Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 5.801
Filtrar
1.
Int J Mol Sci ; 22(6)2021 Mar 13.
Artigo em Inglês | MEDLINE | ID: mdl-33805743

RESUMO

Idiopathic pulmonary fibrosis (IPF) is a lethal age-related lung disease whose pathogenesis involves an aberrant response of alveolar epithelial cells (AEC). Activated epithelial cells secrete mediators that participate in the activation of fibroblasts and the excessive deposition of extracellular matrix proteins. Previous studies indicate that matrix metalloproteinase 14 (MMP14) is increased in the lung epithelium in patients with IPF, however, the role of this membrane-type matrix metalloproteinase has not been elucidated. In this study, the role of Mmp14 was explored in experimental lung fibrosis induced with bleomycin in a conditional mouse model of lung epithelial MMP14-specific genetic deletion. Our results show that epithelial Mmp14 deficiency in mice increases the severity and extension of fibrotic injury and affects the resolution of the lesions. Gain-and loss-of-function experiments with human epithelial cell line A549 demonstrated that cells with a deficiency of MMP14 exhibited increased senescence-associated markers. Moreover, conditioned medium from these cells increased fibroblast expression of fibrotic molecules. These findings suggest a new anti-fibrotic mechanism of MMP14 associated with anti-senescent activity, and consequently, its absence results in impaired lung repair. Increased MMP14 in IPF may represent an anti-fibrotic mechanism that is overwhelmed by the strong profibrotic microenvironment that characterizes this disease.


Assuntos
Células Epiteliais/patologia , Fibrose Pulmonar Idiopática/genética , Metaloproteinase 14 da Matriz/genética , Alvéolos Pulmonares/metabolismo , Células A549 , Actinas/genética , Actinas/metabolismo , Animais , Bleomicina/administração & dosagem , Senescência Celular/genética , Colágeno Tipo I/genética , Colágeno Tipo I/metabolismo , Modelos Animais de Doenças , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/metabolismo , Fibronectinas/genética , Fibronectinas/metabolismo , Regulação da Expressão Gênica , Humanos , Hipoxantina Fosforribosiltransferase/genética , Hipoxantina Fosforribosiltransferase/metabolismo , Fibrose Pulmonar Idiopática/induzido quimicamente , Fibrose Pulmonar Idiopática/metabolismo , Fibrose Pulmonar Idiopática/patologia , Metaloproteinase 14 da Matriz/deficiência , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Cultura Primária de Células , Alvéolos Pulmonares/efeitos dos fármacos , Alvéolos Pulmonares/patologia , Succinato Desidrogenase/genética , Succinato Desidrogenase/metabolismo , Fator de Crescimento Transformador beta1/genética , Fator de Crescimento Transformador beta1/metabolismo
2.
Lancet Haematol ; 8(4): e278-e288, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33770483

RESUMO

BACKGROUND: To improve the long-term tumour control in early, unfavourable Hodgkin Lymphoma, the German Hodgkin Study Group (GHSG) HD14 trial compared four cycles of doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) with an intensified chemotherapy regimen consisting of two cycles of escalated bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone (escalated BEACOPP) plus two cycles of ABVD. The final analysis of the trial showed a significant advantage in terms of freedom from treatment failure (difference 7·2% [95% CI 3·8-10·5] at 5 years) for patients who received two cycles of escalated BEACOPP and two cycles of ABVD. However, there was no difference in overall survival between the two groups. To evaluate long-term efficacy and toxicity of this strategy, we did a follow-up analysis. METHODS: Patients aged 18-60 years with performance status of 2 or less and primary diagnosis of early, unfavourable Hodgkin lymphoma (all histologies) were included in an international, randomised, open-label, phase 3 trial. Patients were randomly assigned to receive four cycles of ABVD (ABVD group) or two cycles of escalated BEACOPP and two cycles of ABVD (2 + 2 group), both groups also received 30 Gy involved field radiotherapy. The ABVD dosing regimen was doxorubicin 25 mg/m2 (days 1 and 15), bleomycin 10 mg/m2 (days 1 and 15), vinblastine 6 mg/m2 (days 1 and 15), and dacarbazine 375 mg/m2 (days 1 and 15), repeated on day 29. The escalated BEACOPP dosing regimen was cyclophosphamide 1250 mg/m2 (day 1), doxorubicin 35 mg/m2 (day 1), etoposide 200 mg/m2 (days 1-3), procarbazine 100 mg/m2 (days 1-7), prednisone 40 mg/m2 (days 1-14), vincristine 1·4 mg/m2 (day 8; maximum 2 mg), and bleomycin 10 mg/m2 (day 8), repeated on day 22. After closure of the ABVD group according to prespecified rules, patients were assigned to receive two cycles of escalated BEACOPP and two cycles of ABVD (non-randomised 2 + 2 group), which continued until the end of the predefined 5-year recruitment period. In this prespecified long-term follow-up analysis, we aimed to evaluate the secondary endpoints progression-free survival, overall survival, and long-term toxicity. To this end, we did a descriptive intention-to-treat analysis of all qualified HD14 patients and on the predefined subsets of randomised qualified HD14 patients and patients in the non-randomised 2 + 2 group. The trial was registered on the International Standard Randomised Controlled Trial database, 04761296. FINDINGS: Between Jan 28, 2003, and Dec 29, 2009, 1686 patients were randomly assigned to the ABVD group (847 [50·2%] patients) and the 2 + 2 group (839 [49·8%] patients). 370 additional patients were recruited to the non-randomised 2 + 2 group. 1550 (92%) randomly assigned patients (median observation time 112 months [IQR 80-132]) and 339 (92%) patients in the non-randomised 2 + 2 group (median observation time 74 months [58-100]) were included in the qualified analysis set. 10-year overall survival in the randomly assigned patients was 94·1% (95% CI 92·0-95·7) for the ABVD group and 94·1% (91·8-95·7) for the 2 + 2 group (HR 1·0 [95% CI 0·6-1·5]; p=0·88). 8-year overall survival in the non-randomised 2 + 2 group was 95·1% (95% CI 91·6-97·2). 10-year progression-free survival in the randomly assigned patients was 85·6% (95% CI 82·6-88·1) for the ABVD group and 91·2% (88·4-93·3) for the 2 + 2 group (HR 0·5% [95% CI 0·4-0·7]; p=0·0001), accounting for a significant difference of 5·6% (95% CI 1·9-9·2) favouring the 2 + 2 group (p=0·0001). In the non-randomised 2 + 2 group, 8-year progression-free survival was 94·5% (95% CI 91·1-96·6). Standardised incidence ratios of second primary malignancies were similar between the ABVD group (2·3 [95% CI 1·6-3·1]) and the 2 + 2 group (2·5 [1·8-3·4]; Gray's p=0·80). Standardised incidence ratio of second primary malignancies was 3·1 (95% CI 1·7-5·0) in the non-randomised 2 + 2 group. INTERPRETATION: This long-term analysis confirms superior tumour control in the 2 + 2 group compared with the ABVD group without translating into an overall survival difference. At longer follow-up, there is no difference regarding second primary malignancies between groups. In conclusion, the 2 + 2 regimen spares a significant number of patients from the burden of relapse and additional treatment without increased long-term toxicity. FUNDING: Deutsche Krebshilfe eV and Swiss Federal Government.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Doença de Hodgkin/tratamento farmacológico , Adulto , Bleomicina/administração & dosagem , Bleomicina/uso terapêutico , Ciclofosfamida/administração & dosagem , Ciclofosfamida/uso terapêutico , Dacarbazina/administração & dosagem , Dacarbazina/uso terapêutico , Doxorrubicina/administração & dosagem , Doxorrubicina/uso terapêutico , Etoposídeo/administração & dosagem , Etoposídeo/uso terapêutico , Feminino , Seguimentos , Alemanha/epidemiologia , Doença de Hodgkin/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias/métodos , Segunda Neoplasia Primária/epidemiologia , Prednisona/administração & dosagem , Prednisona/uso terapêutico , Procarbazina/administração & dosagem , Procarbazina/uso terapêutico , Intervalo Livre de Progressão , Resultado do Tratamento , Vimblastina/administração & dosagem , Vimblastina/uso terapêutico , Vincristina/administração & dosagem , Vincristina/uso terapêutico
3.
Medicine (Baltimore) ; 100(8): e24916, 2021 Feb 26.
Artigo em Inglês | MEDLINE | ID: mdl-33663127

RESUMO

INTRODUCTION: Primary yolk sac tumor (YST) is an infrequently-diagnosed malignant extragonadal germ cell tumors. It is likely to recur locally and may present with widespread metastases once diagnosed. Primary YST of the head is uncommon but can cause severe complications, such as loss of vision once the tumor mass invades the optic nerve. PATIENT CONCERNS: A 20-month-old boy presented to the general clinic of the local children's hospital with a complaint of swelling of left face for 1 year and proptosis of the left eye for over 2 weeks as stated by his parents. Initially, he did have some vision, as he could walk by himself, but a special ophthalmologic examination was not performed. DIAGNOSES: Cranial computed tomography and magnetic resonance imaging revealed a large tumor accompanied by peripheral bone destruction in the left pterygopalatine fossa that extended to sphenoid, ethmoid, left maxillary sinuses, left nasoethmoid, and left orbit. The optic nerve was invaded on both sides. Chest and abdominal imaging were normal. A primary diagnosis of Langerhans cell hyperplasia was made. However, blood tests on the second day of hospitalization revealed significantly elevated serum alpha-fetoprotein levels. On the third day, the boy lost his eyesight, with loss of pupillary and no light sensation during flashlight stimulation on both sides. INTERVENTIONS: Nasal endoscopy was performed on the fourth day, the vast majority of soft tissue mass was resected for biopsy. Histopathological examination revealed features of endodermal sinus tumor. A final diagnosis of primary YST of pterygopalatine fossa was made. Because the mass could not be resected completely, he received combined chemotherapy with bleomycin, etoposide, and carboplatin for 6 cycles over six months. OUTCOMES: The patient recovered with significant tumor shrinkage and without secondary metastasis after 18 months but left permanently blind. CONCLUSION: The worst complication of loss of vision after Primary YST of pterygopalatine fossa alerts us that close physical examination during the initial investigation should be performed, which is especially important in young children who cannot express complaints well. Early detection and treatment with surgical resection and chemotherapy may contribute to satisfactory outcomes and avoidance of visual impairment.


Assuntos
Tumor do Seio Endodérmico/diagnóstico , Tumor do Seio Endodérmico/patologia , Fossa Pterigopalatina/patologia , Neoplasias Cranianas/diagnóstico , Neoplasias Cranianas/patologia , Antibióticos Antineoplásicos/administração & dosagem , Bleomicina/administração & dosagem , Cegueira/etiologia , Carboplatina/administração & dosagem , Quimioterapia Adjuvante , Diagnóstico Tardio , Tumor do Seio Endodérmico/complicações , Tumor do Seio Endodérmico/terapia , Humanos , Lactente , Imagem por Ressonância Magnética , Masculino , Neoplasias Cranianas/complicações , Neoplasias Cranianas/terapia , Tomografia Computadorizada por Raios X
4.
Ann Hematol ; 100(4): 979-986, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33608849

RESUMO

High-dose methotrexate (HD-MTX) at 3 g/m2 is one of the strategies for central nervous system (CNS) prophylaxis in the first-line treatment of aggressive lymphomas, especially in diffuse large B cell lymphoma patients with high-risk CNS-International Prognostic Index. The objective of our study was to retrospectively analyze the safety of 2 cycles of systemic HD-MTX administered as an ambulatory regimen. Between January 2013 and December 2016, 103 patients were carefully selected on 6 criteria, including age < 60, albumin > 34, performance status 0 or 1, normal renal and hepatic functions, good understanding of practical medical guidance, and no loss of weight. Strict procedures of HD-MTX infusion were observed including alkalinization, urine pH monitoring, and leucovorin rescue. Renal and hepatic functions were monitored at days 2 and 7. MTX clearance was not monitored. Toxicities and grades of toxicity were collected according to the NCI-CTCAE (version 4.0). Among the 103 selected patients, 92 (89%) patients successfully completed the planned 2 cycles of HD-MTX on an outpatient basis. Eleven patients completed only 1 cycle, 3 because of lymphoma progression and 8 because of toxicity including 3 grade II hepatotoxicity, 2 grade I/II renal toxicity, 1 grade III neutropenia, 1 active herpetic infection, and 1 grade III ileus reflex. Reported adverse events (AE) included 92 (84%) grade I/II and 18 (16%) grade III/IV. Grade III hepatotoxicity, mostly cytolysis, was the most frequent AE observed with 8 (8%) events. Grade III/IV hematologic toxicities concerned 9 patients with 8 grade III/IV neutropenia and 1 thrombocytopenia. Renal toxicity was rare, mild, and transient, observed with 4 (4%) grade I/II events. Ambulatory administration of HD-MTX at 3 g/m2 without MTX clearance monitoring is safe with strict medical guidance. It requires careful selection of patients before administration, and a renal and hepatic monitoring after the administration.


Assuntos
Antimetabólitos Antineoplásicos/uso terapêutico , Sistema Nervoso Central/patologia , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Linfoma não Hodgkin/tratamento farmacológico , Metotrexato/uso terapêutico , Adolescente , Adulto , Assistência Ambulatorial , Antimetabólitos Antineoplásicos/administração & dosagem , Antimetabólitos Antineoplásicos/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Bleomicina/administração & dosagem , Doença Hepática Induzida por Substâncias e Drogas/etiologia , Ciclofosfamida/administração & dosagem , Doxorrubicina/administração & dosagem , Feminino , Doenças Hematológicas/induzido quimicamente , Humanos , Infusões Intravenosas , Nefropatias/induzido quimicamente , Testes de Função Renal , Leucovorina/uso terapêutico , Testes de Função Hepática , Linfoma Difuso de Grandes Células B/patologia , Linfoma não Hodgkin/patologia , Masculino , Metotrexato/administração & dosagem , Metotrexato/efeitos adversos , Pessoa de Meia-Idade , Invasividade Neoplásica , Ambulatório Hospitalar , Prednisona/administração & dosagem , Estudos Retrospectivos , Rituximab/administração & dosagem , Vincristina/administração & dosagem , Vindesina/administração & dosagem , Adulto Jovem
5.
Ann Hematol ; 100(4): 1049-1058, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33641019

RESUMO

Treatment with ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine) or escalated(e)-BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisolone) remains the international standard of care for advanced-stage classical Hodgkin lymphoma (HL). We performed a retrospective, multicentre analysis of 221 non-trial ("real-world") patients, aged 16-59 years, diagnosed with advanced-stage HL in the Anglia Cancer Network between 2004 and 2014, treated with ABVD or eBEACOPP, and compared outcomes with 1088 patients in the Response-Adjusted Therapy for Advanced Hodgkin Lymphoma (RATHL) trial, aged 18-59 years, with median follow-up of 87.0 and 69.5 months, respectively. Real-world ABVD patients (n=177) had highly similar 5-year progression-free survival (PFS) and overall survival (OS) compared with RATHL (PFS 79.2% vs 81.4%; OS 92.9% vs 95.2%), despite interim positron-emission tomography-computed tomography (PET/CT)-guided dose-escalation being predominantly restricted to trial patients. Real-world eBEACOPP patients (n=44) had superior PFS (95.5%) compared with real-world ABVD (HR 0.20, p=0.027) and RATHL (HR 0.21, p=0.015), and superior OS for higher-risk (international prognostic score ≥3 [IPS 3+]) patients compared with real-world IPS 3+ ABVD (100% vs 84.5%, p=0.045), but not IPS 3+ RATHL patients. Our data support a PFS, but not OS, advantage for patients with advanced-stage HL treated with eBEACOPP compared with ABVD and suggest higher-risk patients may benefit disproportionately from more intensive therapy. However, increased access to effective salvage therapies might minimise any OS benefit from reduced relapse rates after frontline therapy.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Doença de Hodgkin/tratamento farmacológico , Adolescente , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Bleomicina/administração & dosagem , Ensaios Clínicos como Assunto/estatística & dados numéricos , Terapia Combinada , Ciclofosfamida/administração & dosagem , Dacarbazina/administração & dosagem , Doxorrubicina/administração & dosagem , Inglaterra/epidemiologia , Etoposídeo/administração & dosagem , Feminino , Seguimentos , Transplante de Células-Tronco Hematopoéticas , Doença de Hodgkin/mortalidade , Doença de Hodgkin/terapia , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Estudos Multicêntricos como Assunto/estatística & dados numéricos , Prednisona/administração & dosagem , Gravidez , Complicações Neoplásicas na Gravidez/tratamento farmacológico , Complicações Neoplásicas na Gravidez/epidemiologia , Procarbazina/administração & dosagem , Intervalo Livre de Progressão , Estudos Retrospectivos , Resultado do Tratamento , Vimblastina/administração & dosagem , Vincristina/administração & dosagem , Adulto Jovem
6.
Lancet Oncol ; 22(2): 223-234, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33539742

RESUMO

BACKGROUND: Combined-modality treatment consisting of chemotherapy and consolidation radiotherapy is standard of care for patients with early-stage unfavourable Hodgkin lymphoma. However, the use of radiotherapy can have long-term sequelae, which is of particular concern, as Hodgkin lymphoma is frequently diagnosed in young adults with a median age of approximately 30 years. In the German Hodgkin Study Group HD17 trial, we investigated whether radiotherapy can be omitted without loss of efficacy in patients who have a complete metabolic response after receiving two cycles of escalated doses of etoposide, cyclophosphamide, and doxorubicin, and regular doses of bleomycin, vincristine, procarbazine, and prednisone (eBEACOPP) plus two cycles of doxorubicin, bleomycin, vinblastine, dacarbazine (ABVD) chemotherapy (2 + 2). METHODS: In this multicentre, open-label, randomised, phase 3 trial, patients (aged 18-60 years) with newly diagnosed early-stage unfavourable Hodgkin lymphoma (all histologies) and an Eastern Cooperative Oncology Group performance status of 2 or less were enrolled at 224 hospitals and private practices in Germany, Switzerland, Austria, and the Netherlands. Patients were randomly assigned (1:1) to receive either standard combined-modality treatment, consisting of the 2 + 2 regimen (eBEACOPP consisted of 1250 mg/m2 intravenous cyclophosphamide on day 1, 35 mg/m2 intravenous doxorubicin on day 1, 200 mg/m2 intravenous etoposide on days 1-3, 100 mg/m2 oral procarbazine on days 1-7, 40 mg/m2 oral prednisone on days 1-14, 1·4 mg/m2 intravenous vincristine on day 8 [maximum dose of 2 mg per cycle], and 10 mg/m2 intravenous bleomycin on day 8; ABVD consisted of 25 mg/m2 intravenous doxorubicin, 10 mg/m2 intravenous bleomycin, 6 mg/m2 intravenous vinblastine, and 375 mg/m2 intravenous dacarbazine, all given on days 1 and 15) followed by 30 Gy involved-field radiotherapy (standard combined-modality treatment group) or PET4-guided treatment, consisting of the 2 + 2 regimen followed by 30 Gy of involved-node radiotherapy only in patients with positive PET at the end of four cycles of chemotherapy (PET4; PET4-guided treatment group). Randomisation was done centrally and used the minimisation method and seven stratification factors (centre, age, sex, clinical symptoms, disease localisation, albumin concentration, and bulky disease), and patients and investigators were masked to treatment allocation until central review of the PET4 examination had been completed. With the final analysis presented here, the primary objective was to show non-inferiority of the PET4-guided strategy in a per-protocol analysis of the primary endpoint of progression-free survival. We defined non-inferiority as an absolute difference of 8% in the 5-year progression-free survival estimates between the two groups. Safety analyses were done in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, NCT01356680. FINDINGS: Between Jan 13, 2012, and March 21, 2017, we enrolled and randomly assigned 1100 patients to the standard combined-modality treatment group (n=548) or to the PET4-guided treatment group (n=552); two patients in each group were found ineligible after randomisation. At a median follow-up of 46·2 months (IQR 32·7-61·2), 5-year progression-free survival was 97·3% (95% CI 94·5-98·7) in the standard combined-modality treatment group and 95·1% (92·0-97·0) in the PET4-guided treatment group (hazard ratio 0·523 [95% CI 0·226-1·211]). The between-group difference was 2·2% (95% CI -0·9 to 5·3) and excluded the non-inferiority margin of 8%. The most common grade 3 or 4 acute haematological adverse events were leucopenia (436 [83%] of 528 patients in the standard combined-modality treatment group vs 443 [84%] of 529 patients in the PET4-guided treatment group) and thrombocytopenia (139 [26%] vs 176 [33%]), and the most frequent acute non-haematological toxic effects were infection (32 [6%] vs 40 [8%]) and nausea or vomiting (38 [7%] vs 29 [6%]). The most common acute radiotherapy-associated adverse events were dysphagia (26 [6%] in the standard combined-modality treatment group vs three [2%] in the PET4-guided treatment group) and mucositis (nine [2%] vs none). 229 serious adverse events were reported by 161 (29%) of 546 patients in the combined-modality treatment group, and 235 serious adverse events were reported by 164 (30%) of 550 patients in the PET4-guided treatment group. One suspected unexpected serious adverse reaction (infection) leading to death was reported in the PET4-guided treatment group. INTERPRETATION: PET4-negativity after treatment with 2 + 2 chemotherapy in patients with newly diagnosed early-stage unfavourable Hodgkin lymphoma allows omission of consolidation radiotherapy without a clinically relevant loss of efficacy. PET4-guided therapy could thereby reduce the proportion of patients at risk of the late effects of radiotherapy. FUNDING: Deutsche Krebshilfe.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Doença de Hodgkin/tratamento farmacológico , Doença de Hodgkin/radioterapia , Tomografia por Emissão de Pósitrons , Adolescente , Adulto , Bleomicina/administração & dosagem , Terapia Combinada , Ciclofosfamida/administração & dosagem , Dacarbazina/administração & dosagem , Intervalo Livre de Doença , Doxorrubicina/administração & dosagem , Etoposídeo/administração & dosagem , Feminino , Doença de Hodgkin/diagnóstico por imagem , Doença de Hodgkin/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Prednisona/administração & dosagem , Procarbazina/administração & dosagem , Modelos de Riscos Proporcionais , Rituximab/administração & dosagem , Resultado do Tratamento , Vimblastina/administração & dosagem , Vincristina/administração & dosagem , Adulto Jovem
7.
Medicine (Baltimore) ; 99(44): e22931, 2020 Oct 30.
Artigo em Inglês | MEDLINE | ID: mdl-33126356

RESUMO

RATIONALE: Synchronous development of both anaplastic large cell lymphoma (ALCL) and multiple myeloma (MM) in a patient is rare. To our knowledge, until now only one case has been reported. Treatment needs to cover both and is a challenge. Here we reported another case and discussed the diagnosis and treatment. PATIENT CONCERNS: This is a 63-year old woman who presented with a mass in upper abdominal skin. Positron emission tomography/computed tomography (PET/CT) showed the high metabolism in left abdominal skin and left axillary lymph nodes. Histopathologic and immunohistochemical evaluation identified the cutaneous mass as an ALK-negative ALCL. Bone marrow smear showed increased plasma cells which expressed CD38, CD138, and cLambda concomitantly. The increased monoclonal immunoglobulin IgD λ was detected by immunofixation electrophoresis. DIAGNOSES: Diagnosis of both ALCL and MM was confirmed. INTERVENTIONS: The patient successively received 6 cycles of B-CHOD regimen, one cycle of ID regimen, 2 cycles of DHAX regimen, one cycle of L-DA-EPOCH and autologous stem cell transplantation (ASCT). Then lenalidomide was performed as a maintenance therapy. OUTCOMES: Both ALCL and MM achieved complete remission. LESSONS: We reported a very rare case with synchronous development of ALCL and MM, in whom a good therapeutic response to chemotherapies followed by ASCT has been observed.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Transplante de Células-Tronco Hematopoéticas/métodos , Lenalidomida/administração & dosagem , Linfoma Anaplásico de Células Grandes , Mieloma Múltiplo , Neoplasias Cutâneas , Parede Abdominal/patologia , Bleomicina/administração & dosagem , Exame de Medula Óssea/métodos , Ciclofosfamida/administração & dosagem , Dexametasona/administração & dosagem , Doxorrubicina/administração & dosagem , Etoposídeo/administração & dosagem , Feminino , Humanos , Imuno-Histoquímica , Linfoma Anaplásico de Células Grandes/imunologia , Linfoma Anaplásico de Células Grandes/patologia , Linfoma Anaplásico de Células Grandes/terapia , Quimioterapia de Manutenção/métodos , Pessoa de Meia-Idade , Mieloma Múltiplo/imunologia , Mieloma Múltiplo/patologia , Mieloma Múltiplo/terapia , Neoplasias Primárias Múltiplas/patologia , Neoplasias Primárias Múltiplas/terapia , Tomografia Computadorizada com Tomografia por Emissão de Pósitrons/métodos , Prednisona/administração & dosagem , Indução de Remissão , Neoplasias Cutâneas/patologia , Neoplasias Cutâneas/terapia , Transplante Autólogo/métodos , Vincristina/administração & dosagem
8.
Anticancer Res ; 40(11): 6485-6492, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-33109587

RESUMO

BACKGROUND: We aimed to verify the clinical efficacy and safety of the electrochemotherapy in melanoma metastases and in cases of rare non-melanoma tumors that were difficult to treat for the specific anatomical site or for patient comorbidities. PATIENTS AND METHODS: We treated 68 patients (699 cutaneous nodules), 44 patients with metastatic melanomas and 24 patients with non-melanoma tumors, at the Melanoma & Skin Cancer Unit, Florence, Italy. RESULTS: We obtained an objective response of 89.7% (88.6% in melanomas and 91.7% in non-melanoma tumors), complete response 54.4% and partial response 35.3%. CONCLUSION: This study showed that electrochemotherapy is effective in the treatment of melanoma metastases and in rare types of non-melanoma tumors. In particular, we successfully treated rare tumors as angiosarcoma, pleomorphic sarcoma, myxofibrosarcoma, sarcoma di Kaposi, porocarcinoma, sebaceous carcinoma, Merkel cell carcinoma, malignant blue nevus, undifferentiated epitheliomorphic cell neoplasia and metastases from thyroid carcinoma. No serious adverse events were observed.


Assuntos
Eletroquimioterapia , Melanoma/terapia , Segunda Neoplasia Primária/terapia , Neoplasias Cutâneas/terapia , Adulto , Bleomicina/administração & dosagem , Carcinoma de Célula de Merkel , Feminino , Humanos , Itália/epidemiologia , Masculino , Melanoma/patologia , Pessoa de Meia-Idade , Segunda Neoplasia Primária/patologia , Indução de Remissão , Neoplasias Cutâneas/patologia , Resultado do Tratamento
9.
Bull Cancer ; 107(7-8): 756-762, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32513434

RESUMO

INTRODUCTION: Malignant pericardial effusion is a severe complication of lung and breast cancer. The median survival is less than 4 months and recurrences occurs in about 40% of cases. Systemic chemotherapy and/or local treatments are necessary, even if there is no consensus. METHODS: We collected data from patients in our center from 1997 to 2016 who received at least one intrapericardial instillation of bleomycin (60mg). At the same time, we conducted a review of the relevant literature on the subject. RESULTS: We included 46 patients in the analysis. Median survival was 2.6 months [95% CI: 1.7; 4.7]. Overall survival was 49% [33%; 63%] at 3 months and 28% [15%; 42%] at 6 months. In the lung cancer subgroup, overall survival was 18% [3%; 44%] at 3 months. In the breast cancer subgroup, overall survival was 73% [44%; 89%] at 3 months and 46% [21%; 69%] at 6 months. DISCUSSION: The best response rates in the literature are obtained with local instillation of bleomycin or cisplatin. Malignant pericardial effusions in breast cancer patients had a better prognosis. This is certainly related to the prognosis of the underlying disease. We have not found an increase in overall survival with intrapericardial chemotherapy injections, but preventing recurrence of malignant pericardial effusions is a benefit in itself, thus avoiding a lethal complication.


Assuntos
Antibióticos Antineoplásicos/administração & dosagem , Bleomicina/administração & dosagem , Neoplasias da Mama/complicações , Neoplasias Pulmonares/complicações , Derrame Pericárdico/prevenção & controle , Adulto , Idoso , Neoplasias da Mama/mortalidade , Cisplatino/administração & dosagem , Feminino , Humanos , Instilação de Medicamentos , Neoplasias Pulmonares/mortalidade , Pessoa de Meia-Idade , Neoplasias/complicações , Neoplasias/mortalidade , Derrame Pericárdico/etiologia , Derrame Pericárdico/mortalidade , Pericárdio , Estudos Retrospectivos , Prevenção Secundária , Fatores de Tempo , Adulto Jovem
10.
Br J Haematol ; 190(1): e1-e3, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32379903
11.
J Cancer Res Ther ; 16(1): 1-6, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32362601

RESUMO

Background: Hodgkin's lymphoma (HL) can be treated with combined modality treatment (CMT) to limit long-term toxicities in the early favorable stage. Early unfavorable and advanced stage HL is mainly treated with chemotherapy followed by radiation to the bulky site. This study examines the impact of CMT in early as well as advanced stage HL. Materials and Methods: From 2001 to 2011, 125 patients with Stage I to IV HL were analyzed. Median age of the patients was 25 years (range 12-68 years). CMT, chemotherapy, and radiation alone were given to 51, 64, and 10 patients, respectively. Chemotherapy with doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) was given to 100 patients, 6 patients received ABVD-like regimen, and 9 patients received cyclophosphamide, vincristine, procarbazine, and prednisone regimen. Radiotherapy (RT) was given to 61 (49%) patients, involved field RT to 55 (90%), and extended-field RT to 6 (10%) patients, respectively. Median radiation dose was 30 Gy (18-40 Gy). Results: All 25 patients with early-stage achieved complete response (CR) with CMT. At a median follow-up of 70 months (range 12-230 months), relapse was seen in two patients (1 local and 1 distant). Of 26 patients with advanced stage, 25 achieved a CR and 1 had stable disease with CMT. Relapse occurred in one patient (distant). In patients with early-stage treated with chemotherapy only ( n = 30, 24%), 9 patients had relapse (4 local and 5 distant) while in those with RT only ( n = 10, 8%), 4 developed distant relapse. In patients with advanced stage treated with chemotherapy only ( n = 34, 27%), 8 relapsed (5 local and distant, 3 distant only). Patients with relapse were salvaged with CMT ( n = 6), chemotherapy ( n = 15), or RT ( n = 3). Two patients have died. Five years' disease-free survival (DFS) in patients with early favorable stage, early unfavorable stage, and advanced stage was 91%, 82%, and 73%, respectively ( P = 0.026). DFS was significantly better with CMT than chemotherapy or radiation alone. Five years' overall survival (OS) was 93%, 92%, and 84%, respectively ( P = 0.139). Second malignancy occurred in 3 (2.4%) patients; carcinoma of the tongue, pseudomyxoma peritonei, and non-HL each, respectively. None of these patients had received prior radiation. Conclusion: CMT improved DFS in patients with HL. OS was similar in all patients irrespective of treatment combinations. The incidence of second malignancy was 2.4%.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Doença de Hodgkin/terapia , Recidiva Local de Neoplasia/terapia , Radioterapia/mortalidade , Adolescente , Adulto , Idoso , Bleomicina/administração & dosagem , Criança , Terapia Combinada , Ciclofosfamida/administração & dosagem , Dacarbazina/administração & dosagem , Doxorrubicina/administração & dosagem , Feminino , Doença de Hodgkin/mortalidade , Doença de Hodgkin/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/mortalidade , Recidiva Local de Neoplasia/patologia , Estadiamento de Neoplasias , Prednisona/administração & dosagem , Procarbazina/administração & dosagem , Taxa de Sobrevida , Resultado do Tratamento , Vimblastina/administração & dosagem , Vincristina/administração & dosagem , Adulto Jovem
12.
J Vis Exp ; (158)2020 04 21.
Artigo em Inglês | MEDLINE | ID: mdl-32421010

RESUMO

Electrochemotherapy (ECT) is the combination of transient pore formation following electric pulse application with the administration of cytotoxic drugs, which enhances the cytotoxic effect of the applied agent due to membrane changes. In vitro 3D culture systems simulate the in vivo tumor growth and preserve the biological characteristics of tumors more accurately than conventional monolayer cell cultures. We describe a protocol for the development of 3D tumor organoids using conjunctival melanoma (CM) and uveal melanoma (UM) cell lines as well as the use of hand-held customized electrodes, suitable for in vitro ECT in the culture well without destruction of the tumor environment. This protocol analyzes the culture and growth of 3D CM and UM spheroids and their reaction to bleomycin (2.5 µg/mL) alone, electroporation (EP) (750 Volts/cm, 8 pulses, 100 µs, 5 Hz) alone, and ECT as a combination of EP and bleomycin. The drug concentration and the EP settings used in this protocol were established as preferred ECT conditions according to previous experiments. The assay used to determine the spheroid viability was conducted 3-7 days following treatment. The effect on viability and growth of the 3D tumor spheroids was significant only after ECT. The customized electrodes are described in detail in order to facilitate the application of pulses in the culture well. This novel treatment of 3D UM and CM spheroids sets a steppingstone for future clinical application.


Assuntos
Eletroquimioterapia/instrumentação , Eletroquimioterapia/métodos , Neoplasias Oculares/tratamento farmacológico , Melanoma/tratamento farmacológico , Antineoplásicos/administração & dosagem , Bleomicina/administração & dosagem , Bleomicina/uso terapêutico , Linhagem Celular Tumoral , Eletrodos , Eletroporação , Neoplasias Oculares/patologia , Humanos , Melanoma/patologia , Esferoides Celulares/efeitos dos fármacos
13.
Eur J Cancer ; 133: 56-65, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32442924

RESUMO

BACKGROUND: This study assessed the effects of gonadotropin-releasing hormone agonists (GnRHa) on the prevention of chemotherapy-induced ovarian insufficiency among young patients with malignant ovarian germ cell tumour (MOGCT) receiving chemotherapy. METHODS: This multicentre, retrospective study was conducted at 15 sites affiliated with the Korean Gynecologic Oncology Group and enrolled 354 patients between January 1995 and September 2018. Among them, 227 patients were included in this study and divided into two groups according to the use of GnRHa during chemotherapy (GnRHa versus no GnRHa groups). The primary objective was to compare the rates of menstrual resumption between the two groups. We also assessed the clinical determinants affecting menstrual resumption among the study groups. RESULTS: There were no significant differences between the GnRHa (n = 63) and no GnRHa (n = 164) groups regarding age at diagnosis, parity, ethnicity, age at menarche, body mass index, International Federation of Gynecology and Obstetrics stage, mode of surgery and surgery type. The rate of menstrual resumption after chemotherapy was 100% (63 of 63) in the GnRHa group and 90.9% (149 of 164) in the no GnRHa group (p = 0.013). The mean periods from last chemotherapy to menstrual resumption were 7.4 and 7.3 months in the GnRHa and no GnRHa groups, respectively. GnRHa co-administration during chemotherapy reduced the likelihood of amenorrhoea after chemotherapy, although statistical significance was not confirmed in the univariate analysis (odds ratio: 0.276; 95% confidence interval, 0.004-1.317; p = 0.077). CONCLUSION: Temporary ovarian suppression with GnRHa during chemotherapy does not significantly increase the chances of menstrual resumption in young patients with MOGCT.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Fármacos para a Fertilidade Feminina/uso terapêutico , Hormônio Liberador de Gonadotropina/agonistas , Neoplasias Embrionárias de Células Germinativas/tratamento farmacológico , Neoplasias Ovarianas/tratamento farmacológico , Insuficiência Ovariana Primária/induzido quimicamente , Insuficiência Ovariana Primária/prevenção & controle , Adolescente , Adulto , Amenorreia/induzido quimicamente , Amenorreia/epidemiologia , Amenorreia/prevenção & controle , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Bleomicina/administração & dosagem , Bleomicina/efeitos adversos , Cisplatino/administração & dosagem , Cisplatino/efeitos adversos , Etoposídeo/administração & dosagem , Etoposídeo/efeitos adversos , Estudos de Viabilidade , Feminino , Preservação da Fertilidade/métodos , Humanos , Infertilidade Feminina/induzido quimicamente , Infertilidade Feminina/epidemiologia , Infertilidade Feminina/prevenção & controle , Menopausa Precoce/efeitos dos fármacos , Menstruação/efeitos dos fármacos , Neoplasias Embrionárias de Células Germinativas/epidemiologia , Neoplasias Ovarianas/epidemiologia , Ovário/efeitos dos fármacos , Gravidez , Insuficiência Ovariana Primária/epidemiologia , República da Coreia/epidemiologia , Estudos Retrospectivos , Resultado do Tratamento , Adulto Jovem
14.
Cancer Radiother ; 24(4): 335-339, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32444284

RESUMO

Hodgkin lymphoma (HL) is a disease characterized by a high curability rate, and the treatment benefit-risk balance must be carefully addressed to achieve complete disease control with low risk of long-term toxicities. Most patients are treated with a combination of chemotherapy and radiotherapy, after disease staging and response to treatment evaluated by FDG PET/CT. We report the case of a 28-year-old patient concomitantly diagnosed of a Hodgkin lymphoma and active tuberculosis. Initial staging was difficult due to pulmonary and abdominal tuberculosis localization that induced FDG PET/CT hypermetabolism. Anti-tuberculosis treatment was first started, allowing secondary an early accurate Hodgkin lymphoma staging by FDG PET/CT. The patient was then treated by chemotherapy and radiotherapy. Helical TomoTherapy® was used with involved site (IS) irradiation volume was performed to decrease the high doses to organs-at-risk (OAR), especially lungs in this context of tuberculosis.


Assuntos
Doenças do Colo/tratamento farmacológico , Doença de Hodgkin/terapia , Tuberculose Gastrointestinal/tratamento farmacológico , Tuberculose Pulmonar/tratamento farmacológico , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Antituberculosos/uso terapêutico , Bleomicina/administração & dosagem , Doenças do Colo/complicações , Doenças do Colo/diagnóstico por imagem , Doenças do Colo/metabolismo , Dacarbazina/administração & dosagem , Doxorrubicina/administração & dosagem , Doença de Hodgkin/complicações , Doença de Hodgkin/diagnóstico por imagem , Doença de Hodgkin/metabolismo , Humanos , Pulmão , Linfonodos/diagnóstico por imagem , Linfonodos/metabolismo , Masculino , Órgãos em Risco , Tomografia Computadorizada com Tomografia por Emissão de Pósitrons , Radioterapia de Intensidade Modulada , Medição de Risco , Tomografia Computadorizada por Raios X , Tuberculose Gastrointestinal/complicações , Tuberculose Gastrointestinal/diagnóstico por imagem , Tuberculose Pulmonar/complicações , Tuberculose Pulmonar/diagnóstico por imagem , Vimblastina/administração & dosagem
15.
J Ayub Med Coll Abbottabad ; 32(1): 42-45, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32468753

RESUMO

BACKGROUND: This study is aimed to assess the efficacy of intralesional Bleomycin sclerotherapy in macrocystic lymphangioma in children. METHODS: This prospective observational study included 40 children diagnosed with macrocystic lymphangioma and treated with intralesional injection of Bleomycin from March 2016 to Dec 2018. We excluded all the patients above 12 years of age, lesions with size less than 2 cm, and post-surgical recurrent lesions. The response to the treatment was monitored clinically by assessing length, breadth and area of the lesion and ultrasonographically. Mean follow-up period was 2 years. Study variables were analysed by simple descriptive statistics. Mean and standard deviation were calculated for numerical variables (age). Frequency and percentage were calculated for gender, site, size and type of cystic lymphangioma and total number of treatment sessions. RESULTS: The mean age of patients was 3.51±2.98 years. Out of 40 patients, there were 26 (65%) male and 14 (35%) females with female to male ratio of 1:1.8. The commonest site and type of cystic lymphangioma was neck and macrocystic, i.e., 77.5% and 85% respectively. The pre and post procedure size of lesion was 9.71±3.95cm and 3.11±1.02 cm, respectively. Outcome was excellent in 20% patients, good in 72.5% and poor in 7.5% patients. CONCLUSIONS: Intralesional Bleomycin sclerotherapy is effective in the treatment of macrocystic lymphangioma and is found to be harmless as there was no grave complication observed in this study.


Assuntos
Antibióticos Antineoplásicos/administração & dosagem , Bleomicina/administração & dosagem , Linfangioma/terapia , Escleroterapia , Fatores Etários , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Injeções Intralesionais , Masculino , Estudos Prospectivos , Resultado do Tratamento
16.
J Vasc Interv Radiol ; 31(5): 820-830, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32305243

RESUMO

PURPOSE: To prospectively assess safety and efficacy of prostatic artery embolization (PAE) with bleomycin-eluting microspheres for benign prostatic hyperplasia (BPH) in a canine model. MATERIALS AND METHODS: Twelve adult male beagles (mean age, 1.6 y ± 0.2; range, 1.2-2.0 y) were randomly assigned to group A (n = 6; PAE with bleomycin-eluting 30-60-µm HepaSphere microspheres) and group B (n = 6; PAE with bland 30-60-µm HepaSphere microspheres) between April 2017 and November 2018. Plasma bleomycin concentration in group A was measured within 7 days. Prostate volume (PV) and ischemic volume after PAE were measured by magnetic resonance imaging. Prostates and adjacent organs were harvested after the last magnetic resonance study and histopathologically examined. RESULTS: Plasma bleomycin concentration peaked at 10 minutes at 2,055.0 ng/mL ± 606.1 and lasted for 1,440 min at low levels after PAE. PV reduction percentage was greater in group A than in group B at 1 month (74.1% ± 4.3 vs 63.7% ± 3.5; P = .006) and 3 months (61.5% ± 6.7 vs 46.1% ± 3.8; P = .001) after PAE. Proportion of prostate ischemic volume was greater in group A than in group B (75.3% ± 3.0 vs 62.0% ± 7.1; P = .006) at 1 month after PAE. Proportion of prostate ischemic volume at 1 month positively correlated with PV percentage reduction at 3 months in group A (r = 0.840, P = .036) and group B (r = 0.844, P = .035). There were no complications or nontarget embolization to surrounding organs after the procedures. CONCLUSIONS: In a canine model, PAE with bleomycin-eluting microspheres was feasible and well tolerated and caused ischemic necrosis and reduction in PV.


Assuntos
Artérias , Bleomicina/administração & dosagem , Embolização Terapêutica , Próstata/irrigação sanguínea , Hiperplasia Prostática/terapia , Angiografia Digital , Animais , Artérias/diagnóstico por imagem , Modelos Animais de Doenças , Cães , Imagem por Ressonância Magnética , Masculino , Microesferas , Necrose , Próstata/diagnóstico por imagem , Próstata/patologia , Hiperplasia Prostática/diagnóstico por imagem , Hiperplasia Prostática/patologia , Fatores de Tempo
17.
Eur J Cancer ; 132: 85-97, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32334339

RESUMO

BACKGROUND: The clinical impact of the positivity of the Deauville scale (DS) of positron emission tomography (PET) performed at the end of doxorubicin, bleomycin, vinblastine and dacarbazine (ABVD) in patients with advanced Hodgkin lymphoma (HL), in terms of providing rationale to shift poor responders onto a more intensive regimen, remain to be validated by histopathology. PATIENTS AND METHODS: This prospective trial involved patients with stage IIB/IV HL who after six ABVD cycles underwent PET (PET6) and core-needle cutting biopsy (CNCB) of 2-deoxy-2[F-18] fluoro-d-glucose (FDG)-avid lymph nodes. Patients received high-dose chemotherapy/autologous haematopoietic stem cell rescue (HDCT/AHSCR) if CNCB was positive for HL, alternatively, if CNCB or PET was negative, received observation or consolidation radiotherapy (cRT) on residual nodal masses, as initially planned. The end-point was 5-year progression-free survival (PFS). RESULTS: In all, 43 of the 169 (25%) evaluable patients were PET6 positive (DS 4, 32; DS 5, 11). Among them, histology showed malignancy (HL) in 100% of DS 5 scores and in 12.5% of DS 4 scores. Fifteen patients with positive biopsy received HDCT/AHSCR, whereas 28 patients with negative biopsy, as well as 126 patients with negative PET6, continued the original plan (cRT, 78 patients; observation, 76 patients). The 5-year PFS in the negative PET6 group, negative biopsy group and positive biopsy group was 95.4%, 100% and 52.5%, respectively. CONCLUSION: DS positivity of end-of-ABVD PET in advanced HL carried a certain number of CNCB-proven non-malignant FDG-uptakes. The DS 4 scores which were found to have negative histology appeared to benefit from continuing the original non-intensive therapeutic plane as indicated by the successful outcome in more than 95% of them by obtaining similar 5-year PFS to the PET6-negative group. By contrast, the DS 5 score had consistently positive histology and was associated with unsuccessful conventional therapy, promptly requiring treatment intensification or innovative therapeutic approaches.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Fluordesoxiglucose F18/metabolismo , Glucose/metabolismo , Doença de Hodgkin/tratamento farmacológico , Tomografia por Emissão de Pósitrons/métodos , Adolescente , Adulto , Bleomicina/administração & dosagem , Dacarbazina/administração & dosagem , Gerenciamento Clínico , Doxorrubicina/administração & dosagem , Feminino , Seguimentos , Doença de Hodgkin/diagnóstico por imagem , Doença de Hodgkin/metabolismo , Doença de Hodgkin/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Prospectivos , Compostos Radiofarmacêuticos/metabolismo , Taxa de Sobrevida , Vimblastina/administração & dosagem , Adulto Jovem
18.
Lancet ; 395(10231): 1195-1207, 2020 04 11.
Artigo em Inglês | MEDLINE | ID: mdl-32145827

RESUMO

BACKGROUND: Optimal treatment regimens for AIDS-associated Kaposi sarcoma, a frequent contributor to morbidity and mortality among people with HIV, have not been systematically evaluated in low-income and middle-income countries, where the disease is most common. In this study, we aimed to investigate optimal treatment strategies for advanced stage disease in areas of high prevalence and limited resources. METHODS: In this open-label, non-inferiority trial, we enrolled people with HIV and advanced stage AIDS-associated Kaposi sarcoma attending 11 AIDS Clinical Trials Group sites in Brazil, Kenya, Malawi, South Africa, Uganda, and Zimbabwe. Eligible participants were randomly assigned (1:1:1) with a centralised computer system to receive either intravenous bleomycin and vincristine or oral etoposide (the investigational arms), or intravenous paclitaxel (the control arm), together with antiretroviral therapy (ART; combined efavirenz, tenofovir disoproxil fumarate, and emtricitabine). The primary outcome was progression-free survival (PFS) at week 48, using a 15% non-inferiority margin to compare the investigational groups against the active control group. Safety was assessed in all eligible treated study participants. The study was registered with ClinicalTrials.gov, NCT01435018. FINDINGS: 334 participants were enrolled between Oct 1, 2013, and March 8, 2018, when the study was closed early due to inferiority of the bleomycin and vincristine plus ART arm, as per the recommendations of the Data and Safety Monitoring Board (DSMB). The etoposide plus ART arm also closed due to inferiority in March, 2016, following a DSMB recommendation. Week-48 PFS rates were higher in the paclitaxel plus ART arm than in both investigational arms. The absolute differences in PFS were -30% (95% CI -52 to -8) for the comparison of paclitaxel plus ART (week 48 PFS 50%, 32 to 67; n=59) and etoposide plus ART (20%, 6 to 33; n=59), and -20% (-33% to -7%) for the comparison of paclitaxel plus ART (64%, 55 to 73; n=138) and bleomycin and vincristine plus ART (44%, 35 to 53; n=132). Both CIs overlapped the non-inferiority margin. The most common adverse events, in 329 eligible participants who began treatment, were neutropenia (48 [15%]), low serum albumin (33 [10%]), weight loss (29 [9%]), and anaemia (28 [9%]), occurring at similar frequency across treatment arms. INTERPRETATION: Non-inferiority of either investigational intervention was not shown, with paclitaxel plus ART showing superiority to both oral etoposide plus ART and bleomycin and vincristine plus ART, supporting its use in treating advanced AIDS-associated Kaposi sarcoma in resource-limited settings. FUNDING: US National Institute of Allergy and Infectious Diseases and National Cancer Institute, National Institutes of Health.


Assuntos
Infecções Oportunistas Relacionadas com a AIDS/tratamento farmacológico , Antibióticos Antineoplásicos/efeitos adversos , Antineoplásicos Fitogênicos/efeitos adversos , Bleomicina/efeitos adversos , Sarcoma de Kaposi/tratamento farmacológico , Vincristina/efeitos adversos , Infecções Oportunistas Relacionadas com a AIDS/mortalidade , Adulto , África , Fármacos Anti-HIV/administração & dosagem , Antibióticos Antineoplásicos/administração & dosagem , Antineoplásicos Fitogênicos/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica , Terapia Antirretroviral de Alta Atividade/métodos , Bleomicina/administração & dosagem , Países em Desenvolvimento , Quimioterapia Combinada , Etoposídeo/administração & dosagem , Etoposídeo/efeitos adversos , Feminino , Humanos , Masculino , Paclitaxel/administração & dosagem , Paclitaxel/efeitos adversos , Intervalo Livre de Progressão , Sarcoma de Kaposi/mortalidade , Vincristina/administração & dosagem
19.
Am J Physiol Lung Cell Mol Physiol ; 318(5): L1084-L1096, 2020 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-32209025

RESUMO

Alveolar epithelial cell (AEC) apoptosis, arising from mitochondrial dysfunction and mitophagy defects, is important in mediating idiopathic pulmonary fibrosis (IPF). Our group established a role for the mitochondrial (mt) DNA base excision repair enzyme, 8-oxoguanine-DNA glycosylase 1 (mtOGG1), in preventing oxidant-induced AEC mtDNA damage and apoptosis and showed that OGG1-deficient mice have increased lung fibrosis. Herein, we determined whether mice overexpressing the mtOGG1 transgene (mtOgg1tg) are protected against lung fibrosis and whether AEC mtOGG1 preservation of mtDNA integrity mitigates phosphatase and tensin homolog-induced putative kinase 1 (PINK1) deficiency and apoptosis. Compared with wild type (WT), mtOgg1tg mice have diminished asbestos- and bleomycin-induced pulmonary fibrosis that was accompanied by reduced lung and AEC mtDNA damage and apoptosis. Asbestos and H2O2 promote the MLE-12 cell PINK1 deficiency, as assessed by reductions in the expression of PINK1 mRNA and mitochondrial protein expression. Compared with WT, Pink1-knockout (Pink1-KO) mice are more susceptible to asbestos-induced lung fibrosis and have increased lung and alveolar type II (AT2) cell mtDNA damage and apoptosis. AT2 cells from Pink1-KO mice and PINK1-silenced (siRNA) MLE-12 cells have increased mtDNA damage that is augmented by oxidative stress. Interestingly, mtOGG1 overexpression attenuates oxidant-induced MLE-12 cell mtDNA damage and apoptosis despite PINK1 silencing. mtDNA damage is increased in the lungs of patients with IPF as compared with controls. Collectively, these findings suggest that mtOGG1 maintenance of AEC mtDNA is crucial for preventing PINK1 deficiency that promotes apoptosis and lung fibrosis. Given the key role of AEC apoptosis in pulmonary fibrosis, strategies aimed at preserving AT2 cell mtDNA integrity may be an innovative target.


Assuntos
Células Epiteliais Alveolares/efeitos dos fármacos , Asbestose/genética , DNA Glicosilases/genética , Pulmão/efeitos dos fármacos , Mitocôndrias/efeitos dos fármacos , Proteínas Quinases/genética , Fibrose Pulmonar/genética , Células Epiteliais Alveolares/metabolismo , Células Epiteliais Alveolares/patologia , Animais , Apoptose/efeitos dos fármacos , Apoptose/genética , Asbestos/administração & dosagem , Asbestose/etiologia , Asbestose/metabolismo , Asbestose/patologia , Bleomicina/administração & dosagem , Dano ao DNA , DNA Glicosilases/deficiência , DNA Mitocondrial/genética , DNA Mitocondrial/metabolismo , Feminino , Regulação da Expressão Gênica , Peróxido de Hidrogênio/farmacologia , Pulmão/metabolismo , Pulmão/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Mitocôndrias/metabolismo , Cultura Primária de Células , Proteínas Quinases/metabolismo , Fibrose Pulmonar/induzido quimicamente , Fibrose Pulmonar/metabolismo , Fibrose Pulmonar/patologia , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/metabolismo , Transdução de Sinais , Titânio/administração & dosagem
20.
Cancer Radiother ; 24(3): 206-214, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32171674

RESUMO

PURPOSE: The aim of this study was to extensively describe the epidemiological, clinical and therapeutic outcomes of adolescents and young adults (AYA) population with classical Hodgkin Lymphoma (cHL). Then, a comparison between AYAs and adults and between the subgroups of AYAs treated with the same adult protocol was accomplished to further inform on optimal therapy approach of choice for adolescent patients. MATERIAL AND METHODS: In this mono-centric, retrospective study, we reviewed the medical records. We analyzed 112 consecutive North Tunisian patients, including 66 AYAs (15 to 39 years) and 46 adults (≥40years) affected by cHL treated from 2000 to 2015 at Salah Azaiez Institute. Then, we performed a comparative analysis between AYA and 46 adult patients and a subgroup analysis between adolescents and young adults. All patients were treated according to the national protocol for HL, edited by the Tunisian Society of Hematology. The treatment included chemotherapy and involved-field radiotherapy (RT) at a dose of 20 or 30 Grays (Gy) for responders and 36Gy for non-responders. RESULTS: AYA patients presented with adverse features with nodular sclerosis subtype (p=3.88×10-02) and mediastinal mass involvement (p=9.40×10-04). At a median follow-up of 51 and 32 months for AYAs and adults, respectively, no statistical difference in terms of 3 and 5-years overall survival (OS) and event-free survival (EFS) was shown. Using the Kaplan-Meier method, in AYAs, the ABVD regimen has an impact on 3-years EFS (p=4.63×10-02). The 36Gy RT was associated with the best 3-years EFS (p=9.24×10-03). Besides, AYA patients with advanced-stage had the worst 3-years OS (76%) (p=2.41×10-02). Although the adolescents and young adults shared similar clinical presentation, we noted that the adolescent group had the worst 3-years EFS (48%), but the best 3-years OS (91%). We identified 15% of primary refractory patients and a rate of toxicity of 5.3% in AYA. CONCLUSION: The treatment approach used is well tolerated by adult patients. However, the AYA patients and particularly adolescent subgroup had more advanced disease at diagnosis and should be treated more intensively in dedicated units. RT dose<36Gy and ABVD chemotherapy were associated with lower EFS in this population.


Assuntos
Doença de Hodgkin/terapia , Adolescente , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Bleomicina/administração & dosagem , Ciclofosfamida/administração & dosagem , Dacarbazina/administração & dosagem , Intervalo Livre de Doença , Doxorrubicina/administração & dosagem , Etoposídeo/administração & dosagem , Feminino , Doença de Hodgkin/epidemiologia , Doença de Hodgkin/mortalidade , Doença de Hodgkin/patologia , Humanos , Estimativa de Kaplan-Meier , Masculino , Mecloretamina/administração & dosagem , Neoplasias do Mediastino/patologia , Pessoa de Meia-Idade , Órgãos em Risco/efeitos da radiação , Prednisona/administração & dosagem , Procarbazina/administração & dosagem , Dosagem Radioterapêutica , Recidiva , Estudos Retrospectivos , Resultado do Tratamento , Tunísia/epidemiologia , Vimblastina/administração & dosagem , Vincristina/administração & dosagem , Adulto Jovem
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...