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1.
J Neurooncol ; 159(3): 539-549, 2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-35933567

RESUMO

PURPOSE: Limited progress has been made in treating glioblastoma, and we hypothesise that poor concordance between preclinical and clinical efficacy in this disease is a major barrier to drug development. We undertook a systematic review to quantify this issue. METHODS: We identified phase I trials (P1Ts) of tumor targeted drugs, subsequent trial results and preceding relevant preclinical data published in adult glioblastoma patients between 2006-2019 via structured searches of EMBASE/MEDLINE/PUBMED. Detailed clinical/preclinical information was extracted. Associations between preclinical and clinical efficacy metrics were determined using appropriate non-parametric statistical tests. RESULTS: A total of 28 eligible P1Ts were identified, with median ORR of 2.9% (range 0.0-33.3%). Twenty-three (82%) had published relevant preclinical data available. Five (18%) had relevant later phase clinical trial data available. There was overall poor correlation between preclinical and clinical efficacy metrics on univariate testing. However, drugs that had undergone in vivo testing had significantly longer median overall survival (7.9 vs 5.6mo, p = 0.02). Additionally, drugs tested in ≥ 2 biologically-distinct in vivo models ('multiple models') had a significantly better median response rate than those tested using only one ('single model') or those lacking in vivo data (6.8% vs 1.2% vs. 0.0% respectively, p = 0.027). CONCLUSION: Currently used preclinical models poorly predict subsequent activity in P1Ts, and generally over-estimate the anti-tumor activity of these drugs. This underscores the need for better preclinical models to aid the development of novel anti-glioblastoma drugs. Until these become widely available and used, the use of multiple biologically-distinct in vivo models should be strongly encouraged.


Assuntos
Glioblastoma , Adulto , Glioblastoma/terapia , Humanos
2.
Molecules ; 25(20)2020 Oct 16.
Artigo em Inglês | MEDLINE | ID: mdl-33081383

RESUMO

Antibody-drug conjugates (ADCs) are novel drugs that exploit the specificity of a monoclonal antibody (mAb) to reach target antigens expressed on cancer cells for the delivery of a potent cytotoxic payload. ADCs provide a unique opportunity to deliver drugs to tumor cells while minimizing toxicity to normal tissue, achieving wider therapeutic windows and enhanced pharmacokinetic/pharmacodynamic properties. To date, nine ADCs have been approved by the FDA and more than 80 ADCs are under clinical development worldwide. In this paper, we provide an overview of the biology and chemistry of each component of ADC design. We briefly discuss the clinical experience with approved ADCs and the various pathways involved in ADC resistance. We conclude with perspectives about the future development of the next generations of ADCs, including the role of molecular imaging in drug development.


Assuntos
Anticorpos Monoclonais/uso terapêutico , Antineoplásicos/uso terapêutico , Imunoconjugados/uso terapêutico , Neoplasias/tratamento farmacológico , Anticorpos Monoclonais/imunologia , Antineoplásicos/imunologia , Proliferação de Células/efeitos dos fármacos , Humanos , Imunoconjugados/imunologia , Neoplasias/imunologia
3.
Oncologist ; 23(9): 1063-1075, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-29703764

RESUMO

Primary and metastatic tumors of the central nervous system present a difficult clinical challenge, and they are a common cause of disease progression and death. For most patients, treatment consists primarily of surgery and/or radiotherapy. In recent years, systemic therapies have become available or are under investigation for patients whose tumors are driven by specific genetic alterations, and some of these targeted treatments have been associated with dramatic improvements in extracranial and intracranial disease control and survival. However, the success of other systemic therapies has been hindered by inadequate penetration of the drug into the brain parenchyma. Advances in molecular characterization of oncogenic drivers have led to the identification of new gene fusions driving oncogenesis in some of the most common sources of intracranial tumors. Systemic therapies targeting many of these alterations have been approved recently or are in clinical development, and the ability to penetrate the blood-brain barrier is now widely recognized as an important property of such drugs. We review this rapidly advancing field with a focus on recently uncovered gene fusions and brain-penetrant systemic therapies targeting them. IMPLICATIONS FOR PRACTICE: Driver gene fusions involving receptor tyrosine kinases have been identified across a wide range of tumor types, including primary central nervous system (CNS) tumors and extracranial solid tumors that are associated with high rates of metastasis to the CNS (e.g., lung, breast, melanoma). This review discusses the systemic therapies that target emerging gene fusions, with a focus on brain-penetrant agents that will target the intracranial disease and, where present, also extracranial disease.


Assuntos
Neoplasias do Sistema Nervoso Central/genética , Fusão Gênica/genética , Neoplasias do Sistema Nervoso Central/patologia , Neoplasias do Sistema Nervoso Central/terapia , Humanos , Metástase Neoplásica
5.
Intern Med J ; 47(3): 284-290, 2017 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-27860085

RESUMO

BACKGROUND: Neuroendocrine tumours (NET) arise from neuroendocrine cells, which are widely distributed throughout the body. However, diagnosing NET is difficult due to nonspecific symptoms and the paucity of experience among health professionals. This retrospective study was carried out to improve our understanding about NET. This knowledge can be used for optimal utilisation and distribution of limited resources. AIM: To study the clinical profile, treatment and survival outcomes for advanced NET patients in Australian regional and remote settings. METHODS: We reviewed all adult patients who were diagnosed with NET between 1994 and 2012. Patients' data were extracted from electronic databases of The Townsville Cancer Centre. Remoteness was based on postcodes, with patients stratified as regional or rural North Queensland according to Australian Standard Geographical Classification (ASGC). Overall survival was studied using survival analysis. RESULTS: Data from 79 patients were included in the study. The median age at diagnosis was 60 years. A total of 48 patients (60.8%) was male and 31 (39.2%) female. The majority of the patients lived in rural areas (51, 64%) as compared to residing in regional areas (28, 36%). There were 34 deaths at the study cut-off point. Median overall survival of NET patients in rural areas is significantly less than those living in regional areas (1613 days vs. 2935 days, respectively), P = 0.03. CONCLUSION: Remoteness has an adverse impact on overall survival of NET patients. This outcome may be because of varied access to health services and/or lack of access to specialised scans and medical and surgical expertise.


Assuntos
Diagnóstico Tardio/estatística & dados numéricos , Acessibilidade aos Serviços de Saúde/organização & administração , Necessidades e Demandas de Serviços de Saúde/organização & administração , Disparidades em Assistência à Saúde/estatística & dados numéricos , Tumores Neuroendócrinos/terapia , Serviços de Saúde Rural/organização & administração , Idoso , Feminino , Acessibilidade aos Serviços de Saúde/estatística & dados numéricos , Humanos , Masculino , Pessoa de Meia-Idade , Tumores Neuroendócrinos/diagnóstico , Tumores Neuroendócrinos/mortalidade , Queensland/epidemiologia , Estudos Retrospectivos , Fatores de Risco , População Rural , Análise de Sobrevida , Resultado do Tratamento
6.
Chin Clin Oncol ; 13(3): 40, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38769795

RESUMO

BACKGROUND AND OBJECTIVE: Palliative radiotherapy (RT) and systemic immuno- or targeted therapy both play significant roles in the treatment of advanced hepatocellular carcinoma (HCC). Concurrent application of these therapies is increasing, however, no guidelines exist regarding the combination of systemic therapy with RT. This narrative review summarises the existing literature reporting toxicity observed after concurrent treatment with RT and immuno- or targeted therapeutic agents commonly used in HCC. METHODS: The PubMed database was searched for studies published between 2011 and 2023 reporting toxicity data on patients treated concurrently with RT and targeted agents used in HCC. Due to the paucity of relevant literature in HCC, the inclusion criteria were expanded to include non-HCC cohorts treated with targeted therapies commonly used in advanced HCC. KEY CONTENT AND FINDINGS: Sixty-seven articles were included in this review. Twenty-two articles reported combined RT with sorafenib, one with regorafenib, 22 with bevacizumab, three with lenvatinib and 19 with immune checkpoint inhibitors. Significant findings include a high rate severe hepatotoxicity with combination RT and sorafenib, ranging from 0-19% with liver stereotactic body radiotherapy (SBRT) and 3-18% with conventionally fractionated liver RT. Severe gastrointestinal (GI) toxicities including perforation and ulceration were seen with combination bevacizumab and RT, ranging from 0-27% in the acute setting and 0-23% in the late setting. The safety profile of combination immune checkpoint blockade agents and RT was similar to that seen in monotherapy. CONCLUSIONS: Existing data suggests that combination RT and targeted therapy given the risk of severe adverse events including hepatotoxicity and GI toxicity. There is an urgent need for future studies specifically examining the impact of combination therapy in HCC patients to guide clinical decision-making in the evolving landscape of immune- and targeted therapies.


Assuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , Humanos , Carcinoma Hepatocelular/radioterapia , Carcinoma Hepatocelular/tratamento farmacológico , Neoplasias Hepáticas/radioterapia , Terapia de Alvo Molecular/métodos
7.
Case Rep Endocrinol ; 2023: 8801080, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-38116541

RESUMO

Thymic carcinoid tumours, especially in the context of multiple endocrine neoplasia type 1 (MEN 1), present significant clinical challenges due to their rarity and aggressive nature. This case report describes a complex patient with MEN 1, who suffered from multiple manifestations of the disease, including thymic carcinoid. The tumour was initially resected and treated with adjuvant radiotherapy. Due to slow progression over the years, the tumour was treated with two lines of chemotherapy before the patient succumbed to progressive disease. There is currently limited evidence favoring any specific medical treatment for thymic carcinoid.

8.
Expert Opin Biol Ther ; 23(11): 1089-1102, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37955063

RESUMO

INTRODUCTION: Antibody drug conjugates (ADCs) are now a proven therapeutic class for many cancers, combining highly specific targeting with the potency of high effective payloads. This review summarizes the experience with ADCs in brain tumors and examines future paths for their use in these tumors. AREAS COVERED: This review will cover all the key classes of ADCs which have been tested in primary brain tumors, including commentary on the major trials to date. The efficacy of these trials, as well as their limitations, will put in context of the overall landscape of drug development in brain tumors. Importantly, this review will summarize key learnings and insights from these trials that help provide the basis for rational ways in which these drugs can be effectively and appropriate developed for patients with primary brain tumors. EXPERT OPINION: ADC development in brain tumors has occurred in two major phases to date. Key learnings from previous trials provide a strong rationale for the continued development of these drugs for primary brain tumors. However, the unique biology of these tumors requires development strategies specifically tailored to maximize their optimal development.


Assuntos
Antineoplásicos , Neoplasias Encefálicas , Glioblastoma , Imunoconjugados , Humanos , Imunoconjugados/uso terapêutico , Glioblastoma/tratamento farmacológico , Neoplasias Encefálicas/tratamento farmacológico , Desenvolvimento de Medicamentos , Antineoplásicos/efeitos adversos
9.
Neurooncol Adv ; 3(1): vdaa171, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33543145

RESUMO

BACKGROUND: Improving outcomes of patients with glioblastoma (GBM) represents a significant challenge in neuro-oncology. We undertook a systematic review of key parameters of phase II and III trials in GBM to identify and quantify the impact of trial design on this phenomenon. METHODS: Studies between 2005 and 2019 inclusive were identified though MEDLINE search and manual bibliography searches. Phase II studies (P2T) were restricted to those referenced by the corresponding phase III trials (P3T). Clinical and statistical characteristics were extracted. For each P3T, corresponding P2T data was "optimally matched," where same drug was used in similar schedule and similar population; "suboptimally matched" if dis-similar schedule and/or treatment setting; or "lacking." Phase II/III transition data were compared by Pearson Correlation, Fisher's exact or chi-square testing. RESULTS: Of 20 P3Ts identified, 6 (30%) lacked phase II data. Of the remaining 14 P3T, 9 had 1 prior P2T, 4 had 2 P2T, and 1 had 3 P2T, for a total of 20 P3T-P2T pairs (called dyads). The 13 "optimally matched" dyads showed strong concordance for mPFS (r 2 = 0.95, P < .01) and mOS (r 2 = 0.84, P < .01), while 7 "suboptimally matched" dyads did not (P > .05). Overall, 7 P3Ts underwent an ideal transition from P2T to P3T. "Newly diagnosed" P2Ts with mPFS < 14 months and/or mOS< 22 months had subsequent negative P3Ts. "Recurrent" P2Ts with mPFS < 6 months and mOS< 12 months also had negative P3Ts. CONCLUSION: Our findings highlight the critical role of optimally designed phase II trials in informing drug development for GBM.

10.
Expert Rev Anticancer Ther ; 20(12): 1057-1074, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-32981377

RESUMO

INTRODUCTION: The importance of ErbB3 receptor tyrosine kinase in cancer progression, primary and acquired drug resistance, has become steadily evident since its discovery in 1989. ErbB3 overexpression in various solid organ malignancies is associated with shorter survival of patients. However, initial strategies to therapeutically target ErbB3 have not been rewarding. AREAS COVERED: Here, we provide an overview of ErbB3 biology in carcinogenesis. We outline the role of ErbB3 as a critical pathway for resistance to other anti-cancer drugs. We focus on emerging clinical data, which will steer the potential future development of ErbB3 directed therapies. EXPERT OPINION: Initial approaches to ErbB3 targeting have been challenging. However, the lack of success of anti-ErbB3 therapies in ongoing clinical trials may relate more to the complex biology of the receptor and challenges with the biomarkers used to date. Furthermore, it seems certain that the expression of the receptor per se is necessary but not sufficient for the response to ErbB3 therapies. Emerging data suggest that more sophisticated biomarkers are needed. Nonetheless, it is also likely that ErbB3 therapies may have the most efficacy in combination therapy, and their favorable toxicity profile makes this feasible.


Assuntos
Terapia de Alvo Molecular , Neoplasias/tratamento farmacológico , Receptor ErbB-3/metabolismo , Animais , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Antineoplásicos/farmacologia , Biomarcadores Tumorais/metabolismo , Progressão da Doença , Desenvolvimento de Medicamentos , Resistencia a Medicamentos Antineoplásicos , Humanos , Neoplasias/patologia
11.
Neurooncol Adv ; 1(1): vdz013, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-32642651

RESUMO

Glioblastoma (GBM) is the most common primary brain neoplasm with median overall survival (OS) around 15 months. There is a dearth of effective monitoring strategies for patients with high-grade gliomas. Relying on magnetic resonance images of brain has its challenges, and repeated brain biopsies add significant morbidity. Hence, it is imperative to establish a less invasive way to diagnose, monitor, and guide management of patients with high-grade gliomas. Currently, multiple biomarkers are in various phases of development and include tissue, serum, cerebrospinal fluid (CSF), and imaging biomarkers. Here we review and summarize the potential biomarkers found in blood and CSF, including extracellular macromolecules, extracellular vesicles, circulating tumor cells, immune cells, endothelial cells, and endothelial progenitor cells. The ability to detect tumor-specific biomarkers in blood and CSF will potentially not only reduce the need for repeated brain biopsies but also provide valuable information about the heterogeneity of tumor, response to current treatment, and identify disease resistance. This review also details the status and potential scope of brain tumor-related cranial devices and implants including Ommaya reservoir, microelectromechanical systems-based depot device, Alzet mini-osmotic pump, Metronomic Biofeedback Pump (MBP), ipsum G1 implant, ultra-thin needle implant, and putative devices. An ideal smart cranial implant will overcome the blood-brain barrier, deliver various drugs, provide access to brain tissue, and potentially measure and monitor levels of various biomarkers.

12.
J Clin Neurosci ; 68: 45-50, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31371189

RESUMO

There is limited information on the patterns of care and outcomes of high grade gliomas (HGGs) in young adults, in particular, the impact it has on a person's employment. We retrospectively identified young adult patients (age ≤ 40 years old) with newly diagnosed high grade gliomas treated between January 2013 and June 2018 across four major neuro-oncology centres in Australia. Patient demographics, tumour characteristics and treatment parameters were collected and outcomes determined. A total of 113 patients were identified with a median follow up of 27.0 months (range 1.0-70.2 months). The median age was 31 years, majority were male (65%) and employed (71.6%). IDH mutations were detected in 66 (62%) cases. The median progression-free survival (PFS) was 38.0 months (95% CI 23.3-52.7 months) and median overall survival (OS) was not reached. Patients with IDH wild type anaplastic astrocytoma and glioblastoma had a significantly shorter median PFS (19.3 months vs. NR, p = 0.001) and median OS (43.5 months vs NR, p = 0.007) than those with IDH mutated grade III anaplastic astrocytoma and oligodendroglioma. There was no significant difference in median OS or PFS between patients who underwent gross or subtotal tumour resection. Significantly, after diagnosis only 36 (32%) patients reported being employed. Young patients with IDH wild type astrocytomas and glioblastoma had better outcomes than reported historical controls. Most patients did not continue in employment post diagnosis.


Assuntos
Neoplasias Encefálicas , Emprego/estatística & dados numéricos , Glioma , Adolescente , Adulto , Austrália , Neoplasias Encefálicas/mortalidade , Neoplasias Encefálicas/patologia , Neoplasias Encefálicas/cirurgia , Feminino , Glioma/mortalidade , Glioma/patologia , Glioma/cirurgia , Humanos , Masculino , Intervalo Livre de Progressão , Estudos Retrospectivos , Resultado do Tratamento , Adulto Jovem
13.
Curr Opin Pharmacol ; 41: 114-121, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-29883853

RESUMO

Since Nobel laureate Paul Ehrlich proposed the concept of magic bullet in 1906, Köhler and Milstein discovered Hybridoma technology in 1975, and Greg Winter pioneered the technique to humanize monoclonal antibodies in 1988, monoclonal antibodies have been successfully developed to treat medical illnesses. Monoclonal antibodies are effective treatments for inhibition of alloimmune reactivity, haematological malignancies, solid organ malignancies, viral illnesses and are also used as antiplatelet therapy. Their successful use in cancer and autoimmune diseases in humans have made them one of the fastest growing classes of new drugs approved for these indications in last few decades. This review focuses on the role of monoclonal antibodies as an immunomodulatory therapy against cancer and autoimmune diseases, the strategies used to enhance efficacy, and how resistance mechanisms are being addressed to improve therapeutic outcomes for patients.


Assuntos
Anticorpos Monoclonais/uso terapêutico , Doenças Autoimunes/terapia , Imunomodulação , Neoplasias/terapia , Humanos
14.
Postgrad Med ; 122(4): 186-91, 2010 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-20675981

RESUMO

AIM: To explore elderly (aged > or = 75 years) patients' views regarding the use of multicompartment compliance aids (MCAs) and determine whether MCAs would prolong their length of hospital stay. METHODS: A cross-sectional, prospective study in 3 acute geriatric wards in a district general hospital in the United Kingdom. Patients admitted to the hospital who were found to be users of MCAs were interviewed about their perception of MCAs, and their length of hospital stay was monitored. RESULTS: A total of 1080 older patients were admitted over a 3-month period. Only 51 (4.7%) patients were users of MCAs and constituted the study group. The majority (51%) of MCAs were requested by general practitioners. Eight (16%) patients were asked whether they wished to use the MCAs and 3 (6%) had formal assessment prior to MCA start. On the patients' survey, 18 (35%) patients did not prefer the MCA if they were given the choice. This group of patients had better cognitive function assessed by the Mini-Mental State Examination (24.4 [3.6] vs 21.8 [3.6]; P = 0.02) and were less dependent on social services (39% vs 67%; P = 0.04) in comparison with patients who did prefer the MCA. They expressed a greater lack of autonomy (94% vs 52%; P = 0.002) and decision making (78% vs 49%; P = 0.04). They tended to be more informed about their medications' names (44% vs 6%; P = 0.01), indications (28% vs 9%; P = 0.02), and self-administration of medications (89% vs 39%; P = 0.01). Multicompartment compliance aids resulted in delayed discharges of 40 (78%) patients, with a mean of 1.3 days (standard deviation, 0.9 days; range, 0-3 days per patient) and a total of 65 days. CONCLUSION: The use of MCAs resulted in a lack of autonomy and decision making in older patients and a significant delay of discharges, thereby increasing hospital costs.


Assuntos
Idoso/psicologia , Tempo de Internação/estatística & dados numéricos , Cooperação do Paciente , Preparações Farmacêuticas/administração & dosagem , Estudos Transversais , Tomada de Decisões , Feminino , Hospitais Gerais , Humanos , Entrevistas como Assunto , Masculino , Educação de Pacientes como Assunto , Estudos Prospectivos , Reino Unido
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