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OBJECTIVES: This study aimed to estimate the incidence and risk factors for mammary tumours in female cats attending UK primary-care practices. The study hypothesised that middle-aged, intact and certain breeds are associated with increased mammary tumour risk. MATERIALS AND METHODS: A case-control study design identified mammary tumour cases by assessment of electronic patient records, nested within a denominator population of 259,869 female cats attending 886 primary-care VetCompass participating veterinary practices in the UK in 2016. RESULTS: From 2858 potential mammary tumour cases identified within the denominator, 270 cats met the case definition, giving an incidence risk of 104 per 100,000 (0.104%, 95% confidence interval 0.092 to 0.117%) during 2016. In the risk factor analysis increasing age, purebred compared to crossbred and veterinary group were associated with increased odds of mammary tumour. Median survival after the diagnosis of mammary tumour cats was 18.7 months. CLINICAL SIGNIFICANCE: The current study provides an updated estimate of the incidence of mammary cancer in cats seen in primary care veterinary practice in the UK with increasing risk seen in older cats and with purebred status. This study can aid veterinary surgeons to identify cats at greater risk of mammary tumour and advise on survival after diagnosis.
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Doenças do Gato , Neoplasias , Gatos , Feminino , Animais , Estudos de Casos e Controles , Fatores de Risco , Incidência , Neoplasias/veterinária , Doenças do Gato/epidemiologiaRESUMO
Implementation science is a useful tool to consider ways in which we can introduce improvements to burn services in low-and-middle income countries (LMICs), where the majority of the burden of burn injury is now experienced. This paper outlines the development of the Delivery Assessment Tool (DAT), a method for facilitating quality improvement in burn services in LMICs. We used a participatory approach that ensured that local clinicians and experts were fully involved in piloting the tool. The DAT is based on internationally agreed operational standards for burn care service delivery and has undergone an iterative process of improvement and refinement through an initial three-year project in Nepal and Bangladesh. The DAT, a 50-item tool organised into 10 subsections, is used to assess a service through a participatory focus group discussion with a mixed, multidisciplinary team of staff working at the burn service, typically 6-10 participants. This usually lasts 2-3 h. The staff in the unit then select priority areas for quality improvement programmes that are within their control to achieve, which starts a cycle of audit and review. The final version of the tool was used in a further three-year project to evaluate 11 hospitals in Nepal and Bangladesh. Education and training are key components of this work; both were provided by Interburns as part of on-going support for the clinical teams. At the end of the project a>19% improvement in scores was demonstrated using the final version of the DAT in both Nepal and Bangladesh; this achievement is remarkable given the continued difficulties in service provision where patient numbers far outstrip the resources available to care for them. As a result of this work, we have made a digital version of the tool available free of charge.
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Queimaduras , Países em Desenvolvimento , Queimaduras/terapia , Atenção à Saúde , Humanos , Pobreza , Melhoria de QualidadeRESUMO
The patient-provider relationship is a key driver of patient satisfaction as it relates to overall healthcare experience. We surveyed patients undergoing radiation therapy to determine what they consider to be the most valued qualities in their interactions with the healthcare team. An ethics-approved 35-item patient satisfaction survey was developed in-house to gain insights on patients' perception of their relationship with the healthcare team throughout their cancer journey. There were 199 completed survey, median age 68 years, 54% women and 45% men. Almost all (95%) "agreed" or "strongly agreed" that their physicians had been sensitive and compassionate. Over 90% felt that they received adequate explanations about their treatment, and had their questions answered. The vast majority (93%) felt included in the decision-making process. Patients reported the 5 most highly rated qualities among their healthcare providers (HCPs) as knowledge, kindness, honesty, good communication, and a cheerful attitude. Overall satisfaction was high but areas for improvement were identified including being offered future appointments for further discussion, more information about clinical trials, other treatments, and community resources. Patients noted their HCPs tended to focus on the physical and emotional needs of patients, but spiritual and cultural needs were rarely addressed. Patients receiving radiotherapy reported high rates of satisfaction across many aspects of their care. These findings also reinforce the different aspects of holistic care that can be improved, and serve as a reminder to clinicians that patients perceive their role as more than just that of a medical expert.
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Neoplasias , Satisfação do Paciente , Idoso , Comunicação , Feminino , Pessoal de Saúde/educação , Humanos , Masculino , Neoplasias/terapia , Relações Profissional-PacienteRESUMO
Consistent evidence has emerged over many years that the mortality and morbidity outcomes for burn patients in low and middle-income countries (LMICs) lag behind those in more resource rich countries. Interburns is a charity that was set up with the aim of working to reduce the disparity in the number of cases of burns as well as the outcomes for patients in LMICs. This paper provides an overview of a cyclical framework for quality improvement in burn care for use in LMICs that has been developed using an iterative process over the last 10 years. Each phase of the process is outlined together with a description of the tools used to conduct a gap analysis within the service, which is then used to frame a programme of capacity enhancement. Recent externally reviewed projects have demonstrated sustained improvement with the use of this comprehensive and integrated approach over a three-year cycle. This overview paper will be supported by further publications that present these results in detail.
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Queimaduras/terapia , Fortalecimento Institucional/métodos , Melhoria de Qualidade , Unidades de Queimados/economia , Unidades de Queimados/tendências , Queimaduras/economia , Países em Desenvolvimento/estatística & dados numéricos , Humanos , Nepal , Alocação de Recursos/métodosRESUMO
Background: Most people can think of important attributes that they believe physicians should have. The canmeds framework defines domains of attributes in medical training (Leader, Medical Expert, Scholar, Communicator, Advocate, Collaborator, and Professional). Whether some are more valued by various stakeholders is unknown. Previous research has shown that patients can receive suboptimal care if physician and patient expectations of a health care encounter differ. In the present study, we sought to identify what various stakeholders identified as the single most important attribute for a physician to possess. Methods: A simple survey asked the question "What is the single most important attribute a physician should have?" at a single academic teaching hospital and affiliated medical school. The survey was administered to medical students, doctors, nurses, patients, and caregivers. Age and sex were also collected. Responses were assigned to domains and analyzed to identify trends. The primary outcome is a descriptive analysis of the findings. Results: From 362 individuals who responded, 109 different responses were obtained. The single most common answer was "compassion" (n = 86). Responses were categorized into these 5 domains: Caring, n = 209; Professional or Collaborator, n = 58; Medical Expert, n = 54; Communicator, n = 32; and Other, n = 9. Compared with men, women chose attributes in the Caring domain more frequently (64% vs. 49%), although that domain was the most popular for both sexes. Medical students were less likely to highly value Communicator attributes. Conclusions: All stakeholder group identified attributes in the Caring domain as being most important. Although all canmeds roles are important, our research highlights the priorities of stakeholders.
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Médicos/normas , Participação dos Interessados/psicologia , Feminino , Humanos , MasculinoRESUMO
Background: Non-small-cell lung cancer (nsclc) is the most common cause of cancer deaths worldwide, with a 5-year survival of 17%. The low survival rate observed in patients with nsclc is primarily attributable to advanced stage of disease at diagnosis, with more than 50% of cases being stage iv at presentation. For patients with advanced disease, palliative systemic therapy can improve overall survival (os); however, a recent review at our institution of more than 500 consecutive cases of advanced nsclc demonstrated that only 55% of the patients received palliative systemic therapy. What is unknown to date is whether that observed low rate of systemic therapy in our previous study is uniform across oncologists. Methods: With ethics approval, we performed a retrospective analysis of newly diagnosed patients with stage iv nsclc seen as outpatients at our institution between 2009 and 2012 by 4 different oncologists. Demographics, treatment, and survival data were collected and compared for the 4 oncologists. Results: The 4 oncologists saw 528 patients overall, with D seeing 115; L, 158; R, 137; and M, 118. Significant variation was observed in the proportion receiving 1 line or more of chemotherapy: D, 60%; L, 65%; R, 43%; and M, 52%. Physician assignment was not associated with a difference in median os, with D's cohort having a median os of 6.8 months; L, 8.4 months; R, 7.0 months; and M, 7.0 months. Conclusions: Practice size and proportion of patients treated varied between oncologists, but those differences did not translate into significantly different survival outcomes for patients.
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Carcinoma Pulmonar de Células não Pequenas/mortalidade , Carcinoma Pulmonar de Células não Pequenas/terapia , Neoplasias Pulmonares/mortalidade , Neoplasias Pulmonares/terapia , Oncologistas/normas , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma Pulmonar de Células não Pequenas/patologia , Humanos , Neoplasias Pulmonares/patologia , Pessoa de Meia-Idade , Estudos Retrospectivos , Análise de SobrevidaRESUMO
Background The IND.226 study was a phase Ib study to determine the recommended phase II dose of durvalumab + tremelimumab in combination with standard platinum-doublet chemotherapy. Sequential administration of multiple agents increases total chair time adding costs overall and inconvenience for patients. This cohort of the IND.226 study evaluated the safety and tolerability of durvalumab + tremelimumab given either sequentially (SEQ) or concurrently (CON). Methods Patients with advanced solid tumours were enrolled and randomised to either SEQ tremelimumab 75 mg IV over 1 h followed by durvalumab 1500 mg IV over 1 h q4wks on the same day, or CON administration over 1 h. The serum pharmacokinetic profile of SEQ versus CON of durvalumab and tremelimumab administration was also evaluated. Results 14 patients either received SEQ (n = 7pts) or CON (n = 7 pts). There were no infusion related reactions. Drug related adverse events (AEs) were mainly low grade and manageable, and comparable in frequency between SEQ/CON- fatigue (43%/57%), rash (43%/43%), pruritus (43%/29%) and nausea (14%/29%). One patient in each cohort discontinued treatment due to toxicity. The PK profiles of durvalumab and tremelimumab were similar between CON and SEQ, and to historical reference data. Conclusions Concurrent administration of durvalumab and tremelimumab over 1 h is safe with a comparable PK profile to sequential administration.
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Anticorpos Monoclonais Humanizados/administração & dosagem , Anticorpos Monoclonais/administração & dosagem , Antineoplásicos Imunológicos/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Inibidores de Checkpoint Imunológico/administração & dosagem , Neoplasias/tratamento farmacológico , Adulto , Idoso , Anticorpos Monoclonais/efeitos adversos , Anticorpos Monoclonais/sangue , Anticorpos Monoclonais/farmacocinética , Anticorpos Monoclonais Humanizados/efeitos adversos , Anticorpos Monoclonais Humanizados/sangue , Anticorpos Monoclonais Humanizados/farmacocinética , Antineoplásicos Imunológicos/efeitos adversos , Antineoplásicos Imunológicos/sangue , Antineoplásicos Imunológicos/farmacocinética , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Feminino , Humanos , Inibidores de Checkpoint Imunológico/efeitos adversos , Inibidores de Checkpoint Imunológico/sangue , Inibidores de Checkpoint Imunológico/farmacocinética , Masculino , Pessoa de Meia-Idade , Neoplasias/sangue , Neoplasias/metabolismoRESUMO
Fungicide programs for managing target spot of cotton caused by Corynespora cassiicola were evaluated over 15 site-years in the southeastern United States between 2014 and 2016. Two cultivars, hypothesized to vary in target spot susceptibility, PhytoGen 499WRF (PHY499) and Deltapine 1137B2RF (DPL1137), and four fungicides (azoxystrobin, flutriafol, pyraclostrobin, pyraclostrobin + fluxapyroxad) plus nontreated control, were compared. Fungicide programs consisted of 1) a single application at first flower or disease onset and 2) the first application followed by a second 14 days later. Treatments were applied in a factorial, randomized complete block design. Target spot onset and severity varied among site-years. Except when severity was low, target spot-associated defoliation was greater on PHY499 than on DP1137. Fungicides delayed disease development and defoliation, but application number had little impact. Based on a meta-analysis of 15 site-years, pyraclostrobin-based applications resulted in a 4 to 6% yield preservation, and yield preservation was greater at site-years with early disease onset and >40% target spot associated defoliation. Results suggest a single well-timed application of a pyraclostrobin-based fungicide reduces defoliation and protects cotton yield at locations with high target spot severity. Additional research is needed to identify risk factors for target spot-associated yield losses in cotton production systems.
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Ascomicetos , Fungicidas Industriais , Gossypium , Doenças das Plantas , Sudeste dos Estados UnidosRESUMO
We present kilohertz-scale video capture rates in a transmission electron microscope, using a camera normally limited to hertz-scale acquisition. An electrostatic deflector rasters a discrete array of images over a large camera, decoupling the acquisition time per subframe from the camera readout time. Total-variation regularization allows features in overlapping subframes to be correctly placed in each frame. Moreover, the system can be operated in a compressive-sensing video mode, whereby the deflections are performed in a known pseudorandom sequence. Compressive sensing in effect performs data compression before the readout, such that the video resulting from the reconstruction can have substantially more total pixels than that were read from the camera. This allows, for example, 100 frames of video to be encoded and reconstructed using only 15 captured subframes in a single camera exposure. We demonstrate experimental tests including laser-driven melting/dewetting, sintering, and grain coarsening of nanostructured gold, with reconstructed video rates up to 10 kHz. The results exemplify the power of the technique by showing that it can be used to study the fundamentally different temporal behavior for the three different physical processes. Both sintering and coarsening exhibited self-limiting behavior, whereby the process essentially stopped even while the heating laser continued to strike the material. We attribute this to changes in laser absorption and to processes inherent to thin-film coarsening. In contrast, the dewetting proceeded at a relatively uniform rate after an initial incubation time consistent with the establishment of a steady-state temperature profile.
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Mass casualty burn events (MCBs) require intense and complex management. Silver-infused longer use dressings might help optimise management of burns in an MCB setting. We developed a model estimating the impact of dressing choice in the context of an MCB. The model was developed in Excel in collaboration with experienced emergency response clinicians. The model compares use of silver-infused dressings with use of traditional dressings in patients with partial thickness burns covering 30% of their body. Costs were estimated from a UK perspective as a proxy for a funded emergency response team and limited to cost of dressings, bandages, padding, analgesia and staff time. Expected patient costs and resource use were summarised over an acute 2-week intervention period and extrapolated to estimate possible time savings in a hypothetical MCB. Per patient costs were estimated at £2,002 (silver) and £1,124 (traditional) (a daily additional spend of £63). Per patient staff time was estimated at 864 minutes (silver) and 1,200 minutes (traditional) (a daily time saving of 24 minutes). Multiplying up to a possible MCB population of 20 could result in a saving equivalent to 9 staff shifts over the 2-week intervention period. The model was sensitive to type of silver dressing, frequency of dressing change and staff costs. We found increased costs through use of silver dressings but time savings that might help optimise burns management in an MCB. Exploring the balance between costs and staff time might help future MCB response preparation.
Les catastrophes demandent une planification et une organisation rigoureuse. Les pansements à base d'argent nécessitant des changements moins fréquents peuvent être un bon compromis dans ces situations. En collaboration avec des urgentistes expérimentés, nous avons développé, sur un tableur, un modèle simple pour estimer l'impact du choix du pansement lors d'événements engendrant de nombreux blessés. Il compare l'utilisation de pansements à l'argent et celui des pansements généralement utilisés pour les patients avec des brûlures du deuxième degré couvrant 30 % de la surface corporelle. Le coût a été estimé en tenant compte du volume des pansements, de l'analgésie et temps/nombre soignants pour une durée d'intervention sur site de 2 semaines. Le coût par patient a été estimé à 2 002 £ pour les pansements à l'argent et 1 124 £ pour les pansement traditionnels soit une augmentation de 63 £/j. Le temps de soins par patient a été estimé à 864 minutes (pansements à l'argent) et 1 200 minutes (pansements traditionnel) soit un gain de temps 24 mn/j. Dans une hypothèse de 20 blessés, nous arrivons à une économie 9 journées (de 8 heures) de travail. L'utilisation des pansements à l'argent est plus onéreuse en termes de matériel mais permet d'économiser du temps/soignant. Nous pourrions améliorer la prise en charge des victimes dans de telles situations en explorant les possibilités d'un meilleur équilibre entre le coût et le nombre de personnel requis.
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Background: Advanced non-small-cell lung cancer (nsclc) represents a major health issue globally. Systemic treatment decisions are informed by clinical trials, which, over years, have improved the survival of patients with advanced nsclc. The applicability of clinical trial results to the broad lung cancer population is unclear because strict eligibility criteria in trials generally select for optimal patients. Methods: We performed a retrospective chart review of all consecutive patients with advanced nsclc seen in outpatient consultation at our academic institution between September 2009 and September 2012, collecting data about patient demographics and cancer characteristics, treatment, and survival from hospital and pharmacy records. Two sets of arbitrary trial eligibility criteria were applied to the cohort. Scenario A stipulated Eastern Cooperative Oncology Group performance status (ecog ps) 0-1, no brain metastasis, creatinine less than 120 µmol/L, and no second malignancy. Less-strict scenario B stipulated ecog ps 0-2 and creatinine less than 120 µmol/L. We then used the two scenarios to analyze treatment and survival of patients by trial eligibility status. Results: The 528 included patients had a median age of 67 years, with 55% being men and 58% having adenocarcinoma. Of those 528 patients, 291 received at least 1 line of palliative systemic therapy. Using the scenario A eligibility criteria, 73% were trial-ineligible. However, 46% of "ineligible" patients actually received therapy and experienced survival similar to that of the "eligible" treated patients (10.2 months vs. 11.6 months, p = 0.10). Using the scenario B criteria, only 35% were ineligible, but again, the survival of treated patients was similar in the ineligible and eligible groups (10.1 months vs. 10.9 months, p = 0.57). Conclusions: Current trial eligibility criteria are often strict and limit the enrolment of patients in clinical trials. Our results suggest that, depending on the chosen drug, its toxicities and tolerability, eligibility criteria could be carefully reviewed and relaxed.
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Carcinoma Pulmonar de Células não Pequenas/diagnóstico , Neoplasias Pulmonares/diagnóstico , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma Pulmonar de Células não Pequenas/epidemiologia , Feminino , Humanos , Neoplasias Pulmonares/epidemiologia , Masculino , Pessoa de Meia-Idade , Estudos RetrospectivosRESUMO
BACKGROUND: The Ottawa Hospital (toh) defined delay to timely lung cancer care as a system design problem. Recognizing the patient need for an integrated journey and the need for dynamic alignment of providers, toh used a learning health system (lhs) vision to redesign regional diagnostic processes. A lhs is driven by feedback utilizing operational and clinical information to drive system optimization and innovation. An essential component of a lhs is a collaborative platform that provides connectivity across silos, organizations, and professions. METHODS: To operationalize a lhs, we developed the Ottawa Health Transformation Model (ohtm) as a consensus approach that addresses process barriers, resistance to change, and conflicting priorities. A regional Community of Practice (cop) was established to engage stakeholders, and a dedicated transformation team supported process improvements and implementation. RESULTS: The project operationalized the lung cancer diagnostic pathway and optimized patient flow from referral to initiation of treatment. Twelve major processes in referral, review, diagnostics, assessment, triage, and consult were redesigned. The Ottawa Hospital now provides a diagnosis to 80% of referrals within the provincial target of 28 days. The median patient journey from referral to initial treatment decreased by 48% from 92 to 47 days. CONCLUSIONS: The initiative optimized regional integration from referral to initial treatment. Use of a lhs lens enabled the creation of a system that is standardized to best practice and open to ongoing innovation. Continued transformation initiatives across the continuum of care are needed to incorporate best practice and optimize delivery systems for regional populations.
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BACKGROUND: The development and approval of both targeted and immune therapies for patients with advanced non-small cell lung cancer (nsclc) has significantly improved patient survival rates and quality of life. Biomarker testing for patients newly diagnosed with nsclc, as well as for patients progressing after treatment with epidermal growth factor receptor (EGFR) inhibitors, is the standard of care in Canada and many parts of the world. METHODS: A group of thoracic oncology experts in the field of thoracic oncology met to describe the standard for biomarker testing for lung cancer in the Canadian context, focusing on evidence-based recommendations for standard-of-care testing for EGFR, anaplastic lymphoma kinase (ALK), ROS1, BRAF V600 and programmed death-ligand (PD-L1) at the time of diagnosis of advanced disease and EGFR T790M upon progression. As well, additional exploratory molecules and targets are likely to impact future patient care, including MET exon 14 skipping mutations and whole gene amplification, RET translocations, HER2 (ERBB2) mutations, NTRK, RAS (KRAS and NRAS), as well as TP53. RESULTS: The standard of care must include the incorporation of testing for novel biomarkers as they become available, as it will be difficult for national guidelines to keep pace with technological advances in this area. CONCLUSIONS: Canadian patients with nsclc should be treated equally; the minimum standard of care is defined in this paper.
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Reduction of stress is an important factor in improving poultry welfare, especially during periods of heat stress. A study was conducted to evaluate the effects of feeding the functional metabolites of Diamond V Original XPCTM to broilers reared under ambient or heat stress temperatures. Dietary treatments included: control feed (CON) and Original XPC fed continuously at 1.25 kg/MT (XPC). Half the birds in each dietary treatment were subjected to either no heat stress (24°C constant) or heat stress (35°C:24°C for 18:6 h daily) from 28 to 42 d. At the end of the heat stress period, blood was collected from 40 birds/treatment. Blood was analyzed for plasma corticosterone (CORT), plasma HSP70 (HSP70), and heterophil/lymphocyte ratios (H/L). At 42 d, bilateral metatarsal traits were also measured in 40 birds/treatment to assess physical asymmetry. Birds fed XPC had significantly lower CORT levels than CON (P < 0.001; 5,129 ± 617 vs. 8,433 ± 730, respectively). Physical asymmetry scores were also significantly higher in CON compared to XPC fed broilers (P < 0.001; 1.50 ± 0.13 vs. 0.54 ± 0.05, respectively). H/L ratios were significantly greater in CON than for XPC birds (P = 0.01; 0.81 ± 0.05 mm vs. 0.62 ± 0.05 mm, respectively). No differences were observed between CON and XPC fed broilers in HSP70. However, heat stress did increase (P < 0.0001) HSP70 compared to no heat stress birds (5.65 ± 0.12 vs. 4.78 ± 0.11 pg/mL, for heat stress and no heat stress, respectively). Feeding XPC to broiler chickens improved animal welfare via reduced stress indicators while under heat stress or no heat stress conditions. These results indicate that feeding XPC may improve poultry welfare by reducing heat stress susceptibility.
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Galinhas/fisiologia , Dieta/veterinária , Suplementos Nutricionais/análise , Temperatura Alta/efeitos adversos , Estresse Fisiológico , Ração Animal/análise , Animais , Distribuição AleatóriaRESUMO
BACKGROUND: There is insufficient information regarding the prognostic significance of baseline and change in quality of life (QoL) scores on overall survival (OS) in advanced pancreatic cancer. METHODS: QoL was assessed prospectively using the EORTC QLQ-C30 as part of the PA.3 trial of gemcitabine + erlotinib (G + E) vs. gemcitabine + placebo (G + P). Relevant variables and QoL scores at baseline and change at 8 weeks were analyzed by Cox stepwise regression to determine predictors of OS. RESULTS: 222 of 285 patients (pts) treated with G + E and 220 of 284 pts treated with G + P completed baseline QoL assessments. In a multivariable Cox analysis combining all pts, better QoL physical functioning (PF) score independently predicted longer OS (HR 0.86; CI: 0.80-0.93), as did non-white race (HR 0.64; CI: 0.44-0.95), PS 0-1 (HR 0.65; CI: 0.50-0.85), locally advanced disease (HR 0.55; CI: 0.43-0.71) and G + E (HR 0.78; CI: 0.64-0.96). Improvement in physical function at week 8 also predicted for improved survival (HR 0.89; CI: 0.81-0.97 for 10 point increase in score, p = 0.02). CONCLUSION: In addition to clinical variables, patient reported QoL scores at baseline and change from baseline to week 8 added incremental predictive information regarding survival for advanced pancreatic cancer patients.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Pancreáticas/psicologia , Neoplasias Pancreáticas/terapia , Qualidade de Vida , Resultado do Tratamento , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Antibióticos Antineoplásicos/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Criança , Pré-Escolar , Desoxicitidina/administração & dosagem , Desoxicitidina/análogos & derivados , Cloridrato de Erlotinib/administração & dosagem , Feminino , Humanos , Lactente , Avaliação de Estado de Karnofsky , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Grupos Raciais , Análise de Sobrevida , Adulto Jovem , GencitabinaRESUMO
BACKGROUND: Colorectal cancer (crc) has a median diagnostic age of 68 years. Despite significant progress in chemotherapy (ctx) options, few data on outcomes or toxicity from ctx in patients 80 years of age and older are available. We investigated ctx in such patients with metastatic crc (mcrc), hypothesizing high rates of hospitalization and toxicity. METHODS: A retrospective chart review identified patients 80 years of age and older with mcrc who initiated ctx between 2005-2010 at our institution. Patient demographics and ctx data were collected. Endpoints included rates of hospitalization, ctx discontinuation because of toxicity, and overall survival. RESULTS: In 60 patients, ctx was initiated on 88 occasions. Median age in the cohort was 83 years; 52% were men; 72% lived with family; 53% had a modified Charlson comorbidity index of 2 or greater; and 31% were taking 6 or more prescription medications at baseline. At baseline, 33% of the patients were anemic (hemoglobin < 100 g/L), 36% had leukocytosis (white blood cells > 11×10(9)/L), and 48% had renal impairment (estimated glomerular filtration rate < 60 mL/min/1.73 m(2)). In 53%, ctx was given as first-line treatment. The initial ctx dose was adjusted in 67%, and capecitabine was the most common chemotherapeutic agent (45%). In 19 instances (22%), the patient was hospitalized during or within 30 days of ctx; in 26 instances (30%), the ctx was discontinued because of toxicity, and in 48 instances (55%), the patient required at least 1 dose reduction, omission, or delay. Median overall survival was 17.8 months (95% confidence interval: 14.3 to 20.8 months). CONCLUSIONS: In the population 80 years of age and older, ctx for mcrc is feasible; however, most recipients will require dose adjustments, and a significant proportion will be hospitalized or stop ctx because of toxicity. Prospective research incorporating geriatric assessment tools is required to better select these older patients for ctx.
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Cisplatin is a widely used chemotherapeutic agent, yet its efficacy is limited by nephrotoxicity. The severity of nephrotoxicity is associated with the extent of kidney cell death. Previously, we found that cisplatin-induced kidney cell death was dependent on Cdk2 activation, and inhibition of Cdk2 protected cells from cisplatin-induced apoptosis. Using an in vitro kination assay, we showed that Cdk2 phosphorylated Bcl-xL, an anti-apoptotic member of Bcl-2 family proteins, at serine 73. We also found that this phosphorylated Bcl-xL participated in cell death, as a phosphomimetic mutant of Bcl-xL at the serine 73 site (S73D-Bcl-xL) activated caspases. We now find that S73D-Bcl-xL was cleaved at D61 and D76, which are putative caspase cleavage sites, to generate 15-kDa and 12-kDa fragments. Unlike full-length Bcl-xL, these cleavage products of Bcl-xL were previously reported to be pro-apoptotic. We sought to determine whether these Bcl-xL fragments were necessary for the induction of cell death by S73D-Bcl-xL. Mutation of these caspase cleavage sites prevented the formation of the 15-kDa and 12-kDa Bcl-xL cleavage products, but apoptosis still persisted in a S73D modified Bcl-xL. Our findings show that Cdk2 phosphorylation of Bcl-xL at Ser73, but not the Bcl-xL cleavage products, is necessary and sufficient to induce cell death.