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Whole brain radiotherapy (WBRT) is used to improve tumor control in patients with primary brain tumors, or brain metastasis from various primary tumors to improve tumor control. However, WBRT can lead to cognitive decline in patients. We assessed whether fractionated WBRT (fWBRT) affects spontaneous behavior of mice in automated home cages and cognition (spatial memory) using the Barnes maze. Male C57Bl/6j mice received bi-lateral fWBRT at a dosage of 4 Gy/day on 5 consecutive days. In line with previous reports, immunohistochemical analysis of doublecortin positive cells in the dentate gyrus showed a profound reduction in immature neurons 4 weeks after fWBRT. Surprisingly, spontaneous behavior as measured in automated home cages was not affected. Moreover, learning and memory measured with Barnes maze, was also not affected 4-6 weeks after fWBRT. At 10-11 weeks after fWBRT a significant difference in escape latency during the learning phase, but not in the probe test of the Barnes maze was observed. In conclusion, although we confirmed the serious adverse effect of fWBRT on neurogenesis 4 weeks after fWBRT, we did not find similar profound effects on spontaneous behavior in the automated home cage nor on learning abilities as measured by the Barnes maze. The relationship between the neurobiological effects of fWBRT and cognition seems more complex than often assumed and the choice of animal model, cognitive tasks, neurobiological parameters, and experimental set-up might be important factors in these types of experiments.
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BACKGROUND: Historically leptomeningeal metastases (LM) from melanoma have a poor prognosis, with a median survival of only 2 months despite treatment. Targeted therapy and immune checkpoint inhibitors are promising new treatment options in advanced melanoma. We sought to determine the impact of targeted therapy and immunotherapy on the outcome of melanoma patients with LM and to evaluate the influence of prognostic factors. PATIENTS AND METHODS: We analyzed a series of 39 consecutive patients diagnosed with LM from melanoma between May 2010 and March 2015 treated at the Netherlands Cancer Institute. Thirty-four of these patients also had brain metastases (BM). Statistical analyses assessed the influence of clinical and biological characteristics on survival. RESULTS: Median overall survival of the entire cohort was 6.9 weeks (95% confidence interval 0.9-12.8). Due to a poor performance status or rapidly progressive disease, 14 patients received no treatment. Median overall survival of untreated patients after the diagnosis of LM was 2.9 versus 16.9 weeks for treated patients (P < 0.001). The median survival of 21 patients treated with systemic targeted therapy and/or immunotherapy, with or without RT was 21.7 weeks (range 2-235 weeks). Five patients had LM without BM. Three of these patients died within 3 weeks before any treatment was given, whereas 2 patients are in ongoing remission for 26 weeks (following dabrafenib) and 235 weeks (following WBRT and ipilimumab). Elevated serum lactate dehydrogenase and S100B at diagnosis of LM were associated with shorter survival. CONCLUSION: LM from melanoma still has an extremely poor prognosis. As observed in extracranial metastatic disease, new treatment modalities such as systemic targeted therapy and immune checkpoint inhibitors seem to increase overall survival in LM, and may result in long-term remission. These new treatment options should be considered in patients with LM.
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Imunoterapia , Ipilimumab/administração & dosagem , Melanoma/tratamento farmacológico , Neoplasias Meníngeas/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Ipilimumab/efeitos adversos , Masculino , Melanoma/imunologia , Melanoma/patologia , Neoplasias Meníngeas/imunologia , Neoplasias Meníngeas/patologia , Neoplasias Meníngeas/secundário , Pessoa de Meia-Idade , Terapia de Alvo Molecular , Países Baixos , Prognóstico , Estudos RetrospectivosRESUMO
The treatment for central nervous system metastases of solid tumors and gliomas is limited as the blood-brain barrier (BBB) is an obstacle to systemic therapy. Here, we review the physiochemical properties of the BBB and both current and new drug strategies to penetrate brain tumors. We focus on targeting receptor- or carrier-mediated transport mechanisms over the BBB used by drug conjugates, nanoparticles, polymer-based nanocarriers, siRNA, and antibodies.
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Antineoplásicos/uso terapêutico , Neoplasias do Sistema Nervoso Central , Glioma/tratamento farmacológico , Glioma/patologia , Barreira Hematoencefálica/fisiopatologia , Neoplasias do Sistema Nervoso Central/tratamento farmacológico , Neoplasias do Sistema Nervoso Central/patologia , Neoplasias do Sistema Nervoso Central/secundário , HumanosRESUMO
Cognitive deficit is a frequently reported side-effect of adjuvant chemotherapy. A large number of animal studies has been performed to examine the neurobiological mechanisms underlying this phenomenon, however, definite conclusions from these studies are restricted due to differences in experimental set-up. We systematically investigated the effects of 6 cytotoxic agents on various neurobiological parameters. C57Bl/6J mice were treated with cyclophosphamide, docetaxel, doxorubicin, 5-fluorouracil, methotrexate, or topotecan. The animals were sacrificed 3 or 15 weeks after treatment and the effect on neurogenesis, blood vessel density, and neuroinflammation was analyzed using immunohistochemistry. None of the cytostatic agents tested affected neurogenesis (cell survival or cell proliferation). Blood vessel density was increased in the hippocampus and prefrontal cortex 3 weeks after treatment with docetaxel and doxorubicin compared with control animals. A decrease in the number of microglial cells was observed in the prefrontal cortex after treatment with cyclophosphamide, docetaxel, 5-FU, and topotecan compared with control mice. The observed decrease in microglia cells is indicative of inflammation that occurred after treatment. Overall, the magnitude of the effects was relatively modest. Therefore, we conducted a similar study with topotecan in Abcg2;Abcb1a/b knock out and wildtype FVB mice. Animals were sacrificed 3 weeks after treatment and no notable effect was seen in hippocampal cell differentiation (DCX), microglia activation, or blood vessel density. Perhaps the FVB strain is more resistant to the neurotoxic effects of topotecan which makes this not the correct model to study the mechanism of chemotherapy-induced cognitive impairment.
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Antineoplásicos/efeitos adversos , Encéfalo/efeitos dos fármacos , Transtornos Cognitivos/induzido quimicamente , Citotoxinas/efeitos adversos , Imunossupressores/efeitos adversos , Neurobiologia , Animais , Vasos Sanguíneos/efeitos dos fármacos , Quimioterapia Adjuvante/efeitos adversos , Modelos Animais de Doenças , Proteína Duplacortina , Hipocampo/efeitos dos fármacos , Imuno-Histoquímica/métodos , Camundongos , Camundongos Endogâmicos C57BL , Microglia/efeitos dos fármacos , Neurogênese/efeitos dos fármacos , Córtex Pré-Frontal/efeitos dos fármacosRESUMO
RATIONALE AND OBJECTIVES: Adjuvant chemotherapy is associated with changes in cognition in a subgroup of cancer patients. Chemotherapy is generally given as a combination of cytotoxic agents, which makes it hard to define the agent responsible for these observed changes. Literature on animal experiments has been difficult to interpret due to variance in experimental setup. METHODS: We examined the effects of cytotoxic agents administered separately on various cognitive measures in a standardized animal model. Male C57Bl/6 mice received cyclophosphamide, docetaxel, doxorubicin, 5-fluorouracil, methotrexate, or topotecan. These agents represent different compound classes based on their working mechanism and are frequently prescribed in the clinic. A control group received saline. Behavioral testing started 2 or 15 weeks after treatment and included testing general measures of behavior and cognitive task performance: spontaneous behavior in an automated home cage, open field, novel location recognition (NLR), novel object recognition (NOR), Barnes maze, contextual fear conditioning, and a simple choice reaction time task (SCRTT). RESULTS: Cyclophosphamide, docetaxel, and doxorubicin administration affected spontaneous activity in the automated home cage. All cytotoxic agents affected memory (NLR and/or NOR). Spatial memory measured in the Barnes maze was affected after administration with doxorubicin, 5-fluorouracil, and topotecan. Decreased inhibition in the SCRTT was observed after treatment with cyclophosphamide, docetaxel, and topotecan. CONCLUSIONS: Our data show that, in mice, a single treatment with a cytotoxic agent causes cognitive impairment. Not all cytotoxic agents affected the same cognitive domains, which might be explained by differences in working mechanisms of the various agents.
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Antineoplásicos/toxicidade , Transtornos Cognitivos/induzido quimicamente , Transtornos Cognitivos/psicologia , Citotoxinas/toxicidade , Animais , Cognição/efeitos dos fármacos , Relação Dose-Resposta a Droga , Medo/efeitos dos fármacos , Medo/psicologia , Fluoruracila/toxicidade , Masculino , Memória/efeitos dos fármacos , Metotrexato/toxicidade , Camundongos , Camundongos Endogâmicos C57BL , Tempo de Reação/efeitos dos fármacosRESUMO
Chemotherapy induced peripheral neuropathy (CIPN) is a potentially dose limiting side effect of commonly used chemotherapeutic agents like taxanes, vinca-alkaloids, platinum compounds, bortezomib and thalidomide. Supposed pathogenetic mechanisms of CIPN are axonopathy through dying back axon damage and neuronopathy in which the cell bodies of the dorsal root ganglia are involved. The exact pathophysiology however is not clear and different underlying mechanisms have been proposed for different classes of anti-cancer drugs. Sensory symptoms, like pain, numbness and tingling are most common, but motor weakness, autonomic dysfunction and even cranial nerve involvement may occur. CIPN can be painful and/or disabling, causing significant loss of functional abilities and decreasing quality of life. This can lead to dose reductions, discontinuation of treatment and may thus, ultimately, affect survival. Risk factors for CIPN include dose per cycle, cumulative dose, treatment schedule, duration of infusion, administration of other chemotherapeutics, comorbidity and pre-existing peripheral neuropathy. The exploration of polymorphisms in genes associated with incidence or severity of neuropathy might result in identifying individuals being at higher risk of neurotoxicity. An update on genes possibly associated with CIPN is given. CIPN may be reversible or be more or less permanent. Many preventive and treatment strategies have been explored, without significant efficacy up till now. In this review we describe the different drug-related characteristics of CIPN, pharmacogenomic studies, neurophysiological findings, treatment and outcome, and neuroprotective strategies.
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Antineoplásicos/efeitos adversos , Doenças do Sistema Nervoso Periférico/induzido quimicamente , Animais , Antineoplásicos/toxicidade , Humanos , Fatores de RiscoRESUMO
Reports on the outcome of patients with primary central nervous system lymphoma (PCNSL) are mainly based on results obtained in the context of clinical trials. However, due to poor performance status and cognitive impairment, most patients are actually treated outside clinical studies. The aim of this retrospective study was to get more insight into the outcome of HIV-negative PCNSL patients, treated between 2000-2010 in two hospitals (one academic centre and one categorical cancer centre). Fifty-two patients were identified. Eight patients were treated with corticosteroids only. Sixteen patients received high-dose methotrexate (MTX)-based chemotherapy, ten received radiotherapy and 18 patients were treated with a combination of MTX-based chemotherapy and radiotherapy. At a median follow-up of 63.1 months, the median overall survival for all patients was 24.4 months (95% CI: 11.5-39.8 months), with an event-free survival of 14 months (95% CI: 7.3-24.4 months). Causes of death were progressive PCNSL in 29 patients, MTX toxicity in four patients and epileptic seizures in one patient. These results are comparable with the outcome of prospective clinical trials in this disease, which still has a relatively poor prognosis.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias do Sistema Nervoso Central/tratamento farmacológico , Neoplasias do Sistema Nervoso Central/radioterapia , Linfoma/tratamento farmacológico , Linfoma/radioterapia , Corticosteroides/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Ensaios Clínicos como Assunto , Terapia Combinada , Intervalo Livre de Doença , Feminino , Humanos , Masculino , Metotrexato/administração & dosagem , Pessoa de Meia-Idade , Estudos Retrospectivos , Taxa de Sobrevida , Resultado do TratamentoRESUMO
BACKGROUND: The different perception and assessment of chemotherapy-induced peripheral neurotoxicity (CIPN) between healthcare providers and patients has not yet been fully addressed, although these two approaches might eventually lead to inconsistent, possibly conflicting interpretation, especially regarding sensory impairment. PATIENTS AND METHODS: A cohort of 281 subjects with stable CIPN was evaluated with the National Cancer Institute-Common Toxicity Criteria (NCI-CTC v. 2.0) sensory scale, the clinical Total Neuropathy Score (TNSc©), the modified Inflammatory Neuropathy Cause and Treatment (INCAT) sensory sumscore (mISS) and the European Organization for Research and Treatment of Cancer CIPN specific self-report questionnaire (EORTC QOL-CIPN20). RESULTS: Patients' probability estimates showed that the EORTC QLQ-CIPN20 sensory score was overall more highly related to the NCI-CTC sensory score. However, the vibration perception item of the TNSc had a higher probability to be scored 0 for EORTC QLQ-CIPN20 scores lower than 35, as vibration score 2 for EORTC QLQ-CIPN20 scores between 35 and 50 and as grade 3 or 4 for EORTC QLQ-CIPN20 scores higher than 50. The linear models showed a significant trend between each mISS item and increasing EORTC QLQ-CIPN20 sensory scores. CONCLUSION: None of the clinical items had a perfect relationship with patients' perception, and most of the discrepancies stood in the intermediate levels of CIPN severity. Our data indicate that to achieve a comprehensive knowledge of CIPN including a reliable assessment of both the severity and the quality of CIPN-related sensory impairment, clinical and PRO measures should be always combined.
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Antineoplásicos/efeitos adversos , Avaliação de Resultados da Assistência ao Paciente , Doenças do Sistema Nervoso Periférico/induzido quimicamente , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/uso terapêutico , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias/tratamento farmacológico , Doenças do Sistema Nervoso Periférico/patologia , Qualidade de Vida , Autorrelato , Resultado do TratamentoRESUMO
Chemotherapy-induced peripheral neuropathy (CIPN) is a common neurological side-effect of cancer treatment and may lead to declines in patients' daily functioning and quality of life. To date, there are no modern clinimetrically well-evaluated outcome measures available to assess disability in CIPN patients. The objective of the study was to develop an interval-weighted scale to capture activity limitations and participation restrictions in CIPN patients using the Rasch methodology and to determine its validity and reliability properties. A preliminary Rasch-built Overall Disability Scale (pre-R-ODS) comprising 146 items was assessed twice (interval: 2-3 weeks; test-retest reliability) in 281 CIPN patients with a stable clinical condition. The obtained data were subjected to Rasch analyses to determine whether model expectations would be met, and if necessarily, adaptations were made to obtain proper model fit (internal validity). External validity was obtained by correlating the CIPN-R-ODS with the National Cancer Institute-Common Toxicity Criteria (NCI-CTC) neuropathy scales and the Pain-Intensity Numeric-Rating-Scale (PI-NRS). The preliminary R-ODS did not meet Rasch model's expectations. Items displaying misfit statistics, disordered thresholds, item bias or local dependency were systematically removed. The final CIPN-R-ODS consisting of 28 items fulfilled all the model's expectations with proper validity and reliability, and was unidimensional. The final CIPN-R-ODS is a Rasch-built disease-specific, interval measure suitable to detect disability in CIPN patients and bypasses the shortcomings of classical test theory ordinal-based measures. Its use is recommended in future clinical trials in CIPN.
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Antineoplásicos/efeitos adversos , Avaliação da Deficiência , Doenças do Sistema Nervoso Periférico/induzido quimicamente , Doenças do Sistema Nervoso Periférico/diagnóstico , Inquéritos e Questionários , Atividades Cotidianas , Adulto , Idoso , Idoso de 80 Anos ou mais , Distribuição de Qui-Quadrado , Consenso , Europa (Continente) , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Medição da Dor , Doenças do Sistema Nervoso Periférico/fisiopatologia , Doenças do Sistema Nervoso Periférico/psicologia , Valor Preditivo dos Testes , Qualidade de Vida , Reprodutibilidade dos Testes , Índice de Gravidade de DoençaRESUMO
BACKGROUND: Chemotherapy-induced peripheral neuropathy (CIPN) is a debilitating and dose-limiting complication of cancer treatment. Thus far, the impact of CIPN has not been studied in a systematic clinimetric manner. The objective of the study was to select outcome measures for CIPN evaluation and to establish their validity and reproducibility in a cross-sectional multicenter study. PATIENTS AND METHODS: After literature review and a consensus meeting among experts, face/content validity were obtained for the following selected scales: the National Cancer Institute-Common Toxicity Criteria (NCI-CTC), the Total Neuropathy Score clinical version (TNSc), the modified Inflammatory Neuropathy Cause and Treatment (INCAT) group sensory sumscore (mISS), the European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30, and CIPN20 quality-of-life measures. A total of 281 patients with stable CIPN were examined. Validity (correlation) and reliability studies were carried out. RESULTS: Good inter-/intra-observer scores were obtained for the TNSc, mISS, and NCI-CTC sensory/motor subscales. Test-retest values were also good for the EORTC QLQ-C30 and CIPN20. Acceptable validity scores were obtained through the correlation among the measures. CONCLUSION: Good validity and reliability scores were demonstrated for the set of selected impairment and quality-of-life outcome measures in CIPN. Future studies are planned to investigate the responsiveness aspects of these measures.
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Antineoplásicos/efeitos adversos , Antineoplásicos/uso terapêutico , Neoplasias/tratamento farmacológico , Doenças do Sistema Nervoso Periférico/induzido quimicamente , Estudos Transversais , Nível de Saúde , Humanos , Avaliação de Resultados em Cuidados de Saúde , Qualidade de Vida , Resultado do TratamentoRESUMO
OBJECTIVE: This study aimed to evaluate self-reported cognitive functioning of postmenopausal breast cancer patients before and during endocrine treatment compared with healthy female controls, and to investigate associations between self-reported cognitive functioning, cognitive test performance and anxiety/depression, fatigue, and menopausal complaints. METHODS: Self-reported cognitive functioning, anxiety/depression, fatigue, menopausal complaints, and cognitive tests performance were assessed before (T1) and after 1 year (T2) of adjuvant endocrine treatment in postmenopausal chemotherapy-naïve breast cancer patients. Self-reported cognitive functioning was assessed by the cognitive failures questionnaire and interview questions concerning cognitive complaints. Patients participated in the TEAM-trial, a prospective randomized study investigating tamoxifen versus exemestane as adjuvant therapy for hormone-sensitive breast cancer. Identical information was obtained from healthy postmenopausal volunteers. RESULTS: Two measures for self-reported cognitive functioning provided the distinctive results. At T1 and T2, healthy controls reported a higher frequency of cognitive failures than patients; change over time did not differ between groups. The prevalence of cognitive complaints did not differ between the groups at T1, but change over time regarding attention/concentration complaints differed between groups, due to an increased prevalence in tamoxifen users. Self-reported cognitive functioning showed moderate associations with anxiety/depression, fatigue, and menopausal complaints. Cognitive test performance was not associated with self-reported cognitive functioning, but weakly with anxiety/depression and fatigue. CONCLUSION: Adjuvant therapy with tamoxifen and exemestane did not influence the self-reported frequency of cognitive failures. Increased attention/concentration complaints were observed in tamoxifen users, but not in exemestane users. This latter finding should be confirmed with better validated instruments.
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Antineoplásicos Hormonais/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/psicologia , Cognição , Pós-Menopausa/psicologia , Idoso , Idoso de 80 Anos ou mais , Androstadienos/uso terapêutico , Ansiedade , Estudos de Casos e Controles , Quimioterapia Adjuvante/psicologia , Transtornos Cognitivos , Depressão , Feminino , Humanos , Pessoa de Meia-Idade , Testes Neuropsicológicos , Estudos Prospectivos , Ensaios Clínicos Controlados Aleatórios como Assunto , Autorrelato , Inquéritos e Questionários , Tamoxifeno/uso terapêuticoRESUMO
PURPOSE: This study aimed to identify medical and psychological predictors for cognitive performance of breast cancer (BC) patients before the start of adjuvant systemic treatment and to compare cognitive performance between BC patients and healthy controls adjusting for medical and psychological variables. MATERIAL: 205 postmenopausal BC patients underwent pre-treatment neuropsychological tests and provided medical and psychological data. 124 healthy controls underwent the same assessment. RESULTS: 'Treatment for diabetes mellitus' and/or 'hypertension', 'less hours spent on cognitively stimulating activities', 'fewer days since surgery' and 'more reproductive years' were associated with worse cognitive performance in the BC patients, independent of age and IQ. Cognitive differences between BC patients and healthy controls could partly be explained by the evaluated variables. CONCLUSION: The results stress the need for adjustment for pre-treatment cognitive differences between study groups, and also indicate that further research into pre-treatment cognitive dysfunction is warranted.
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Antineoplásicos/efeitos adversos , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/psicologia , Transtornos Cognitivos/epidemiologia , Cognição/efeitos dos fármacos , Idoso , Idoso de 80 Anos ou mais , Androstadienos/efeitos adversos , Neoplasias da Mama/epidemiologia , Quimioterapia Adjuvante/efeitos adversos , Quimioterapia Adjuvante/psicologia , Transtornos Cognitivos/induzido quimicamente , Comorbidade , Diabetes Mellitus/epidemiologia , Diabetes Mellitus/psicologia , Feminino , Humanos , Hipertensão/epidemiologia , Hipertensão/psicologia , Testes de Inteligência , Pessoa de Meia-Idade , Estudos Multicêntricos como Assunto , Testes Neuropsicológicos , Pós-Menopausa , Ensaios Clínicos Controlados Aleatórios como Assunto , Fatores de Risco , Tamoxifeno/efeitos adversosRESUMO
BACKGROUND: Mutations in isocitrate dehydrogenase 1 and 2 (IDH1 and IDH2) have been implicated in tumorigenesis of gliomas. Patients with high-grade astrocytomas with IDH1 or IDH2 mutations were reported to have a better survival, but it is unknown if this improved survival also holds for low-grade astrocytoma and whether these mutations predict outcome to specific treatment. METHODS: We retrospectively investigated the correlation of IDH1 and IDH2 mutations with overall survival and response to temozolomide in a cohort of patients with dedifferentiated low-grade astrocytomas treated with temozolomide at the time of progression after radiotherapy. RESULTS: IDH1 mutations were present in 86% of the 49 progressive astrocytomas. No mutations in IDH2 were found. Presence of IDH1 mutations were early events and significantly improved overall survival (median survival 48 vs 98 months), but did not affect outcome of temozolomide treatment. CONCLUSION: These results indicate that IDH1 mutations identify a subgroup of gliomas with an improved survival, but are unrelated to the temozolomide response.
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Antineoplásicos Alquilantes/uso terapêutico , Astrocitoma , Neoplasias Encefálicas , Dacarbazina/análogos & derivados , Isocitrato Desidrogenase/genética , Mutação/genética , Adulto , Antineoplásicos Alquilantes/efeitos adversos , Astrocitoma/tratamento farmacológico , Astrocitoma/genética , Astrocitoma/mortalidade , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/mortalidade , Estudos de Coortes , Análise Mutacional de DNA , Dacarbazina/efeitos adversos , Dacarbazina/uso terapêutico , Feminino , Humanos , Masculino , Estudos Retrospectivos , Análise de Sobrevida , Temozolomida , Resultado do TratamentoRESUMO
Because of possible long-term toxicity, cranial radiotherapy (RT) was withheld as part of standard treatment for brain metastasis (BM) from non-seminomatous germ cell tumours (NSGCT). This study evaluates this change in management in our institute. Twenty-two consecutive patients with BM from NSGCT were analysed. Ten patients presented with BM at initial diagnosis (group 1), two patients developed BM at extra-cranial complete remission (CR) (group 2), and ten patients during treatment of the primary tumour without achieving CR (group 3). All patients received cisplatin-based induction chemotherapy. In group 1, three patients with a single metastasis and three patients with multiple BM underwent craniotomy. Five patients received chemotherapy and whole brain RT (WBRT), and five patients received chemotherapy without WBRT. In group 2, both patients underwent craniotomy for a relapse with multiple BM. One patient received additional high-dose (HD) chemotherapy with WBRT, and the other HD chemotherapy without WBRT. In group 3, one patient underwent craniotomy, seven patients received WBRT, and four patients additional HD chemotherapy. In group 1, five of ten patients (50%) achieved CR (follow-up 49-245 months), in four of those five without WBRT. In group 2, both patients achieved CR (follow-up 146 and 211 months). In group 3, one of ten patients (10%) achieved CR after HD chemotherapy and WBRT (follow-up 107 months). It is concluded that cure in patients with BM from NSGCT can be achieved with standard induction chemotherapy without WBRT.
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Antineoplásicos/uso terapêutico , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/secundário , Cisplatino/uso terapêutico , Neoplasias Embrionárias de Células Germinativas/patologia , Adolescente , Adulto , Neoplasias Encefálicas/classificação , Neoplasias Encefálicas/cirurgia , Craniotomia/métodos , Estudos de Avaliação como Assunto , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias Embrionárias de Células Germinativas/classificação , Indução de Remissão , Estudos Retrospectivos , Adulto JovemRESUMO
In view of recent progressive insight in the diagnosis and treatment of leptomeningeal metastases of solid tumours, a new guideline has been designed on the initiative of the Dutch Association of NeuroOncology and the Netherlands Society of Neurology, with methodological support from the Dutch Institute for Healthcare Improvement (CBO). - There are no neurological symptoms or signs, nor MRI characteristics that are unique to leptomeningeal metastasis. However, clinical suspicion of leptomeningeal metastasis in a patient known to have cancer, in combination with specific MRI characteristics is sufficient to make the diagnosis. If MRI or CT results are negative or inconclusive cerebrospinal-fluid assessment should be conducted. - Management of care of patients with leptomeningeal metastasis without brain metastases can be based on a series of categories that have been developed using prognostic factors such as Karnofsky performance status, serious encephalopathy or neurological dysfunction, systemic disease, sensitivity of the tumour for chemotherapy or hormonal treatment - In the context of meaningful palliation, systemic treatment, if necessary in combination with radiotherapy to clinically relevant sites, is preferable to intrathecal chemotherapy. - Intrathecal chemotherapy combined with local radiotherapy is recommended if effective systemic treatment is not available, and if the tumour is potentially sensitive to methotrexate, cytarabine or thiotepa. The combination of intrathecal methotrexate and whole-brain radiotherapy should be avoided.
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Neoplasias Meníngeas/secundário , Neoplasias/patologia , Guias de Prática Clínica como Assunto , Antimetabólitos Antineoplásicos/uso terapêutico , Terapia Combinada , Irradiação Craniana , Diagnóstico Diferencial , Humanos , Avaliação de Estado de Karnofsky , Neoplasias Meníngeas/diagnóstico , Neoplasias Meníngeas/terapia , Meninges/patologia , Metotrexato/uso terapêutico , Metástase Neoplásica , Neoplasias/diagnóstico , Neoplasias/terapia , Exame Neurológico , PrognósticoRESUMO
The blood-brain barrier (BBB) is considered one of the major causes for the low efficacy of cytotoxic compounds against primary brain tumours. The aim of this study was to develop intracranial tumour models in mice featuring intact or locally disrupted BBB properties, which can be used in testing chemotherapy against brain tumours. These tumours were established by intracranial injection of suspensions of different tumour cell lines. All cell lines had been transfected with luciferase to allow non-invasive imaging of tumour development using a super-cooled CCD-camera. Following their implantation, tumours developed which displayed the infiltrative, invasive or expansive growth patterns that are also found in primary brain cancer or brain metastases. Contrast-enhanced magnetic resonance imaging showed that the Mel57, K1735Br2 and RG-2 lesions grow without disruption of the BBB, whereas the BBB was leaky in the U87MG and VEGF-A-transfected Mel57 lesions. This was confirmed by immunohistochemistry. Bioluminescence measurements allowed the visualisation of tumour burden already within 4 days after injection of the tumour cells. The applicability of our models for performing efficacy studies was demonstrated in an experiment using temozolomide as study drug. In conclusion, we have developed experimental brain tumour models with partly disrupted, or completely intact BBB properties. In vivo imaging by luciferase allows convenient follow-up of tumour growth and these models will be useful for chemotherapeutic intervention studies.
Assuntos
Neoplasias Encefálicas/enzimologia , Luciferases/metabolismo , Animais , Antineoplásicos Alquilantes/uso terapêutico , Barreira Hematoencefálica/fisiologia , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/patologia , Divisão Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Meios de Contraste , Dacarbazina/análogos & derivados , Dacarbazina/uso terapêutico , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Gadolínio DTPA , Imuno-Histoquímica , Luminescência , Imageamento por Ressonância Magnética , Masculino , Camundongos , Camundongos Nus , Invasividade Neoplásica , TemozolomidaRESUMO
Phenytoin dosing is critical in cancer patients as to decreased absorption secondary to chemotherapy-induced gastrointestinal toxicity, increased phenytoin metabolism in the liver secondary to chemotherapy, extreme patient profile that falls outside the predicted pharmacokinetic population, frequent hypoalbuminaemia and polydrug treatment. A retrospective study to assess the variability of free phenytoin and the free fraction of phenytoin, as well as the influence of comedication on these parameters was performed in cancer patients by using a population approach. Two hundred fifty-eight data pairs of total phenytoin and free phenytoin were analysed from 155 cancer patients on stable phenytoin using non-linear mixed-effect modeling (NONMEM). Total and free phenytoin were determined using a fluorescence polarization immunoassay. An extensive model building procedure was subsequently used for covariate testing on the free fraction of phenytoin. Mean total phenytoin concentration was 11.7 mg/l, free phenytoin 1.25 mg/l and phenytoin free fraction 0.107. Free phenytoin was <1 mg/l on 132 occasions (51.2%) and >2 mg/l on 37 occasions (14.3%). Total and free phenytoin were significantly correlated (r(S)=0.827, P<0.01). The free fraction of phenytoin was independent of time after drug intake. Serum albumin concentrations and comedication with valproic acid or carbamazepine were identified by NONMEM as significant determinants of phenytoin free fraction. Co-medication with valproic acid and carbamazepine led to a 52.5% and 38.5% increase of the free fraction of phenytoin, respectively, and a 10 g/l decrease of serum albumin to a 15.1% increase of the free fraction of phenytoin. Phenytoin pharmacokinetics could reliably be estimated from oral doses and steady-state concentrations of protein-bound and free phenytoin. The variability in the free fraction of phenytoin could partly be explained by the influence of albumin concentrations and antiepileptic comedication. Significant alterations of the free fraction of phenytoin and free phenytoin by co-administration of valproic acid or carbamazepine suggest therapeutic drug monitoring of free phenytoin to be of potential benefit in cancer patients.
Assuntos
Carbamazepina/farmacologia , Fenitoína/farmacocinética , Albumina Sérica/metabolismo , Ácido Valproico/farmacologia , Administração Oral , Adulto , Idoso , Idoso de 80 Anos ou mais , Algoritmos , Análise de Variância , Antineoplásicos Hormonais/sangue , Antineoplásicos Hormonais/farmacologia , Antineoplásicos Hormonais/uso terapêutico , Carbamazepina/sangue , Carbamazepina/uso terapêutico , Creatinina/sangue , Dexametasona/sangue , Dexametasona/farmacologia , Dexametasona/uso terapêutico , Feminino , Humanos , Injeções Intravenosas , Masculino , Pessoa de Meia-Idade , Modelos Biológicos , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Fenitoína/sangue , Fenitoína/uso terapêutico , Estudos Retrospectivos , Distribuição Tecidual , Ácido Valproico/sangue , Ácido Valproico/uso terapêuticoRESUMO
Median survival of patients with leptomeningeal metastases (LM) is 4 to 6 months, with a few long-term survivors. Current prognostic factors for survival have limited value. The authors measured the CSF levels of nine inflammatory proteins in 57 patients with LM and determined their prognostic value. High interleukin (IL)-8 CSF levels predicted short-term survival independently. The data indicate that IL-8 CSF levels may serve as a prognosticator in patients with LM, but prospective validation is needed.
Assuntos
Aracnoide-Máter , Interleucina-8/líquido cefalorraquidiano , Neoplasias Meníngeas/fisiopatologia , Neoplasias Meníngeas/secundário , Pia-Máter , Sobreviventes , Adulto , Idoso , Feminino , Humanos , Imunoensaio , Masculino , Neoplasias Meníngeas/mortalidade , Neoplasias Meníngeas/terapia , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Prognóstico , Fatores Sexuais , Análise de SobrevidaRESUMO
The authors determined the levels of vascular endothelial growth factor (VEGF) and urokinase-type plasminogen activator (uPA) in the CSF of patients with leptomeningeal metastases (LM; n = 53), cancer patients without LM (n = 18), and subjects without malignancy (n = 25). Median levels of uPA and VEGF were significantly higher in patients with LM, supporting the hypothesis that angiogenesis contributes to LM. VEGF was negatively correlated with survival in patients with LM, suggesting its use as a prognostic factor.
Assuntos
Biomarcadores Tumorais/líquido cefalorraquidiano , Neoplasias Meníngeas/líquido cefalorraquidiano , Neoplasias Meníngeas/secundário , Neovascularização Patológica/diagnóstico , Ativador de Plasminogênio Tipo Uroquinase/líquido cefalorraquidiano , Fator A de Crescimento do Endotélio Vascular/líquido cefalorraquidiano , Adulto , Idoso , Aracnoide-Máter/irrigação sanguínea , Aracnoide-Máter/patologia , Aracnoide-Máter/fisiopatologia , Vasos Sanguíneos/metabolismo , Vasos Sanguíneos/patologia , Vasos Sanguíneos/fisiopatologia , Carcinoma/secundário , Feminino , Humanos , Linfoma não Hodgkin/patologia , Masculino , Neoplasias Meníngeas/diagnóstico , Pessoa de Meia-Idade , Mieloma Múltiplo/secundário , Metástase Neoplásica , Neovascularização Patológica/líquido cefalorraquidiano , Neovascularização Patológica/fisiopatologia , Pia-Máter/irrigação sanguínea , Pia-Máter/patologia , Pia-Máter/fisiopatologia , Valor Preditivo dos Testes , Prognóstico , Taxa de SobrevidaRESUMO
A man (78 years) and a woman (55 years) experienced one-sided weakness and a woman (61 years) had language-expression problems between 4 and 37 years after having received radiotherapy for carcinoma of the larynx. All three patients had a significant degree of stenosis of the carotid artery. In two patients angioplasty and stenting was carried out. It was decided not to operate or stent the younger woman as her right internal carotid artery was occluded. No new symptoms developed in any of the patients. Radiation-induced stroke is not an uncommon disorder after radiotherapy for a laryngeal carcinoma in the past. The interval between radiation treatment and occurrence of stroke varies, but after a follow-up period of more than 5 years the risk of stroke is significantly increased. In the first instance the work-up should be similar to that in stroke patients with classical age-related atherosclerosis. However treatment of symptomatic radiation-induced carotid stenosis is often a challenge due to fibrotic changes and alterations of the anatomical layers within the radiation field. Screening and modification of additional cerebrovascular risk factors is recommended before radiation treatment is started, in order to prevent worsening of atherosclerotic changes.