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1.
J Med Genet ; 60(12): 1218-1223, 2023 Nov 27.
Artículo en Inglés | MEDLINE | ID: mdl-37460202

RESUMEN

BACKGROUND: Cancer predisposition syndromes (CPSs) are responsible for at least 10% of cancer diagnoses in children and adolescents, most of which are not clinically recognised prior to cancer diagnosis. A variety of clinical screening guidelines are used in healthcare settings to help clinicians detect patients who have a higher likelihood of having a CPS. The McGill Interactive Pediatric OncoGenetic Guidelines (MIPOGG) is an electronic health decision support tool that uses algorithms to help clinicians determine if a child/adolescent diagnosed with cancer should be referred to genetics for a CPS evaluation. METHODS: This study assessed MIPOGG's performance in identifying Li-Fraumeni, DICER1, Constitutional mismatch repair deficiency and Gorlin (nevoid basal cell carcinoma) syndromes in a retrospective series of 84 children diagnosed with cancer and one of these four CPSs in Canadian hospitals over an 18-year period. RESULTS: MIPOGG detected 82 of 83 (98.8%) evaluable patients with any one of these four genetic conditions and demonstrated an appropriate rationale for suggesting CPS evaluation. When compared with syndrome-specific clinical screening criteria, MIPOGG's ability to correctly identify children with any of the four CPSs was equivalent to, or outperformed, existing clinical criteria respective to each CPS. CONCLUSION: This study adds evidence that MIPOGG is an appropriate tool for CPS screening in clinical practice. MIPOGG's strength is that it starts with a specific cancer diagnosis and incorporates criteria relevant for associated CPSs, making MIPOGG a more universally accessible diagnostic adjunct that does not require in-depth knowledge of each CPS.


Asunto(s)
Sistemas de Apoyo a Decisiones Clínicas , Síndromes Neoplásicos Hereditarios , Niño , Humanos , Algoritmos , Síndromes Neoplásicos Hereditarios/diagnóstico , Síndromes Neoplásicos Hereditarios/genética , Estudios Retrospectivos
2.
Paediatr Child Health ; 29(4): 224-230, 2024 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-39045479

RESUMEN

Objectives: Access to early phase trials for children with relapsed, refractory or progressive (RRPD) cancer is limited in Canada. Patients and families face barriers to access trials, which are poorly understood. The aims of this study were to assess availability of early phase trials and examine the impact of distance from home to study centre on trial enrolment among paediatric oncology patients with RRPD. Methods: Oncology patients ≤18 years at diagnosis who later had RRPD were identified retrospectively via registry at the only quaternary paediatric oncology centre in British Columbia (BC). We determined if distance to home, as calculated using geocoding software, was predictive of trial offer or enrolment. Results: Between January 2015 and July 2021, 266 patients experienced 396 RRPD events. Seventy-five patients (28.2%) were eligible for an early phase trial at least once. At first eligible event, 61 patients (22.9%) were offered trial (median age 11.8 years; 69.0% male; 46.0% with CNS tumour) and thirty patients (11.3%) enrolled. Distance was not associated with odds of offer (OR 1.01, CI 0.98 to 1.05) or enrolment (OR 0.99, CI 0.95 to 1.03) on univariate or multivariable analysis adjusted for sex and disease (OR 0.93, CI 0.86 to 1.00). For offered patients, 2-year event-free survival (EFS) and overall survival (OS) were 39.1% (CI 28.0% to 54.8%) and 51.8% (CI 39.9% to 67.2%), respectively. EFS/OS did not differ with distance or enrolment, but varied by disease (EFS P = 0.002, OS P < 0.0001). Conclusions: Children in BC with cancer and RRPD have limited access to early phase trials. Distance was not predictive of enrolment, suggesting that families travel to access therapy.

3.
Cancer ; 129(22): 3620-3632, 2023 11 15.
Artículo en Inglés | MEDLINE | ID: mdl-37382186

RESUMEN

BACKGROUND: Germline genome sequencing in childhood cancer precision medicine trials may reveal pathogenic or likely pathogenic variants in cancer predisposition genes in more than 10% of children. These findings can have implications for diagnosis, treatment, and the child's and family's future cancer risk. Understanding parents' perspectives of germline genome sequencing is critical to successful clinical implementation. METHODS: A total of 182 parents of 144 children (<18 years of age) with poor-prognosis cancers enrolled in the Precision Medicine for Children with Cancer trial completed a questionnaire at enrollment and after the return of their child's results, including clinically relevant germline findings (received by 13% of parents). Parents' expectations of germline genome sequencing, return of results preferences, and recall of results received were assessed. Forty-five parents (of 43 children) were interviewed in depth. RESULTS: At trial enrollment, most parents (63%) believed it was at least "somewhat likely" that their child would receive a clinically relevant germline finding. Almost all expressed a preference to receive a broad range of germline genomic findings, including variants of uncertain significance (88%). Some (29%) inaccurately recalled receiving a clinically relevant germline finding. Qualitatively, parents expressed confusion and uncertainty after the return of their child's genome sequencing results by their child's clinician. CONCLUSIONS: Many parents of children with poor-prognosis childhood cancer enrolled in a precision medicine trial expect their child may have an underlying cancer predisposition syndrome. They wish to receive a wide scope of information from germline genome sequencing but may feel confused by the reporting of trial results.


Asunto(s)
Neoplasias , Humanos , Niño , Neoplasias/genética , Neoplasias/terapia , Neoplasias/diagnóstico , Motivación , Medicina de Precisión/métodos , Padres , Genotipo
4.
Pediatr Blood Cancer ; 69(1): e29306, 2022 01.
Artículo en Inglés | MEDLINE | ID: mdl-34455698

RESUMEN

BACKGROUND: Delay in diagnosis and treatment initiation can be associated with adverse outcomes in children with cancer. Diagnostic interval (DI) is defined as the time between the date of first health care contact for symptoms related to cancer to the date of cancer diagnosis, and treatment interval (TI) is defined as interval between the definitive cancer diagnosis and cancer treatment initiation. We aimed to determine the predictors of DI and TI in children with rhabdomyosarcoma (RMS) and their association with event-free survival (EFS) and overall survival (OS). METHODS: Using the Cancer in Young People in Canada (CYP-C) national population-based database, we conducted a retrospective cohort study of children (0-14.99 years) newly diagnosed with RMS between 2001 and 2015 in Canada. Quantile regression was used to assess the predictors of DI and TI, and Cox regression was used to determine if these intervals were associated with EFS and OS. RESULTS: Median DI and TI were 16.5 days (interquartile range [IQR] 6.0-38.0) and 5 days (IQR 0-12), respectively. DI and TI were not significantly associated with age at diagnosis, sex, race, tumor site, stage or histology, treatment region, distance from treatment center, income quintile or diagnosis year (all p > .05). DI and TI were not associated with EFS (DI: hazard ratio [HR] 1.00, 95% CI 0.96-1.05, p = .871; TI: HR 1.03, 95% CI 1.00-1.05, p = .053) or OS (DI: HR 0.99, 95% CI 0.94-1.05, p = .797; TI: HR 1.02, 95% CI 0.99-1.05, p = .155). CONCLUSIONS: In the publicly funded Canadian health care system, DI and TI did not affect the survival of children with RMS.


Asunto(s)
Rabdomiosarcoma , Adolescente , Canadá/epidemiología , Humanos , Supervivencia sin Progresión , Estudios Retrospectivos , Rabdomiosarcoma/diagnóstico , Rabdomiosarcoma/epidemiología , Rabdomiosarcoma/terapia , Tasa de Supervivencia
5.
Int J Cancer ; 149(9): 1691-1704, 2021 11 01.
Artículo en Inglés | MEDLINE | ID: mdl-34213775

RESUMEN

Malignant sarcomas are rare accounting for <1% of all adult solid malignancies and approximately 11% to 13% of all pediatric malignancies. TRK-inhibitors have demonstrated robust and long-lasting responses in patients with NTRK fusion-positive solid tumors, including sarcoma. Access to these agents in many jurisdictions such as Canada remains limited. We undertook a modified Delphi consensus to articulate and convey the clinical importance of these agents for the Canadian sarcoma community. A systematic search of published and presented literature was conducted to identify clinical trials reporting outcomes on the use of TRK-inhibitors in relapsed/refractory NTRK fusion-positive sarcoma. Three main consensus questions were identified: (a) is there currently an unmet clinical need for systemic therapy options in relapsed/refractory sarcoma? (b) do TRK-inhibitors confer a clinical benefit to patients with NTRK fusion-positive sarcoma? (c) do phase I/II basket trials provide sufficient evidence to justify funding of TRK-inhibitors in NTRK fusion-positive sarcoma? Response rates to the first and second surveys were 57% (n = 30) and 42% (n = 22), respectively. There was strong agreement among the Canadian sarcoma community that there was unmet clinical need for effective systemic therapy options in relapsed/refractory sarcoma, that TRK-inhibitors are a safe and effective treatment option for patients with NTRK fusion-positive sarcoma, and that available phase I/II basket trials provide sufficient evidence to support funding of these agents in relapsed/refractory NTRK fusion-positive sarcoma. TRK-inhibitors are a safe and effective systemic therapy option for patients with relapsed/refractory NTRK fusion-positive sarcoma.


Asunto(s)
Proteínas de Fusión Oncogénica/metabolismo , Inhibidores de Proteínas Quinasas/uso terapéutico , Receptor trkA/metabolismo , Receptor trkC/antagonistas & inhibidores , Sarcoma/tratamiento farmacológico , Encuestas y Cuestionarios/estadística & datos numéricos , Adolescente , Adulto , Anciano , Canadá , Consenso , Progresión de la Enfermedad , Humanos , Persona de Mediana Edad , Proteínas de Fusión Oncogénica/genética , Receptor trkA/genética , Receptor trkC/genética , Receptor trkC/metabolismo , Sarcoma/genética , Sarcoma/metabolismo , Análisis de Supervivencia , Adulto Joven
6.
Pediatr Blood Cancer ; 68(12): e29289, 2021 12.
Artículo en Inglés | MEDLINE | ID: mdl-34411405

RESUMEN

BACKGROUND: Meta-iodobenzylguanidine(MIBG) scans are used to detect neuroblastoma metastatic lesions at diagnosis and during posttreatment surveillance. MIBG positivity following induction chemotherapy correlates with poor outcome; however, there are reports of patients with progression-free survival despite MIBG positivity at the end of therapy. The factors distinguishing these survivors from patients who progress or relapse are unclear. FDG-positron-emission tomography (PET) scans can also detect metastatic lesions at diagnosis; however, their role in posttherapy surveillance is less well studied. METHODS: We performed a retrospective analysis of International Neuroblastoma Staging System (INSS) stage 4 patients to identify those with residual MIBG-avid metastatic lesions on end-of-therapy scans without prior progression. Data collected included age, disease sites, histopathology, biomarkers, treatment, imaging studies, and response. RESULTS: Eleven of 265 patients met inclusion criteria. At diagnosis three of 11 patients were classified as intermediate and eight of 11 high risk; nine of 11 had documented marrow involvement. Histologic classification was favorable for four of 10 and MYCN amplification was detected in zero of 11 cases. The median time with persistent MIBG positivity following treatment was 1.5 years. Seven patients had at least one PET scan with low or background activity. Biopsies of three of three MIBG-avid residual lesions showed differentiation. All patients remain alive with no disease progression at a median of 4.0 years since end of therapy. CONCLUSION: Persistently MIBG-avid metastatic lesions in subsets of patients following completion of therapy may not represent active disease that will progress. Further studies are needed to determine whether MYCN status or other biomarkers, and/or PET scans, may help identify patients with residual inactive MIBG lesions who require no further therapy.


Asunto(s)
Neoplasias Primarias Secundarias , Neuroblastoma , 3-Yodobencilguanidina , Guanidina/uso terapéutico , Humanos , Proteína Proto-Oncogénica N-Myc , Recurrencia Local de Neoplasia , Neuroblastoma/tratamiento farmacológico , Neuroblastoma/terapia , Tomografía de Emisión de Positrones/métodos , Estudios Retrospectivos
7.
J Pediatr Hematol Oncol ; 43(8): e1099-e1104, 2021 11 01.
Artículo en Inglés | MEDLINE | ID: mdl-33273412

RESUMEN

BACKGROUND: This study explores how parents of children with high-risk neuroblastoma incorporate information from multiple sources into treatment decision-making for their children as they evaluate the trustworthiness of the sources. METHODS: Following ethics board approval, parents of children with high-risk neuroblastoma were recruited through purposive sampling from a tertiary care pediatric oncology program in Vancouver, BC, Canada. Participants completed an in-depth, semistructured interview with a study member. The qualitative descriptive methodology was utilized to code interview transcripts and identify emergent themes. RESULTS: Nine parents of children with high-risk neuroblastoma during upfront therapy (n=4) or treatment of refractory disease (n=5) were included. Despite almost universal access of web-based information, parents acknowledged distrust in the reliability and consistency of these sources. Open communication between parents and physicians about sources of information outside the clinic and access to regulated, accurate information is highly valued. The impact on the quality of life and the costs, both financial and personal, of travel are key factors in decision-making. DISCUSSION: Health care providers shoulder an immense responsibility to augment and contextualize information available about high-risk neuroblastoma for parents to maximize benefit in decision-making. Health care providers should guide access to accurate, evidence-based resources that can be monitored and continuously updated.


Asunto(s)
Toma de Decisiones , Conducta en la Búsqueda de Información , Neuroblastoma/terapia , Padres/psicología , Médicos/psicología , Confianza , Preescolar , Femenino , Estudios de Seguimiento , Humanos , Lactante , Masculino , Neuroblastoma/patología , Neuroblastoma/psicología , Relaciones Profesional-Familia
8.
Pediatr Blood Cancer ; 67(4): e28167, 2020 04.
Artículo en Inglés | MEDLINE | ID: mdl-31925920

RESUMEN

We describe 12 pediatric patients (8-16 years) with primary refractory (N = 6) or first relapse (N = 6) Hodgkin lymphoma (HL) treated with ifosfamide, gemcitabine, and vinorelbine (IGEV). The overall response rate to IGEV was 100%, with seven (58%) complete responses (CR) and five (42%) partial responses. Successful CD34+ stem cell mobilization was achieved in all patients. Following subsequent autologous stem cell transplantation, 10 patients (83%) achieved CR. At a median follow-up of 71 months, 11 patients had no evidence of disease. Five-year second event-free survival and overall survival were 83% ± 11.0% and 90.0% ± 9.5%, respectively. IGEV is an effective salvage regimen for children with relapsed/refractory HL.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Movilización de Célula Madre Hematopoyética , Enfermedad de Hodgkin , Terapia Recuperativa , Trasplante de Células Madre , Adolescente , Autoinjertos , Niño , Desoxicitidina/administración & dosificación , Desoxicitidina/análogos & derivados , Supervivencia sin Enfermedad , Femenino , Enfermedad de Hodgkin/mortalidad , Enfermedad de Hodgkin/terapia , Humanos , Ifosfamida/administración & dosificación , Masculino , Tasa de Supervivencia , Vinorelbina/administración & dosificación , Gemcitabina
9.
J Pediatr Hematol Oncol ; 42(2): e87-e93, 2020 03.
Artículo en Inglés | MEDLINE | ID: mdl-31259825

RESUMEN

ABVD (doxorubicin, bleomycin, vinblastine, dacarbazine) is standard upfront chemotherapy for adults diagnosed with Hodgkin lymphoma (HL), but positron emission tomography (PET)-based response data following ABVD is lacking for pediatrics. Among children who received ABVD for HL, we document interim and end of therapy PET-computed tomography (CT) response by Deauville criteria, and survival outcomes following a response-based reduction in involved field radiotherapy (IFRT). Children 18 years of age or below with HL treated with ABVD between 2006 and 2015 who had interim PET/CT scans after 2 cycles of chemotherapy were included. Interim and end of therapy PET/CT scans were retrospectively re-evaluated using Deauville criteria by 3 radiologists. Among 45 children, 32 (71%) met criteria for intermediate risk, 86% achieved rapid early response (RER) and only 4 (9%) received upfront IFRT. Patients achieving RER had superior 5-year event-free survival (EFS) 95%±4% versus 50%±18% (P≤0.001) and overall survival (OS) 100% versus 83%±15% (P=0.025). Patients with bulk who achieved RER and received no IFRT achieved 5-year EFS of 92%±6% and OS 100%. Low, intermediate, and high risk patients had 5-year EFS of 100%, 94%±4%, and 50%±18% (P=0.002) and 5-year OS of 100%, 100%, and 75%±15% (P=0.03). RER following 2 cycles of ABVD is predictive of survival outcomes in children and adolescents with HL and may identify a group who may omit IFRT.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Quimioradioterapia/mortalidad , Enfermedad de Hodgkin/patología , Tomografía Computarizada por Tomografía de Emisión de Positrones/métodos , Radioterapia Guiada por Imagen/mortalidad , Radioterapia/mortalidad , Adolescente , Adulto , Bleomicina/administración & dosificación , Niño , Preescolar , Dacarbazina/administración & dosificación , Doxorrubicina/administración & dosificación , Femenino , Fluorodesoxiglucosa F18/metabolismo , Estudios de Seguimiento , Enfermedad de Hodgkin/diagnóstico por imagen , Enfermedad de Hodgkin/terapia , Humanos , Lactante , Masculino , Pronóstico , Radiofármacos/metabolismo , Estudios Retrospectivos , Tasa de Supervivencia , Vinblastina/administración & dosificación , Adulto Joven
10.
Pediatr Blood Cancer ; 66(6): e27676, 2019 06.
Artículo en Inglés | MEDLINE | ID: mdl-30786157

RESUMEN

BACKGROUND: Melatonin is a natural health product used for sleep disturbances. In preliminary studies of adults with advanced cancer, 20 mg of melatonin daily was associated with reduction in anorexia and weight loss-symptoms that also impact pediatric oncology patients. High doses of melatonin have not been studied in pediatrics. METHODS: This was a multicenter single-arm phase I dose-escalation study utilizing a 3 + 3 design to determine the safety and tolerability of escalating doses of melatonin in pediatric oncology patients with relapsed solid tumors. Melatonin was given for 8 weeks at three dose levels-0.075 mg/kg (maximum 5 mg), 0.15 mg/kg (maximum 10 mg), and 0.3 mg/kg (maximum 20 mg). RESULTS: Melatonin was well tolerated at all three dose levels with no significant adverse events or dose-limiting toxicities. The only grade 3/4 toxicities were myelosuppression, which was attributed to the concomitant chemotherapy and occurred at all dose levels. Weight gain occurred in seven of nine patients, with a median increase of 1.1 kg (range -3.3 to 4.5) or 3.4% (range -10.2 to 8.7), with two patients losing weight (one in dose level 1 and one level 3). CONCLUSIONS: Melatonin is well tolerated at a dose of 0.3 mg/kg (maximum 20 mg), in the pediatric population. This study provides the background for further study of high-dose melatonin in pediatric oncology patients.


Asunto(s)
Anorexia/tratamiento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Antioxidantes/uso terapéutico , Melatonina/uso terapéutico , Neoplasias/tratamiento farmacológico , Trastornos del Sueño-Vigilia/tratamiento farmacológico , Pérdida de Peso/efectos de los fármacos , Adolescente , Anorexia/inducido químicamente , Anorexia/diagnóstico , Niño , Preescolar , Relación Dosis-Respuesta a Droga , Femenino , Estudios de Seguimiento , Humanos , Masculino , Dosis Máxima Tolerada , Neoplasias/patología , Pronóstico , Trastornos del Sueño-Vigilia/inducido químicamente , Trastornos del Sueño-Vigilia/diagnóstico
11.
Pediatr Blood Cancer ; 66(3): e27540, 2019 03.
Artículo en Inglés | MEDLINE | ID: mdl-30393943

RESUMEN

Combining mammalian target of rapamycin (mTOR) inhibitors and vinca alkaloids has shown therapeutic synergy in xenograft models of pediatric cancers. This phase I study assessed safety and toxicity of temsirolimus in combination with vinblastine in children. PROCEDURE: Patients ≥ 1 and ≤ 18 years with recurrent/refractory solid or CNS tumors were eligible. Vinblastine (4 mg/m2 ) and temsirolimus (15 mg/m2 ) were administered i.v. weekly, with planned dose escalation of vinblastine using a rolling six phase I design. Pharmacokinetic and pharmacodynamic data were collected. RESULTS: Seven patients with median age 12 years (range, 8-18 years) were enrolled; all were evaluable for toxicity and six for response. At dose level 1, four of six patients developed grade 3 mucositis, of which one met duration criteria for dose-limiting toxicity (DLT). Four patients required dose omissions for grade 3 or 4 hematologic toxicity, including one prolonged neutropenia DLT. A subsequent patient was enrolled on dose level -2 (temsirolimus 10 mg/m2 , vinblastine 4 mg/m2 ) with no protocol-related toxicity > grade 1, except grade 2 neutropenia. Two serious adverse events (SAE) occurred-an allergic reaction to temsirolimus (grade 2) and an intracranial hemorrhage in a CNS tumor patient (grade 3)-unlikely related to study therapy. Soluble VEGFR2 was reduced at cycle 1, day 36 in keeping with inhibition of angiogenesis. Four patients achieved prolonged stable disease for a median of 5.0 months (range, 3.1-8.3 months). CONCLUSION: The combination of weekly temsirolimus (15 mg/m2 ) and vinblastine (4 mg/m2 ) exceeds the maximum tolerated dose in children, with frequent oral mucositis and hematologic toxicity.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Resistencia a Antineoplásicos , Recurrencia Local de Neoplasia/tratamiento farmacológico , Neoplasias/tratamiento farmacológico , Terapia Recuperativa , Adolescente , Canadá , Niño , Femenino , Estudios de Seguimiento , Humanos , Masculino , Dosis Máxima Tolerada , Recurrencia Local de Neoplasia/patología , Neoplasias/patología , Pronóstico , Sirolimus/administración & dosificación , Sirolimus/análogos & derivados , Tasa de Supervivencia , Vinblastina/administración & dosificación
12.
Pediatr Blood Cancer ; 66(5): e27604, 2019 05.
Artículo en Inglés | MEDLINE | ID: mdl-30666782

RESUMEN

Clostridium difficile is the leading cause of healthcare-associated infections worldwide. The diagnosis of C. difficile infection (CDI) in pediatric oncology patients is complex as diarrhea is common, and there is a high rate of colonization in infants and young children. This study was conducted to assess the accuracy of the surveillance definitions of healthcare-associated CDI (HA-CDI) and to determine the prevalence of toxigenic C. difficile colonization among pediatric oncology and stem cell transplant patients. METHODS: A prospective cohort study was conducted over a three-year period in an inpatient pediatric oncology and stem cell transplant setting. Baseline stool samples were collected within three days of admission and were genotypically compared with clinically indicated samples submitted after three days of admission. RESULTS: A total of 175 patients were recruited with a total of 536 admissions. The adjusted prevalence of baseline toxigenic C. difficile colonization among admissions was 32.8%. Seventy-eight percent of positive admissions did not have history of CDI. Colonization with a toxigenic strain on admission was predictive of CDI (OR = 28.6; 95% CI, 6.58-124.39; P < 0.001). Nearly all clinical isolates (8/9) shared identical pulsed-field gel electrophoresis patterns with baseline isolates or were closely related (1/9). Only one of the 11 cases that were considered HA-CDI was potentially nosocomially acquired. CONCLUSION: The prevalence of colonization with toxigenic C. difficile in our cohort is high. Unfortunately, the current CDI surveillance definitions overestimate the incidence of HA-CDI in pediatric oncology and stem cell transplantation settings.


Asunto(s)
Clostridioides difficile/aislamiento & purificación , Infecciones por Clostridium/epidemiología , Infección Hospitalaria/epidemiología , Neoplasias Hematológicas/terapia , Hospitalización/estadística & datos numéricos , Trasplante de Células Madre/efectos adversos , Canadá/epidemiología , Niño , Preescolar , Infecciones por Clostridium/etiología , Infección Hospitalaria/etiología , Femenino , Estudios de Seguimiento , Humanos , Incidencia , Masculino , Pronóstico , Estudios Prospectivos
14.
J Pediatr Hematol Oncol ; 39(5): e263-e266, 2017 07.
Artículo en Inglés | MEDLINE | ID: mdl-27841828

RESUMEN

The programmed death-1 (PD-1) pathway of immune evasion is exploited by many malignancies to limit host T-cell-mediated immune responses. Nivolumab is a PD-1-blocking monoclonal antibody that disrupts this pathway and is FDA approved for the treatment of metastatic melanoma, renal cell carcinoma, and squamous non-small cell lung cancer. In this case report, we describe the first published pediatric experience of nivolumab in refractory classic Hodgkin lymphoma. In this patient with primary refractory disease and high disease burden, cytokine release syndrome requiring inotropic support developed following the first infusion of nivolumab. The patient subsequently demonstrated a dramatic clinical response with resolution of fevers, transfusion independence, improvement in functional status, and very good partial response on PET/CT following a single dose. Nivolumab was continued with corticosteroid and antihistamine premedication without further adverse events and clinical benefit was sustained at 11 months after therapy initiation, despite evidence of slow radiographic disease progression.


Asunto(s)
Anticuerpos Monoclonales/uso terapéutico , Enfermedad de Hodgkin/tratamiento farmacológico , Antineoplásicos/uso terapéutico , Cardiotónicos/uso terapéutico , Niño , Enfermedad de Hodgkin/diagnóstico , Enfermedad de Hodgkin/diagnóstico por imagen , Humanos , Masculino , Nivolumab , Tomografía Computarizada por Tomografía de Emisión de Positrones , Terapia Recuperativa/métodos , Resultado del Tratamiento
17.
Br J Haematol ; 164(5): 717-21, 2014 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-24236830

RESUMEN

The significance of paroxysmal nocturnal haemoglobinuria (PNH(pos) ) cells and leucocyte subset telomere lengths in paediatric aplastic anaemia (AA) is unknown. Among 22 children receiving immunosuppressive therapy (IST) for AA, 73% (16/22) were PNH(pos) , of whom 94% achieved at least a partial response (PR) to IST; 11/16 (69%) achieved complete response (CR). Only 2/6 (33%) PNH(neg) patients achieved PR. PNH(pos) patients were less likely to fail IST compared to PNH(neg) patients (odds ratio 0·033; 95% confidence interval 0·002-0·468; P = 0·012). Children with AA had short granulocyte (P = 7·8 × 10(-9) ), natural killer cell (P = 6·0 × 10(-4) ), naïve T lymphocyte (P = 0·002) and B lymphocyte (P = 0·005) telomeres compared to age-matched normative data.


Asunto(s)
Anemia Aplásica/complicaciones , Hemoglobinuria Paroxística/complicaciones , Leucocitos/ultraestructura , Telómero/ultraestructura , Adolescente , Anemia Aplásica/tratamiento farmacológico , Anemia Aplásica/genética , Anemia Aplásica/inmunología , Niño , Preescolar , Femenino , Hemoglobinuria Paroxística/genética , Hemoglobinuria Paroxística/inmunología , Humanos , Inmunofenotipificación , Inmunosupresores/uso terapéutico , Lactante , Masculino , Pronóstico , Estudios Retrospectivos , Homeostasis del Telómero , Resultado del Tratamiento
18.
Pediatr Blood Cancer ; 61(4): 627-35, 2014 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-24038992

RESUMEN

BACKGROUND: Neuroblastoma in older children and adolescents has a distinctive, indolent phenotype, but little is known about the clinical and biological characteristics that distinguish this rare subgroup. Our goal was to determine if an optimal age cut-off exists that defines indolent disease and if accepted prognostic factors and treatment approaches are applicable to older children. PROCEDURE: Using data from the International Neuroblastoma Risk Group, among patients ≥18 months old (n = 4,027), monthly age cut-offs were tested to determine the effect of age on survival. The prognostic effect of baseline characteristics and autologous hematopoietic cell transplant (AHCT) for advanced disease was assessed within two age cohorts; ≥5 to <10 years (n = 730) and ≥10 years (n = 200). RESULTS: Older age was prognostic of poor survival, with outcome gradually worsening with increasing age at diagnosis, without statistical evidence for an optimal age cut-off beyond 18 months. Among patients ≥5 years, factors significantly prognostic of lower event-free survival (EFS) and overall survival (OS) in multivariable analyses were INSS stage 4, MYCN amplification and unfavorable INPC histology classification. Among stage 4 patients, AHCT provided a significant EFS and OS benefit. Following relapse, patients in both older cohorts had prolonged OS compared to those ≥18 months to <5 years (P < 0.0001). CONCLUSIONS: Despite indolent disease and infrequent MYCN amplification, older children with advanced disease have poor survival, without evidence for a specific age cut-off. Our data suggest that AHCT may provide a survival benefit in older children with advanced disease. Novel therapeutic approaches are required to more effectively treat these patients.


Asunto(s)
Neoplasias Óseas/mortalidad , Neuroblastoma/mortalidad , Adolescente , Adulto , Factores de Edad , Neoplasias Óseas/genética , Neoplasias Óseas/patología , Niño , Preescolar , Cromosomas Humanos Par 1/genética , Cromosomas Humanos Par 11/genética , Femenino , Estudios de Seguimiento , Eliminación de Gen , Humanos , Lactante , Agencias Internacionales , Masculino , Proteína Proto-Oncogénica N-Myc , Clasificación del Tumor , Neuroblastoma/genética , Neuroblastoma/patología , Proteínas Nucleares/genética , Proteínas Oncogénicas/genética , Pronóstico , Tasa de Supervivencia , Adulto Joven
19.
Cancer Med ; 13(3): e7033, 2024 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-38400668

RESUMEN

BACKGROUND: The need for new therapies to improve survival and outcomes in pediatric oncology along with the lack of approval and accessible clinical trials has led to "out-of-trial" use of innovative therapies. We conducted a retrospective analysis of requests for innovative anticancer therapy in Canadian pediatric oncology tertiary centers for patients less than 30 years old between 2013 and 2020. METHODS: Innovative therapies were defined as cancer-directed drugs used (a) off-label, (b) unlicensed drugs being used outside the context of a clinical trial, or (c) approved drugs with limited evidence in pediatrics. We excluded cytotoxic chemotherapy, cellular products, and cytokines. RESULTS: We retrieved data on 352 innovative therapy drug requests. Underlying diagnosis was primary CNS tumor 31%; extracranial solid tumor 37%, leukemia/lymphoma 22%, LCH 2%, and plexiform neurofibroma 6%. RAS/MAP kinase pathway inhibitors were the most frequently requested innovative therapies in 28% of all requests followed by multi-targeted tyrosine kinase inhibitors (17%), inhibitors of the PIK3CA-mTOR-AKT pathway (8%), immune checkpoints inhibitors (8%), and antibody drug conjugates (8%). In 112 out of 352 requests, innovative therapies were used in combination with another anticancer agent. 48% of requests were motivated by the presence of an actionable molecular target. Compassionate access accounted for 52% of all requests while public insurance was used in 27%. Mechanisms of funding varied between provinces. CONCLUSION: This real-world data collection illustrates an increasing use of "out-of-trial" innovative therapies in pediatric oncology. This new field of practice warrants further studies to understand the impact on patient trajectory and equity in access to innovative therapies.


Asunto(s)
Antineoplásicos , Neoplasias , Humanos , Niño , Adulto , Estudios Retrospectivos , Canadá , Neoplasias/tratamiento farmacológico , Oncología Médica , Antineoplásicos/uso terapéutico , Terapias en Investigación
20.
Nat Commun ; 15(1): 4165, 2024 May 16.
Artículo en Inglés | MEDLINE | ID: mdl-38755180

RESUMEN

The role for routine whole genome and transcriptome analysis (WGTA) for poor prognosis pediatric cancers remains undetermined. Here, we characterize somatic mutations, structural rearrangements, copy number variants, gene expression, immuno-profiles and germline cancer predisposition variants in children and adolescents with relapsed, refractory or poor prognosis malignancies who underwent somatic WGTA and matched germline sequencing. Seventy-nine participants with a median age at enrollment of 8.8 y (range 6 months to 21.2 y) are included. Germline pathogenic/likely pathogenic variants are identified in 12% of participants, of which 60% were not known prior. Therapeutically actionable variants are identified by targeted gene report and whole genome in 32% and 62% of participants, respectively, and increase to 96% after integrating transcriptome analyses. Thirty-two molecularly informed therapies are pursued in 28 participants with 54% achieving a clinical benefit rate; objective response or stable disease ≥6 months. Integrated WGTA identifies therapeutically actionable variants in almost all tumors and are directly translatable to clinical care of children with poor prognosis cancers.


Asunto(s)
Variaciones en el Número de Copia de ADN , Perfilación de la Expresión Génica , Neoplasias , Humanos , Niño , Neoplasias/genética , Neoplasias/terapia , Femenino , Adolescente , Masculino , Preescolar , Pronóstico , Perfilación de la Expresión Génica/métodos , Lactante , Transcriptoma , Adulto Joven , Secuenciación Completa del Genoma , Mutación de Línea Germinal , Mutación , Genoma Humano/genética , Predisposición Genética a la Enfermedad
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