RESUMO
BACKGROUND: Patients with localized intracranial germinoma have excellent survival. Reducing treatment burden and long-term sequelae is a priority. Intensive inpatient chemotherapy (e.g., carboPEI = carboplatin/etoposide/ifosfamide) has been effectively employed to reduce radiotherapy treatment volume/dose. Outpatient-based carboplatin monotherapy is associated with excellent outcomes in metastatic testicular seminoma (an identical pathology), and successful vinblastine monotherapy induction (with 77% tumor volume reduction after just two weekly vinblastine doses) has recently been reported in an intracranial germinoma patient. METHODS: Adapted UK guidelines for germ cell tumor management were distributed during the COVID-19 pandemic, including nonstandard treatment options to reduce hospital visits and/or admissions. This included vinblastine monotherapy for intracranial germinoma (6 mg/m2 intravenously, or 4 mg/m2 for moderate count suppression, delivered weekly). We describe two such patients treated using this approach. RESULTS: A 30-year-old male with a localized pineal tumor received 12-week vinblastine induction, with >60% volume reduction, prior to definitive radiotherapy. A 12-year-old female with a metastatic suprasellar tumor and progression at all sites of disease whilst awaiting proton radiotherapy received two vinblastine doses with good early response, including 36% primary tumor volume reduction. The patients tolerated vinblastine well. CONCLUSION: Patients with intracranial germinoma have excellent outcomes, and reduction of late effects remains a priority. The description of vinblastine monotherapy in these intracranial germinoma patients warrants further exploration.
Assuntos
Neoplasias Encefálicas , Germinoma , Neoplasias Embrionárias de Células Germinativas , Vimblastina , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/radioterapia , COVID-19 , Carboplatina/uso terapêutico , Criança , Etoposídeo/uso terapêutico , Feminino , Germinoma/tratamento farmacológico , Germinoma/radioterapia , Humanos , Masculino , Neoplasias Embrionárias de Células Germinativas/tratamento farmacológico , Neoplasias Embrionárias de Células Germinativas/radioterapia , Pandemias , Vimblastina/uso terapêuticoRESUMO
Pediatric ependymomas are highly recurrent tumors resistant to conventional chemotherapy. Telomerase, a ribonucleoprotein critical in permitting limitless replication, has been found to be critically important for the maintenance of tumor-initiating cells (TICs). These TICs are chemoresistant, repopulate the tumor from which they are identified, and are drivers of recurrence in numerous cancers. In this study, telomerase enzymatic activity was directly measured and inhibited to assess the therapeutic potential of targeting telomerase. Telomerase repeat amplification protocol (TRAP) (n = 36) and C-circle assay/telomere FISH/ATRX staining (n = 76) were performed on primary ependymomas to determine the prevalence and prognostic potential of telomerase activity or alternative lengthening of telomeres (ALT) as telomere maintenance mechanisms, respectively. Imetelstat, a phase 2 telomerase inhibitor, was used to elucidate the effect of telomerase inhibition on proliferation and tumorigenicity in established cell lines (BXD-1425EPN, R254), a primary TIC line (E520) and xenograft models of pediatric ependymoma. Over 60 % of pediatric ependymomas were found to rely on telomerase activity to maintain telomeres, while no ependymomas showed evidence of ALT. Children with telomerase-active tumors had reduced 5-year progression-free survival (29 ± 11 vs 64 ± 18 %; p = 0.03) and overall survival (58 ± 12 vs 83 ± 15 %; p = 0.05) rates compared to those with tumors lacking telomerase activity. Imetelstat inhibited proliferation and self-renewal by shortening telomeres and inducing senescence in vitro. In vivo, Imetelstat significantly reduced subcutaneous xenograft growth by 40 % (p = 0.03) and completely abolished the tumorigenicity of pediatric ependymoma TICs in an orthotopic xenograft model. Telomerase inhibition represents a promising therapeutic approach for telomerase-active pediatric ependymomas found to characterize high-risk ependymomas.
Assuntos
Neoplasias Encefálicas/tratamento farmacológico , Inibidores Enzimáticos/farmacologia , Ependimoma/tratamento farmacológico , Indóis/farmacologia , Células-Tronco Neoplásicas/efeitos dos fármacos , Niacinamida/análogos & derivados , Telomerase/antagonistas & inibidores , Animais , Neoplasias Encefálicas/diagnóstico , Neoplasias Encefálicas/enzimologia , Carcinogênese/efeitos dos fármacos , Carcinogênese/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/fisiologia , Pré-Escolar , Estudos de Coortes , Intervalo Livre de Doença , Ependimoma/diagnóstico , Ependimoma/enzimologia , Feminino , Humanos , Camundongos , Recidiva Local de Neoplasia/diagnóstico , Recidiva Local de Neoplasia/enzimologia , Transplante de Neoplasias , Células-Tronco Neoplásicas/enzimologia , Niacinamida/farmacologia , Oligonucleotídeos , Telomerase/metabolismo , Telômero/efeitos dos fármacos , Telômero/metabolismoRESUMO
Inflammatory myofibroblastic tumors (IMT) are rare, mostly benign soft tissue tumors. Occurring mainly in children the presentation, clinical features, and diagnostic dilemmas raised are well reported. Here we describe 4 patients diagnosed with IMT after the treatment of childhood cancer, and review the literature regarding IMT and malignancy. Discussing them in this context raises clinical questions; Are these tumors incidental or a consequence of treatment? Are they more common than we think and are any miss-diagnosed as tumor recurrence? This paper aims to raise awareness of IMT as diagnostic possibilities after treatment for childhood malignancies.
Assuntos
Granuloma de Células Plasmáticas/diagnóstico , Granuloma de Células Plasmáticas/etiologia , Neoplasias/terapia , Adolescente , Criança , Pré-Escolar , Terapia Combinada , Feminino , Humanos , MasculinoRESUMO
Preparing for disasters both natural and anthropogenic requires assessment of risk through hazard vulnerability analysis and formulation of facility and critical care-specific disaster plans. Disaster surge conditions often require movement from conventional to contingency or crisis-level operations to meet the needs of the many under our care. Predisaster planning for modification of critical care space, staffing, and supplies is essential to successful execution of operations during a surge. Expansion of intensive care unit beds to nonconventional units such as perioperative areas, general care units, and even external temporary units may be necessary. Creative, tiered staffing models as well as just-in-time education of noncritical care clinicians and support staff are important to multiply capable personnel under surge conditions. Finally, anticipation of demand for key equipment and supplies is essential to maintain stockpiles, establish supply chains, and sustain operations under prolonged disaster scenarios.
Assuntos
Planejamento em Desastres , Incidentes com Feridos em Massa , Cuidados Críticos , Humanos , Unidades de Terapia Intensiva , Capacidade de Resposta ante EmergênciasRESUMO
BACKGROUND: Gram negative infection is an important cause of mortality in patients receiving chemotherapy for malignant disease or as conditioning for stem cell transplantation. The risk of infection is thought to be greatest in those patients who are neutropenic and it is routine for these patients to receive broad spectrum antibiotic therapy when febrile. This study evaluates the outcome of gram negative infection in a mixed haematology/oncology population in a single institution. PROCEDURE: All episodes of laboratory proven gram negative infection in patients receiving chemotherapy between January 2004 and March 2006 were included. A retrospective case-note based analysis was carried out to identify diagnosis, treatment, neutrophil count at time of infection, antibiotic therapy and clinical outcome. RESULTS: One hundred six episodes of gram negative infection in 72 patients were identified. Sixty-seven percent of these were in patients receiving chemotherapy for malignant disease, 33% were in patients undergoing stem cell transplantation. Overall ICU admission rate was 13% and mortality was 6%. Coliforms, Pseudomonas and Klebsiella were the commonest isolates, and ICU admission and mortality rates were higher with Pseudomonas and Klebsiella infection than coliforms. After stem cell transplantation most episodes of gram negative infection occurred in non-neutropenic patients, while the reverse was true after chemotherapy. CONCLUSION: Gram negative infection remains a significant cause of both ICU admission and mortality. Gram negative infection is largely confined to neutropenic periods after chemotherapy but not after stem cell transplantation. The isolation of Pseudomonas or Klebsiella confers a higher chance of both ICU admission and death.
Assuntos
Infecções por Bactérias Gram-Negativas/imunologia , Hospedeiro Imunocomprometido/imunologia , Adolescente , Antineoplásicos/uso terapêutico , Células Cultivadas , Criança , Pré-Escolar , Infecções por Bactérias Gram-Negativas/complicações , Infecções por Bactérias Gram-Negativas/epidemiologia , Infecções por Bactérias Gram-Negativas/microbiologia , Humanos , Lactente , Contagem de Leucócitos , Neoplasias/complicações , Neoplasias/tratamento farmacológico , Neoplasias/imunologia , Neoplasias/cirurgia , Neutrófilos/citologia , Transplante de Células-TroncoRESUMO
BACKGROUND: The advent of integrated genomics has fundamentally changed our understanding of medulloblastoma. Although survival differences exist among the 4 principal subgroups, this has yet to be elucidated in a North American cohort of irradiated patients. METHODS: Ninety-two consecutive patients between the ages of 3 and 17 treated with surgery, craniospinal irradiation, and chemotherapy were identified at the Hospital for Sick Children. Molecular subgrouping was performed using nanoString. RESULTS: Two treatment periods were identified: prior to 2006 as per the protocols of the Children's Oncology Group, and after 2006 per the St Jude Medulloblastoma 03 protocol. Five-year progression-free survival (PFS) over the entire cohort was 0.801 (95% CI: 0.692-0.875) with no significant difference between treatment protocols. Strikingly, we found that Group 4 patients had excellent 5-year PFS of 0.959 (95% CI: 0.744-0.994) for average risk and 0.887 (95% CI: 0.727-0.956) across all Group 4 patients. Group 3 patients had 5-year PFS of 0.733 (95% CI: 0.436-0.891). Sonic hedgehog patients did poorly across both treatment protocols, with 5-year PFS of 0.613 (95% CI: 0.333-0.804), likely owing to a high proportion of TP53 mutated patients in this age group. CONCLUSIONS: In a cohort of irradiated patients over 3 years of age, PFS for Group 4 patients was significantly improved compared with initial reports. The impact of subgroup affiliation in these children needs to be assessed in large prospectively treated cooperative protocols to determine if more than just WNT patients can be safely selected for de-escalation of therapy.
Assuntos
Neoplasias Cerebelares/patologia , Irradiação Craniana , Meduloblastoma/patologia , Adolescente , Neoplasias Cerebelares/classificação , Neoplasias Cerebelares/radioterapia , Criança , Pré-Escolar , Feminino , Seguimentos , Humanos , Masculino , Meduloblastoma/classificação , Meduloblastoma/radioterapia , Gradação de Tumores , Prognóstico , Fatores de Risco , Taxa de SobrevidaRESUMO
Survival rates from childhood cancer have improved dramatically in the last 40 years, such that over 80% of children are now cured. However in certain subgroups, including metastatic osteosarcoma, survival has remained stubbornly poor, despite dose intensive multi-agent chemotherapy regimens, and new therapeutic approaches are needed. Hypoxia is common in adult solid tumours and is associated with treatment resistance and poorer outcome. Hypoxia induces chemotherapy resistance in paediatric tumours including neuroblastoma, rhabdomyosarcoma and Ewing's sarcoma, in vitro, and this drug resistance is dependent on the oxygen-regulated transcription factor hypoxia inducible factor-1 (HIF-1). In this study the effects of hypoxia on the response of the osteosarcoma cell lines 791T, HOS and U2OS to the clinically relevant cytotoxics cisplatin, doxorubicin and etoposide were evaluated. Significant hypoxia-induced resistance to all three agents was seen in all three cell lines and hypoxia significantly reduced drug-induced apoptosis. Hypoxia also attenuated drug-induced activation of p53 in the p53 wild-type U2OS osteosarcoma cells. Drug resistance was not induced by HIF-1α stabilisation in normoxia by cobalt chloride nor reversed by the suppression of HIF-1α in hypoxia by shRNAi, siRNA, dominant negative HIF or inhibition with the small molecule NSC-134754, strongly suggesting that hypoxia-induced drug resistance in osteosarcoma cells is independent of HIF-1α. Inhibition of the phosphoinositide 3-kinase (PI3K) pathway using the inhibitor PI-103 did not reverse hypoxia-induced drug resistance, suggesting the hypoxic activation of Akt in osteosarcoma cells does not play a significant role in hypoxia-induced drug resistance. Targeting hypoxia is an exciting prospect to improve current anti-cancer therapy and combat drug resistance. Significant hypoxia-induced drug resistance in osteosarcoma cells highlights the potential importance of hypoxia as a target to reverse drug resistance in paediatric osteosarcoma. The novel finding of HIF-1α independent drug resistance suggests however other hypoxia related targets may be more relevant in paediatric osteosarcoma.