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1.
Childs Nerv Syst ; 36(2): 291-296, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31292757

RESUMO

PURPOSE: To demonstrate the paradigm shift in management strategies of pediatric craniopharyngioma at our institution over the past six decades. METHODS: Retrospective analysis of all pediatric patients with craniopharyngioma treated at Boston Children's Hospital between 1960 and 2017. RESULTS: One hundred seventy-eight patients with craniopharyngioma were treated between 1960 and 2017; 135 (70 males and 65 females) fulfilled the inclusion criteria. Forty-five patients were treated in the old era (1960-1984) and 90 patients were treated in the new era (1985-2017). Gross total resection (GTR) was achieved in 4% and 43% of patients in old and new eras respectively. Sub-total resection (STR) and radiotherapy (XRT) were performed in 27% and 28% of patients in old and new eras respectively. STR without XRT was performed in 20% and 29% of patients in old and new era respectively. Cyst drainage and adjuvant radiotherapy were performed in 49% of patients in the old era while no patients in the new era underwent such conservative management. Aggressive surgical resection was associated with a higher risk of worsening visual outcomes (20% vs 16%), panhypopituitarism and diabetes insipidus (86% vs 53%), psycho-social impairment (42% vs 26%), and new-onset obesity (33% vs 22%). The mortality rate was higher in the old era in comparison with that of the new one (9% vs 2%). CONCLUSION: There was a paradigm shift in management strategies of pediatric craniopharyngioma over the past six decades which in turn affected the long-term outcomes and quality of life of patients.

2.
Clin Cancer Res ; 25(24): 7303-7311, 2019 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-31811016

RESUMO

PURPOSE: Pediatric low-grade glioma (pLGG) is the most prevalent childhood brain tumor. Patients with BRAF V600 mutation-positive pLGG may benefit from treatment with dabrafenib. Part 2 of a phase I/IIa study, open-label study (NCT01677741) explores the activity and safety of dabrafenib treatment in these patients. PATIENTS AND METHODS: Patients ages 1 to <18 years who had BRAF V600-mutant solid tumors (≥1 evaluable lesion) with recurrent, refractory, or progressive disease after ≥1 standard therapy were treated with oral dabrafenib 3.0 to 5.25 mg/kg/day (part 1) or at the recommended phase II dose (RP2D; part 2). Primary objectives were to determine the RP2D (part 1, results presented in a companion paper) and assess clinical activity (part 2). Here, we report the clinical activity, including objective response rates (ORRs) using Response Assessment in Neuro-Oncology criteria and safety across parts 1 and 2. RESULTS: Overall, 32 patients with pLGG were enrolled (part 1, n = 15; part 2, n = 17). Minimum follow-up was 26.2 months. Among all patients, the ORR was 44% [95% confidence interval (CI), 26-62] by independent review. The 1-year progression-free survival rate was 85% (95% CI, 64-94). Treatment-related adverse events (AE) were reported in 29 patients (91%); the most common was fatigue (34%). Grade 3/4 treatment-related AEs were reported in 9 patients (28%). CONCLUSIONS: Dabrafenib demonstrated meaningful clinical activity and acceptable tolerability in patients with BRAF V600-mutant pLGG.

3.
J Neurooncol ; 145(2): 349-355, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31571114

RESUMO

BACKGROUND: Pediatric brain tumors are associated with high morbidity and mortality, in part due to insufficient understanding of tumor biology. With limited tissue allocation for research from surgical specimens, a key barrier to improving biological understanding, brain tumor autopsies have become an increasingly valuable resource. This study reviews the brain tumor autopsy practice at our institution and describes specific emerging research utilization patterns beyond the clinical autopsy report. METHODS: We performed a retrospective analysis of brain tumor autopsies at Boston Children's Hospital (BCH) between 2007 and 2017 and reviewed their consents, neuropathology reports and final diagnoses. We reviewed the method of tissue triaging for research consented autopsies (bioregistry, frozen and fresh tissue) and documented their specific uses. RESULTS: Ninety-six deaths at BCH were due to brain tumors; 56 autopsies were performed (58.3%), of which 49 (87.5%) were consented for research. Tumor mapping was performed on all cases and tissue was allocated for DNA- and RNA-based sequencing studies (published and ongoing). Three tissue allocations with a postmortem interval of 8 h or less resulted in successful cell lines. Tissue from 14 autopsies was contributed to the National DIPG Registry. CONCLUSION: Our institutional pediatric brain tumor autopsy clinical experience demonstrates the increased utility and wide utilization of autopsy-derived tissue for multiple types of research. These results support the increased efforts to obtain research consent for brain tumor autopsy and active collection of unfixed autopsy material in the molecular era.

4.
Clin Cancer Res ; 25(24): 7294-7302, 2019 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-31506385

RESUMO

PURPOSE: The 2-part, phase I/IIa, open-label study (NCT01677741) sought to determine the safety, tolerability, pharmacokinetics, and preliminary activity of dabrafenib in pediatric patients with advanced BRAF V600-mutated cancers. PATIENTS AND METHODS: This phase I dose-finding part treated patients ages 1 to <18 years with BRAF V600 mutation-positive tumors with oral dabrafenib 3 to 5.25 mg/kg/day to determine the RP2D based on safety and drug exposure target. RESULTS: Between May 2013 and November 2014, 27 patients [12 male; median age, 9 years (range, 1-17 years)] with BRAF V600-mutant solid tumors recurrent/refractory to treatment (low- or high-grade glioma, Langerhans cell histiocytosis, neuroblastoma, or thyroid cancer) were enrolled. The median treatment duration was 75.6 weeks (range, 5.6-148.7 weeks), with 63% treated for >52 weeks and 52% undergoing treatment at data cutoff date. The most common grade 3/4 adverse events suspected to be related to study drug were maculopapular rash and arthralgia (2 patients each). No dose-limiting toxicities were observed. Pharmacokinetic analyses showed a dose-dependent increase in AUC0-12 and achievement of adult exposure levels at the recommended phase II doses of 5.25 mg/kg/day (age <12 years) and 4.5 mg/kg/day (age ≥12 years) divided into 2 equal doses daily, not exceeding 300 mg daily. CONCLUSIONS: In this first clinical trial in pediatric patients with pretreated BRAF V600-mutant tumors, dabrafenib was well tolerated while achieving target exposure levels; the average treatment duration was >1 year with many patients still on treatment. The phase II component is also closed and will be reported separately.

5.
Nat Commun ; 10(1): 3731, 2019 08 19.
Artigo em Inglês | MEDLINE | ID: mdl-31427603

RESUMO

Pilocytic astrocytoma (PA), the most common childhood brain tumor, is a low-grade glioma with a single driver BRAF rearrangement. Here, we perform scRNAseq in six PAs using methods that enabled detection of the rearrangement. When compared to higher-grade gliomas, a strikingly higher proportion of the PA cancer cells exhibit a differentiated, astrocyte-like phenotype. A smaller proportion of cells exhibit a progenitor-like phenotype with evidence of proliferation. These express a mitogen-activated protein kinase (MAPK) programme that was absent from higher-grade gliomas. Immune cells, especially microglia, comprise 40% of all cells in the PAs and account for differences in bulk expression profiles between tumor locations and subtypes. These data indicate that MAPK signaling is restricted to relatively undifferentiated cancer cells in PA, with implications for investigational therapies directed at this pathway.


Assuntos
Astrocitoma/genética , Astrocitoma/patologia , Neoplasias Encefálicas/patologia , Células-Tronco Neurais/citologia , Proteínas Proto-Oncogênicas B-raf/genética , Animais , Neoplasias Encefálicas/genética , Humanos , Sistema de Sinalização das MAP Quinases/genética , Camundongos , Microglia/patologia , Proteínas Quinases Ativadas por Mitógeno/genética , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Oligodendroglia/citologia , Proteínas de Fusão Oncogênica/metabolismo , Células Tumorais Cultivadas
6.
Nat Commun ; 10(1): 2400, 2019 06 03.
Artigo em Inglês | MEDLINE | ID: mdl-31160565

RESUMO

BET-bromodomain inhibition (BETi) has shown pre-clinical promise for MYC-amplified medulloblastoma. However, the mechanisms for its action, and ultimately for resistance, have not been fully defined. Here, using a combination of expression profiling, genome-scale CRISPR/Cas9-mediated loss of function and ORF/cDNA driven rescue screens, and cell-based models of spontaneous resistance, we identify bHLH/homeobox transcription factors and cell-cycle regulators as key genes mediating BETi's response and resistance. Cells that acquire drug tolerance exhibit a more neuronally differentiated cell-state and expression of lineage-specific bHLH/homeobox transcription factors. However, they do not terminally differentiate, maintain expression of CCND2, and continue to cycle through S-phase. Moreover, CDK4/CDK6 inhibition delays acquisition of resistance. Therefore, our data provide insights about the mechanisms underlying BETi effects and the appearance of resistance and support the therapeutic use of combined cell-cycle inhibitors with BETi in MYC-amplified medulloblastoma.


Assuntos
Azepinas/farmacologia , Ciclo Celular/efeitos dos fármacos , Neoplasias Cerebelares/tratamento farmacológico , Meduloblastoma/tratamento farmacológico , Neurogênese/efeitos dos fármacos , Proteínas/antagonistas & inibidores , Triazóis/farmacologia , Animais , Fatores de Transcrição Hélice-Alça-Hélice Básicos/efeitos dos fármacos , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Sistemas CRISPR-Cas , Proteínas de Ciclo Celular/efeitos dos fármacos , Proteínas de Ciclo Celular/metabolismo , Linhagem Celular Tumoral , Linhagem da Célula , Neoplasias Cerebelares/genética , Ciclina D2/efeitos dos fármacos , Ciclina D2/metabolismo , Quinase 4 Dependente de Ciclina/antagonistas & inibidores , Quinase 6 Dependente de Ciclina/antagonistas & inibidores , Resistencia a Medicamentos Antineoplásicos , Perfilação da Expressão Gênica , Humanos , Meduloblastoma/genética , Camundongos , Células-Tronco Neurais/efeitos dos fármacos , Células-Tronco Neurais/metabolismo , Proteínas Proto-Oncogênicas c-myc/genética , Fase S/efeitos dos fármacos
8.
J Clin Invest ; 129(7): 2964-2979, 2019 06 17.
Artigo em Inglês | MEDLINE | ID: mdl-31205032

RESUMO

Cancer therapy is a double-edged sword, as surgery and chemotherapy can induce an inflammatory/immunosuppressive injury response that promotes dormancy escape and tumor recurrence. We hypothesized that these events could be altered by early blockade of the inflammatory cascade and/or by accelerating the resolution of inflammation. Preoperative, but not postoperative, administration of the nonsteroidal antiinflammatory drug ketorolac and/or resolvins, a family of specialized proresolving autacoid mediators, eliminated micrometastases in multiple tumor-resection models, resulting in long-term survival. Ketorolac unleashed anticancer T cell immunity that was augmented by immune checkpoint blockade, negated by adjuvant chemotherapy, and dependent on inhibition of the COX-1/thromboxane A2 (TXA2) pathway. Preoperative stimulation of inflammation resolution via resolvins (RvD2, RvD3, and RvD4) inhibited metastases and induced T cell responses. Ketorolac and resolvins exhibited synergistic antitumor activity and prevented surgery- or chemotherapy-induced dormancy escape. Thus, simultaneously blocking the ensuing proinflammatory response and activating endogenous resolution programs before surgery may eliminate micrometastases and reduce tumor recurrence.

9.
Artigo em Inglês | MEDLINE | ID: mdl-31233466

RESUMO

PURPOSE: Infantile hepatic hemangioendothelioma (IHHE) is the most common hepatic vascular tumor in children. We report on the treatment outcome of our large single-center experience of patients with IHHE over a 9-year period. MATERIALS AND METHODS: A retrospective analysis of all IHHE patients treated at the Children Cancer Hospital Egypt from April 2008 through April 2017. RESULTS: In total, 28 patients (18 females, 10 males) were diagnosed with IHHE with a median age at diagnosis of 3 months. The lesions were multifocal (n=12), focal (n=10), and diffuse (n=6). Six (21.4%) patients initially had low T3 and T4. Eleven patients did not receive any treatment, whereas 1 patient underwent resectional surgery. Sixteen patients received drug treatment, 9 of whom responded well to first-line propranolol/prednisolone, whereas 7 patients needed salvage treatment. Twenty-five patients are alive, whereas 3 patients have died. CONCLUSIONS: Overall, patients with IHHE do well, a significant percentage of whom do not require drug therapy, particularly for those with small focal lesions. In patients with multifocal/diffuse disease, there is a high incidence of low T3 and T4 and while some of these patients did well without additional therapy, those with rapidly progressive lesions during treatment may do poorly.

10.
Cancer Treat Rev ; 76: 41-50, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31125907

RESUMO

BACKGROUND: The hedgehog signaling pathway is normally tightly regulated. Mutations in hedgehog pathway components may lead to abnormal activation. Aberrantly activated hedgehog signaling plays a major role in the development of solid and hematological cancer. In recent years, inhibitors have been developed that attenuate hedgehog signaling; 2 have been approved for use in basal cell carcinoma (BCC), while others are under development or in clinical trials. The aim of this review is to provide an overview of known hedgehog inhibitors (HHIs) and their potential for the treatment of hematological cancers and solid tumors beyond BCC. DESIGN: Published literature was searched to identify articles relating to HHIs in noncutaneous cancer. Both preclinical and clinical research articles were included. In addition, relevant clinical trial results were identified from www.clinicaltrials.gov. Information on the pharmacology of HHIs is also included. RESULTS: HHIs show activity in a variety of solid and hematological cancers. In preclinical studies, HHIs demonstrated efficacy in pancreatic cancer, rhabdomyosarcoma, breast cancer, and acute myeloid leukemia (AML). In clinical studies, HHIs showed activity in medulloblastoma, as well as prostate, pancreatic, and hematological cancers. Current clinical trials testing the efficacy of HHIs are underway for prostate, pancreatic, and breast cancers, as well as multiple myeloma and AML. CONCLUSIONS: As clinical trial results become available, it will be possible to discern which additional tumor types are suited to HHI mono- or combination therapy with other anticancer agents. The latter strategy may be useful for delaying or overcoming drug resistance.


Assuntos
Proteínas Hedgehog/antagonistas & inibidores , Neoplasias Hematológicas/tratamento farmacológico , Neoplasias Hematológicas/metabolismo , Transdução de Sinais/efeitos dos fármacos , Animais , Ensaios Clínicos como Assunto , Proteínas Hedgehog/metabolismo , Humanos , Ensaios Clínicos Controlados Aleatórios como Assunto
11.
Neuro Oncol ; 21(4): 537-546, 2019 03 18.
Artigo em Inglês | MEDLINE | ID: mdl-30883662

RESUMO

BACKGROUND: Gene-mediated cytotoxic immunotherapy (GMCI) is a tumor-specific immune stimulatory strategy implemented through local delivery of aglatimagene besadenovec (AdV-tk) followed by anti-herpetic prodrug. GMCI induces T-cell dependent tumor immunity and synergizes with radiotherapy. Clinical trials in adult malignant gliomas demonstrated safety and potential efficacy. This is the first trial of GMCI in pediatric brain tumors. METHODS: This phase I dose escalation study was conducted to evaluate GMCI in patients 3 years of age or older with malignant glioma or recurrent ependymoma. AdV-tk at doses of 1 × 1011 and 3 × 1011 vector particles (vp) was injected into the tumor bed at the time of surgery followed by 14 days of valacyclovir. Radiation started within 8 days of surgery, and if indicated, chemotherapy began after completion of valacyclovir. RESULTS: Eight patients (6 glioblastoma, 1 anaplastic astrocytoma, 1 recurrent ependymoma) were enrolled and completed therapy: 3 on dose level 1 and 5 on dose level 2. Median age was 12.5 years (range 7-17) and Lansky/Karnofsky performance scores were 60-100. Five patients had multifocal/extensive tumors that could not be resected completely and 3 had gross total resection. There were no dose-limiting toxicities. The most common possibly GMCI-related adverse events included Common Terminology Criteria for Adverse Events grade 1-2 fever, fatigue, and nausea/vomiting. Three patients, in dose level 2, lived more than 24 months, with 2 alive without progression 37.3 and 47.7 months after AdV-tk injection. CONCLUSIONS: GMCI can be safely combined with radiation therapy with or without temozolomide in pediatric patients with brain tumors and the present results strongly support further investigation. CLINICAL TRIAL REGISTRY: ClinicalTrials.gov NCT00634231.

12.
Pediatr Blood Cancer ; 66(6): e27682, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30821092

RESUMO

BACKGROUND: MAPK (RAS-RAF-MEK-ERK-MAP) and mTOR inhibitors are novel treatments for pediatric central nervous system (CNS) tumors. The literature on common cutaneous adverse reactions to these therapies is sparse in the pediatric population. The aim of this study was to describe common cutaneous adverse reactions to BRAF, MEK, and mTOR inhibitors in children with CNS tumors. METHODS: In this cross-sectional study, patients younger than 21 years of age receiving BRAF, MEK, and mTOR inhibitor monotherapy for a CNS tumor were enrolled over a one-year period. Full body skin examination, photographs of dermatologic findings, and initial treatment recommendations were included at the initial visit, and follow-up skin examinations were recommended every three months. RESULTS: Twenty-two patients were enrolled in the study. Fifty percent (11/22) received trametinib, a MEK inhibitor, 27.3% (6/22) received dabrafenib, a BRAF inhibitor, and 22.7% (5/22) received everolimus, an mTOR inhibitor. Median age at visit was 11 years (range, 3-19). Median time from treatment initiation to skin examination was 4.5 months (range, 0-43). Ninety-six percent (21/22) of all patients had at least one skin reaction. The most common reactions across treatment groups included follicular/acneiform eruptions and xerosis. Two patients on MEK inhibitors and one patient on a BRAF inhibitor required therapy cessation due to severe cutaneous reactions. CONCLUSIONS: Cutaneous reactions to targeted anticancer therapy in children are common, treatable, and rarely require drug dose reduction or discontinuation. Routine surveillance and early intervention may improve quality of life and facilitate continuation of life-saving therapy.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Neoplasias do Sistema Nervoso Central/tratamento farmacológico , Erupção por Droga/etiologia , Terapia de Alvo Molecular/efeitos adversos , Dermatopatias/induzido quimicamente , Adolescente , Adulto , Neoplasias do Sistema Nervoso Central/patologia , Criança , Pré-Escolar , Estudos Transversais , Feminino , Seguimentos , Humanos , Imidazóis/administração & dosagem , Masculino , Oximas/administração & dosagem , Prognóstico , Piridonas/administração & dosagem , Pirimidinonas/administração & dosagem , Adulto Jovem
13.
Proc Natl Acad Sci U S A ; 116(13): 6292-6297, 2019 03 26.
Artigo em Inglês | MEDLINE | ID: mdl-30862734

RESUMO

Inflammation in the tumor microenvironment is a strong promoter of tumor growth. Substantial epidemiologic evidence suggests that aspirin, which suppresses inflammation, reduces the risk of cancer. The mechanism by which aspirin inhibits cancer has remained unclear, and toxicity has limited its clinical use. Aspirin not only blocks the biosynthesis of prostaglandins, but also stimulates the endogenous production of anti-inflammatory and proresolving mediators termed aspirin-triggered specialized proresolving mediators (AT-SPMs), such as aspirin-triggered resolvins (AT-RvDs) and lipoxins (AT-LXs). Using genetic and pharmacologic manipulation of a proresolving receptor, we demonstrate that AT-RvDs mediate the antitumor activity of aspirin. Moreover, treatment of mice with AT-RvDs (e.g., AT-RvD1 and AT-RvD3) or AT-LXA4 inhibited primary tumor growth by enhancing macrophage phagocytosis of tumor cell debris and counter-regulating macrophage-secreted proinflammatory cytokines, including migration inhibitory factor, plasminogen activator inhibitor-1, and C-C motif chemokine ligand 2/monocyte chemoattractant protein 1. Thus, the pro-resolution activity of AT-resolvins and AT-lipoxins may explain some of aspirin's broad anticancer activity. These AT-SPMs are active at considerably lower concentrations than aspirin, and thus may provide a nontoxic approach to harnessing aspirin's anticancer activity.


Assuntos
Antineoplásicos/farmacologia , Aspirina/farmacologia , Neoplasias/tratamento farmacológico , Neoplasias/prevenção & controle , Animais , Aspirina/administração & dosagem , Quimiocina CCL2/metabolismo , Quimiocinas/metabolismo , Citocinas/metabolismo , Modelos Animais de Doenças , Ácidos Docosa-Hexaenoicos/metabolismo , Eicosanoides/metabolismo , Ácidos Graxos Insaturados/metabolismo , Feminino , Inflamação/tratamento farmacológico , Lipoxinas/metabolismo , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Metabolômica , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Proteínas Associadas aos Microtúbulos/metabolismo , Metástase Neoplásica/tratamento farmacológico , Metástase Neoplásica/prevenção & controle , Proteínas do Tecido Nervoso/metabolismo , Fagocitose/efeitos dos fármacos , Inativadores de Plasminogênio/metabolismo , Prostaglandinas/metabolismo
14.
Nat Rev Clin Oncol ; 16(8): 509-520, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-30733593

RESUMO

Despite decades of research, brain tumours remain among the deadliest of all forms of cancer. The ability of these tumours to resist almost all conventional and novel treatments relates, in part, to the unique cell-intrinsic and microenvironmental properties of neural tissues. In an attempt to encourage progress in our understanding and ability to successfully treat patients with brain tumours, Cancer Research UK convened an international panel of clinicians and laboratory-based scientists to identify challenges that must be overcome if we are to cure all patients with a brain tumour. The seven key challenges summarized in this Position Paper are intended to serve as foci for future research and investment.


Assuntos
Neoplasias Encefálicas/terapia , Humanos
15.
Proc Natl Acad Sci U S A ; 116(5): 1698-1703, 2019 01 29.
Artigo em Inglês | MEDLINE | ID: mdl-30647111

RESUMO

Although chemotherapy is a conventional cancer treatment, it may induce a protumorigenic microenvironment by triggering the release of proinflammatory mediators. In this study, we demonstrate that ovarian tumor cell debris generated by first-line platinum- and taxane-based chemotherapy accelerates tumor progression by stimulating a macrophage-derived "surge" of proinflammatory cytokines and bioactive lipids. Thus, targeting a single inflammatory mediator or pathway is unlikely to prevent therapy-induced tumor progression. Here, we show that combined pharmacological abrogation of the cyclooxygenase-2 (COX-2) and soluble epoxide hydrolase (sEH) pathways prevented the debris-induced surge of both cytokines and lipid mediators by macrophages. In animal models, the dual COX-2/sEH inhibitor PTUPB delayed the onset of debris-stimulated ovarian tumor growth and ascites leading to sustained survival over 120 days postinjection. Therefore, dual inhibition of COX-2/sEH may be an approach to suppress debris-stimulated ovarian tumor growth by preventing the therapy-induced surge of cytokines and lipid mediators.


Assuntos
Antineoplásicos/efeitos adversos , Antineoplásicos/farmacologia , Inibidores de Ciclo-Oxigenase 2/farmacologia , Ciclo-Oxigenase 2/metabolismo , Citocinas/metabolismo , Epóxido Hidrolases/antagonistas & inibidores , Neoplasias Ovarianas/tratamento farmacológico , Animais , Hidrocarbonetos Aromáticos com Pontes/farmacologia , Carcinoma Epitelial do Ovário/tratamento farmacológico , Carcinoma Epitelial do Ovário/metabolismo , Proliferação de Células/efeitos dos fármacos , Modelos Animais de Doenças , Progressão da Doença , Feminino , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Lipídeos , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos SCID , Neoplasias Ovarianas/metabolismo , Platina/farmacologia , Transdução de Sinais/efeitos dos fármacos , Taxoides/farmacologia
16.
FASEB J ; 33(1): 114-125, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-29957058

RESUMO

Colon cancer recurrence after therapy, such as 5-fluorouracil (5-FU), remains a challenge in the clinical setting. Chemotherapy reduces tumor burden by inducing cell death; however, the resulting dead tumor cells, or debris, may paradoxically stimulate angiogenesis, inflammation, and tumor growth. Here, we demonstrate that 5-FU-generated colon carcinoma debris stimulates the growth of a subthreshold inoculum of living tumor cells in subcutaneous and orthotopic models. Debris triggered the release of osteopontin (OPN) by tumor cells and host macrophages. Both coinjection of debris and systemic treatment with 5-FU increased plasma OPN levels in tumor-bearing mice. RNA expression levels of secreted phosphoprotein 1, the gene that encodes OPN, correlate with poor prognosis in patients with colorectal cancer and are elevated in chemotherapy-treated patients who experience tumor recurrence vs. no recurrence. Pharmacologic and genetic ablation of OPN inhibited debris-stimulated tumor growth. Systemic treatment with a combination of a neutralizing OPN antibody and 5-FU dramatically inhibited tumor growth. These results demonstrate a novel mechanism of tumor progression mediated by OPN released in response to chemotherapy-generated tumor cell debris. Neutralization of debris-stimulated OPN represents a potential therapeutic strategy to overcome the inherent limitation of cytotoxic therapies as a result of the generation of cell debris.-Chang, J., Bhasin, S. S., Bielenberg, D. R., Sukhatme, V. P., Bhasin, M., Huang, S., Kieran, M. W., Panigrahy, D. Chemotherapy-generated cell debris stimulates colon carcinoma tumor growth via osteopontin.


Assuntos
Neoplasias do Colo/patologia , Fluoruracila/farmacologia , Neovascularização Patológica/patologia , Osteopontina/metabolismo , Animais , Antimetabólitos Antineoplásicos/farmacologia , Apoptose , Proliferação de Células , Neoplasias do Colo/tratamento farmacológico , Neoplasias do Colo/metabolismo , Humanos , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Macrófagos/patologia , Masculino , Camundongos , Neovascularização Patológica/tratamento farmacológico , Neovascularização Patológica/metabolismo , Prognóstico , Taxa de Sobrevida , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto
17.
J Neurosurg Pediatr ; 22(6): 678-683, 2018 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-30192215

RESUMO

OBJECTIVEDiffuse intrinsic pontine glioma (DIPG) is a highly aggressive and lethal brainstem tumor in children. In the 1980s, routine biopsy at presentation was abandoned since it was claimed "unnecessary" for diagnosis. In the last decade, however, several groups have reincorporated this procedure as standard of care or in the context of clinical trials. Expert neurosurgical teams report no mortality and acceptable morbidity, and no relevant complications have been previously described. The aim of this study was to review needle tract dissemination as a potential complication in DIPG.METHODSThe authors retrospectively analyzed the incidence of dissemination through surgical tracts in DIPG patients who underwent biopsy procedures at diagnosis in 3 dedicated centers. Clinical records and images as well as radiation dosimetry from diagnosis to relapse were reviewed.RESULTSFour patients (2 boys and 2 girls, age range 6-12 years) had surgical tract dissemination: in 3 cases in the needle tract and in 1 case in the Ommaya catheter tract. The median time from biopsy to identification of dissemination was 5 months (range 4-6 months). The median overall survival was 11 months (range 7-12 months). Disseminated lesions were in the marginal radiotherapy field (n = 2), out of the field (n = 1), and in the radiotherapy field (n = 1).CONCLUSIONSAlthough surgical tract dissemination in DIPG is a rare complication (associated with 2.4% of procedures in this study), it should be mentioned to patients and family when procedures involving a surgical tract are proposed. The inclusion of the needle tract in the radiotherapy field may have only limited benefit. Future studies are warranted to explore the benefit of larger radiotherapy fields in patients with DIPG.


Assuntos
Biópsia/efeitos adversos , Neoplasias do Tronco Encefálico/patologia , Glioma/patologia , Invasividade Neoplásica/patologia , Ponte/patologia , Criança , Feminino , Humanos , Masculino
18.
Front Oncol ; 8: 169, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29868485

RESUMO

Dramatic advances in the molecular analysis of diffuse intrinsic pontine glioma have occurred over the last decade and resulted in the identification of potential therapeutic targets. In spite of these advances, no significant improvement in the outcome has been achieved and median survival remains approximately 10 months. An understanding of the approaches that have been taken to date, why they failed, and how that information can lead the field forward is critical if we are to change the status quo. In this review, we will discuss the clinical trial landscape in North America with an overview of historical approaches that failed and what might account for this failure. We will then provide a discussion of how our understanding of the genotype of this disease has led to the development of a number of trials targeting the mutations and epigenome of diffuse intrinsic pontine gliomas and the issues related to these trials. Similarly, the introduction of methodologies to address penetration across the blood-brain barrier will be considered in the context of both targeted approaches, epigenetic modification, and immune surveillance of these tumors. The comprehensive analysis of these data, generated through cooperative groups, collaborative clinical trials, and pilot studies in North America will be the focus of the IVth Memorial Alicia Pueyo international symposium in Barcelona on March 12th, 2018 and will be compared and contrasted with a similar comprehensive analysis of the European data with the goal of bringing all of these data together to develop a uniform platform on which new rational trials can be based.

19.
JAMA ; 319(16): 1687-1695, 2018 04 24.
Artigo em Inglês | MEDLINE | ID: mdl-29710166

RESUMO

Importance: Hutchinson-Gilford progeria syndrome (HGPS) is an extremely rare fatal premature aging disease. There is no approved treatment. Objective: To evaluate the association of monotherapy using the protein farnesyltransferase inhibitor lonafarnib with mortality rate in children with HGPS. Design, Setting, and Participants: Cohort study comparing contemporaneous (birth date ≥1991) untreated patients with HGPS matched with treated patients by age, sex, and continent of residency using conditional Cox proportional hazards regression. Treatment cohorts included patients from 2 single-group, single-site clinical trials (ProLon1 [n = 27; completed] and ProLon2 [n = 36; ongoing]). Untreated patients originated from a separate natural history study (n = 103). The cutoff date for patient follow-up was January 1, 2018. Exposure: Treated patients received oral lonafarnib (150 mg/m2) twice daily. Untreated patients received no clinical trial medications. Main Outcomes and Measures: The primary outcome was mortality. The primary analysis compared treated patients from the first lonafarnib trial with matched untreated patients. A secondary analysis compared the combined cohorts from both lonafarnib trials with matched untreated patients. Results: Among untreated and treated patients (n = 258) from 6 continents, 123 (47.7%) were female; 141 (54.7%) had a known genotype, of which 125 (88.7%) were classic (c.1824C>T in LMNA). When identified (n = 73), the primary cause of death was heart failure (79.4%). The median treatment duration was 2.2 years. Median age at start of follow-up was 8.4 (interquartile range [IQR], 4.8-9.5) years in the first trial cohort and 6.5 (IQR, 3.7-9.0) years in the combined cohort. There was 1 death (3.7%) among 27 patients in the first trial group and there were 9 deaths (33.3%) among 27 patients in the matched untreated group. Treatment was associated with a lower mortality rate (hazard ratio, 0.12; 95% CI, 0.01-0.93; P = .04). In the combined cohort, there were 4 deaths (6.3%) among 63 patients in the treated group and 17 deaths (27.0%) among 63 patients in the matched untreated group (hazard ratio, 0.23; 95% CI, 0.06-0.90; P = .04). Conclusions and Relevance: Among patients with HGPS, lonafarnib monotherapy, compared with no treatment, was associated with a lower mortality rate after 2.2 years of follow-up. Study interpretation is limited by its observational design.


Assuntos
Inibidores Enzimáticos/uso terapêutico , Fosfotransferases (Aceptor do Grupo Fosfato)/antagonistas & inibidores , Piperidinas/uso terapêutico , Progéria/tratamento farmacológico , Piridinas/uso terapêutico , Adolescente , Adulto , Causas de Morte , Criança , Estudos de Coortes , Feminino , Humanos , Estimativa de Kaplan-Meier , Lamina Tipo A/biossíntese , Lamina Tipo A/metabolismo , Masculino , Progéria/genética , Progéria/mortalidade , Processamento de Proteína Pós-Traducional , Adulto Jovem
20.
J Clin Oncol ; 36(19): 1963-1972, 2018 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-29746225

RESUMO

Purpose Diffuse intrinsic pontine glioma (DIPG) is a brainstem malignancy with a median survival of < 1 year. The International and European Society for Pediatric Oncology DIPG Registries collaborated to compare clinical, radiologic, and histomolecular characteristics between short-term survivors (STSs) and long-term survivors (LTSs). Materials and Methods Data abstracted from registry databases included patients from North America, Australia, Germany, Austria, Switzerland, the Netherlands, Italy, France, the United Kingdom, and Croatia. Results Among 1,130 pediatric and young adults with radiographically confirmed DIPG, 122 (11%) were excluded. Of the 1,008 remaining patients, 101 (10%) were LTSs (survival ≥ 2 years). Median survival time was 11 months (interquartile range, 7.5 to 16 months), and 1-, 2-, 3-, 4-, and 5-year survival rates were 42.3% (95% CI, 38.1% to 44.1%), 9.6% (95% CI, 7.8% to 11.3%), 4.3% (95% CI, 3.2% to 5.8%), 3.2% (95% CI, 2.4% to 4.6%), and 2.2% (95% CI, 1.4% to 3.4%), respectively. LTSs, compared with STSs, more commonly presented at age < 3 or > 10 years (11% v 3% and 33% v 23%, respectively; P < .001) and with longer symptom duration ( P < .001). STSs, compared with LTSs, more commonly presented with cranial nerve palsy (83% v 73%, respectively; P = .008), ring enhancement (38% v 23%, respectively; P = .007), necrosis (42% v 26%, respectively; P = .009), and extrapontine extension (92% v 86%, respectively; P = .04). LTSs more commonly received systemic therapy at diagnosis (88% v 75% for STSs; P = .005). Biopsies and autopsies were performed in 299 patients (30%) and 77 patients (10%), respectively; 181 tumors (48%) were molecularly characterized. LTSs were more likely to harbor a HIST1H3B mutation (odds ratio, 1.28; 95% CI, 1.1 to 1.5; P = .002). Conclusion We report clinical, radiologic, and molecular factors that correlate with survival in children and young adults with DIPG, which are important for risk stratification in future clinical trials.


Assuntos
Neoplasias do Tronco Encefálico/diagnóstico , Sobreviventes de Câncer/estatística & dados numéricos , Glioma/diagnóstico , Adolescente , Adulto , Neoplasias do Tronco Encefálico/diagnóstico por imagem , Neoplasias do Tronco Encefálico/genética , Neoplasias do Tronco Encefálico/terapia , Criança , Pré-Escolar , Glioma/diagnóstico por imagem , Glioma/genética , Glioma/terapia , Humanos , Lactente , Recém-Nascido , Estimativa de Kaplan-Meier , Sistema de Registros , Adulto Jovem
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