RESUMO
OBJECTIVE: Prior experience of an adverse event following immunisation is a known barrier to vaccination. Limited Australian data evaluating adverse event recurrence among children exists to inform clinical decisions. We aimed to assess adverse event following immunisation recurrence among children with prior adverse events and to evaluate if family history increased adverse event risk. METHODS: A prospective cohort study was conducted from March 3rd until August 18th, 2023. Children ≤ 16 years with prior adverse events following immunisation in themselves or family were recruited from specialist immunisation clinics at two quaternary paediatric hospitals. Adverse event outcomes were collected via surveys administered at presentation, three, and eight days post vaccination, and analysed by key characteristics and potential risk factors. RESULTS: Forty three of forty nine (43/49, 87.8 %) children enrolled received further vaccines. Of those who completed the follow up surveys, 50.0 % (16/32) reported an adverse event. Recurrence of prior adverse events occurred for 23.3 % (10/43, 95 % CI: 11.8 % - 38.6 %) of the cohort. Two of twelve (2/12, 16.7 %) participants with prior serious adverse events who received further vaccines reported a serious adverse event recurrence. No post review serious adverse events were observed in children with prior non serious adverse events. Neurological conditions were a risk factor for prior (neurological condition 3/3 versus no neurological condition 2/40, p < 0.001) and post review (neurological condition 2/3 versus no neurological condition 0/28, p = 0.006) post vaccination seizures. Family history had no relationship to post review adverse events (family history 5/8 versus no family history 11/23, p = 0.685). CONCLUSION: Revaccination is safe for the majority of children with a personal or family history of adverse event following immunisation.
Assuntos
Vacinação , Vacinas , Criança , Humanos , Austrália , Imunização Secundária , Estudos Prospectivos , Vacinação/efeitos adversos , Vacinas/efeitos adversos , AdolescenteRESUMO
BACKGROUND: Oncogenic fusion genes consisting of EML4 and anaplastic lymphoma kinase (ALK) are present in a subgroup of non-small-cell lung cancers, representing 2 to 7% of such tumors. We explored the therapeutic efficacy of inhibiting ALK in such tumors in an early-phase clinical trial of crizotinib (PF-02341066), an orally available small-molecule inhibitor of the ALK tyrosine kinase. METHODS: After screening tumor samples from approximately 1500 patients with non-small-cell lung cancer for the presence of ALK rearrangements, we identified 82 patients with advanced ALK-positive disease who were eligible for the clinical trial. Most of the patients had received previous treatment. These patients were enrolled in an expanded cohort study instituted after phase 1 dose escalation had established a recommended crizotinib dose of 250 mg twice daily in 28-day cycles. Patients were assessed for adverse events and response to therapy. RESULTS: Patients with ALK rearrangements tended to be younger than those without the rearrangements, and most of the patients had little or no exposure to tobacco and had adenocarcinomas. At a mean treatment duration of 6.4 months, the overall response rate was 57% (47 of 82 patients, with 46 confirmed partial responses and 1 confirmed complete response); 27 patients (33%) had stable disease. A total of 63 of 82 patients (77%) were continuing to receive crizotinib at the time of data cutoff, and the estimated probability of 6-month progression-free survival was 72%, with no median for the study reached. The drug resulted in grade 1 or 2 (mild) gastrointestinal side effects. CONCLUSIONS: The inhibition of ALK in lung tumors with the ALK rearrangement resulted in tumor shrinkage or stable disease in most patients. (Funded by Pfizer and others; ClinicalTrials.gov number, NCT00585195.).
Assuntos
Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Tirosina Quinases/antagonistas & inibidores , Pirazóis/uso terapêutico , Piridinas/uso terapêutico , Administração Oral , Adulto , Idoso , Quinase do Linfoma Anaplásico , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , Proteínas de Ciclo Celular/genética , Crizotinibe , Progressão da Doença , Feminino , Humanos , Hibridização in Situ Fluorescente , Estimativa de Kaplan-Meier , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Masculino , Proteínas Associadas aos Microtúbulos/genética , Pessoa de Meia-Idade , Mutação , Proteínas de Fusão Oncogênica/genética , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/efeitos adversos , Proteínas Tirosina Quinases/genética , Proteínas Proto-Oncogênicas c-met/antagonistas & inibidores , Pirazóis/administração & dosagem , Pirazóis/efeitos adversos , Piridinas/administração & dosagem , Piridinas/efeitos adversos , Receptores Proteína Tirosina Quinases , Receptores de Fatores de Crescimento/antagonistas & inibidores , Serina Endopeptidases/genéticaRESUMO
We report a case of a never-smoker female with non-small-cell lung cancer (NSCLC) who experienced a striking tumor response to combined low-dose radiation and the epidermal growth factor receptor inhibitor erlotinib, even though erlotinib alone was not effective in preventing tumor progression. Furthermore, the patient developed symptomatic pneumonitis, which is unusual for the small volume of lung that was exposed to a significant dose of radiation. This case demonstrates that combination therapy with radiation and erlotinib has the potential to significantly benefit a subset of patients with NSCLC in addition to those approximately 10% who have tumors which respond to erlotinib alone. It also highlights the potential risks of molecular targeted radiation therapy.
Assuntos
Antineoplásicos/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/terapia , Neoplasias Pulmonares/terapia , Quinazolinas/uso terapêutico , Pneumonite por Radiação/etiologia , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/patologia , Carcinoma Pulmonar de Células não Pequenas/radioterapia , Terapia Combinada , Cloridrato de Erlotinib , Feminino , Humanos , Pulmão/efeitos da radiação , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/radioterapia , Pessoa de Meia-Idade , Pneumonite por Radiação/patologia , Radioterapia/efeitos adversos , Resultado do TratamentoRESUMO
Illegal hunting (poaching) is a global threat to wildlife. Anti-poaching initiatives are making increasing use of technology, such as infrared thermography (IRT), to support traditional foot and vehicle patrols. To date, the effectiveness of IRT for poacher location has not been tested under field conditions, where thermal signatures are often complex. Here, we test the hypothesis that IRT will increase the distance over which a poacher hiding in African scrub bushveldt can be detected relative to a conventional flashlight. We also test whether any increase in effectiveness is related to the cost and complexity of the equipment by comparing comparatively expensive (22,000 USD) and relatively inexpensive (2000 USD) IRT devices. To test these hypotheses we employ a controlled, fully randomised, double-blind procedure to find a poacher in nocturnal field conditions in African bushveldt. Each of our 27 volunteer observers walked three times along a pathway using one detection technology on each pass in randomised order. They searched a prescribed search area of bushveldt within which the target was hiding. Hiding locations were pre-determined, randomised, and changed with each pass. Distances of first detection and positive detection were noted. All technologies could be used to detect the target. Average first detection distance for flashlight was 37.3 m, improving by 19.8 m to 57.1 m using LIRT and by a further 11.2m to 68.3m using HIRT. Although detection distances were significantly greater for both IRTs compared to flashlight, there was no significant difference between LIRT and HIRT. False detection rates were low and there was no significant association between technology and accuracy of detection. Although IRT technology should ideally be tested in the specific environment intended before significant investment is made, we conclude that IRT technology is promising for anti-poaching patrols and that for this purpose low cost IRT units are as effective as units ten times more expensive.
Assuntos
Computadores de Mão , Comportamento Criminoso , Espécies em Perigo de Extinção , Pradaria , Atividades Humanas , Termografia , Adulto , Animais , Animais Selvagens , Computadores de Mão/economia , Conservação dos Recursos Naturais/métodos , Análise Custo-Benefício , Método Duplo-Cego , Armas de Fogo , Humanos , Raios Infravermelhos , Masculino , Aplicativos Móveis/economia , Parques Recreativos , Distribuição Aleatória , África do Sul , Termografia/economia , Termografia/instrumentação , Termografia/métodosRESUMO
Targeted cancer therapy requires the rapid and accurate identification of genetic abnormalities predictive of therapeutic response. We sought to develop a high-throughput genotyping platform that would allow prospective patient selection to the best available therapies, and that could readily and inexpensively be adopted by most clinical laboratories. We developed a highly sensitive multiplexed clinical assay that performs very well with nucleic acid derived from formalin fixation and paraffin embedding (FFPE) tissue, and tests for 120 previously described mutations in 13 cancer genes. Genetic profiling of 250 primary tumours was consistent with the documented oncogene mutational spectrum and identified rare events in some cancer types. The assay is currently being used for clinical testing of tumour samples and contributing to cancer patient management. This work therefore establishes a platform for real-time targeted genotyping that can be widely adopted. We expect that efforts like this one will play an increasingly important role in cancer management.
Assuntos
Análise Mutacional de DNA/métodos , Mutação , Neoplasias/genética , Medicina de Precisão/métodos , Técnicas de Laboratório Clínico/métodos , Genótipo , Humanos , Neoplasias/terapia , Reação em Cadeia da Polimerase/métodosRESUMO
Copy number variants are a recently discovered source of large-scale genomic diversity present in all individuals. We capitalize on these inherent genomic differences, focusing on deletion polymorphisms, to develop informative fluorescence in situ hybridization probes with the ability to unequivocally distinguish between donor and recipient cells in situ. These probes are accurate, specific, highly polymorphic and, notably, can be used to assign genetic identity in situ in a completely gender-independent fashion. We anticipate that these polymorphic deletion probes will be useful in further understanding the dynamics of cellular chimerism after transplantation, including the details of chronic organ rejection, post-transplant lymphoproliferative disorder and graft-versus-host disease, and in optimizing future tissue engineering and pluripotent stem cell therapies.
Assuntos
Quimera/genética , Transplante de Medula Óssea , Feminino , Humanos , Imuno-Histoquímica , Hibridização in Situ Fluorescente , Cariotipagem , Masculino , Sondas Moleculares , Polimorfismo GenéticoRESUMO
Uterine tumor resembling ovarian sex cord tumor (UTROSCT) is a rare uterine neoplasm composed predominantly or exclusively of cells which resemble those seen in sex cord tumors of the ovary. Since its initial morphologic description, it has been unclear whether UTROSCT represents a variant within the spectrum of endometrial stromal tumors (ESTs), which may rarely exhibit areas of sex cord-like differentiation, or whether it is a distinct uterine neoplasm unrelated to ESTs. Recently, several studies have revealed a recurrent t(7;17) translocation resulting in a JAZF1-JJAZ1 gene fusion in over 60% of EST and its variants, including 2 out of 4 endometrial stromal tumors with sex cord-like elements (ESTSCLE). We examined UTROSCTs for evidence of the JAZF1-JJAZ1 gene fusion by fluorescence in situ hybridization and by reverse transcriptase polymerase chain reaction in 24 and 20 cases, respectively. The JAZF1-JJAZ1 gene fusion was not identified in any tumor by either method. Although we cannot entirely exclude that UTROSCT represents a variant of ESTSCLE which lacks this translocation, our findings suggest that UTROSCT does not share the genetic mechanism common to the majority of ESTs with or without sex cord-like differentiation, and therefore most likely represents a distinct neoplasm unrelated to ESTSCLE.
Assuntos
Proteínas de Neoplasias/genética , Tumores do Estroma Gonadal e dos Cordões Sexuais/genética , Fatores de Transcrição/genética , Neoplasias Uterinas/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Proteínas Correpressoras , Proteínas de Ligação a DNA , Feminino , Humanos , Hibridização in Situ Fluorescente , Pessoa de Meia-Idade , Neoplasias Ovarianas/patologia , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Tumores do Estroma Gonadal e dos Cordões Sexuais/patologia , Translocação Genética , Neoplasias Uterinas/patologiaRESUMO
PURPOSE: The anaplastic large cell kinase gene (ALK) is rearranged in approximately 5% of lung adenocarcinomas within the Asian population. We evaluated the incidence and the characteristics of ALK-rearranged lung adenocarcinomas within the western population and the optimal diagnostic modality to detect ALK rearrangements in routine clinical practice. EXPERIMENTAL DESIGN: We tested 358 lung adenocarcinomas from three institutions for ALK rearrangements by fluorescent in situ hybridization (FISH) and immunohistochemistry with and without tyramide amplification. The clinicopathologic characteristics of tumors with and without ALK rearrangements were compared. RESULTS: We identified 20 (5.6%) lung adenocarcinomas with ALK rearrangements within our cohort of western patients. ALK rearrangement was associated with younger age (P = 0.0002), never smoking (P < 0.0001), advanced clinical stage (P = 0.0001), and a solid histology with signet-ring cells (P < 0.0001). ALK rearrangement was identified by FISH in 95% of cases and immunohistochemistry with and without tyramide amplification in 80% and 40% of cases, respectively, but neither FISH nor immunohistochemistry alone detected all cases with ALK rearrangement on initial screening. None of the ALK-rearranged tumors harbored coexisting EGFR mutations. CONCLUSIONS: Lung adenocarcinomas with ALK rearrangements are uncommon in the western population and represent a distinct entity of carcinomas with unique characteristics. For suspected cases, dual diagnostic testing, with FISH and immunohistochemistry, should be considered to accurately identify lung adenocarcinomas with ALK rearrangement.
Assuntos
Adenocarcinoma/genética , Adenocarcinoma/patologia , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Proteínas Tirosina Quinases/genética , Adenocarcinoma/metabolismo , Adenocarcinoma/cirurgia , Adulto , Idoso , Idoso de 80 Anos ou mais , Quinase do Linfoma Anaplásico , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Carcinoma Pulmonar de Células não Pequenas/patologia , Carcinoma Pulmonar de Células não Pequenas/cirurgia , Análise Citogenética , Análise Mutacional de DNA , Feminino , Genética Populacional , Mutação em Linhagem Germinativa , Humanos , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/cirurgia , Masculino , Pessoa de Meia-Idade , Mutação/fisiologia , Proteínas Tirosina Quinases/metabolismo , Receptores Proteína Tirosina Quinases , OcidenteRESUMO
Platelet-derived growth factor (PDGF) receptors (PDGFR) and their ligands play critical roles in several human malignancies. Sunitinib is a clinically approved multitargeted tyrosine kinase inhibitor that inhibits vascular endothelial growth factor receptor, c-KIT, and PDGFR, and has shown clinical activity in various solid tumors. Activation of PDGFR signaling has been described in gastrointestinal stromal tumors (PDGFRA mutations) as well as in chronic myeloid leukemia (BCR-PDGFRA translocation), and sunitinib can yield clinical benefit in both settings. However, the discovery of PDGFR activating mutations or gene rearrangements in other tumor types could reveal additional patient populations who might benefit from treatment with anti-PDGFR therapies, such as sunitinib. Using a high-throughput cancer cell line screening platform, we found that only 2 of 637 tested human tumor-derived cell lines show significant sensitivity to single-agent sunitinib exposure. These two cell lines [a non-small-cell lung cancer (NSCLC) and a rhabdomyosarcoma] showed expression of highly phosphorylated PDGFRA. In the sunitinib-sensitive adenosquamous NSCLC cell line, PDGFRA expression was associated with focal PFGRA gene amplification, which was similarly detected in a small fraction of squamous cell NSCLC primary tumor specimens. Moreover, in this NSCLC cell line, focal amplification of the gene encoding the PDGFR ligand PDGFC was also detected, and silencing PDGFRA or PDGFC expression by RNA interference inhibited proliferation. A similar codependency on PDGFRA and PDGFC was observed in the sunitinib-sensitive rhabdomyosarcoma cell line. These findings suggest that, in addition to gastrointestinal stromal tumors, rare tumors that show PDGFC-mediated PDGFRA activation may also be clinically responsive to pharmacologic PDGFRA or PDGFC inhibition.
Assuntos
Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Indóis/farmacologia , Neoplasias Pulmonares/tratamento farmacológico , Pirróis/farmacologia , Receptor alfa de Fator de Crescimento Derivado de Plaquetas/metabolismo , Rabdomiossarcoma/tratamento farmacológico , Anticorpos/imunologia , Anticorpos/farmacologia , Carcinoma Pulmonar de Células não Pequenas/enzimologia , Carcinoma Pulmonar de Células não Pequenas/genética , Linhagem Celular Tumoral , Amplificação de Genes , Perfilação da Expressão Gênica , Humanos , Ligantes , Neoplasias Pulmonares/enzimologia , Neoplasias Pulmonares/genética , Linfocinas/genética , Linfocinas/imunologia , Fator de Crescimento Derivado de Plaquetas/genética , Fator de Crescimento Derivado de Plaquetas/imunologia , RNA Interferente Pequeno/genética , Receptor alfa de Fator de Crescimento Derivado de Plaquetas/antagonistas & inibidores , Receptor alfa de Fator de Crescimento Derivado de Plaquetas/genética , Rabdomiossarcoma/enzimologia , Rabdomiossarcoma/genética , SunitinibeRESUMO
PURPOSE: The EML4-ALK fusion oncogene represents a novel molecular target in a small subset of non-small-cell lung cancers (NSCLC). To aid in identification and treatment of these patients, we examined the clinical characteristics and treatment outcomes of patients who had NSCLC with and without EML4-ALK. PATIENTS AND METHODS: Patients with NSCLC were selected for genetic screening on the basis of two or more of the following characteristics: female sex, Asian ethnicity, never/light smoking history, and adenocarcinoma histology. EML4-ALK was identified by using fluorescent in situ hybridization for ALK rearrangements and was confirmed by immunohistochemistry for ALK expression. EGFR and KRAS mutations were determined by DNA sequencing. RESULTS: Of 141 tumors screened, 19 (13%) were EML4-ALK mutant, 31 (22%) were EGFR mutant, and 91 (65%) were wild type (WT/WT) for both ALK and EGFR. Compared with the EGFR mutant and WT/WT cohorts, patients with EML4-ALK mutant tumors were significantly younger (P < .001 and P = .005) and were more likely to be men (P = .036 and P = .039). Patients with EML4-ALK-positive tumors, like patients who harbored EGFR mutations, also were more likely to be never/light smokers compared with patients in the WT/WT cohort (P < .001). Eighteen of the 19 EML4-ALK tumors were adenocarcinomas, predominantly the signet ring cell subtype. Among patients with metastatic disease, EML4-ALK positivity was associated with resistance to EGFR tyrosine kinase inhibitors (TKIs). Patients in the EML4-ALK cohort and the WT/WT cohort showed similar response rates to platinum-based combination chemotherapy and no difference in overall survival. CONCLUSION: EML4-ALK defines a molecular subset of NSCLC with distinct clinical characteristics. Patients who harbor this mutation do not benefit from EGFR TKIs and should be directed to trials of ALK-targeted agents.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Proteínas de Fusão Oncogênica/genética , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Quinase do Linfoma Anaplásico , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , Receptores ErbB/genética , Cloridrato de Erlotinib , Feminino , Gefitinibe , Genes ras/genética , Genótipo , Humanos , Imuno-Histoquímica , Hibridização in Situ Fluorescente , Estimativa de Kaplan-Meier , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Mutação , Proteínas de Fusão Oncogênica/metabolismo , Inibidores de Proteínas Quinases/administração & dosagem , Proteínas Tirosina Quinases/genética , Proteínas Tirosina Quinases/metabolismo , Quinazolinas/administração & dosagem , Receptores Proteína Tirosina Quinases , Fatores Sexuais , Resultado do TratamentoRESUMO
Activating BRAF kinase mutations arise in approximately 7% of all human tumors, and preclinical studies have validated the RAF-mitogen-activated protein/extracellular signal-regulated kinase (ERK) kinase-ERK signaling cascade as a potentially important therapeutic target in this setting. Selective RAF kinase inhibitors are currently undergoing clinical development, and based on the experience with other kinase-targeted therapeutics, it is expected that clinical responses to these agents, if observed, will lead to the eventual emergence of drug resistance in most cases. Thus, it is important to establish molecular mechanisms underlying such resistance to develop effective therapeutic strategies to overcome or prevent drug resistance. To anticipate potential mechanisms of acquired resistance to RAF inhibitors during the course of treatment, we established drug-resistant clones from a human melanoma-derived cell line harboring the recurrent V600E activating BRAF mutation, which exhibits exquisite sensitivity to AZ628, a selective RAF kinase inhibitor. We determined that elevated CRAF protein levels account for the acquisition of resistance to AZ628 in these cells, associated with a switch from BRAF to CRAF dependency in tumor cells. We also found that elevated CRAF protein levels may similarly contribute to primary insensitivity to RAF inhibition in a subset of BRAF mutant tumor cells. Interestingly, AZ628-resistant cells demonstrating either primary drug insensitivity or acquired drug resistance exhibit exquisite sensitivity to the HSP90 inhibitor geldanamycin. Geldanamycin effectively promotes the degradation of CRAF, thereby revealing a potential therapeutic strategy to overcome resistance to RAF inhibition in a subset of BRAF mutant tumors.