , Resultado do Tratamento , Adulto JovemRESUMO
Purpose MG1102 is a potent inhibitor of angiogenesis in both in vitro and in vivo models. The purpose of the study was to investigate the safety and tolerability, pharmacokinetic (PK) profile, and preliminary antitumor efficacy of MG1102. Methods Patients with refractory solid tumors were eligible. Each patient received 1 dose of MG1102 followed by a 6-day rest period, during which they underwent PK assessments and safety monitoring. If the initial dose was tolerated, the patient continued with the 21-day treatment of MG1102 (5 days on, 2 days off for 3 weeks). Dose escalation was planned in 6 cohorts (6, 12, 24, 48, 96, and 192 mg/m2). Primary objectives included safety and maximum tolerated dose (MTD) assessment. Secondary objectives included assessment of PK, pharmacodynamics, and efficacy. Results A total of 16 patients were enrolled and 12 (75%) completed the study. The most common cancer type was colorectal cancer (n = 10). There was no dose limiting toxicity and the MTD was not reached at 192 mg/m2. The most frequent treatment-emergent adverse events were gastrointestinal disorders, including nausea (30.8%), abdominal pain (23.1%), constipation (23.1%), and dyspepsia (23.1%). The PK of MG1102 was slightly less than dose proportional from Cohorts 3 to 6. Among 13 response-evaluable patients, 1 unconfirmed partial response (PR) was seen (in the 48 mg/m2 cohort) and 4 patients had stable disease. Conclusions The safety profile of MG1102 was generally manageable and the toxicities resolved quickly. Potential antitumor activity was observed with 1 unconfirmed PR (60% size reduction).
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Apolipoproteínas A/farmacocinética , Apolipoproteínas A/uso terapêutico , Neoplasias/tratamento farmacológico , Fragmentos de Peptídeos/farmacocinética , Fragmentos de Peptídeos/uso terapêutico , Idoso , Idoso de 80 Anos ou mais , Estudos de Coortes , Relação Dose-Resposta a Droga , Feminino , Seguimentos , Humanos , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Neoplasias/patologia , Prognóstico , SegurançaRESUMO
BACKGROUND: Epigenetic alterations have been strongly associated with tumour formation and resistance to chemotherapeutic drugs, and epigenetic modifications are an attractive target in cancer research. RRx-001 is activated by hypoxia and induces the generation of reactive oxygen and nitrogen species that can epigenetically modulate DNA methylation, histone deacetylation, and lysine demethylation. The aim of this phase 1 study was to assess the safety, tolerability, and pharmacokinetics of RRx-001. METHODS: In this open-label, dose-escalation, phase 1 study, we recruited adult patients (aged >18 years) with histologically or cytologically confirmed diagnosis of advanced, malignant, incurable solid tumours from University of California at San Diego, CA, USA, and Sarah Cannon Research Institute, Nashville, TN, USA. Key eligibility criteria included evaluable disease, Eastern Cooperative Group performance status of 2 or less, an estimated life expectancy of at least 12 weeks, adequate laboratory parameters, discontinuation of all previous antineoplastic therapies at least 6 weeks before intervention, and no residual side-effects from previous therapies. Patients were assigned to receive intravenous infusions of RRx-001 at increasing doses (10 mg/m(2), 16·7 mg/m(2), 24·6 mg/m(2), 33 mg/m(2), 55 mg/m(2), and 83 mg/m(2)) either once or twice-weekly for at least 4 weeks, with at least three patients per dose cohort and allowing a 2-week observation period before dose escalation. Samples for safety and pharmacokinetics analysis, including standard chemistry and haematological panels, were taken on each treatment day. The primary objective was to assess safety, tolerability, and dose-limiting toxic effects of RRx-001, to determine single-dose pharmacokinetics, and to identify a recommended dose for phase 2 trials. All analyses were done per protocol. Accrual is complete and follow-up is still on-going. This trial is registered with ClinicalTrials.gov, number NCT01359982. FINDINGS: Between Oct 10, 2011, and March 18, 2013, we enrolled 25 patients and treated six patients in the 10 mg/m(2) cohort, three patients in the 16·7 mg/m(2) cohort, three patients in the 24·6 mg/m(2) cohort, four patients in the 33 mg/m(2) cohort, three patients in the 55 mg/m(2), and six patients in the 83 mg/m(2) cohort. Pain at the injection site, mostly grade 1 and grade 2, was the most common adverse event related to treatment, experienced by 21 (84%) patients. Other common drug-related adverse events included arm swelling or oedema (eight [32%] patients), and vein hardening (seven [28%] patients). No dose-limiting toxicities were observed. Time constraints related to management of infusion pain from RRx-001 resulted in a maximally feasible dose of 83 mg/m(2). Of the 21 evaluable patients, one (5%) patient had a partial response, 14 (67%) patients had stable disease, and six (29%) patients had progressive disease; all responses were across a variety of tumour types. Four patients who had received RRx-001 were subsequently rechallenged with a treatment that they had become refractory to; all four responded to the rechallenge. INTERPRETATION: RRx-001 is a well-tolerated novel compound without clinically significant toxic effects at the tested doses. Preliminary evidence of activity is promising and, on the basis of all findings, a dose of 16·7 mg/m(2) was recommended as the targeted dose for phase 2 trials. FUNDING: EpicentRx (formerly RadioRx).
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Azetidinas/administração & dosagem , Epigênese Genética/efeitos dos fármacos , Neoplasias/tratamento farmacológico , Nitrocompostos/administração & dosagem , Adulto , Idoso , Azetidinas/efeitos adversos , Azetidinas/farmacocinética , Relação Dose-Resposta a Droga , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/patologia , Epigênese Genética/genética , Feminino , Humanos , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Neoplasias/genética , Neoplasias/patologia , Nitrocompostos/efeitos adversos , Nitrocompostos/farmacocinética , Prognóstico , Resultado do TratamentoRESUMO
OBJECTIVES: To assess the care of hypertension, diabetes mellitus and/or HIV patients enrolled into Medication Adherence Clubs (MACs). METHODS: Retrospective descriptive study was carried out using routinely collected programme data from a primary healthcare clinic at informal settlement in Nairobi, Kenya. All patients enrolled into MACs were selected for the study. MACs are nurse-facilitated mixed groups of 25-35 stable hypertension, diabetes mellitus and/or HIV patients who met quarterly to confirm their clinical stability, have brief health discussions and receive medication. Clinical officer reviewed MACs yearly, when a patient developed complications or no longer met stable criteria. RESULTS: A total of 1432 patients were enrolled into 47 clubs with 109 sessions conducted between August 2013 and August 2014. There were 1020 (71%) HIV and 412 (29%) non-communicable disease patients. Among those with NCD, 352 (85%) had hypertension and 60 (15%) had DM, while 12 had HIV concurrent with hypertension. A total of 2208 consultations were offloaded from regular clinic. During MAC attendance, blood pressure, weight and laboratory testing were completed correctly in 98-99% of consultations. Only 43 (2%) consultations required referral for clinical officer review before their routine yearly appointment. Loss to follow-up from the MACs was 3.5%. CONCLUSIONS: This study demonstrates the feasibility and early efficacy of MACs for mixed chronic disease in a resource-limited setting. It supports burden reduction and flexibility of regular clinical review for stable patients. Further assessment regarding long-term outcomes of this model should be completed to increase confidence for deployment in similar contexts.
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Diabetes Mellitus/tratamento farmacológico , Infecções por HIV/tratamento farmacológico , Hipertensão/tratamento farmacológico , Adesão à Medicação , Atenção Primária à Saúde/métodos , Adulto , Idoso , Doença Crônica , Feminino , Infecções por HIV/complicações , Humanos , Quênia , Masculino , Pessoa de Meia-Idade , Estudos RetrospectivosRESUMO
OBJECTIVE: In three primary health care clinics run by Médecins Sans Frontières in the informal settlement of Kibera, Nairobi, Kenya, we describe the caseload, management and treatment outcomes of patients with hypertension (HT) and/or diabetes mellitus (DM) receiving care from January 2010 to June 2012. METHOD: Descriptive study using prospectively collected routine programme data. RESULTS: Overall, 1465 patients were registered in three clinics during the study period, of whom 87% were hypertensive only and 13% had DM with or without HT. Patients were predominantly female (71%) and the median age was 48 years. On admission, 24% of the patients were obese, with a body mass index (BMI) > 30 kg/m2. Overall, 55% of non-diabetic hypertensive patients reached their blood pressure (BP) target at 24 months. Only 28% of diabetic patients reached their BP target at 24 months. For non-diabetic patients, there was a significant decrease in BP between first consultation and 3 months of treatment, maintained over the 18-month period. Only 20% of diabetic patients with or without hypertension achieved glycaemic control. By the end of the study period,1003 (68%) patients were alive and in care, one (<1%) had died, eight (0.5%) had transferred out and 453 (31%) were lost to follow-up. CONCLUSION: Good management of HT and DM can be achieved in a primary care setting within an informal settlement. This model of intervention appears feasible to address the growing burden of non-communicable diseases in developing countries.
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Diabetes Mellitus/terapia , Gerenciamento Clínico , Hipertensão/terapia , Educação de Pacientes como Assunto/métodos , Atenção Primária à Saúde/organização & administração , Adolescente , Adulto , Idoso , Anti-Hipertensivos/uso terapêutico , Diabetes Mellitus/diagnóstico , Diabetes Mellitus/tratamento farmacológico , Feminino , Comportamentos Relacionados com a Saúde , Humanos , Hipertensão/diagnóstico , Hipertensão/tratamento farmacológico , Hipoglicemiantes/uso terapêutico , Quênia , Masculino , Pessoa de Meia-Idade , Avaliação de Resultados em Cuidados de Saúde , Atenção Primária à Saúde/métodos , Atenção Primária à Saúde/normas , Estudos Prospectivos , Autocuidado/métodos , Resultado do Tratamento , Adulto JovemRESUMO
The purpose of this commentary is to highlight the high occurrence of clinical pseudoprogression and delayed responses that have been observed to date with the locally injected oncolytic adenovirus, AdAPT-001, currently in a Phase 1/2 clinical trial (NCT04673942) for the treatment of treatment-refractory tumors. Not surprisingly, these have led to confusion about response assessment and whether to continue patients on treatment. AdAPT-001 carries a transforming growth factor (TGF)-beta trap (TGF-ß), which sequesters TGF-ß, a cytokine that potently regulates inflammation, fibrosis, and immunosuppression in cancer. Pseudoprogression (PsP) or progression prior to response or stabilization, has been widely recognized with radiotherapy for primary brain tumors and immune checkpoint inhibitors (ICIs). PsP has also been described and documented in the context of oncolytic virotherapy but perhaps to a lesser extent. However, repeated intratumoral injections with these immunostimulatory agents may induce a more intense immune response and release more antigenic epitopes than with ICIs, for example, which are strictly T-cell directed rather than also tumor-directed like AdAPT-001.
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Progressão da Doença , Terapia Viral Oncolítica , Humanos , Terapia Viral Oncolítica/métodos , Vírus Oncolíticos , Neoplasias/tratamento farmacológico , Neoplasias/imunologia , Neoplasias/terapia , AdenoviridaeRESUMO
AdAPT-001 is an oncolytic adenovirus (OAV) with a transforming growth factor beta (TGF-ß) trap, which neutralizes the immunosuppressive and profibrotic cytokine, TGF-ß. The aim or purpose of this phase 1 study was to assess the safety and tolerability and, secondarily, the efficacy of AdAPT-001 after single intratumoral injection (IT) (Part 1) and multidose IT injection (Part 2) in patients with superficially accessible, advanced refractory solid tumors. Part 1 enrolled 9 patients with a 3 + 3 single dose-escalation safety run-in involving 2.5 × 1011, 5.0 × 1011, 1.0 × 1012 viral particles (vps). No dose-limiting toxicities or treatment-related serious adverse events (SAEs) were seen. In Part 2, a dose-expansion phase, 19 patients received AdAPT-001 at 1.0 × 1012 vps until disease progression according to Response Evaluation Criteria in Solid Tumors or RECIST 1.1. The overall responses to treatment included confirmed partial responses (3), durable stable disease ≥ 6 months (5), and progressive disease (13). AdAPT-001 is well tolerated. Evidence of an anti-tumor effect was seen in both injected and uninjected lesions. The recommended Phase 2 dose was 1.0 × 1012 vp administered by intratumoral injection once every 2 weeks. Combination of AdAPT-001 with a checkpoint inhibition is enrolling.
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Infecções por Adenoviridae , Neoplasias , Humanos , Adenoviridae/genética , Neoplasias/patologia , Critérios de Avaliação de Resposta em Tumores SólidosRESUMO
BACKGROUND: In this multicenter, open-label, randomized phase 2 trial, the authors evaluated the vascular endothelial growth factor receptor inhibitor axitinib, bevacizumab, or both in combination with chemotherapy as first-line treatment of metastatic colorectal cancer (mCRC). METHODS: Patients with previously untreated mCRC were randomized 1:1:1 to receive continuous axitinib 5 mg twice daily, bevacizumab 5 mg/kg every 2 weeks, or axitinib 5 mg twice daily plus bevacizumab 2 mg/kg every 2 weeks, each in combination with modified 5-fluorouracil/leucovorin/oxaliplatin (FOLFOX-6). The primary endpoint was the objective response rate (ORR). RESULTS: In all, 126 patients were enrolled from August 2007 to September 2008. The ORR was numerically inferior in the axitinib arm (n = 42) versus the bevacizumab arm (n = 43; 28.6% vs 48.8%; 1-sided P = .97). Progression-free survival (PFS) (11.0 months vs 15.9 months; 1-sided P = .57) and overall survival (OS) (18.1 months vs 21.6 months; 1-sided P = .69) also were numerically inferior in the axitinib arm. Similarly, efficacy endpoints for the axitinib/bevacizumab arm (n = 41) were numerically inferior (ORR, 39%; PFS, 12.5 months; OS, 19.7 months). The patients who received axitinib had fewer treatment cycles compared with other arms. Common all-grade adverse events across all 3 treatment arms were fatigue, diarrhea, and nausea (all ≥49%). Hypertension and headache were more frequent in the patients who received axitinib. Patients in the bevacizumab arm had the longest treatment exposures and the highest rates of peripheral neuropathy. CONCLUSIONS: Neither the addition of continuous axitinib nor the axitinib/bevacizumab combination to FOLFOX-6 improved ORR, PFS, or OS compared with bevacizumab as first-line treatment of mCRC.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Colorretais/tratamento farmacológico , Adulto , Idoso , Anticorpos Monoclonais Humanizados/administração & dosagem , Anticorpos Monoclonais Humanizados/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Axitinibe , Bevacizumab , Neoplasias Colorretais/mortalidade , Esquema de Medicação , Feminino , Fluoruracila/administração & dosagem , Fluoruracila/efeitos adversos , Humanos , Imidazóis/administração & dosagem , Imidazóis/efeitos adversos , Indazóis/administração & dosagem , Indazóis/efeitos adversos , Infusões Intravenosas , Injeções Intravenosas , Estimativa de Kaplan-Meier , Leucovorina/administração & dosagem , Leucovorina/efeitos adversos , Masculino , Pessoa de Meia-Idade , Compostos Organoplatínicos/administração & dosagem , Compostos Organoplatínicos/efeitos adversos , Resultado do TratamentoRESUMO
OBJECTIVES: To understand patients' challenges in adhering to treatment for MDR-TB/HIV co-infection within the context of their life circumstances and access to care and support. METHODS: Qualitative study using in-depth interviews with 12 HIV/MDR-TB co-infected patients followed in a Médecins Sans Frontières (MSF) clinic in Mumbai, India, five lay caregivers and ten health professionals. The data were thematically analysed along three dimensions of patients' experience of being and staying on treatment: physiological, psycho-social and structural. RESULTS: By the time patients and their families initiate treatment for co-infection, their financial and emotional resources were often depleted. Side effects of the drugs were reported to be severe and debilitating, and patients expressed the burden of care and stigma on the social and financial viability of the household. Family caregivers were crucial to maintaining the mental and physical health of patients, but reported high levels of fatigue and stress. Médecins Sans Frontières providers recognised that the barriers to patient adherence were fundamentally social, rather than medical, yet were limited in their ability to support patients and their families. CONCLUSIONS: The treatment of MDR-TB among HIV-infected patients on antiretroviral therapy is hugely demanding for patients, caregivers and families. Current treatment regimens and case-holding strategies are resource intensive and require high levels of support from family and lay caregivers to encourage patient adherence and retention in care.
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Fármacos Anti-HIV/efeitos adversos , Antituberculosos/efeitos adversos , Cuidadores/psicologia , Infecções por HIV/psicologia , Estigma Social , Tuberculose Resistente a Múltiplos Medicamentos/psicologia , Adulto , Fármacos Anti-HIV/administração & dosagem , Fármacos Anti-HIV/uso terapêutico , Antituberculosos/administração & dosagem , Antituberculosos/uso terapêutico , Coinfecção , Características da Família , Feminino , Infecções por HIV/tratamento farmacológico , Infecções por HIV/economia , Acessibilidade aos Serviços de Saúde , Humanos , Índia , Entrevistas como Assunto , Masculino , Pessoa de Meia-Idade , Cooperação do Paciente/psicologia , Pesquisa Qualitativa , Apoio Social , Tuberculose Resistente a Múltiplos Medicamentos/tratamento farmacológico , Tuberculose Resistente a Múltiplos Medicamentos/economiaRESUMO
OBJECTIVE: The microbiologic causes of bloodstream infections (BSI) may differ between HIV-positive and HIV-negative patients and direct initial empiric antibiotic treatment (i.e. treatment before culture results are available). We retrospectively assessed community-acquired BSI episodes in adults in Cambodia according to HIV status for spectrum of bacterial pathogens, antibiotic resistance patterns and appropriateness of empiric antibiotics. METHODS: Blood cultures were systematically performed in patients suspected of BSI in a referral hospital in Phnom Penh, Cambodia. Data were collected between 1 January 2009 and 31 December 2011. RESULTS: A total of 452 culture-confirmed episodes of BSI were recorded in 435 patients, of whom 17.9% and 82.1% were HIV-positive and HIV-negative, respectively. Escherichia coli accounted for one-third (n = 155, 32.9%) of 471 organisms, with similar rates in both patient groups. Staphylococcus aureus and Salmonella cholereasuis were more frequent in HIV-positive vs. HIV-negative patients (17/88 vs. 38/383 (P = 0.02) and 10/88 vs. 5/383 (P < 0.001)). Burkholderia pseudomallei was more common in HIV-negative than in HIV-positive patients (39/383 vs. 2/88, P < 0.001). High resistance rates among commonly used antibiotics were observed, including 46.6% ceftriaxone resistance among E. coli isolates. Empiric antibiotic treatments were similarly appropriate in both patient groups but did not cover antibiotic-resistant E. coli (both patient groups), S. aureus (both groups) and B. pseudomallei (HIV-negative patients). CONCLUSION: The present data do not warrant different empiric antibiotic regimens for HIV-positive vs. HIV-negative patients in Cambodia. The overall resistance rates compromise the appropriateness of the current treatment guidelines.
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Antibacterianos/uso terapêutico , Bacteriemia/microbiologia , Bactérias/isolamento & purificação , Farmacorresistência Bacteriana , Soronegatividade para HIV , Soropositividade para HIV/microbiologia , Adulto , Bacteriemia/tratamento farmacológico , Bactérias/efeitos dos fármacos , Camboja , Infecções Comunitárias Adquiridas/tratamento farmacológico , Infecções Comunitárias Adquiridas/microbiologia , Feminino , Soropositividade para HIV/tratamento farmacológico , Humanos , Masculino , Testes de Sensibilidade Microbiana , Pessoa de Meia-Idade , Estudos RetrospectivosRESUMO
Oncolytic virotherapy is an emerging technology that uses engineered viruses to treat malignancies. Viruses can be designed with biological specificity to infect cancerous cells preferentially, and to replicate in these cells exclusively. Malignant cells may be killed directly by overwhelming viral infection and lysis, which releases additional viral particles to infect neighboring cells and distant metastases. Viral infections may also activate the immune system, unmask stealthy tumor antigens, and aid the immune system to recognize and attack neoplasms. Delivery of live virus particles is potentially complex, and may require the expertise of the interventional community.
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Neoplasias/terapia , Terapia Viral Oncolítica , Vírus Oncolíticos/patogenicidade , Animais , Efeito Citopatogênico Viral , História do Século XX , História do Século XXI , Especificidade de Hospedeiro , Humanos , Neoplasias/história , Neoplasias/patologia , Neoplasias/virologia , Terapia Viral Oncolítica/efeitos adversos , Terapia Viral Oncolítica/história , Vírus Oncolíticos/genética , Radiografia Intervencionista , Resultado do TratamentoRESUMO
BACKGROUND: In Burundi, the annual incidence of obstetric fistula is estimated to be 0.2-0.5% of all deliveries, with 1000-2000 new cases per year. Despite this relatively high incidence, national capacity for identifying and managing obstetric fistula is very limited. Thus, in July 2010, Medecins Sans Frontieres (MSF) set up a specialised Obstetric Fistula Centre in Gitega (Gitega Fistula Centre, GFC), the only permanent referral centre for obstetric fistula in Burundi. A comprehensive model of care is offered including psychosocial support, conservative and surgical management, post-operative care and follow-up. We describe this model of care, patient outcomes and the operational challenges. METHODS: Descriptive study using routine programme data. RESULTS: Between July 2010 and December 2011, 470 women with obstetric fistula presented for the first time at GFC, of whom 458 (98%) received treatment. Early urinary catheterization (conservative management) was successful in four out of 35 (11%) women. Of 454 (99%) women requiring surgical management, 394 (87%) were discharged with a closed fistula, of whom 301 (76%) were continent of urine and/or faeces, while 93 (24%) remained incontinent of urine and/or faeces. In 59 (13%) cases, the fistula was complex and could not be closed. Outcome status was unknown for one woman. Median duration of stay at GFC was 39 days (Interquartile range IQR, 31-51 days). CONCLUSION: In a rural African setting, it is feasible to implement a comprehensive package of fistula care using a dedicated fistula facility, and satisfactory surgical repair outcomes can be achieved. Several operational challenges are discussed.
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Parto Obstétrico/efeitos adversos , Fístula Retovaginal/terapia , Reto/cirurgia , Bexiga Urinária/cirurgia , Vagina/cirurgia , Fístula Vesicovaginal/terapia , Adulto , Burundi , Feminino , Humanos , Fístula Retovaginal/etiologia , Estudos Retrospectivos , Cateterismo Urinário , Fístula Vesicovaginal/etiologia , Adulto JovemRESUMO
Whither oncolytic viruses? From the peak of their popularity in the early 2000s, when the ONYX-015 adenovirus had just entered the clinic, and then again in 2015 when the Food and Drug Administration-approved talimogene laherparepvec (also known as OncoVEXGM-CSF), which briefly revived interest, oncolytic viruses (OVs) have mostly fallen out of favor despite the many pharmaceutical companies with OVs in development.This commentary enumerates and addresses the core conceptions, perceptions, and misconceptions that characterize the current 'trough of disillusionment' in which the field of anticancer virotherapy finds itself and suggests reasons for optimism.