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The ability to sense prey-derived cues is essential for predatory lifestyles. Under low-nutrient conditions, Arthrobotrys oligospora and other nematode-trapping fungi develop dedicated structures for nematode capture when exposed to nematode-derived cues, including a conserved family of pheromones, the ascarosides. A. oligospora senses ascarosides via conserved MAPK and cAMP-PKA pathways; however, the upstream receptors remain unknown. Here, using genomic, transcriptomic and functional analyses, we identified two families of G protein-coupled receptors (GPCRs) involved in sensing distinct nematode-derived cues. GPCRs homologous to yeast glucose receptors are required for ascaroside sensing, whereas Pth11-like GPCRs contribute to ascaroside-independent nematode sensing. Both GPCR classes activate conserved cAMP-PKA signalling to trigger trap development. This work demonstrates that predatory fungi use multiple GPCRs to sense several distinct nematode-derived cues for prey recognition and to enable a switch to a predatory lifestyle. Identification of these receptors reveals the molecular mechanisms of cross-kingdom communication via conserved pheromones also sensed by plants and animals.
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Ascomicetos , Feromônios , Receptores Acoplados a Proteínas G , Animais , Receptores Acoplados a Proteínas G/metabolismo , Receptores Acoplados a Proteínas G/genética , Ascomicetos/metabolismo , Ascomicetos/genética , Ascomicetos/fisiologia , Feromônios/metabolismo , Nematoides/microbiologia , Proteínas Fúngicas/metabolismo , Proteínas Fúngicas/genética , Transdução de Sinais , Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , Proteínas Quinases Dependentes de AMP Cíclico/genética , Caenorhabditis elegans/microbiologiaRESUMO
INTRODUCTION: Lung cancer is the leading cause of cancer mortality, comprising the largest national cancer disease burden in Australia and New Zealand. Regional reports identify substantial evidence-practice gaps, unwarranted variation from best practice, and variation in processes and outcomes of care between treating centres. The Australia and New Zealand Lung Cancer Registry (ANZLCR) will be developed as a Clinical Quality Registry to monitor the safety, quality and effectiveness of lung cancer care in Australia and New Zealand. METHODS AND ANALYSIS: Patient participants will include all adults >18 years of age with a new diagnosis of non-small-cell lung cancer (NSCLC), SCLC, thymoma or mesothelioma. The ANZLCR will register confirmed diagnoses using opt-out consent. Data will address key patient, disease, management processes and outcomes reported as clinical quality indicators. Electronic data collection facilitated by local data collectors and local, state and federal data linkage will enhance completeness and accuracy. Data will be stored and maintained in a secure web-based data platform overseen by registry management. Central governance with binational representation from consumers, patients and carers, governance, administration, health department, health policy bodies, university research and healthcare workers will provide project oversight. ETHICS AND DISSEMINATION: The ANZLCR has received national ethics approval under the National Mutual Acceptance scheme. Data will be routinely reported to participating sites describing performance against measures of agreed best practice and nationally to stakeholders including federal, state and territory departments of health. Local, regional and (bi)national benchmarks, augmented with online dashboard indicator reporting will enable local targeting of quality improvement efforts.
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Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Adulto , Austrália/epidemiologia , Carcinoma Pulmonar de Células não Pequenas/epidemiologia , Carcinoma Pulmonar de Células não Pequenas/terapia , Humanos , Neoplasias Pulmonares/epidemiologia , Neoplasias Pulmonares/terapia , Nova Zelândia/epidemiologia , Sistema de RegistrosRESUMO
Approximately 1-2% of unselected patients with Non-small Cell Lung Cancer (NSCLC) harbor RET rearrangements resulting in enhanced cell survival and proliferation. The initial treatment strategy for RET rearranged NSCLC has been multi-target tyrosine kinase inhibition. With overall response rates (ORR) of 16-53% and a median progression-free survival (PFS) of 4.5-7.3 months these outcomes are clearly inferior to the efficacy outcomes of selective tyrosine kinase inhibitors (TKI) in other oncogene-addicted NSCLC. Additionally, multi-kinase inhibition in RET-driven NSCLC patients showed concerning rates of high-grade toxicity, mainly induced by anti-VEGFR-kinase activity. Novel selective RET inhibitors like BLU-667, LOXO-292 and RXDX-105 have been recently investigated in early phase clinical trials showing promising efficacy with a manageable toxicity profile.
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Despite the highly immunogenic potential of small cell lung cancer (SCLC), progress in evaluating the therapeutic value of immune checkpoint agents has lagged behind that of non-small cell lung cancer. Results from a number of phase I-III clinical trials that specifically address the use of anti-PD-1, anti-PD-L1 and anti-CTLA-4 agents in SCLC have now been reported. This review will focus on the available evidence for immune checkpoint blockade in SCLC and review current biomarker strategies with the aim of providing perspective and interpretation of this data for clinical practice.
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Antineoplásicos Imunológicos/uso terapêutico , Antígeno B7-H1/antagonistas & inibidores , Antígeno CTLA-4/antagonistas & inibidores , Imunoterapia/métodos , Neoplasias Pulmonares/tratamento farmacológico , Carcinoma de Pequenas Células do Pulmão/tratamento farmacológico , Animais , Antígeno B7-H1/imunologia , Antígeno CTLA-4/imunologia , Humanos , Neoplasias Pulmonares/imunologia , Carcinoma de Pequenas Células do Pulmão/imunologiaRESUMO
Brain metastases are common events in the natural course of many advanced solid cancers like breast, lung and renal cancer or melanoma with a cumulative risk of 10-30% in adults [1-3]. Non-small cell lung cancer (NSCLC) is associated with an increased risk for the development of brain metastases and the prognosis until recently has been poor except for some patients' subgroups and depending on the disease-specific GPA prognostic factors [4]. For patients receiving only best supportive care, average survival is about 3 months and it is assumed that through additional whole brain radiotherapy average survival may be improved up to 6-9 months in selected patients [5]. In recent years, complex treatment strategies for different solid tumors have been developed and this has impacted on the general management of brain metastases. Most of the studies on brain metastases have included different histological subtypes and therefore have made tumor- specific recommendations difficult. In this review, we discuss the current evidence on management of brain metastases and incorporate specific recent data on oncogenic-driven NSCLC in order to suggest recommendations on the optimal management of brain metastases in this subgroup of NSCLC where formal level I evidence is lacking.
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Neoplasias Encefálicas/terapia , Carcinoma Pulmonar de Células não Pequenas/terapia , Neoplasias Pulmonares/terapia , Animais , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/secundário , Carcinogênese , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/secundário , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Oncogenes/genética , Fenótipo , Prognóstico , RadiocirurgiaRESUMO
Immune checkpoint blockade has been a pivotal development in the management of advanced non-small-cell lung cancer (NSCLC). Although durable antitumour activity and improved survival have been observed in a subset of patients, there is a need for additional predictive biomarkers to improve patient selection and avoid toxicity in potential non-responders. This review will address the use and limitations of tumour programmed death-ligand 1 expression as a predictive biomarker and review emerging biomarker strategies specifically related to NSCLC including genetic alterations (tumour mutation burden, loss and gain activated mutations), tumour-related factors (tumour microenvironment) and factors related to the host immune system. Novel approaches in biomarker detection such as peripheral blood monitoring will also be reviewed.
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Antineoplásicos Imunológicos/uso terapêutico , Antígeno B7-H1/antagonistas & inibidores , Biomarcadores Tumorais/antagonistas & inibidores , Biomarcadores Tumorais/genética , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Antineoplásicos Imunológicos/efeitos adversos , Antígeno B7-H1/imunologia , Biomarcadores Tumorais/imunologia , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/imunologia , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/mortalidade , Mutação , Valor Preditivo dos Testes , Receptor de Morte Celular Programada 1/imunologia , Medição de Risco , Fatores de Risco , Transdução de Sinais , Transcriptoma , Resultado do Tratamento , Microambiente TumoralRESUMO
Lung cancer is predominantly a disease of the elderly. This subgroup of patients poses many challenges and an appropriate geriatric assessment is crucial for treatment personalisation in order to reduce the risk of over- or under-treatment. Whilst cytotoxic chemotherapy has been the backbone of advanced non-small cell lung cancer (NSCLC) treatment for decades, the development of targeted agents for driver mutations such as EGFR, ALK, BRAF and ROS1 has changed the treatment paradigm and natural history of this disease. More recently, the development of immune checkpoint inhibitors has revolutionised treatment for a larger group of patients with locally advanced/metastatic disease. Limited data exist on safety and efficacy of these agents in the elderly population. Many questions remain regarding the available evidence for targeted therapies and immune checkpoint blockade in NSCLC and, in particular, their role in this subgroup of patients.
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Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Imunoterapia/métodos , Neoplasias Pulmonares/tratamento farmacológico , Terapia de Alvo Molecular/métodos , Fatores Etários , Idoso , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/imunologia , Humanos , Imunoterapia/efeitos adversos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/imunologia , Terapia de Alvo Molecular/efeitos adversos , SegurançaRESUMO
Immune checkpoint blockade has shown anti-tumour activity and improved survival in advanced non-small cell lung cancer (NSCLC). A number of anti-PD-1/PD-L1 and CTLA-4 monoclonal antibody agents have been evaluated in metastatic non-small cell lung cancer. Nivolumab, pembrolizumab and atezolizumab are currently approved for use in clinical practice due to demonstrated improvement in response rate, overall survival (OS) and quality of life (QoL) over standard chemotherapy. We present a series of cases that highlight the clinical challenges that these novel agents present. A review of rare immune-related adverse events (AEs), optimal treatment duration and patient selection will be presented. This series will also address real-life clinical scenarios such as treatment re-challenge and management of immune-related AEs.
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BACKGROUND: Advanced biliary tract cancers (BTCs) have a poor prognosis and limited treatment options. This exploratory phase II study aimed to evaluate the activity of the mTOR inhibitor everolimus in advanced BTC and explore prognostic biomarkers. METHODS: Patients with advanced BTCs, who had not received chemotherapy for advanced disease, were enroled to receive everolimus (10 mg daily). The primary endpoint was disease control rate (DCR) at 12 weeks. Secondary endpoints included overall response rate, progression-free survival (PFS), overall survival (OS) and adverse events. Activation status of the RAS and phosphatidylinositol 3-kinase (PI3K)/AKT/mTOR pathways was assessed by DNA sequencing and immunohistochemistry on archival tumour tissue. RESULTS: The study enroled 27 patients and the DCR at 12 weeks was 48%. Median PFS was 5.5 months (95% confidence interval (CI): 2.1-10.0 months) and median OS was 9.5 months (95% CI: 5.5-16.6 months). DCR at 12 weeks was significantly worse for gall bladder carcinoma compared to other anatomical sites, and there was a trend towards a worsened PFS and OS. Treatment was well tolerated. KRAS (12%) and PIK3CA mutations (12%) were uncommon. Immunohistochemical staining for PI3K/AKT/mTOR pathways did not significantly correlate with outcome. CONCLUSION: In unselected patients, everolimus demonstrated clinical activity as first-line monotherapy in advanced BTC.
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Adenocarcinoma/tratamento farmacológico , Neoplasias do Sistema Biliar/tratamento farmacológico , Biomarcadores Tumorais/análise , Everolimo/uso terapêutico , Adenocarcinoma/mortalidade , Adenocarcinoma/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias do Sistema Biliar/mortalidade , Neoplasias do Sistema Biliar/patologia , Biomarcadores Tumorais/metabolismo , Progressão da Doença , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Terapia Neoadjuvante , Análise de SobrevidaRESUMO
INTRODUCTION: Small-cell lung cancer (SCLC) is a very aggressive disease characterized by a high response rate to first-line chemotherapy, but most patients relapse within 1 year with disappointing results to second-line treatments. Chemotherapy has reached a plateau of effectiveness and new therapeutic strategies are needed to change the natural history of SCLC. Areas covered: This review will focus on the current results and the future development of the therapeutic approaches for the treatment of SCLC. Expert commentary: Immunotherapy is becoming a new frontier for the management of SCLC with preliminary interesting results. To date, no targeted drugs have been approved for clinical practice but several novel agents are in an advanced stage of clinical development in SCLC.
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Antineoplásicos/administração & dosagem , Neoplasias Pulmonares/terapia , Carcinoma de Pequenas Células do Pulmão/terapia , Antineoplásicos/farmacologia , Desenho de Fármacos , Humanos , Imunoterapia/métodos , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/patologia , Terapia de Alvo Molecular , Carcinoma de Pequenas Células do Pulmão/imunologia , Carcinoma de Pequenas Células do Pulmão/patologiaRESUMO
BACKGROUND: Immune-mediated myocarditis is an uncommon adverse effect of immune checkpoint inhibition and is associated with a high rate of mortality. METHODS: In this reported case, a 64-year-old woman with right temporo-parietal glioblastoma IDH-WT was treated with nivolumab, temozolomide and radiation therapy on a clinical trial. She developed malignant arrhythmias secondary to histologically confirmed severe immune-mediated myocarditis. She was treated with equine anti-thymocyte globulin (ATGAM) due to development of malignant arrhythmias refractory to high-dose corticosteroids. RESULTS: This report describes the only case of immune-mediated myocarditis treated with ATGAM resulting in a favourable outcome. CONCLUSIONS: Use of ATGAM should be considered in cases of steroid-refractory immune-mediated myocarditis and administered in close consultation with a cardiac transplant team experienced in the use of this agent.
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Soro Antilinfocitário/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Encefálicas/terapia , Glioblastoma/terapia , Miocardite/induzido quimicamente , Miocardite/terapia , Animais , Anticorpos Monoclonais/administração & dosagem , Anticorpos Monoclonais/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Quimiorradioterapia , Dacarbazina/administração & dosagem , Dacarbazina/análogos & derivados , Feminino , Cavalos , Humanos , Pessoa de Meia-Idade , Miocardite/imunologia , Nivolumabe , TemozolomidaRESUMO
BACKGROUND: Recent data has created uncertainty regarding the benefit of adjuvant fluoropyrimidine-containing chemotherapy following preoperative chemoradiotherapy and surgical resection for locally advanced rectal cancer (LARC). In particular, patients with a pathologic complete response (pCR) may derive no benefit from adjuvant chemotherapy. PATIENTS AND METHODS: This is a retrospective analysis of patients with LARC, diagnosed between January 1, 2003 and December 31, 2014 at 3 Melbourne health services. Patients were identified from the Australian Comprehensive Cancer Outcomes and Research Database, where a defined data set is prospectively collected on consecutive patients. Patient demographics, pCR rates, postoperative treatment, recurrence, and survival were analyzed. RESULTS: A total of 717 patients with LARC were identified, of whom 555 (77%) had received preoperative long-course chemoradiation followed by surgery. Four hundred fifty-two of 555 patients (81%) subsequently received adjuvant fluoropyrimidine-based chemotherapy. At a median follow-up of 45.9 months, 95 (21%) patients in the adjuvant chemotherapy group and 20 (19%) in the surveillance group had relapsed. Five-year relapse-free survival was 77% in the adjuvant chemotherapy group and 71% in the surveillance group with no significant difference on univariate analysis (hazard ratio [HR], 0.93; 95% confidence interval [CI], 0.58-1.51; P = .780). No significant impact on relapse-free survival was seen for either pCR or non-pCR patients. Five-year overall survival (OS) was 85% in the adjuvant chemotherapy group and 74% in the surveillance group with a nonsignificant trend towards OS benefit (HR, 0.62; 95% CI, 0.37-1.05; P = .074). A significant OS benefit favoring adjuvant chemotherapy was seen in the non-pCR subset of patients (HR, 0.49; 95% CI, 0.28-0.86; P = .014). CONCLUSION: A high proportion of patients in this routine practice cohort received adjuvant chemotherapy following preoperative treatment and surgery for LARC. Adjuvant chemotherapy administration was associated with a significant improvement in 5-year OS only in the patients with a non-pCR.
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Adenocarcinoma/terapia , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Neoplasias Retais/terapia , Adenocarcinoma/patologia , Idoso , Austrália , Quimioterapia Adjuvante/métodos , Intervalo Livre de Doença , Feminino , Seguimentos , Humanos , Masculino , Recidiva Local de Neoplasia , Modelos de Riscos Proporcionais , Neoplasias Retais/patologia , Estudos Retrospectivos , Taxa de SobrevidaRESUMO
BACKGROUND: Surgical complications after resection for locally advanced rectal cancer may influence adjuvant treatment outcomes and survival. Few studies have examined this effect. OBJECTIVE: This study aimed to examine the impact of surgical complications on adjuvant therapy delivery and survival in patients with locally advanced rectal cancer treated with long-course chemoradiation followed by surgery. DESIGN: This is a retrospective analysis of a prospectively collected multicenter colorectal cancer database. SETTINGS: Data were collected from the Australian Comprehensive Cancer Outcomes and Research Database. PATIENTS: All patients who completed neoadjuvant chemoradiotherapy followed by surgery for locally advanced rectal cancer between January 2003 and December 2014 were selected. MAIN OUTCOME MEASURES: We examined the types and frequency of surgical complications and their impact on the delivery of adjuvant chemotherapy and survival. RESULTS: Data were available for 517 patients, of whom 147 (28%) had a surgical complication. Patients with a surgical complication were less likely to commence adjuvant chemotherapy (33% vs 66%; p = 0.0005) and more likely to have adjuvant treatment commencing more than 8 weeks from surgery (71.8% vs 21.2%; p = 0.004). Wound-related complications (p = 0.001), return to operating theater (p = 0.004), and readmission within 30 days (p = 0.02) had the most significant negative impact on the delivery of adjuvant chemotherapy. Surgical complications were significantly more likely in males (31.6% vs 20.8%, p = 0.003) and laparoscopic converted cases (47.8% vs 21.8%, p = 0.03). For the entire patient population, adjuvant chemotherapy compared with surveillance was not associated with an improved recurrence-free survival (HR, 1.06; p = 0.83) but was associated with an improved overall survival (HR, 0.53; p = 0.04). LIMITATIONS: This study was limited by its retrospective design. CONCLUSION: Surgical complications in patients having surgery following neoadjuvant chemoradiotherapy for locally advanced rectal cancer were associated with significantly reduced uptake and delays to receiving adjuvant therapy. Surgical complications, however, were not associated with either significantly reduced recurrence-free or overall survival. Adjuvant chemotherapy delivery was associated with improved overall survival.
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Adenocarcinoma , Quimiorradioterapia Adjuvante/métodos , Colectomia , Terapia Neoadjuvante/métodos , Complicações Pós-Operatórias , Neoplasias Retais , Adenocarcinoma/epidemiologia , Adenocarcinoma/patologia , Adenocarcinoma/terapia , Adulto , Idoso , Austrália/epidemiologia , Colectomia/efeitos adversos , Colectomia/métodos , Terapia Combinada/métodos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Invasividade Neoplásica , Estadiamento de Neoplasias , Complicações Pós-Operatórias/fisiopatologia , Complicações Pós-Operatórias/terapia , Neoplasias Retais/epidemiologia , Neoplasias Retais/patologia , Neoplasias Retais/terapia , Estudos Retrospectivos , Análise de Sobrevida , Resultado do Tratamento , Estados Unidos/epidemiologiaRESUMO
Targeted agents are an important therapeutic option in the treatment of metastatic colorectal cancer (mCRC). Panitumumab is a recombinant, fully humanized, immunoglobulin G2 monoclonal antibody that targets the epidermal growth factor receptor (EGFR) with efficacy in mCRC as monotherapy and in combination with chemotherapy. Kirsten rat sarcoma (KRAS) mutation status has emerged as an important biomarker to predict response to anti-EGFR therapy. Optimal timing for panitumumab use in the mCRC treatment algorithm has not been established. This review discusses the mechanism of action, predictive biomarkers, and role of panitumumab in the treatment of mCRC.