RESUMEN
The factors driving therapy resistance in diffuse glioma remain poorly understood. To identify treatment-associated cellular and genetic changes, we analyzed RNA and/or DNA sequencing data from the temporally separated tumor pairs of 304 adult patients with isocitrate dehydrogenase (IDH)-wild-type and IDH-mutant glioma. Tumors recurred in distinct manners that were dependent on IDH mutation status and attributable to changes in histological feature composition, somatic alterations, and microenvironment interactions. Hypermutation and acquired CDKN2A deletions were associated with an increase in proliferating neoplastic cells at recurrence in both glioma subtypes, reflecting active tumor growth. IDH-wild-type tumors were more invasive at recurrence, and their neoplastic cells exhibited increased expression of neuronal signaling programs that reflected a possible role for neuronal interactions in promoting glioma progression. Mesenchymal transition was associated with the presence of a myeloid cell state defined by specific ligand-receptor interactions with neoplastic cells. Collectively, these recurrence-associated phenotypes represent potential targets to alter disease progression.
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Neoplasias Encefálicas , Glioma , Microambiente Tumoral , Adulto , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patología , Evolución Molecular , Genes p16 , Glioma/genética , Glioma/patología , Humanos , Isocitrato Deshidrogenasa/genética , Mutación , Recurrencia Local de NeoplasiaRESUMEN
BACKGROUND: Breast cancer is rare in men, but management is focused on tumor characteristics commonly found in female breast cancer. The tumor microenvironment of male breast cancer is less well understood, and insight may improve male breast cancer management. The hepatocyte growth factor (HGF)/c-MET axis and the stromal cell-derived factor-1 (CXCL12)/C-X-C chemokine receptor type 4 (CXCR4) axis are prognostic in women with breast cancer. We aimed to investigate these factors in male breast cancer and correlate them with patient survival. METHODS: From 841 Dutch males with breast cancer who were enrolled in the EORTC 10085/TBCRC/BIG/NABCG International Male Breast Cancer Program (NCT01101425) and diagnosed between 1990 and 2010, archival primary tumor samples were collected. Tissue microarrays were constructed with 3 cores per sample and used for immunohistochemical analysis of HGF, c-MET, CXCL12, and CXCR4. Overall survival (OS) of the patients without metastases (M0) was analyzed using the Kaplan-Meier method. The value of the markers regarding OS was determined using univariable and multivariable Cox regression analyses, providing hazard ratios (HRs) and 95% confidence intervals (95% CIs). RESULTS: Of 720 out of 841 patients, sufficient tissue was available for analysis; 487 out of 720 patients had M0 disease. Patients with high HGF expression and high CXCL12 expression had a superior OS (low vs high expression of both markers, 7.5 vs 13.0 years, hazard ratio [HR] 0.64, 95% CI 0.49-0.84, P = 0.001 [HGF]; 9.1 vs 15.3 years, HR 0.63, 95% CI 0.45-0.87, P = 0.005 [CXCL12]). Multivariate analysis identified HGF as an independent predictor for OS (HR 0.64, 95% CI 0.47-0.88, P = 0.001). CONCLUSIONS: HGF and CXCL12 tumor expression appear to identify male breast cancer patients with a relatively good prognosis. Possibly, this could support male breast cancer-specific management strategies in the future.
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Biomarcadores de Tumor/metabolismo , Neoplasias de la Mama Masculina/mortalidad , Quimiocina CXCL12/metabolismo , Factor de Crecimiento de Hepatocito/metabolismo , Microambiente Tumoral , Anciano , Neoplasias de la Mama Masculina/metabolismo , Neoplasias de la Mama Masculina/patología , Humanos , Masculino , Persona de Mediana Edad , Pronóstico , Estudios Retrospectivos , Transducción de Señal , Tasa de SupervivenciaRESUMEN
BACKGROUND: Late effects of cisplatin-based chemotherapy in testicular cancer survivors (TCS) include cardiovascular morbidity, but little data is available beyond 20 years. The objective was to assess vascular damage in very long-term TCS. METHODS: TCS (treated with chemotherapy or orchiectomy only) and age-matched healthy controls were invited. Study assessment included vascular stiffness with ultrasound measurement of carotid-femoral pulse wave velocity (cf-PWV). RESULTS: We included 127 TCS consisting of a chemotherapy group (70 patients) and an orchiectomy group (57 patients) along with 70 controls. Median follow-up was 28 years (range: 20-42). The cf-PWV (m/s) was higher in TCS than in controls (geometrical mean 8.05 (SD 1.23) vs. 7.60 (SD 1.21), p = 0.04). The cf-PWV was higher in the chemotherapy group than in the orchiectomy group (geometrical mean 8.39 (SD 1.22) vs. 7.61 (SD 1.21), p < 0.01). In the chemotherapy group cf-PWV increased more rapidly as a function of age compared to controls (regression coefficient b 7.59 × 10-3 vs. 4.04 × 10-3; p = 0.03). CONCLUSION: Very long-term TCS treated with cisplatin-based chemotherapy show increased vascular damage compatible with "accelerated vascular aging" and continue to be at risk for cardiovascular morbidity, thus supporting the need for intensive cardiovascular risk management. CLINICAL TRIAL REGISTRATION: The clinical trial registration number is NCT02572934.
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Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Supervivientes de Cáncer , Cisplatino/efectos adversos , Neoplasias Testiculares/tratamiento farmacológico , Rigidez Vascular/efectos de los fármacos , Adolescente , Adulto , Velocidad de la Onda del Pulso Carotídeo-Femoral , Humanos , Masculino , Persona de Mediana Edad , Adulto JovenRESUMEN
Tumours can escape the immune system by expressing programmed death-ligand-1 (PD-L1), which allows them to bind to PD-1 on T-cells and avoid recognition by the immune system. Regulatory T-cells (Tregs), indoleamine 2,3-dioxygenase (IDO) and tryptophan 2,3-dioxygenase (TDO) also play a role in immune suppression. Knowledge about the interaction of neuroendocrine tumours (NETs) with their immune microenvironment and the role of immunotherapy in patients with NET is scarce. Here, we investigated the immune microenvironment of serotonin-producing (SP) and non-serotonin-producing NETs (NSP-NETs). Tumours of 33 patients with SP-NET and 18 patients with NSP-NET were studied. Immunohistochemical analyses were performed for PD-L1, T-cells, IDO, TDO, mismatch repair proteins (MMRp) and activated fibroblasts. PD-L1 expression was seen in < 1% of tumour and T-cells. T-cells were present in 33% of NETs, varying between 1 and 10% T-cells per high power field. IDO was expressed in tumour cells in 55% of SP-NETs and 22% of NSP-NETs (p = 0.039). TDO was expressed in stromal cells in 64% of SP-NETs and 13% of NSP-NETs (p = 0.001). No tumours had loss of MMRp. TDO-expressing stromal cells also strongly expressed α-SMA and were identified as cancer-associated fibroblasts (CAFs). Factors that are associated with a response to checkpoint inhibitor treatment were absent or only present to a limited extent in the tumour microenvironment of NETs. The expression of IDO and TDO in a substantial part of NETs and the presence of CAFs suggest two mechanisms that could be responsible for the cold immune microenvironment, which should be explored to enhance anti-tumour immunity and clinical responses.
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Antígeno B7-H1/metabolismo , Biomarcadores de Tumor/metabolismo , Indolamina-Pirrol 2,3,-Dioxigenasa/metabolismo , Linfocitos Infiltrantes de Tumor/inmunología , Tumores Neuroendocrinos/inmunología , Triptófano Oxigenasa/metabolismo , Microambiente Tumoral/inmunología , Femenino , Estudios de Seguimiento , Regulación Neoplásica de la Expresión Génica , Humanos , Masculino , Persona de Mediana Edad , Tumores Neuroendocrinos/metabolismo , Tumores Neuroendocrinos/patología , Pronóstico , Tasa de Supervivencia , Linfocitos T Reguladores/inmunologíaRESUMEN
BACKGROUND: Currently, several indole markers are measured separately to support diagnosis and follow-up of patients with neuroendocrine tumors (NETs). We have developed a sensitive mass spectrometry method that simultaneously quantifies all relevant tryptophan-related indoles (tryptophan, 5-hydroxytryptophan, serotonin, 5-hydroxyindoleacetic acid) in platelet-rich plasma. Direct-matrix derivatization was used to make the chemical properties of the indoles uniform and to improve the analytical sensitivity and specificity of the assay. METHODS: In situ derivatization was performed directly in platelet-rich plasma with propionic anhydride at an ambient temperature. The derivatized indoles were extracted by online solid-phase extraction and eluted to the analytical column for separation followed by mass spectrometric detection. The method was validated according to international guidelines. Platelet-rich plasma samples from 68 healthy individuals and 40 NET patients were analyzed for tryptophan, 5-hydroxytryptophan, serotonin, and 5-hydroxyindoleacetic acid. RESULTS: The method reproducibly quantified relevant indoles in 8.5 min, including online sample cleanup. Intra- and interassay imprecision, evaluated at 3 different concentrations, ranged from 2.0% to 12% and 1.9% to 13%, respectively. The limit of quantification was sufficient to measure endogenous concentrations of all 4 indoles. Healthy individuals and NET patients had different concentrations of 5-hydroxytryptophan, serotonin, and 5-hydroxyindoleacetic acid, but tryptophan concentrations were the same. CONCLUSIONS: Direct-matrix derivatization in combination with LC-MS/MS is a powerful tool for the simultaneous quantification of all tryptophan-related indoles in platelet-rich plasma. Simultaneous profiling of relevant indoles improves the biochemical characterization and follow-up of NETs.
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Biomarcadores de Tumor/sangre , Indoles/sangre , Tumores Neuroendocrinos/sangre , Plasma Rico en Plaquetas/química , 5-Hidroxitriptófano/sangre , Adulto , Anciano , Cromatografía Liquida , Femenino , Humanos , Ácido Hidroxiindolacético/sangre , Masculino , Persona de Mediana Edad , Serotonina/sangre , Espectrometría de Masas en Tándem , Triptófano/sangreRESUMEN
PURPOSE: Epidermal growth factor receptor (EGFR) amplification has been reported to occur in ~ 50% of glioblastomas (GBMs). We are conducting several global studies that require central testing for EGFR amplification during screening, representing an opportunity to confirm the frequency of amplification in GBM in a large cohort and to evaluate whether EGFR amplification differs by region of the world. METHODS: EGFR amplification was measured by fluorescence in situ hybridization during screening for therapeutic trials of an EGFR antibody-drug conjugate: two Phase 2/3 global trials (INTELLANCE-1, INTELLANCE-2), and a Japanese Phase 1/2 trial (INTELLANCE-J). We evaluated the proportion of tumor tissue samples harboring EGFR amplification among those tested and differences in amplification frequency by geography. RESULTS: EGFR was amplified in 54% of 3150 informative cases screened for INTELLANCE-1 and -2, consistent with historic controls, but was significantly lower in patients from Asia versus the rest of the world (35% vs. 56%, P < 0.0030). The independent INTELLANCE-J trial validated this finding (33% amplified of 153 informative cases). CONCLUSIONS: EGFR amplification occurs less frequently in patients from Asia than elsewhere. Further study is required to understand biological differences to optimize treatment in glioblastoma.
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Biomarcadores de Tumor/genética , Neoplasias Encefálicas/genética , Amplificación de Genes , Glioblastoma/genética , Tamizaje Masivo/normas , Selección de Paciente , Neoplasias Encefálicas/tratamiento farmacológico , Neoplasias Encefálicas/patología , Método Doble Ciego , Receptores ErbB/genética , Glioblastoma/tratamiento farmacológico , Glioblastoma/patología , Humanos , PronósticoRESUMEN
PURPOSE: Response evaluation in patients with glioblastoma after chemoradiotherapy is challenging due to progressive, contrast-enhancing lesions on MRI that do not reflect true tumour progression. In this study, we prospectively evaluated the ability of the PET tracer 18F-fluorothymidine (FLT), a tracer reflecting proliferative activity, to discriminate between true progression and pseudoprogression in newly diagnosed glioblastoma patients treated with chemoradiotherapy. METHODS: FLT PET and MRI scans were performed before and 4 weeks after chemoradiotherapy. MRI scans were also performed after three cycles of adjuvant temozolomide. Pseudoprogression was defined as progressive disease on MRI after chemoradiotherapy with stabilisation or reduction of contrast-enhanced lesions after three cycles of temozolomide, and was compared with the disease course during long-term follow-up. Changes in maximum standardized uptake value (SUVmax) and tumour-to-normal uptake ratios were calculated for FLT and are presented as the mean SUVmax for multiple lesions. RESULTS: Between 2009 and 2012, 30 patients were included. Of 24 evaluable patients, 7 showed pseudoprogression and 7 had true progression as defined by MRI response. FLT PET parameters did not significantly differ between patients with true progression and pseudoprogression defined by MRI. The correlation between change in SUVmax and survival (p = 0.059) almost reached the standard level of statistical significance. Lower baseline FLT PET uptake was significantly correlated with improved survival (p = 0.022). CONCLUSION: Baseline FLT uptake appears to be predictive of overall survival. Furthermore, changes in SUVmax over time showed a tendency to be associated with improved survival. However, further studies are necessary to investigate the ability of FLT PET imaging to discriminate between true progression and pseudoprogression in patients with glioblastoma.
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Didesoxinucleósidos , Progresión de la Enfermedad , Glioblastoma/diagnóstico por imagen , Tomografía de Emisión de Positrones , Adulto , Anciano , Proliferación Celular , Quimioradioterapia , Diagnóstico Diferencial , Femenino , Estudios de Seguimiento , Glioblastoma/patología , Glioblastoma/terapia , Humanos , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Imagen MultimodalRESUMEN
PURPOSE: Evidence accumulates that an active lifestyle positively influences cancer treatment outcome. A "smartphone application" (app) such as "RunKeeper," to self-monitor physical activity (PA) might be helpful. This study aimed to examine whether using RunKeeper to increase self-reported PA is feasible in cancer patients and to evaluate patients' opinion about using RunKeeper in a 12-week program. METHODS: Adult patients (n = 32), diagnosed with cancer, were randomized between usual care (n = 16) or a 12-week intervention with instructions to self-monitor PA with RunKeeper (n = 16). Changes in PA were determined with the Physical Activity Scale for the Elderly (PASE) at baseline (T0), 6 weeks (T1), and 12 weeks (T2). Usability and patients' experiences were tested at T2 with the System Usability Scale (SUS) and a semi-structured interview. RESULTS: Patient mean age was 33.6 years. Between T0 and T1, an increase in PA of 51% (medium estimated effect size r = 0.40) was found in PASE sum score in the intervention group compared with usual care. In addition, total minutes of PA increased with 46% (r = 0.37). These effects decreased over time (T2). Sedentary time decreased with 19% between T0 and T1 and 27% between T0 and T2. Usability was rated "good" and most patients found RunKeeper use helpful to improve PA. CONCLUSIONS: Self-monitoring PA with RunKeeper was safe and feasible in cancer patients. The RunKeeper use resulted in an increase in PA after 6 weeks. RunKeeper usability was rated good and can be used to study PA in cancer patients. TRIAL REGISTRATION: NCT02391454.
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Actigrafía , Ejercicio Físico , Aplicaciones Móviles , Neoplasias/terapia , Autocuidado/métodos , Teléfono Inteligente , Actigrafía/instrumentación , Actigrafía/métodos , Adulto , Anciano , Estudios de Factibilidad , Femenino , Humanos , Masculino , Persona de Mediana Edad , Monitoreo Fisiológico/instrumentación , Monitoreo Fisiológico/métodos , Neoplasias/epidemiología , Autoinforme , Autoevaluación (Psicología) , Resultado del TratamientoRESUMEN
Glioblastoma (GBM) is a highly vascularized and aggressive type of primary brain tumor in adults with dismal survival. Molecular subtypes of GBM have been identified that are related to clinical outcome and response to therapy. Although the mesenchymal type has been ascribed higher angiogenic activity, extensive characterization of the vascular component in GBM subtypes has not been performed. Therefore, we aimed to investigate the differential vascular status and angiogenic signaling levels in molecular subtypes. GBM tissue samples representing proneural IDH1 mutant, classical-like and mesenchymal-like subtypes were analyzed by morphometry for the number of vessels, vessel size and vessel maturity. Also the expression levels of factors from multiple angiogenic signaling pathways were determined. We found that necrotic and hypoxic areas were relatively larger in mesenchymal-like tumors and these tumors also had larger vessels. However, the number of vessels, basement membrane deposition and pericyte coverage did not vary between the subtypes. Regarding signaling patterns the majority of factors were expressed at similar levels in the subtypes, and only ANGPT2, MMP2, TIMP1, VEGFA and MMP9/TIMP2 were higher expressed in GBMs of the classical-like subtype. In conclusion, although morphological differences were observed between the subtypes, the angiogenic signaling status of GBM subtypes seemed to be rather similar. These results challenge the concept of mesenchymal GBMs being more angiogenic than other subclasses.
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Antígenos de Neoplasias/metabolismo , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patología , Glioblastoma/metabolismo , Glioblastoma/patología , Neovascularización Patológica/etiología , Actinas/metabolismo , Anciano , Antígenos CD34/metabolismo , Neoplasias Encefálicas/diagnóstico por imagen , Neoplasias Encefálicas/genética , Anhidrasa Carbónica IX/metabolismo , Estudios de Cohortes , Endoglina/metabolismo , Femenino , Regulación Neoplásica de la Expresión Génica/fisiología , Glioblastoma/diagnóstico por imagen , Glioblastoma/genética , Hormona Liberadora de Gonadotropina/metabolismo , Humanos , Isocitrato Deshidrogenasa/genética , Masculino , Persona de Mediana Edad , Mutación/genética , Necrosis/etiología , Transducción de Señal/fisiologíaRESUMEN
Glioblastoma multiforme (GBM) universally recurs with dismal prognosis. We evaluated the efficacy of standard treatment strategies for patients with recurrent GBM (rGBM). From two centers in the Netherlands, 299 patients with rGBM after first-line treatment, diagnosed between 2005 and 2014, were retrospectively evaluated. Four different treatment strategies were defined: systemic treatment (SYST), re-irradiation (RT), re-resection followed by adjuvant treatment (SURG) and best supportive care (BSC). Median OS for all patients was 6.5 months, and median PFS (excluding patients receiving BSC) was 5.5 months. Older age, multifocal lesions and steroid use were significantly associated with a shorter survival. After correction for confounders, patients receiving SYST (34.8%) and SURG (18.7%) had a significantly longer survival than patients receiving BSC (39.5%), 7.3 and 11.0 versus 3.1 months, respectively [HR 0.46 (p < 0.001) and 0.36 (p < 0.001)]. Median survival for patients receiving RT (7.0%) was 9.2 months, but this was not significantly different from patients receiving BSC (p = 0.068). Patients receiving SURG compared to SYST had a longer PFS (9.0 vs. 4.3 months, respectively; p < 0.001), but no difference in OS was observed. After adjustments for confounders, patients with rGBM selected for treatment with SURG or SYST do survive significantly longer than patients who are selected for BSC based on clinical parameters. The value of reoperation versus systemic treatment strategies needs further investigation.
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Neoplasias Encefálicas/terapia , Glioblastoma/terapia , Recurrencia Local de Neoplasia/terapia , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Países Bajos , Estudios Retrospectivos , Análisis de Supervivencia , Resultado del Tratamiento , Adulto JovenRESUMEN
PURPOSE: Patients with a neuroendocrine tumor (NET) frequently experience physical and psychosocial complaints. Novel strategies to provide information to optimize supportive care in these patients are of interest. The aim of this study was to examine whether the use of a web-based system consisting of self-screening of problems and care needs, patient education, and self-referral to professional health care is feasible in NET patients and to evaluate their opinion on this. METHODS: Newly diagnosed NET patients were randomized between standard care (n = 10) or intervention with additional access to the web-based system (n = 10) during 12 weeks. Patients completed questionnaires regarding received information, distress, quality of life (QoL), and empowerment. The intervention group completed a semi-structured interview to assess patients' opinion on the web-based system. RESULTS: The participation rate was 77% (20/26 invited patients) with no dropouts. The use of the web-based system had a negative effect on patients' perception and satisfaction of received information (range Cohen's d -0.88 to 0.13). Positive effects were found for distress (Cohen's d 0.75), global QoL (subscale European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30, Cohen's d 0.46), resolving problems with social functioning and finding information (subscales EORTC QLQ-GINET 21, Cohen's d 0.69, respectively, 1.04), and feeling informed (subscale empowerment questionnaire, Cohen's d 0.51). The interview indicated that the web-based system was of additional value to standard care. CONCLUSIONS: Use of this web-based system is feasible. Contradictory effects on informing and supporting NET patients were found and should be subject of further research. TRIAL REGISTRATION: NCT01849523.
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Internet/estadística & datos numéricos , Tumores Neuroendocrinos/diagnóstico , Calidad de Vida/psicología , Anciano , Estudios de Factibilidad , Femenino , Humanos , Masculino , Persona de Mediana EdadRESUMEN
BACKGROUND/AIMS: Tryptophan is the precursor of serotonin and niacin (vitamin B3). The latter is critical for normal cellular metabolism. Tryptophan and niacin can be deficient in patients with serotonin-producing neuroendocrine tumors (NETs). Niacin deficiency may lead to severe symptoms including pellagra. In patients with serotonin-producing NET, data on niacin status are scarce and niacin supplementation hardly receives attention. We aimed to assess the niacin status before and after supplementation in these patients. METHODS: We identified serotonin-producing NET patients who had received oral niacin supplementation (mean dose 144 mg daily) for tryptophan deficiency and/or pellagra-associated symptoms. Presupplementation plasma tryptophan levels and niacin status based on the urinary niacin metabolite N1-methylnicotinamide (N1-MN) before (n = 42) and after the start of the supplementation (in 34 paired samples) were assessed. Reference values for urinary N1-MN levels were established in 133 healthy individuals. RESULTS: The mean presupplementation plasma tryptophan level was 31.8 ± 9.7 µmol/l (reference value 40.0-70.0). Presupplementation urinary N1-MN levels were lower in patients (median 17.9 µmol/24 h, range 2.6-70.3) compared to healthy controls (median 43.7 µmol/24 h, range 9.5-169.3, p < 0.0001) and below normal in 45% of the patients. Niacin supplementation increased urinary N1-MN levels to high normal levels (median 55.5 µmol/24 h, range 7.4-489.0) in 86% of the niacin-deficient patients. CONCLUSION: In serotonin-producing NET patients, niacin deficiency is prevalent. Therefore, urinary N1-MN deserves to be included in their standard biochemical evaluation. Niacin supplementation normalizes the niacin status in most niacin-deficient serotonin-producing NET patients. A prospective study is warranted.
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Tumores Neuroendocrinos/metabolismo , Tumores Neuroendocrinos/terapia , Niacinamida/administración & dosificación , Serotonina/metabolismo , Complejo Vitamínico B/administración & dosificación , Administración Oral , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Masculino , Persona de Mediana Edad , Tumores Neuroendocrinos/orina , Niacinamida/análogos & derivados , Niacinamida/uso terapéutico , Niacinamida/orina , Triptófano/metabolismo , Adulto JovenRESUMEN
The biogenic amines dopamine and serotonin are neurotransmitters and hormones, which are mainly produced in the central nervous system and in the gastro-intestinal tract. They execute local and systemic functions such as intestinal motility and tissue repair. Dopamine and serotonin are primarily stored in and transported by platelets. This review focuses on the recently recognized role of dopamine and serotonin in the regulation of tumor behavior by affecting angiogenesis and tumor cell proliferation. Preclinical studies demonstrate that dopamine inhibits tumor growth via activation of dopamine receptor D2 on endothelial and tumor cells. Serotonin stimulates tumor growth via activation of serotonin receptor 2B on endothelial cells and serotonin receptors on tumor cells. Drugs that stimulate dopamine receptor D2 or inhibit serotonin receptors are available and therefore clinical intervention studies for cancer patients are within reach.
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Dopamina/metabolismo , Neoplasias/irrigación sanguínea , Serotonina/metabolismo , Animales , Proliferación Celular/fisiología , Células Endoteliales/metabolismo , Células Endoteliales/patología , Humanos , Neoplasias/metabolismo , Neoplasias/patología , Neovascularización Patológica/metabolismo , Neovascularización Patológica/patología , Receptores de Dopamina D2/metabolismo , Receptores de Serotonina/metabolismoRESUMEN
BACKGROUND: Treatment options for recurrent glioblastoma are scarce, with second-line chemotherapy showing only modest activity against the tumour. Despite the absence of well controlled trials, bevacizumab is widely used in the treatment of recurrent glioblastoma. Nonetheless, whether the high response rates reported after treatment with this drug translate into an overall survival benefit remains unclear. We report the results of the first randomised controlled phase 2 trial of bevacizumab in recurrent glioblastoma. METHODS: The BELOB trial was an open-label, three-group, multicentre phase 2 study undertaken in 14 hospitals in the Netherlands. Adult patients (≥18 years of age) with a first recurrence of a glioblastoma after temozolomide chemoradiotherapy were randomly allocated by a web-based program to treatment with oral lomustine 110 mg/m(2) once every 6 weeks, intravenous bevacizumab 10 mg/kg once every 2 weeks, or combination treatment with lomustine 110 mg/m(2) every 6 weeks and bevacizumab 10 mg/kg every 2 weeks. Randomisation of patients was stratified with a minimisation procedure, in which the stratification factors were centre, Eastern Cooperative Oncology Group performance status, and age. The primary outcome was overall survival at 9 months, analysed by intention to treat. A safety analysis was planned after the first ten patients completed two cycles of 6 weeks in the combination treatment group. This trial is registered with the Nederlands Trial Register (www.trialregister.nl, number NTR1929). FINDINGS: Between Dec 11, 2009, and Nov 10, 2011, 153 patients were enrolled. The preplanned safety analysis was done after eight patients had been treated, because of haematological adverse events (three patients had grade 3 thrombocytopenia and two had grade 4 thrombocytopenia) which reduced bevacizumab dose intensity; the lomustine dose in the combination treatment group was thereafter reduced to 90 mg/m(2). Thus, in addition to the eight patients who were randomly assigned to receive bevacizumab plus lomustine 110 mg/m(2), 51 patients were assigned to receive bevacizumab alone, 47 to receive lomustine alone, and 47 to receive bevacizumab plus lomustine 90 mg/m(2). Of these patients, 50 in the bevacizumab alone group, 46 in the lomustine alone group, and 44 in the bevacizumab and lomustine 90 mg/m(2) group were eligible for analyses. 9-month overall survival was 43% (95% CI 29-57) in the lomustine group, 38% (25-51) in the bevacizumab group, 59% (43-72) in the bevacizumab and lomustine 90 mg/m(2) group, 87% (39-98) in the bevacizumab and lomustine 110 mg/m(2) group, and 63% (49-75) for the combined bevacizumab and lomustine groups. After the reduction in lomustine dose in the combination group, the combined treatment was well tolerated. The most frequent grade 3 or worse toxicities were hypertension (13 [26%] of 50 patients in the bevacizumab group, three [7%] of 46 in the lomustine group, and 11 [25%] of 44 in the bevacizumab and lomustine 90 mg/m(2) group), fatigue (two [4%], four [9%], and eight [18%]), and infections (three [6%], two [4%], and five [11%]). At the time of this analysis, 144/148 (97%) of patients had died and three (2%) were still on treatment. INTERPRETATION: The combination of bevacizumab and lomustine met prespecified criteria for assessment of this treatment in further phase 3 studies. However, the results in the bevacizumab alone group do not justify further studies of this treatment. FUNDING: Roche Nederland and KWF Kankerbestrijding.
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Anticuerpos Monoclonales Humanizados/administración & dosificación , Neoplasias Encefálicas/terapia , Glioblastoma/terapia , Lomustina/administración & dosificación , Recurrencia Local de Neoplasia/tratamiento farmacológico , Recurrencia Local de Neoplasia/mortalidad , Administración Oral , Adolescente , Adulto , Anticuerpos Monoclonales Humanizados/efectos adversos , Bevacizumab , Neoplasias Encefálicas/mortalidad , Neoplasias Encefálicas/patología , Supervivencia sin Enfermedad , Relación Dosis-Respuesta a Droga , Esquema de Medicación , Combinación de Medicamentos , Quimioterapia Combinada , Femenino , Estudios de Seguimiento , Glioblastoma/mortalidad , Glioblastoma/patología , Humanos , Infusiones Intravenosas , Lomustina/efectos adversos , Masculino , Dosis Máxima Tolerada , Persona de Mediana Edad , Invasividad Neoplásica/patología , Recurrencia Local de Neoplasia/patología , Estadificación de Neoplasias , Análisis de Supervivencia , Adulto JovenRESUMEN
PURPOSE: This study aimed to gain insight into the experiences of, and reasons for, cancer survivors participating in a primary care PA program. METHODS: We interviewed 17 patients from 11 Dutch GP practices. Patients were selected by purposive sampling based on their general practice, gender, educational level, motivation for PA, and change in PA. Interviews were audio recorded, transcribed verbatim, and pseudonymized for inductive thematic analysis. RESULTS: Three domains were identified with five themes: institutional domain: GP practice; program-specific domain: content sessions and PA, and activity tracker and goal setting; individual domain: experienced benefits, and personalized care needs. Participants valued the PA program because it was offered close to home, without additional costs, and by a trusted practice nurse familiar with the patients' medical background. Activity tracker use and goal setting motivated many participants but also led to demotivation and feelings of failure in others. Reported benefits included behavior change and favorable health outcomes. Many patients expressed the need to personalize psychological support and the program's timing. CONCLUSIONS: Access to a PA program in a primary care setting is valued for its accessibility and experienced health benefits, but also seems to meet an unmet need for support in picking up life during cancer recovery. IMPLICATIONS FOR CANCER SURVIVORS: Primary care is important for continued care of cancer survivors. An accessible PA program in this setting may fulfil a need for not only lifestyle support but also continuing life after cancer treatment.
RESUMEN
Previously, the tyrosine kinase inhibitor sunitinib failed to show clinical benefit in patients with recurrent glioblastoma. Low intratumoural sunitinib accumulation in glioblastoma patients was reported as a possible explanation for the lack of therapeutic benefit. We designed a randomized phase II/III trial to evaluate whether a high-dose intermittent sunitinib schedule, aimed to increase intratumoural drug concentrations, would result in improved clinical benefit compared to standard treatment with lomustine. Patients with recurrent glioblastoma were randomized 1:1 to high-dose intermittent sunitinib 300 mg once weekly (Q1W, part 1) or 700 mg once every two weeks (Q2W, part 2) or lomustine. The primary end-point was progression-free survival. Based on the pre-planned interim analysis, the trial was terminated for futility after including 26 and 29 patients in parts 1 and 2. Median progression-free survival of sunitinib 300 mg Q1W was 1.5 months (95% CI 1.4-1.7) compared to 1.5 months (95% CI 1.4-1.6) in the lomustine arm (P = 0.59). Median progression-free survival of sunitinib 700 mg Q2W was 1.4 months (95% CI 1.2-1.6) versus 1.6 months (95% CI 1.3-1.8) for lomustine (P = 0.70). Adverse events (≥grade 3) were observed in 25%, 21% and 31% of patients treated with sunitinib 300 mg Q1W, sunitinib 700 mg Q2W and lomustine, respectively (P = 0.92). To conclude, high-dose intermittent sunitinib treatment failed to improve the outcome of patients with recurrent glioblastoma when compared to standard lomustine therapy. Since lomustine remains a poor standard treatment strategy for glioblastoma, innovative treatment strategies are urgently needed.
RESUMEN
(11)C-methionine (MET) is the most popular amino acid tracer used in PET imaging of brain tumours. Because of its characteristics, MET PET provides a high detection rate of brain tumours and good lesion delineation. This review focuses on the role of MET PET in imaging cerebral gliomas. The Introduction provides a clinical overview of what is important in primary brain tumours, recurrent brain tumours and brain metastases. The indications for radiotherapy and the results and problems arising after chemoradiotherapy in relation to imaging (pseudoprogression or radionecrosis) are discussed. The working mechanism, scan interpretation and quantification possibilities of MET PET are then explained. A literature overview is given of the role of MET PET in primary gliomas (diagnostic accuracy, grading, prognosis, assessment of tumour extent, biopsy and radiotherapy planning), in brain metastases, and in the differentiation between tumour recurrence and radiation necrosis. Finally, MET PET is compared to other nuclear imaging possibilities in brain tumour imaging.
Asunto(s)
Neoplasias Encefálicas/diagnóstico por imagen , Glioma/diagnóstico por imagen , Metionina , Tomografía de Emisión de Positrones , Radiofármacos , Neoplasias Encefálicas/patología , Glioma/secundario , Humanos , PronósticoRESUMEN
PURPOSE: Bleomycin, etoposide, and cisplatin combination chemotherapy (BEP) improves the survival of patients with testicular cancer, but is associated with potentially life-threatening toxicities like pneumonitis and thromboembolic events. This study explored the effects of physical exercise in patients with testicular cancer during or after BEP-chemotherapy on pulmonary and vascular endothelial toxicity. METHODS: In this post hoc analysis of a multicenter randomized clinical trial (NCT01642680), patients with metastatic testicular cancer scheduled to receive BEP-chemotherapy were randomized to a 24-week exercise intervention, initiated during (group A) or after BEP-chemotherapy (group B). Endpoints were pulmonary function (forced vital capacity (FVC), forced expiratory volume in one second (FEV1), lung transfer-coefficient and transfer factor for carbon monoxide (KCO, DLCO) and markers of vascular endothelial dysfunction (von Willebrand factor (vWF) and factor VIII). RESULTS: Thirty patients were included. Post-chemotherapy, patients declined less in FVC, FEV1 and DLCO in group A compared to group B. Post-chemotherapy, vWF and factor VIII were significantly lower in group A compared to group B. After completion of exercise, started either during BEP-chemotherapy or thereafter, no between-group differences were found. At 1-year post-intervention, significant between-group differences were found in favour of group A in DLCO and KCO. CONCLUSIONS: Patients who exercised during BEP-chemotherapy better preserved FVC, FEV1 and DLCO, measured directly post-chemotherapy and 1-year post-intervention (DLCO, KCO). This coincided with less increase in vWF and factor VIII measured directly post-chemotherapy. These data support a beneficial role of a physical exercise intervention during BEP-chemotherapy on pulmonary and vascular damage in patients with testicular cancer. TRIAL REGISTRY: Optimal Timing of Physical Activity in Cancer Treatment (ACT) Registry URL: https://clinicaltrials.gov/ct2/show/NCT01642680 . TRIAL REGISTRATION NUMBER: NCT01642680.