RESUMEN
Diffuse intrinsic pontine glioma (DIPG) is a highly aggressive paediatric brain tumour and nowadays has not had satisfactory result, with most patients do not survive within 1 year of diagnosis. Due to its proximity to critical organs, surgery is avoided, and radiation is the mainstay of treatment. In this case report, we present a case of DIPG treated with radiation and concurrent temozolomide. A 7- year-old child was admitted with complaints of weakness in the eyelid, upper and lower limbs 2 months ago. Physical examination showed tetra paresis and bilateral cranial nerve palsy. Magnetic resonance imaging (MRI) scan showed intracranial tumour consistent with DIPG. Diagnosis was made based on imaging as surgery or biopsy can lead to further morbidity. The patient underwent radiotherapy with concurrent chemotherapy of temozolomide. Radiation was given by dose of 54 Gy/30 fractions (30 × 1.8 Gy) with volumetric arc therapy (VMAT). Due to technical issue after the first five irradiations resulting in 2 weeks delay, boosting of dose by 5 × 1.8 Gy was then given, hence, the total dose was 63 Gy. The booster only targeted the gross tumour volume. Following radiation, the patient felt clinical improvement. Eyelid and limb movement improved since the 15th fraction. At the last fraction, the patient's condition improved symptomatically, but experienced complaints related to post radiation oedema including dizziness and nausea. These complaints were improved upon steroids administration. The MRI evaluation will be done after 8 to 12 weeks of radiation, considering the effects of acute radiation could still occur at this period. In conclusion, a combination of radiotherapy and temozolomide could be an option for DIPG management, with tolerable acute toxicity and possible clinical improvements.
Asunto(s)
Neoplasias del Tronco Encefálico , Temozolomida , Humanos , Niño , Temozolomida/uso terapéutico , Temozolomida/administración & dosificación , Neoplasias del Tronco Encefálico/radioterapia , Neoplasias del Tronco Encefálico/terapia , Neoplasias del Tronco Encefálico/tratamiento farmacológico , Glioma Pontino Intrínseco Difuso/terapia , Glioma Pontino Intrínseco Difuso/tratamiento farmacológico , Glioma Pontino Intrínseco Difuso/radioterapia , Masculino , Antineoplásicos Alquilantes/uso terapéutico , Antineoplásicos Alquilantes/administración & dosificación , Dacarbazina/análogos & derivados , Dacarbazina/uso terapéutico , Imagen por Resonancia Magnética , QuimioradioterapiaRESUMEN
Patients with advanced-stage Hodgkin lymphoma treated with ABVD who have a positive interim FDG-PET (iPET) have a poor prognosis. Escalation to BEACOPP has been shown to improve progression-free survival (PFS). However, randomized trials are lacking to determine the best strategy for intensification. We report on A-AVD escalation treatment outcomes for 15 iPET-positive patients post-ABVD. Overall response and complete response rates were 80% and 60%, respectively. Four patients underwent salvage therapy followed by autologous stem cell transplantation. At a median 17-month follow-up, all patients are alive, 87% in complete remission, and 1-year PFS was 57.8%. For patients ineligible for BEACOPP due to age, comorbidities, or preference, A-AVD escalation may be a viable alternative.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica , Bleomicina , Brentuximab Vedotina , Dacarbazina , Doxorrubicina , Enfermedad de Hodgkin , Tomografía de Emisión de Positrones , Vinblastina , Humanos , Enfermedad de Hodgkin/tratamiento farmacológico , Enfermedad de Hodgkin/diagnóstico por imagen , Enfermedad de Hodgkin/terapia , Enfermedad de Hodgkin/mortalidad , Enfermedad de Hodgkin/patología , Brentuximab Vedotina/uso terapéutico , Masculino , Femenino , Adulto , Bleomicina/administración & dosificación , Bleomicina/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Persona de Mediana Edad , Doxorrubicina/administración & dosificación , Doxorrubicina/uso terapéutico , Vinblastina/uso terapéutico , Vinblastina/administración & dosificación , Dacarbazina/uso terapéutico , Dacarbazina/administración & dosificación , Adulto Joven , Estadificación de Neoplasias , Anciano , Resultado del Tratamiento , Estudios de SeguimientoRESUMEN
Drug resistance is one of the biggest challenges in the fight against cancer. In particular, in the case of glioblastoma, the most lethal brain tumour, resistance to temozolomide (the standard of care drug for chemotherapy in this tumour) is one of the main reasons behind treatment failure and hence responsible for the poor prognosis of patients diagnosed with this disease. In this work, we combine the power of three-dimensional in vitro experiments of treated glioblastoma spheroids with mathematical models of tumour evolution and adaptation. We use a novel approach based on internal variables for modelling the acquisition of resistance to temozolomide that was observed in experiments for a group of treated spheroids. These internal variables describe the cell's phenotypic state, which depends on the history of drug exposure and affects cell behaviour. We use model selection to determine the most parsimonious model and calibrate it to reproduce the experimental data, obtaining a high level of agreement between the in vitro and in silico outcomes. A sensitivity analysis is carried out to investigate the impact of each model parameter in the predictions. More importantly, we show how the model is useful for answering biological questions, such as what is the intrinsic adaptation mechanism, or for separating the sensitive and resistant populations. We conclude that the proposed in silico framework, in combination with experiments, can be useful to improve our understanding of the mechanisms behind drug resistance in glioblastoma and to eventually set some guidelines for the design of new treatment schemes.
Asunto(s)
Neoplasias Encefálicas , Resistencia a Antineoplásicos , Glioblastoma , Modelos Biológicos , Temozolomida , Temozolomida/farmacología , Temozolomida/uso terapéutico , Glioblastoma/tratamiento farmacológico , Humanos , Resistencia a Antineoplásicos/efectos de los fármacos , Neoplasias Encefálicas/tratamiento farmacológico , Neoplasias Encefálicas/patología , Antineoplásicos Alquilantes/uso terapéutico , Antineoplásicos Alquilantes/farmacología , Línea Celular Tumoral , Esferoides Celulares/efectos de los fármacos , Dacarbazina/análogos & derivados , Dacarbazina/uso terapéutico , Dacarbazina/farmacología , Simulación por Computador , Adaptación FisiológicaRESUMEN
Hodgkin lymphoma (HL) occuring during pregnancy is a rare condition, and management relies on sparse literature. The specificity of pregnancy requires the clinician to take into account the clinical emergency, the stage of the lymphoma, the trimester of pregnancy, and the patient's choices. The main objective is twofold: to limit the risk of toxicity and adverse events for both mother and fetus, without reducing the chances of a successful outcome. Current literature data suggest that the use of ABVD-type polychemotherapy (adriamycin, bleomycin, vinblastine, dacarbazine) is associated with obstetrical events and long-term fetal toxicity. We report here the results of a homogeneous management considering wait-and-see, vinblastine monotherapy and ABVD polychemotherapy options. The outcomes in terms of obstetrical complications, response rate, and overall survival (100â¯%) reinforce the idea that strategies that do not involve the use of multidrug therapy are possible and are associated with very good results.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica , Enfermedad de Hodgkin , Complicaciones Neoplásicas del Embarazo , Humanos , Enfermedad de Hodgkin/tratamiento farmacológico , Embarazo , Femenino , Complicaciones Neoplásicas del Embarazo/tratamiento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Vinblastina/uso terapéutico , Vinblastina/administración & dosificación , Vinblastina/efectos adversos , Dacarbazina/uso terapéutico , Dacarbazina/administración & dosificación , Dacarbazina/efectos adversos , Resultado del Tratamiento , Bleomicina/administración & dosificación , Bleomicina/uso terapéutico , Bleomicina/efectos adversos , Adulto , Doxorrubicina/uso terapéutico , Doxorrubicina/efectos adversos , Doxorrubicina/administración & dosificación , Resultado del EmbarazoRESUMEN
INTRODUCTION: The current treatment regimens for Hodgkin's lymphoma (HL) are associated with high incidences of adverse events. PURPOSE: This study aimed to compare the efficacy and safety of doxorubicin + bleomycin + vincristine + dacarbazine (ABVD) and standard bleomycin + etoposide + doxorubicin + cyclophosphamide + vincristine + procarbazine + prednisone (BEACOPP) chemotherapy in the treatment of advanced stage HL. METHODS: This multicenter, randomized, parallel, open, positive control noninferiority trial was conducted from 2016 to 2019 and comprised 93 subjects who were randomized in a 1:1 ratio between the treatment (BEACOPP; n = 44) and control (ABVD; n = 49) groups. RESULTS: The primary efficacy endpoint of this trial was the objective response rate (ORR) after eight cycles of chemotherapy, which was 100.00% (36/36) in the treatment group and 95.74% (45/49) in the control group. The incidence of adverse reactions was 100% in both groups. Significant differences (P < 0.05) in the incidences of grade 3 (39/44 [88.64%] vs. 23/49 [46.94%]) and grade 4 (27/44 [61.36%] vs. 8/49 [16.94%]) adverse events were observed between the treatment and control groups, respectively. However, most of these reactions were manageable, with no serious consequences, and were reversible after discontinuation of the treatment. CONCLUSION: Both regimens had a similar ORR and were associated with a high number of adverse events. The ABVD regimen was better tolerated and safer than the standard BEACOPP regimen. This study indicates that the standard BEACOPP regimen may be considered as a treatment option for patients with advanced HL.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica , Bleomicina , Ciclofosfamida , Dacarbazina , Doxorrubicina , Etopósido , Enfermedad de Hodgkin , Prednisona , Procarbazina , Vincristina , Humanos , Enfermedad de Hodgkin/tratamiento farmacológico , Enfermedad de Hodgkin/patología , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Bleomicina/administración & dosificación , Bleomicina/efectos adversos , Bleomicina/uso terapéutico , Doxorrubicina/administración & dosificación , Doxorrubicina/efectos adversos , Doxorrubicina/uso terapéutico , Vincristina/efectos adversos , Vincristina/uso terapéutico , Vincristina/administración & dosificación , Masculino , Procarbazina/administración & dosificación , Procarbazina/efectos adversos , Procarbazina/uso terapéutico , Adulto , Ciclofosfamida/administración & dosificación , Ciclofosfamida/efectos adversos , Ciclofosfamida/uso terapéutico , Femenino , Etopósido/administración & dosificación , Etopósido/efectos adversos , Etopósido/uso terapéutico , Prednisona/administración & dosificación , Prednisona/efectos adversos , Prednisona/uso terapéutico , Dacarbazina/efectos adversos , Dacarbazina/administración & dosificación , Dacarbazina/uso terapéutico , Persona de Mediana Edad , Adulto Joven , Vinblastina/administración & dosificación , Vinblastina/efectos adversos , Vinblastina/uso terapéutico , Adolescente , Estadificación de Neoplasias , Resultado del TratamientoRESUMEN
Glioblastoma (GBM) is an aggressive nervous system tumor with a poor prognosis. Although, surgery, radiation therapy, and chemotherapy are the current standard protocol for GBM patients, there is still a poor prognosis in these patients. Temozolomide (TMZ) as a first-line therapeutic agent in GBM can easily cross from the blood-brain barrier to inhibit tumor cell proliferation. However, there is a high rate of TMZ resistance in GBM patients. Since, there are limited therapeutic choices for GBM patients who develop TMZ resistance; it is required to clarify the molecular mechanisms of chemo resistance to introduce the novel therapeutic targets. MicroRNAs (miRNAs) regulate chemo resistance through regulation of drug metabolism, absorption, DNA repair, apoptosis, and cell cycle. In the present review we discussed the role of miRNAs in TMZ response of GBM cells. It has been reported that miRNAs mainly induced TMZ sensitivity by regulation of signaling pathways and autophagy in GBM cells. Therefore, miRNAs can be used as the reliable diagnostic/prognostic markers in GBM patients. They can also be used as the therapeutic targets to improve the TMZ response in GBM cells.
Asunto(s)
Neoplasias Encefálicas , Resistencia a Antineoplásicos , Glioblastoma , MicroARNs , Temozolomida , Humanos , Temozolomida/farmacología , Temozolomida/uso terapéutico , Glioblastoma/genética , Glioblastoma/tratamiento farmacológico , Glioblastoma/patología , MicroARNs/genética , MicroARNs/metabolismo , Resistencia a Antineoplásicos/genética , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/tratamiento farmacológico , Neoplasias Encefálicas/patología , Animales , Dacarbazina/análogos & derivados , Dacarbazina/uso terapéutico , Dacarbazina/farmacología , Autofagia/efectos de los fármacos , Autofagia/genética , Regulación Neoplásica de la Expresión Génica/efectos de los fármacosRESUMEN
BACKGROUND: Intensified systemic chemotherapy has the highest primary cure rate for advanced-stage, classical Hodgkin lymphoma but this comes with a cost of severe and potentially life long, persisting toxicities. With the new regimen of brentuximab vedotin, etoposide, cyclophosphamide, doxorubicin, dacarbazine, and dexamethasone (BrECADD), we aimed to improve the risk-to-benefit ratio of treatment of advanced-stage, classical Hodgkin lymphoma guided by PET after two cycles. METHODS: This randomised, multicentre, parallel, open-label, phase 3 trial was done in 233 trial sites across nine countries. Eligible patients were adults (aged ≤60 years) with newly diagnosed, advanced-stage, classical Hodgkin lymphoma (ie, Ann Arbor stage III/IV, stage II with B symptoms, and either one or both risk factors of large mediastinal mass and extranodal lesions). Patients were randomly assigned (1:1) to four or six cycles (21-day intervals) of escalated doses of etoposide (200 mg/m2 intravenously on days 1-3), doxorubicin (35 mg/m2 intravenously on day 1), and cyclophosphamide (1250 mg/m2 intravenously on day 1), and standard doses of bleomycin (10 mg/m2 intravenously on day 8), vincristine (1·4 mg/m2 intravenously on day 8), procarbazine (100 mg/m2 orally on days 1-7), and prednisone (40 mg/m2 orally on days 1-14; eBEACOPP) or BrECADD, guided by PET after two cycles. Patients and investigators were not masked to treatment assignment. Hierarchical coprimary objectives were to show (1) improved tolerability defined by treatment-related morbidity and (2) non-inferior efficacy defined by progression-free survival with an absolute non-inferiority margin of 6 percentage points of BrECADD compared with eBEACOPP. An additional test of superiority of progression-free survival was to be done if non-inferiority had been established. Analyses were done by intention to treat; the treatment-related morbidity assessment required documentation of at least one chemotherapy cycle. This trial was registered at ClinicalTrials.gov (NCT02661503). FINDINGS: Between July 22, 2016, and Aug 27, 2020, 1500 patients were enrolled, of whom 749 were randomly assigned to BrECADD and 751 to eBEACOPP. 1482 patients were included in the intention-to-treat analysis. The median age of patients was 31 years (IQR 24-42). 838 (56%) of 1482 patients were male and 644 (44%) were female. Most patients were White (1352 [91%] of 1482). Treatment-related morbidity was significantly lower with BrECADD (312 [42%] of 738 patients) than with eBEACOPP (430 [59%] of 732 patients; relative risk 0·72 [95% CI 0·65-0·80]; p<0·0001). At a median follow-up of 48 months, BrECADD improved progression-free survival with a hazard ratio of 0·66 (0·45-0·97; p=0·035); 4-year progression-free survival estimates were 94·3% (95% CI 92·6-96·1) for BrECADD and 90·9% (88·7-93·1) for eBEACOPP. 4-year overall survival rates were 98·6% (97·7-99·5) and 98·2% (97·2-99·3), respectively. INTERPRETATION: BrECADD guided by PET after two cycles is better tolerated and more effective than eBEACOPP in first-line treatment of adult patients with advanced-stage, classical Hodgkin lymphoma. FUNDING: Takeda Oncology.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica , Enfermedad de Hodgkin , Adulto , Femenino , Humanos , Masculino , Adulto Joven , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Brentuximab Vedotina/administración & dosificación , Brentuximab Vedotina/efectos adversos , Brentuximab Vedotina/uso terapéutico , Ciclofosfamida/uso terapéutico , Ciclofosfamida/efectos adversos , Ciclofosfamida/administración & dosificación , Dacarbazina/uso terapéutico , Dacarbazina/administración & dosificación , Dacarbazina/efectos adversos , Dexametasona/administración & dosificación , Dexametasona/uso terapéutico , Dexametasona/efectos adversos , Doxorrubicina/administración & dosificación , Doxorrubicina/efectos adversos , Doxorrubicina/uso terapéutico , Etopósido/administración & dosificación , Etopósido/efectos adversos , Etopósido/uso terapéutico , Enfermedad de Hodgkin/tratamiento farmacológico , Enfermedad de Hodgkin/diagnóstico por imagen , Enfermedad de Hodgkin/patología , Enfermedad de Hodgkin/mortalidad , Estadificación de Neoplasias , Tomografía de Emisión de Positrones , Resultado del TratamientoRESUMEN
BACKGROUND/AIM: There is limited evidence regarding the systemic treatment of retroperitoneal soft-tissue sarcoma, and the current Japanese guidelines fail to make definitive suggestions. Here, we report our experience with combination chemotherapy of mesna, doxorubicin, ifosfamide, and dacarbazine (MAID) in this population. PATIENTS AND METHODS: We retrospectively reviewed the records of eight patients (three male and five female) who received MAID for pathologically diagnosed metastatic unresectable retroperitoneal sarcoma (either leiomyosarcoma or pleomorphic sarcoma) between October 2019 and January 2022. Treatment efficacy, tolerability (need for dose reduction), and safety profiles were evaluated and summarized. RESULTS: At initiation, the median age was 56.0 years, and the body mass index was 20.0 kg/cm2 Six patients had Eastern Cooperative Oncology Group performance status scores of 0. The net clinical benefit was a partial response in three (37.5%) patients, stable disease in four (50.0%), and progressive disease in one (12.5%). During the median 90.8 weeks of follow-up, disease in five patients progressed, resulting in a median progression-free survival of 48.4 weeks, and five deaths occurred, resulting in an overall survival of 95.1 weeks. Commonly observed adverse events were neutropenia (eight patients), anemia (eight patients), and decreased platelet count (seven patients), which led to dose reduction (60-80%) in six patients. CONCLUSION: MAID combination therapy may be an acceptable option for advanced retroperitoneal sarcoma; however, its benefits must be carefully assessed owing to its not insignificant toxicity.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica , Dacarbazina , Doxorrubicina , Ifosfamida , Mesna , Neoplasias Retroperitoneales , Sarcoma , Humanos , Masculino , Femenino , Persona de Mediana Edad , Ifosfamida/administración & dosificación , Ifosfamida/efectos adversos , Doxorrubicina/administración & dosificación , Doxorrubicina/efectos adversos , Doxorrubicina/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Neoplasias Retroperitoneales/tratamiento farmacológico , Neoplasias Retroperitoneales/patología , Sarcoma/tratamiento farmacológico , Sarcoma/patología , Mesna/administración & dosificación , Mesna/uso terapéutico , Anciano , Dacarbazina/administración & dosificación , Dacarbazina/efectos adversos , Dacarbazina/uso terapéutico , Estudios Retrospectivos , AdultoRESUMEN
Vanishing bile duct syndrome is an uncommon condition characterised by the progressive loss and disappearance of bile ducts. It is an acquired form of cholestatic liver disease presenting with hepatic ductopenia (loss of >50% bile ducts in the portal areas). We present a case of vanishing bile duct syndrome as a presentation of Hodgkin's lymphoma who was treated with standard-of-care chemotherapy-doxorubicin, bleomycin, vinblastine and dacarbazine (along with brief administration of rituximab), which led to complete response and normalisation of liver function.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica , Bleomicina , Enfermedad de Hodgkin , Adulto , Femenino , Humanos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Enfermedades de los Conductos Biliares/diagnóstico , Bleomicina/administración & dosificación , Bleomicina/uso terapéutico , Dacarbazina/uso terapéutico , Dacarbazina/administración & dosificación , Doxorrubicina/uso terapéutico , Enfermedad de Hodgkin/complicaciones , Enfermedad de Hodgkin/tratamiento farmacológico , Enfermedad de Hodgkin/diagnóstico , Rituximab/uso terapéutico , Rituximab/administración & dosificación , Síndrome , Vinblastina/uso terapéutico , Vinblastina/administración & dosificaciónRESUMEN
PURPOSE: To evaluate the chemotherapeutic activity of temozolomide counter to mammary carcinoma. METHODS: In-vitro anticancer activity has been conducted on MCF7 cells, and mammary carcinoma has been induced in Wistar rats by introduction of 7, 12-Dimethylbenz(a)anthracene (DMBA), which was sustained for 24 weeks. Histopathology, immunohistochemistry, cell proliferation study and apoptosis assay via TUNEL method was conducted to evaluate an antineoplastic activity of temozolomide in rat breast tissue. RESULTS: IC50 value of temozolomide in MCF7 cell has been obtained as 103 µM, which demonstrated an initiation of apoptosis. The temozolomide treatment facilitated cell cycle arrest in G2/M and S phase dose dependently. The treatment with temozolomide suggested decrease of the hyperplastic abrasions and renovation of the typical histological features of mammary tissue. Moreover, temozolomide therapy caused the downregulation of epidermal growth factor receptor, extracellular signal-regulated kinase, and metalloproteinase-1 expression and upstream of p53 and caspase-3 proliferation to indicate an initiation of apoptotic events. CONCLUSIONS: The occurrence of mammary carcinoma has been significantly decreased by activation of apoptotic pathway and abrogation of cellular propagation that allowable for developing a suitable mechanistic pathway of temozolomide in order to facilitate chemotherapeutic approach.
Asunto(s)
Antineoplásicos Alquilantes , Apoptosis , Receptores ErbB , Ratas Wistar , Temozolomida , Temozolomida/farmacología , Temozolomida/uso terapéutico , Animales , Apoptosis/efectos de los fármacos , Femenino , Receptores ErbB/efectos de los fármacos , Receptores ErbB/antagonistas & inhibidores , Antineoplásicos Alquilantes/farmacología , Antineoplásicos Alquilantes/uso terapéutico , Metaloproteinasa 1 de la Matriz/efectos de los fármacos , Metaloproteinasa 1 de la Matriz/metabolismo , Proliferación Celular/efectos de los fármacos , Dacarbazina/análogos & derivados , Dacarbazina/farmacología , Dacarbazina/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/patología , Humanos , Células MCF-7 , Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Quinasas MAP Reguladas por Señal Extracelular/efectos de los fármacos , Inmunohistoquímica , Reproducibilidad de los Resultados , Ratas , Neoplasias Mamarias Experimentales/tratamiento farmacológico , Neoplasias Mamarias Experimentales/patologíaRESUMEN
BACKGROUND OBJECTIVES: The role of consolidation radiation therapy (CRT) after complete metabolic response to chemotherapy in advanced-stage (stage III and IV) Hodgkin lymphoma (HL) is controversial. This study was undertaken to assess the clinical outcomes in terms of event free survival, local failure free survival and overall survival in individuals with advanced HL treated with chemotherapy and CRT. METHODS: A retrospective review was conducted to study the long-term clinical outcomes in individuals diagnosed with HL and treated with chemotherapy and CRT from 2012 to 2016 at a tertiary cancer care hospital in India. RESULTS: Data from 203 study participants with advanced-stage HL were analyzed. Positron emission tomography-computed tomography (PET-CT) was done at baseline and after 2 cycles for response assessment. The median age at presentation was 32 yr [interquartile range (IQR): 26-46]. Early metabolic response (after 2 cycles) and delayed metabolic response (after 4 or 6 cycles) were observed in 74.4 and 25.6 per cent of individuals, respectively. With a median follow up of 52 months (IQR: 40-67), the five-year event-free survival (EFS), local failure-free survival (LFFS) and overall survival (OS) were 83.2, 95.1 and 94.6 per cent, respectively. On univariate analysis, extranodal disease was associated with inferior EFS (P=0.043). Haemoglobin <10.5 g/dl (P=0.002) and Hasenclever index >3 (P=0.00047) were associated with poorer OS. Relapses were observed in 28/203 (13.8%) study participants with predominance at central nodal stations. The median time to relapse was 19.4 months (IQR: 13-33). Local relapse alone (at the irradiated site) was observed in 5/28 study participants, systemic (distant) relapse in 14/28 individuals, while both systemic and local relapse was observed in 9/28 participants. Extranodal disease (P=0.05), bulky disease (P=0.005) and haemoglobin concentration ≤10.5 g/dl (P=0.036) were significant predictors for disease relapse. INTERPRETATION CONCLUSIONS: Individuals with advanced-stage HL treated with anthracycline-based chemotherapy (anthracycline-based chemotherapy with doxorubicin, bleomycin, vinblastine and dacarbazine regimen) and CRT had excellent long-term outcomes. As isolated infield failures are uncommon, selective consolidation with conformal RT to high-risk sites improves final disease outcomes.
Asunto(s)
Enfermedad de Hodgkin , Humanos , Enfermedad de Hodgkin/diagnóstico por imagen , Enfermedad de Hodgkin/tratamiento farmacológico , Estudios Retrospectivos , Tomografía Computarizada por Tomografía de Emisión de Positrones , Dacarbazina/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Recurrencia Local de Neoplasia/diagnóstico por imagen , Recurrencia Local de Neoplasia/tratamiento farmacológico , Recurrencia Local de Neoplasia/patología , Terapia Combinada , Doxorrubicina , Recurrencia , Hemoglobinas , Estadificación de Neoplasias , Resultado del TratamientoRESUMEN
OBJECTIVE: To elucidate the relationship between USP19 and O(6)-methylguanine-DNA methyltransferase (MGMT) after temozolomide treatment in glioblastoma (GBM) patients with chemotherapy resistance. METHODS: Screening the deubiquitinase pannel and identifying the deubiquitinase directly interacts with and deubiquitination MGMT. Deubiquitination assay to confirm USP19 deubiquitinates MGMT. The colony formation and tumor growth study in xenograft assess USP19 affects the GBM sensitive to TMZ was performed by T98G, LN18, U251, and U87 cell lines. Immunohistochemistry staining and survival analysis were performed to explore how USP19 is correlated to MGMT in GBM clinical management. RESULTS: USP19 removes the ubiquitination of MGMT to facilitate the DNA methylation damage repair. Depletion of USP19 results in the glioblastoma cell sensitivity to temozolomide, which can be rescued by overexpressing MGMT. USP19 is overexpressed in glioblastoma patient samples, which positively correlates with the level of MGMT protein and poor prognosis in these patients. CONCLUSION: The regulation of MGMT ubiquitination by USP19 plays a critical role in DNA methylation damage repair and GBM patients' temozolomide chemotherapy response.
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Antineoplásicos Alquilantes , Metilación de ADN , Metilasas de Modificación del ADN , Enzimas Reparadoras del ADN , Resistencia a Antineoplásicos , Temozolomida , Proteínas Supresoras de Tumor , Humanos , Temozolomida/farmacología , Temozolomida/uso terapéutico , Enzimas Reparadoras del ADN/metabolismo , Enzimas Reparadoras del ADN/genética , Metilasas de Modificación del ADN/metabolismo , Antineoplásicos Alquilantes/farmacología , Antineoplásicos Alquilantes/uso terapéutico , Animales , Línea Celular Tumoral , Resistencia a Antineoplásicos/efectos de los fármacos , Resistencia a Antineoplásicos/genética , Proteínas Supresoras de Tumor/metabolismo , Proteínas Supresoras de Tumor/genética , Metilación de ADN/efectos de los fármacos , Ratones Desnudos , Neoplasias Encefálicas/tratamiento farmacológico , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/metabolismo , Glioblastoma/tratamiento farmacológico , Glioblastoma/genética , Glioblastoma/metabolismo , Ratones , Masculino , Femenino , Dacarbazina/análogos & derivados , Dacarbazina/farmacología , Dacarbazina/uso terapéutico , Reparación del ADN/efectos de los fármacos , Endopeptidasas/metabolismo , Endopeptidasas/genética , Ensayos Antitumor por Modelo de Xenoinjerto , Ubiquitinación/efectos de los fármacosRESUMEN
The article "The impact of bleomycin deficit on survival in Hodgkin's lymphoma patients: A retrospective study" have presented the experience of AVD chemotherapy regimen in newly diagnosed Hodgkin's lymphoma (HL) in a single center in Brazil. Though being a small retrospective study, results from this study have provided the medical community a real-world data on HL in Brazil. ABVD has remained the standard of care for patients of newly diagnosed HL both in early and advance stages. Newer targeted molecules have also come for use in novel combinations with existing drugs. However, in a situation of temporary scarcity of bleomycin due to lack of supply during 2017 in Brazil led to use of incomplete ABVD regimen without bleomycin, i.e. AVD for HL. However, Soldi et al. utilized the opportunity to retrospectively study if the omission of bleomycin leads to subnormal treatment or unwarranted effects.
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Bleomicina , Enfermedad de Hodgkin , Enfermedad de Hodgkin/tratamiento farmacológico , Enfermedad de Hodgkin/mortalidad , Bleomicina/uso terapéutico , Bleomicina/administración & dosificación , Humanos , Estudios Retrospectivos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Vinblastina/uso terapéutico , Brasil/epidemiología , Doxorrubicina/uso terapéutico , Dacarbazina/uso terapéuticoAsunto(s)
Neoplasias del Sistema Nervioso Central , Temozolomida , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Masculino , Persona de Mediana Edad , Antineoplásicos Alquilantes/uso terapéutico , Antineoplásicos Alquilantes/efectos adversos , Supervivientes de Cáncer , Neoplasias del Sistema Nervioso Central/tratamiento farmacológico , Neoplasias del Sistema Nervioso Central/mortalidad , Dacarbazina/uso terapéutico , Dacarbazina/administración & dosificación , Estudios de Seguimiento , Linfoma/tratamiento farmacológico , Linfoma/mortalidad , Quimioterapia de Mantención , Temozolomida/uso terapéutico , Resultado del TratamientoRESUMEN
PURPOSE: Adult Diffuse midline glioma (DMG) is a very rare disease. DMGs are currently treated with radiotherapy and chemotherapy even if only a few retrospective studies assessed the impact on overall survival (OS) of these approaches. METHODS: We carried out an Italian multicentric retrospective study of adult patients with H3K27-altered DMG to assess the effective role of systemic therapy in the treatment landscape of this rare tumor type. RESULTS: We evaluated 49 patients from 6 Institutions. The median age was 37.3 years (range 20.1-68.3). Most patients received biopsy as primary approach (n = 30, 61.2%) and radiation therapy after surgery (n = 39, 79.6%). 25 (51.0%) of patients received concurrent chemotherapy and 26 (53.1%) patients received adjuvant temozolomide. In univariate analysis, concurrent chemotherapy did not result in OS improvement while adjuvant temozolomide was associated with longer OS (21.2 vs. 9.0 months, HR 0.14, 0.05-0.41, p < 0.001). Multivariate analysis confirmed the role of adjuvant chemotherapy (HR 0.1, 95%CI: 0.03-0.34, p = 0.003). In patients who progressed after radiation and/or chemotherapy the administration of a second-line systemic treatment had a significantly favorable impact on survival (8.0 vs. 3.2 months, HR 0.2, 95%CI 0.1-0.65, p = 0.004). CONCLUSION: In our series, adjuvant treatment after radiotherapy can be useful in improving OS of patients with H3K27-altered DMG. When feasible another systemic treatment after treatment progression could be proposed.
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Neoplasias Encefálicas , Glioma , Adulto , Humanos , Adulto Joven , Persona de Mediana Edad , Anciano , Temozolomida/uso terapéutico , Estudios Retrospectivos , Neoplasias Encefálicas/tratamiento farmacológico , Neoplasias Encefálicas/patología , Antineoplásicos Alquilantes/uso terapéutico , Glioma/tratamiento farmacológico , Glioma/patología , Dacarbazina/uso terapéutico , Quimioterapia AdyuvanteRESUMEN
BACKGROUND: Glioblastoma (GBM) is the most common devastating primary brain cancer in adults. In our clinical practice, median overall survival (mOS) of GBM patients seems increasing over time. METHODS: To address this observation, we have retrospectively analyzed the prognosis of 722 newly diagnosed GBM patients, aged below 70, in good clinical conditions (i.e. Karnofsky Performance Status -KPS- above 70%) and treated in our department according to the standard of care (SOC) between 2005 and 2018. Patients were divided into two groups according to the year of diagnosis (group 1: from 2005 to 2012; group 2: from 2013 to 2018). RESULTS: Characteristics of patients and tumors of both groups were very similar regarding confounding factors (age, KPS, MGMT promoter methylation status and treatments). Follow-up time was fixed at 24 months to ensure comparable survival times between both groups. Group 1 patients had a mOS of 19 months ([17.3-21.3]) while mOS of group 2 patients was not reached. The recent period of diagnosis was significantly associated with a longer mOS in univariate analysis (HR=0.64, 95% CI [0.51 - 0.81]), p < 0.001). Multivariate Cox analysis showed that the period of diagnosis remained significantly prognostic after adjustment on confounding factors (adjusted Hazard Ratio (aHR) 0.49, 95% CI [0.36-0.67], p < 0.001). CONCLUSION: This increase of mOS over time in newly diagnosed GBM patients could be explained by better management of potentially associated non-neurological diseases, optimization of validated SOC, better management of treatments side effects, supportive care and participation in clinical trials.
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Neoplasias Encefálicas , Glioblastoma , Adulto , Humanos , Anciano , Glioblastoma/terapia , Glioblastoma/tratamiento farmacológico , Temozolomida/uso terapéutico , Dacarbazina/uso terapéutico , Antineoplásicos Alquilantes/uso terapéutico , Estudios Retrospectivos , Neoplasias Encefálicas/terapia , Neoplasias Encefálicas/tratamiento farmacológico , PronósticoRESUMEN
Glioblastoma (GBM) is the most common malignant brain tumor and has the poorest prognosis attributed to its chemoresistance to temozolomide (TMZ), the first-line drug for treating GBM. TMZ resistance represents a significant obstacle to successful GBM treatment, necessitating the development of new strategies to overcome this resistance and augment the chemosensitivity of GBM cells to TMZ. This study established a TMZ-resistant U251 (U251-TMZ) cell line by exposing it to increasing doses of TMZ in vitro. We focused on the DNA methyltransferase 3B (DNMT3B) gene, phosphorylated Akt (p-Akt), total Akt (t-Akt), phosphorylated PI3K (p-PI3K), and total PI3K (t-PI3K) protein expression. Results showed that the DNMT3B gene was significantly upregulated in the U251-TMZ cell line. The p-Akt and p-PI3K protein expression in U251-TMZ cells was also significantly elevated. Moreover, we found that DNMT3B downregulation was correlated with the increased chemosensitivity of GBM cells to TMZ. LY294002 suppressed the PI3K/Akt signaling pathway, leading to a notable inhibition of PI3K phosphorylation and a significant decrease in DNMT3B expression in U251-TMZ cells. Given that DNMT3B expression is mediated by the PI3K/Akt signaling pathway, its downregulation further increased the chemosensitivity of GBM cells to TMZ and therefore is a promising therapeutic for GBM treatment. Our results suggested that DNMT3B downregulation can inhibit the proliferation of GBM cells and induce GBM cell apoptosis in vitro. In addition, the PI3K/Akt signaling pathway plays an important role in the chemosensitivity of GBM cells to TMZ by regulating DNMT3B expression.
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ADN (Citosina-5-)-Metiltransferasas , ADN Metiltransferasa 3B , Regulación hacia Abajo , Glioblastoma , Fosfatidilinositol 3-Quinasas , Proteínas Proto-Oncogénicas c-akt , Transducción de Señal , Temozolomida , Temozolomida/farmacología , Temozolomida/uso terapéutico , Humanos , ADN (Citosina-5-)-Metiltransferasas/metabolismo , Glioblastoma/tratamiento farmacológico , Glioblastoma/patología , Glioblastoma/metabolismo , Glioblastoma/genética , Transducción de Señal/efectos de los fármacos , Proteínas Proto-Oncogénicas c-akt/metabolismo , Fosfatidilinositol 3-Quinasas/metabolismo , Línea Celular Tumoral , Regulación hacia Abajo/efectos de los fármacos , Resistencia a Antineoplásicos/efectos de los fármacos , Dacarbazina/análogos & derivados , Dacarbazina/farmacología , Dacarbazina/uso terapéutico , Neoplasias Encefálicas/tratamiento farmacológico , Neoplasias Encefálicas/patología , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/metabolismo , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Antineoplásicos Alquilantes/farmacología , Antineoplásicos Alquilantes/uso terapéutico , Fosforilación/efectos de los fármacosRESUMEN
Temozolomide (TMZ) is a DNA alkylating agent that produces objective responses in patients with neuroendocrine tumors (NETs) when the DNA repair enzyme O6-methylguanine-DNA methyltransferase (MGMT) is inactivated. At high doses, TMZ therapy exhausts MGMT activity but also produces dose-limiting toxicities. To reduce off-target effects, we converted the clinically approved radiotracer 68Ga-DOTA-TOC into a peptide-drug conjugate (PDC) for targeted delivery of TMZ to somatostatin receptor subtype-2 (SSTR2)-positive tumor cells. We used an integrated radiolabeling strategy for direct quantitative assessment of receptor binding, pharmacokinetics, and tissue biodistribution. In vitro studies revealed selective binding to SSTR2-positive cells with high affinity (5.98 ± 0.96 nmol/L), internalization, receptor-dependent DNA damage, cytotoxicity, and MGMT depletion. Imaging and biodistribution analysis showed preferential accumulation of the PDC in receptor-positive tumors and high renal clearance. This study identified a trackable SSTR2-targeting system for TMZ delivery and utilizes a modular design that could be broadly applied in PDC development.
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Dacarbazina , Receptores de Somatostatina , Humanos , Temozolomida/farmacología , Dacarbazina/farmacología , Dacarbazina/uso terapéutico , Receptores de Somatostatina/metabolismo , Distribución Tisular , O(6)-Metilguanina-ADN Metiltransferasa/genética , O(6)-Metilguanina-ADN Metiltransferasa/metabolismo , Enzimas Reparadoras del ADN/metabolismo , Metilasas de Modificación del ADN/metabolismo , Antineoplásicos Alquilantes/farmacología , Línea Celular TumoralRESUMEN
Glioblastoma multiforme (GBM) is usually treated with surgery followed by adjuvant partial radiotherapy combined with temozolomide (TMZ) chemotherapy. Recent studies demonstrated a better survival and good response to TMZ in methylguanine-DNA methyltransferase (MGMT)-methylated GBM cases. However, approximately 20% of patients with MGMT-unmethylated GBM display an unexpectedly favorable outcome. Therefore, additional mechanisms related to the TMZ response need to be investigated. As such, we decided to investigate the clinical relevance of six miRNAs involved in brain tumorigenesis (miR-181c, miR-181d, miR-21, miR-195, miR-196b, miR-648) as additional markers of response and survival in patients receiving TMZ for GBM. We evaluated miRNA expression and the interplay between miRNAs in 112 IDH wt GBMs by applying commercial assays. Then, we correlated the miRNA expression with patients' clinical outcomes. Upon bivariate analyses, we found a significant association between the expression levels of the miRNAs analyzed, but, more interestingly, the OS curves show that the combination of low miR-648 and miR-181c or miR-181d expressions is associated with a worse prognosis than cases with other low-expression miRNA pairs. To conclude, we found how specific miRNA pairs can influence survival in GBM cases treated with TMZ.