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1.
Contemp Clin Trials ; 140: 107496, 2024 05.
Artigo em Inglês | MEDLINE | ID: mdl-38467274

RESUMO

BACKGROUND: To develop medicines that are safe and efficacious to all patients, clinical trials must enroll appropriate target populations, but imbalances related to race, ethnicity and sex have been reported. A comprehensive analysis and improvement in understanding representativeness of patient enrollment in industry-sponsored trials are key public health needs. METHODS: We assessed race/ethnicity and sex representation in AstraZeneca (AZ)-sponsored clinical trials in the United States (US) from 2010 to 2022, compared with the 2019 US Census. RESULTS: In total, 246 trials representing 95,372 patients with complete race/ethnicity and sex records were analyzed. The proportions of different race/ethnicity subgroups in AZ-sponsored clinical trials and the US Census were similar (White: 69.5% vs 60.1%, Black or African American: 13.3% vs 12.5%, Asian: 1.8% vs 5.8%, Hispanic: 14.4% vs 18.5%). We also observed parity in the proportions of males and females between AZ clinical trials and US Census (males: 52.4% vs 49.2%, females: 47.6% vs 50.8%). Comparisons of four distinct therapy areas within AZ (Respiratory and Immunology [R&I]; Cardiovascular, Renal, and Metabolism [CVRM]; Solid Tumors; and Hematological Malignancies), including by trial phases, revealed greater variability, with proportions observed above and below US Census levels. CONCLUSION: This analysis provides the first detailed insights into the representativeness of AZ trials. Overall, the proportions of different race/ethnicity and sex subgroups in AZ-sponsored clinical trials were broadly aligned with the US Census. We outline some of AZ's planned health equity initiatives that are intended to continue to improve equitable patient enrollment.


Assuntos
Ensaios Clínicos como Assunto , Feminino , Humanos , Masculino , Ensaios Clínicos como Assunto/estatística & dados numéricos , Indústria Farmacêutica , Etnicidade/estatística & dados numéricos , Seleção de Pacientes , Grupos Raciais/estatística & dados numéricos , Fatores Sexuais , Estados Unidos , Brancos , Negro ou Afro-Americano , Asiático , Hispânico ou Latino
3.
Cancer Discov ; 13(5): 1058-1083, 2023 05 04.
Artigo em Inglês | MEDLINE | ID: mdl-37067191

RESUMO

Despite some notable successes, there are still relatively few agents approved for cancer prevention. Here we review progress thus far in the development of medicines for cancer prevention, and we outline some key concepts that could further enable or accelerate drug development for cancer prevention in the future. These are summarized under six key themes: (i) unmet clinical need, (ii) patient identification, (iii) risk stratification, (iv) pharmacological intervention, (v) clinical trials, and (vi) health care policy. These concepts, if successfully realized, may help to increase the number of medicines available for cancer prevention. SIGNIFICANCE: The huge potential public health benefits of preventing cancer, combined with recent advances in the availability of novel early detection technologies and new treatment modalities, has caused us to revisit the opportunities and challenges associated with developing medicines to prevent cancer. Here we review progress in the field of developing medicines to prevent cancer to date, and we present a series of ideas that might help in the development of more medicines to prevent cancer in the future.


Assuntos
Neoplasias , Humanos , Neoplasias/tratamento farmacológico , Neoplasias/prevenção & controle , Desenvolvimento de Medicamentos
4.
Ther Adv Med Oncol ; 14: 17588359221133893, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36324736

RESUMO

Background: SARS-CoV-2 (COVID-19) elicits a T-cell antigen-mediated immune response of variable efficacy. To understand this variability, we explored transcriptomic expression of angiotensin-converting enzyme 2 (ACE2, the SARS-CoV-2 receptor) and of immunoregulatory genes in normal lung tissues from patients with non-small cell lung cancer (NSCLC). Methods: This study used the transcriptomic and the clinical data for NSCLC patients generated during the CHEMORES study [n = 123 primary resected (early-stage) NSCLC] and the WINTHER clinical trial (n = 32 metastatic NSCLC). Results: We identified patient subgroups with high and low ACE2 expression (p = 1.55 × 10-19) in normal lung tissue, presumed to be at higher and lower risk, respectively, of developing severe COVID-19 should they become infected. ACE2 transcript expression in normal lung tissues (but not in tumor tissue) of patients with NSCLC was higher in individuals with more advanced disease. High-ACE2 expressors had significantly higher levels of CD8+ cytotoxic T lymphocytes and natural killer cells but with presumably impaired function by high Thymocyte Selection-Associated High Mobility Group Box Protein TOX (TOX) expression. In addition, immune checkpoint-related molecules - PD-L1, CTLA-4, PD-1, and TIGIT - are more highly expressed in normal (but not tumor) lung tissues; these molecules might dampen immune response to either viruses or cancer. Importantly, however, high inducible T-cell co-stimulator (ICOS), which can amplify immune and cytokine reactivity, significantly correlated with high ACE2 expression in univariable analysis of normal lung (but not lung tumor tissue). Conclusions: We report a normal lung immune-tolerant state that may explain a potential comorbidity risk between two diseases - NSCLC and susceptibility to COVID-19 pneumonia. Further, a NSCLC patient subgroup has normal lung tissue expressing high ACE2 and high ICOS transcripts, the latter potentially promoting a hyperimmune response, and possibly leading to severe COVID-19 pulmonary compromise.

5.
JCO Precis Oncol ; 6: e2200072, 2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-36108261

RESUMO

PURPOSE: The prognosis of patients with non-small-cell lung cancer (NSCLC), traditionally determined by anatomic histology and TNM staging, neglects the biological features of the tumor that may be important in determining patient outcome and guiding therapeutic interventions. Identifying patients with NSCLC at increased risk of recurrence after curative-intent surgery remains an important unmet need so that known effective adjuvant treatments can be offered to those at highest risk of recurrence. METHODS: Relative gene expression level in the primary tumor and normal bronchial tissues was used to retrospectively assess their association with disease-free survival (DFS) in a cohort of 120 patients with NSCLC who underwent curative-intent surgery. RESULTS: Low versus high Digital Display Precision Predictor (DDPP) score (a measure of relative gene expression) was significantly associated with shorter DFS (highest recurrence risk; P = .006) in all patients and in patients with TNM stages 1-2 (P = .00051; n = 83). For patients with stages 1-2 and low DDPP score (n = 29), adjuvant chemotherapy was associated with improved DFS (P = .0041). High co-overexpression of CTLA-4, PD-L1, and ICOS in normal lung (28 of 120 patients) was also significantly associated with decreased DFS (P = .0013), suggesting an immune tolerance to tumor neoantigens in some patients. Patients with DDPP low and immunotolerant normal tissue had the shortest DFS (P = 2.12E-11). CONCLUSION: TNM stage, DDPP score, and immune competence status of normal lung are independent prognostic factors in multivariate analysis. Our findings open new avenues for prospective prognostic assessment and treatment assignment on the basis of transcriptomic profiling of tumor and normal lung tissue in patients with NSCLC.


Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Carcinoma de Pequenas Células do Pulmão , Antígeno B7-H1/análise , Antígeno CTLA-4/genética , Carcinoma Pulmonar de Células não Pequenas/genética , Humanos , Pulmão/química , Neoplasias Pulmonares/tratamento farmacológico , Estudos Prospectivos , Estudos Retrospectivos , Transcriptoma
6.
Mol Oncol ; 15(10): 2507-2543, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34515408

RESUMO

Key stakeholders from the cancer research continuum met in May 2021 at the European Cancer Research Summit in Porto to discuss priorities and specific action points required for the successful implementation of the European Cancer Mission and Europe's Beating Cancer Plan (EBCP). Speakers presented a unified view about the need to establish high-quality, networked infrastructures to decrease cancer incidence, increase the cure rate, improve patient's survival and quality of life, and deal with research and care inequalities across the European Union (EU). These infrastructures, featuring Comprehensive Cancer Centres (CCCs) as key components, will integrate care, prevention and research across the entire cancer continuum to support the development of personalized/precision cancer medicine in Europe. The three pillars of the recommended European infrastructures - namely translational research, clinical/prevention trials and outcomes research - were pondered at length. Speakers addressing the future needs of translational research focused on the prospects of multiomics assisted preclinical research, progress in Molecular and Digital Pathology, immunotherapy, liquid biopsy and science data. The clinical/prevention trial session presented the requirements for next-generation, multicentric trials entailing unified strategies for patient stratification, imaging, and biospecimen acquisition and storage. The third session highlighted the need for establishing outcomes research infrastructures to cover primary prevention, early detection, clinical effectiveness of innovations, health-related quality-of-life assessment, survivorship research and health economics. An important outcome of the Summit was the presentation of the Porto Declaration, which called for a collective and committed action throughout Europe to develop the cancer research infrastructures indispensable for fostering innovation and decreasing inequalities within and between member states. Moreover, the Summit guidelines will assist decision making in the context of a unique EU-wide cancer initiative that, if expertly implemented, will decrease the cancer death toll and improve the quality of life of those confronted with cancer, and this is carried out at an affordable cost.


Assuntos
Neoplasias , Qualidade de Vida , Europa (Continente)/epidemiologia , Humanos , Neoplasias/epidemiologia , Neoplasias/prevenção & controle , Medicina de Precisão , Pesquisa Translacional Biomédica
8.
Mol Cancer Ther ; 20(9): 1614-1626, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34158341

RESUMO

Radiotherapy is an effective anticancer treatment, but combinations with targeted agents that maximize efficacy while sparing normal tissue are needed. Here, we assess the radiopotentiation profiles of DNA damage response inhibitors (DDRi) olaparib (PARP1/2), ceralasertib (ATR), adavosertib (WEE1), AZD0156 (ATM), and KU-60648 (DNA-PK). We performed a radiotherapy combination screen and assessed how drug concentration and cellular DDR deficiencies influence the radiopotentiation ability of DDRi. We pre-selected six lung cancer cell lines with different genetic/signaling aberrations (including mutations in TP53 and ATM) and assessed multiple concentrations of DDRi in combination with a fixed radiotherapy dose by clonogenic assay. The effective concentration of DDRi in radiotherapy combinations is lower than that required for single-agent efficacy. This has the potential to be exploited further in the context of DDR deficiencies to increase therapeutic index and we demonstrate that low concentrations of AZD0156 preferentially sensitized p53-deficient cells. Moreover, testing multiple concentrations of DDRi in radiotherapy combinations indicated that olaparib, ceralasertib, and adavosertib have a desirable safety profile showing moderate increases in radiotherapy dose enhancement with increasing inhibitor concentration. Small increases in concentration of AZD0156 and particularly KU-60648, however, result in steep increases in dose enhancement. Radiopotentiation profiling can inform on effective drug doses required for radiosensitization in relation to biomarkers, providing an opportunity to increase therapeutic index. Moreover, multiple concentration testing demonstrates a relationship between drug concentration and radiotherapy effect that provides valuable insights that, with future in vivo validation, can guide dose-escalation strategies in clinical trials.


Assuntos
Antineoplásicos/farmacologia , Dano ao DNA , Reparo do DNA , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/radioterapia , Radiossensibilizantes/farmacologia , Apoptose , Proliferação de Células , Humanos , Neoplasias Pulmonares/patologia , Ftalazinas/farmacologia , Piperazinas/farmacologia , Inibidores de Poli(ADP-Ribose) Polimerases/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Piridinas/farmacologia , Quinolinas/farmacologia , Células Tumorais Cultivadas
9.
Artigo em Inglês | MEDLINE | ID: mdl-33468509

RESUMO

OBJECTIVES: Development of evidence-based good practice recommendations for clinicians considering the use of antibiotics in patients towards the end of life. DESIGN: A multiprofessional group of experts in end-of-life care and antimicrobial stewardship was convened. Findings from a scoping review of the literature and a consultation of clinicians were triangulated. Expert discussion was used to generate consensus on how to approach decision-making. SETTING: Representatives from hospital and a range of community health and care settings. PARTICIPANTS: Medical, pharmacy and nursing professionals. MAIN OUTCOME MEASURES: Good practice recommendations based on published evidence and the experience of prescribers in Scotland. RESULTS: The findings of 88 uncontrolled, observational studies of variable quality were considered alongside a survey of over 200 prescribers. No national or international guidelines were identified. Antibiotic use towards the end of life was common but practice was highly variable. The potential harms associated with giving antibiotics tended to be less well considered than the potential benefits. Antibiotics often extended the length of time to death but this was sometimes at the cost of higher symptom burden. There was strong consensus around the importance of effective communication with patients and their families and making treatment decisions aligned to a patient's goals and priorities. CONCLUSIONS: Good practice recommendations were agreed with focus on three areas: making shared decisions about future care; agreeing clear goals and limits of therapy; reviewing all antibiotic prescribing decisions regularly. These will be disseminated widely to support optimal care for patients towards the end of life. A patient version of the recommendations has also been produced to support implementation.

10.
Clin Cancer Res ; 24(15): 3500-3509, 2018 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-29661779

RESUMO

The Radiation Therapy Committee of SWOG periodically evaluates its strategic plan in an effort to maintain a current and relevant scientific focus, and to provide a standard platform for future development of protocol concepts. Participants in the 2017 Strategic Planning Workshop included leaders in cancer basic sciences, molecular theragnostics, pharmaceutical and technology industries, clinical trial design, oncology practice, and statistical analysis. The committee discussed high-priority research areas, such as optimization of combined modality therapy, radiation oncology-specific drug design, identification of molecular profiles predictive of radiation-induced local or distant tumor responses, and methods for normal tissue-specific mitigation of radiation toxicity. The following concepts emerged as dominant questions ready for national testing: (i) what is the role of radiotherapy in the treatment of oligometastatic, oligorecurrent, and oligoprogressive disease? (ii) How can combined modality therapy be used to enhance systemic and local response? (iii) Can we validate and optimize liquid biopsy and other biomarkers (such as novel imaging) to supplement current response criteria to guide therapy and clinical trial design endpoints? (iv) How can we overcome deficiencies of randomized survival endpoint trials in an era of increasing molecular stratification factors? And (v) how can we mitigate treatment-related side effects and maximize quality of life in cancer survivors? The committee concluded that many aspects of these questions are ready for clinical evaluation and example protocol concepts are provided that could improve rates of cancer cure and quality of survival. Clin Cancer Res; 24(15); 3500-9. ©2018 AACR.


Assuntos
Neoplasias/radioterapia , Especificidade de Órgãos/efeitos da radiação , Lesões por Radiação/patologia , Radioterapia (Especialidade) , Terapia Combinada , Humanos , Neoplasias/patologia , Qualidade de Vida , Radioterapia/efeitos adversos
11.
Oncotarget ; 6(16): 14139-52, 2015 Jun 10.
Artigo em Inglês | MEDLINE | ID: mdl-25944621

RESUMO

Non-small cell lung cancer (NSCLC) is a leading cause of death worldwide. Targeted monotherapies produce high regression rates, albeit for limited patient subgroups, who inevitably succumb. We present a novel strategy for identifying customized combinations of triplets of targeted agents, utilizing a simplified interventional mapping system (SIMS) that merges knowledge about existent drugs and their impact on the hallmarks of cancer. Based on interrogation of matched lung tumor and normal tissue using targeted genomic sequencing, copy number variation, transcriptomics, and miRNA expression, the activation status of 24 interventional nodes was elucidated. An algorithm was developed to create a scoring system that enables ranking of the activated interventional nodes for each patient. Based on the trends of co-activation at interventional points, combinations of drug triplets were defined in order to overcome resistance. This methodology will inform a prospective trial to be conducted by the WIN consortium, aiming to significantly impact survival in metastatic NSCLC and other malignancies.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Medicina de Precisão/métodos , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Carcinoma Pulmonar de Células não Pequenas/patologia , Feminino , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Terapia de Alvo Molecular/métodos , Transcriptoma
12.
Chin Clin Oncol ; 3(2): 20, 2014 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-25841416

RESUMO

Recent approvals for oncology drugs have seen an increasing proportion directed to specific genetic targets identified with an associated companion diagnostic test. In addition, there is a wave of drugs directed against immune 'checkpoints' which promise to transform the way cancer is treated in the next decade. We can increase the probability of success in drug development based on a thorough mechanistic understanding of how a target drug affects cancer biology and the specific biological and genotypic context in which it operates. This article compares and contrasts the discovery and development of gefitinib-the first EGFR tyrosine kinase inhibitor and AZD9291, an irreversible inhibitor of both sensitizing and resistant mutated EGFR. This demonstrates how the better understanding we now have of the genetic changes driving the cancer growth and the biochemical structure and function of the mutated proteins, has led to a much faster developmental path with higher likelihood of success in pivotal trials. An emerging trend in response to the challenge of the increasing segmentation of cancers based on their genetic makeup is the development of 'basket' studies which include one or more screening tests for multiple genetic aberrations and the direction of patients to one of several arms of a clinical trial based on the specific aberration in their tumor. In the face of both the wealth of genetic information about cancer and the challenges of drug development, collaboration across academia and industry is vital. There is great potential to benefit from more 'open innovation' to address some of these challenges and opportunities. Far from there being a decline in innovation in pharmaceutical development, I see that we are in one of the most exciting times in cancer drug development with innovation in every aspect of how we discover and develop new therapies.

13.
Br J Gen Pract ; 63(609): e244-9, 2013 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-23540480

RESUMO

BACKGROUND: Urinary tract infections (UTIs) are one of the most common conditions seen in female patients within primary care. Community pharmacists are familiar with symptomatic UTI management and supplying trimethoprim under patient group direction (PGD) for moderate-to-severe uncomplicated UTIs could improve patient access to treatment. AIM: To compare the care pathway of patients with UTI symptoms attending GP services with those receiving management, including trimethoprim supply under PGD, via community pharmacies. DESIGN AND SETTING: Prospective, cross-sectional, mixed methods approach in 10 community pharmacies within NHS Greater Glasgow and Clyde. METHOD: Pharmacies invited a purposive sample of female patients to participate. Pharmacists had the option of supplying trimethoprim under PGD to patients with moderate-to-severe infection meeting the PGD inclusion criteria. Data from patient (questionnaires and semi-structured telephone interviews) and pharmacist (questionnaires and semi-structured, face-to-face interviews) were quantitatively and qualitatively analysed. RESULTS: Data were recorded on 153 patients, 97 presenting with GP prescriptions and 56 presenting directly in the pharmacy with symptoms suggestive of UTI, of whom 41 received trimethoprim via PGD and 15 received symptomatic management. Both GP adherence to local infection management guidelines and pharmacist application of PGD inclusion/exclusion criteria required improvement. There was demand and support, from patients and pharmacists, for access to antibiotic treatments for UTIs, without prescription, through community pharmacies. CONCLUSION: Operating within PGD controls, antibiotic treatments for UTIs could be provided via community pharmacy to improve patient access to treatment which may also maintain antibiotic stewardship and reduce GP workload.


Assuntos
Anti-Infecciosos Urinários/uso terapêutico , Serviços Comunitários de Farmácia , Medicina Geral , Trimetoprima/uso terapêutico , Infecções Urinárias/tratamento farmacológico , Adolescente , Adulto , Idoso , Estudos Transversais , Feminino , Conhecimentos, Atitudes e Prática em Saúde , Acessibilidade aos Serviços de Saúde/estatística & dados numéricos , Humanos , Pessoa de Meia-Idade , Estudos Prospectivos , Escócia/epidemiologia , Inquéritos e Questionários , Infecções Urinárias/epidemiologia
14.
J Immunother ; 35(1): 89-97, 2012 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-22130166

RESUMO

Ipilimumab, a fully human monoclonal antibody, which blocks cytotoxic T-lymphocyte antigen-4, has demonstrated an improvement in overall survival in 2 phase III trials of patients with advanced melanoma. To gain an understanding of its mechanism of action, the effects of ipilimumab on T-cell populations and on humoral immune responses were studied in patients with advanced melanoma from 2 phase II trials. Antibody levels against 5 tumor antigens were assessed at baseline and up to 12 weeks after ipilimumab treatment. Serologic reactivity to the cancer-testis antigen NY-ESO-1 increased by at least 5-fold at week 12 of treatment in 10% to 13% of patients. Increased antibody levels were also observed to the tumor antigens Melan-A, MAGE-A4, SSX2, and p53. Immunocompetence was evaluated with tetanus boosters administered before ipilimumab and pneumococcal and influenza vaccines given 5 days after ipilimumab treatment. At week 7, most patients who received ipilimumab and vaccine showed greater humoral responses relative to baseline titers. For peripheral T-cell populations, statistically significant increases in the percent of activated (HLA-DR) CD4 and CD8 T cells with concomitant decreases in naive CD4 and CD8 T cells were observed after ipilimumab treatment. These changes were evident by week 4 of treatment. Increases were also observed in central memory, effector memory, and activated ICOS CD4 T cells, but not in ICOS CD8 T cells or in FoxP3 CD4 regulatory T cells. These results suggest that ipilimumab can enhance immune responses mediated by different T-cell populations, and humoral immunity, in melanoma patients.


Assuntos
Anticorpos Monoclonais/administração & dosagem , Melanoma/tratamento farmacológico , Melanoma/imunologia , Neoplasias Cutâneas/tratamento farmacológico , Neoplasias Cutâneas/imunologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais/efeitos adversos , Antígenos de Neoplasias/imunologia , Linfócitos T CD4-Positivos/efeitos dos fármacos , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/metabolismo , Linfócitos T CD4-Positivos/patologia , Linfócitos T CD8-Positivos/efeitos dos fármacos , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/metabolismo , Linfócitos T CD8-Positivos/patologia , Contagem de Células , Progressão da Doença , Feminino , Seguimentos , Antígenos HLA-DR/metabolismo , Humanos , Imunidade Humoral/efeitos dos fármacos , Imunocompetência/efeitos dos fármacos , Memória Imunológica/efeitos dos fármacos , Proteína Coestimuladora de Linfócitos T Induzíveis/metabolismo , Ipilimumab , Ativação Linfocitária/efeitos dos fármacos , Masculino , Melanoma/patologia , Melanoma/fisiopatologia , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Neoplasias Cutâneas/patologia , Neoplasias Cutâneas/fisiopatologia , Vacinas/administração & dosagem
15.
Cancer Immun ; 10: 11, 2010 Nov 24.
Artigo em Inglês | MEDLINE | ID: mdl-21090563

RESUMO

Blockade of cytotoxic T-lymphocyte antigen-4 (CTLA-4) by ipilimumab leads to immune-mediated tumor regression and immune-related adverse events (irAEs), including diarrhea and colitis. The current analyses were undertaken to promote an understanding of the underlying mechanism of action and to identify potential biomarkers that could help in the prediction and management of ipilimumab-induced gastrointestinal irAEs. Treatment-naïve or previously treated patients with unresectable stage III/IV melanoma (n = 115) received open-label ipilimumab (10 mg/kg every 3 weeks for four doses) and were randomized to receive concomitant blinded prophylactic oral budesonide (9 mg/d with gradual taper through week 16) or placebo. Outcome measures included histologic assessment of bowel biopsies and assessment of serologic markers of inflammatory bowel disease (IBD), fecal calprotectin levels, and polymorphisms in immune-related genes. Ipilimumab resulted in dysregulation of gastrointestinal mucosal immunity as evidenced by altered antibody levels to enteric flora, inflammatory cell infiltration into gastrointestinal mucosa, and increased fecal calprotectin associated with diarrhea and clinical evidence of colitis. The pattern of ipilimumab-induced antibody titers to microbial flora and the histologic features and location of the inflammation were distinct from classic IBD. Prophylactic budesonide did not prevent ipilimumab-induced bowel inflammation. Despite an observed association between colonic inflammation and grade 2 or higher diarrhea, no baseline biomarkers could reliably predict development of gastrointestinal toxicity. Although classic IBD and ipilimumab-related gastrointestinal toxicity are both immune mediated, the observed pattern of biomarkers suggests ipilimumab-related gastrointestinal toxicity may be a distinct clinicopathologic entity.


Assuntos
Anticorpos Monoclonais/efeitos adversos , Antígenos CD/imunologia , Budesonida/uso terapêutico , Melanoma/tratamento farmacológico , Melanoma/imunologia , Neoplasias Cutâneas/tratamento farmacológico , Neoplasias Cutâneas/imunologia , Anticorpos Monoclonais/uso terapêutico , Antígeno CTLA-4 , Colite/induzido quimicamente , Colite/imunologia , Diarreia/induzido quimicamente , Diarreia/imunologia , Humanos , Imunidade nas Mucosas/efeitos dos fármacos , Ipilimumab , Melanoma/patologia , Neoplasias Cutâneas/patologia
16.
Am Surg ; 76(6): 587-94, 2010 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-20583513

RESUMO

Multiple strategies have been used in an effort to increase the pool of organs for transplantation. Standardizing donor management has produced promising results. Donor management goals (DMGs) are now being used as end points of intensive care unit care during the prerecovery phase but no prospective results have been reported. Data from the United Network for Organ Sharing Region 11 were collected for successful achievement of eight common donor management goals (mean airway pressure [MAP], central venous pressure [CVP], pH, PaO2, sodium, glucose, single pressor use, and urine output) before organ recovery. Two time periods were studied with different panels of DMGs. The analysis identified the success rate of transplantation. Goals were stratified by their statistical correlation with the number of organs transplanted per donor (OTPD) in an effort to identify the most important parameter(s). Eight hundred five organ donors were studied with 2685 organs transplanted. DMGs were assessed through two phases of the study. Achieving DMGs rose from 18 to 66 per cent associated with significant improvement in OTPD (range, 2.96 to 3.45). The success of transplantation was primarily associated with limitations in vasopressor use and PaO2. Tight glucose control did affect the rate of pancreatic transplants. Thoracic organs were the most sensitive to DMGs with a 10- to 15-fold increase in lung transplantation when PaO2 rose above 100 mmHg. MAP, CVP, pH, sodium, and urine output had little effect on transplantation. Standardization of end points of donor management was associated with increased rates of transplantation. Surprisingly, not all standard goals are necessary for optimal organ use. The most significant parameters were the low use of vasopressor agents and oxygenation. Donor management strategies should strive to optimize these goals.


Assuntos
Transplante de Órgãos/estatística & dados numéricos , Obtenção de Tecidos e Órgãos/organização & administração , Protocolos Clínicos , Cuidados Críticos , Humanos , Transplante de Pulmão/estatística & dados numéricos , Análise Multivariada , Transplante de Órgãos/normas , Objetivos Organizacionais , Sudeste dos Estados Unidos , Doadores de Tecidos/estatística & dados numéricos
17.
Mol Cancer Ther ; 9(2): 369-78, 2010 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-20103604

RESUMO

Tumor angiogenesis is a complex and tightly regulated network mediated by various proangiogenic factors. The fibroblast growth factor (FGF) and vascular endothelial growth factor (VEGF) family of growth factors, and associated tyrosine kinase receptors have a major influence in tumor growth and dissemination and may work synergistically to promote angiogenesis. Brivanib alaninate is the orally active prodrug of brivanib, a selective dual inhibitor of FGF and VEGF signaling. Here, we show that brivanib demonstrates antitumor activity in a broad range of xenograft models over multiple dose levels and that brivanib alaninate shows dose-dependent efficacy equivalent to brivanib in L2987 human tumor xenografts. Brivanib alaninate (107 mg/kg) reduced tumor cell proliferation as determined by a 76% reduction in Ki-67 staining and reduced tumor vascular density as determined by a 76% reduction in anti-CD34 endothelial cell staining. Furthermore, Matrigel plug assays in athymic mice showed that brivanib alaninate inhibited angiogenesis driven by VEGF or basic FGF alone, or combined. Dynamic contrast-enhanced magnetic resonance imaging, used to assess the effects of brivanib alaninate on tumor microcirculation, showed a marked decrease in gadopentetate dimeglumine contrast agent uptake at 107 mg/kg dose, with a reduction in area under the plasma concentration-time curve from time 0 to 60 minutes at 24 and 48 hours of 54% and 64%, respectively. These results show that brivanib alaninate is an effective antitumor agent in preclinical models across a range of doses, and that efficacy is accompanied by changes in cellular and vascular activities.


Assuntos
Pirróis/farmacologia , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/metabolismo , Triazinas/farmacologia , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismo , Alanina/análogos & derivados , Animais , Antígenos CD34/biossíntese , Linhagem Celular Tumoral , Colágeno/química , Relação Dose-Resposta a Droga , Combinação de Medicamentos , Feminino , Humanos , Laminina/química , Camundongos , Camundongos Endogâmicos BALB C , Transplante de Neoplasias , Proteoglicanas/química , Transdução de Sinais , Fatores de Tempo
18.
J Nucl Med ; 50(10): 1646-54, 2009 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-19759105

RESUMO

UNLABELLED: (18)F-FDG PET is often used to monitor tumor response in multicenter oncology clinical trials. This study assessed the repeatability of several semiquantitative standardized uptake values (mean SUV [SUV(mean)], maximum SUV [SUV(max)], peak SUV [SUV(peak)], and the 3-dimensional isocontour at 70% of the maximum pixel value [SUV(70%)]) as measured by repeated baseline (18)F-FDG PET studies in a multicenter phase I oncology trial. METHODS: Double-baseline (18)F-FDG PET studies were acquired for 62 sequentially enrolled patients. Tumor metabolic activity was assessed by SUV(mean), SUV(max), SUV(peak), and SUV(70%). The effect on SUV repeatability of compliance with recommended image-acquisition guidelines and quality assurance (QA) standards was assessed. Summary statistics for absolute differences relative to the average of baseline values and repeatability analysis were performed for all patients and for a subgroup that passed QA, in both a multi- and a single-observer setting. Intrasubject precision of baseline measurements was assessed by repeatability coefficients, intrasubject coefficients of variation (CV), and confidence intervals on mean baseline differences for all SUV parameters. RESULTS: The mean differences between the 2 SUV baseline measurements were small, varying from -2.1% to 1.9%, and the 95% confidence intervals for these mean differences had a maximum half-width of about 5.6% across the SUV parameters assessed. For SUV(max), the intrasubject CV varied from 10.7% to 12.8% for the QA multi- and single-observer datasets and was 16% for the full dataset. The 95% repeatability coefficients ranged from -28.4% to 39.6% for the QA datasets and up to -34.3% to 52.3% for the full dataset. CONCLUSION: Repeatability results of double-baseline (18)F-FDG PET scans were similar for all SUV parameters assessed, for both the full and the QA datasets, in both the multi- and the single-observer settings. Centralized quality assurance and analysis of data improved intrasubject CV from 15.9% to 10.7% for averaged SUV(max). Thresholds for metabolic response in the multicenter multiobserver non-QA settings were -34% and 52% and in the range of -26% to 39% with centralized QA. These results support the use of (18)F-FDG PET for tumor assessment in multicenter oncology clinical trials.


Assuntos
Fluordesoxiglucose F18 , Neoplasias Gastrointestinais/diagnóstico por imagem , Neoplasias Gastrointestinais/patologia , Adulto , Idoso , Feminino , Fluordesoxiglucose F18/metabolismo , Neoplasias Gastrointestinais/metabolismo , Humanos , Masculino , Pessoa de Meia-Idade , Tomografia por Emissão de Pósitrons , Controle de Qualidade , Reprodutibilidade dos Testes , Projetos de Pesquisa
19.
J Clin Oncol ; 27(4): 526-34, 2009 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-19075286

RESUMO

PURPOSE: This phase II study evaluated the efficacy and safety of ixabepilone as neoadjuvant therapy for invasive breast cancer not amenable to breast conservation surgery. Gene expression studies were undertaken using genes that were identified as potentially associated with sensitivity/resistance to ixabepilone in prior preclinical investigations. PATIENTS AND METHODS: Patients with invasive breast cancer >or= 3 cm were eligible. Ixabepilone 40 mg/m(2) was administered as a 3-hour intravenous infusion on day 1 of a 21-day cycle for four or fewer cycles. RESULTS: One hundred sixty-one patients were treated. The overall complete pathologic response (pCR) rate was 18% in breast and 29% in estrogen receptor (ER) -negative patients. Gene expression data were available for 134 patients. ER gene expression (ER1) was inversely related to pCR in breast and had a positive predictive value (PPV) of 37% and negative predictive value (NPV) of 92%. A 10-gene penalized logistic regression (PLR) model developed from 200 genes predictive of ixabepilone sensitivity in preclinical experiments included ER and tau and had higher PPV (45%) and comparable NPV (89%) to ER1. Grade 3 to 4 adverse events (AEs) were reported for 32% of patients. Except for neutropenia and leukopenia, all grade 3 to 4 AEs occurred in

Assuntos
Adenocarcinoma/tratamento farmacológico , Antineoplásicos/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Epotilonas/uso terapêutico , Adenocarcinoma/genética , Adenocarcinoma/patologia , Adenocarcinoma/cirurgia , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Neoplasias da Mama/cirurgia , Resistencia a Medicamentos Antineoplásicos/genética , Epotilonas/administração & dosagem , Epotilonas/efeitos adversos , Feminino , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Humanos , Linfonodos/patologia , Terapia Neoadjuvante , Valor Preditivo dos Testes , RNA Mensageiro/análise , Receptores de Estrogênio/análise
20.
Drug Metab Dispos ; 36(7): 1357-64, 2008 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-18420784

RESUMO

SPRYCEL (dasatinib, BMS-354825; Bristol-Myers Squibb, Princeton, NJ), a multiple kinase inhibitor, is currently approved to treat chronic myelogenous leukemia and Philadelphia chromosome-positive acute lymphoblastic leukemia tumors in patients who are resistant or intolerant to imatinib mesylate (Gleevec; Novartis, Basel, Switzerland). After a 100-mg single p.o. dose of [(14)C]dasatinib to healthy volunteers, the radioactivity was rapidly absorbed (T(max) approximately 0.5 h). Both dasatinib and total radioactivity (TRA) plasma concentrations decreased rapidly with elimination half-life values of <4 h. Dasatinib was the major drug-related component in human plasma. At 2 h, dasatinib accounted for 25% of the TRA in plasma, suggesting that metabolites contributed significantly to the total drug-related component. There were many circulating metabolites detected that included hydroxylated metabolites (M20 and M24), an N-dealkylated metabolite (M4), an N-oxide (M5), an acid metabolite (M6), glucuronide conjugates (M8a,b), and products of further metabolism of these primary metabolites. Most of the administered radioactivity was eliminated in the feces (85%). Urine recovery accounted for <4% of the dose. Dasatinib accounted for <1 and 19% of the dose in urine and feces, respectively, suggesting that dasatinib was well absorbed after p.o. administration and extensively metabolized before being eliminated from the body. The exposures of pharmacologically active metabolites M4, M5, M6, M20, and M24 in patients, along with their cell-based IC(50) for Src and Bcr-Abl kinase inhibition, suggested that these metabolites were not expected to contribute significantly toward in vivo activity.


Assuntos
Antineoplásicos/farmacocinética , Inibidores de Proteínas Quinases/farmacocinética , Pirimidinas/farmacocinética , Tiazóis/farmacocinética , Administração Oral , Antineoplásicos/administração & dosagem , Antineoplásicos/sangue , Antineoplásicos/urina , Dasatinibe , Humanos , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/sangue , Inibidores de Proteínas Quinases/urina , Pirimidinas/administração & dosagem , Pirimidinas/sangue , Pirimidinas/urina , Tiazóis/administração & dosagem , Tiazóis/sangue , Tiazóis/urina
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