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1.
Dermatol Online J ; 26(2)2020 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-32239890

RESUMO

Thiotepa is a common alkylating agent known to precipitate cutaneous reactions consistent with toxic erythema of chemotherapy, including erythema and hyperpigmentation. Herein, we describe an atypical case of malignant intertrigo involving preferential erythema and desquamation not only of skin folds but also of occluded areas after thiotepa-based conditioning. The diagnosis was complicated by concurrent stomatitis and oral petechiae in the setting of autologous stem cell transplant 11 days prior for diffuse large B-cell lymphoma. Histopathological examination from two cutaneous sites demonstrated epidermal dysmaturation and eccrine gland necrosis consistent with thiotepa-induced desquamation and not Stevens-Johnson syndrome or graft-versus-host-disease. Malignant intertrigo can present with extensive cutaneous involvement, as evidenced by our patient who had 25% body surface area affected. Mucosal involvement is common with most chemotherapeutic regimens and its presence should not deter the astute clinician from consideration of a diagnosis of toxic erythema of chemotherapy. No further interventions were needed and the patient healed spontaneously.


Assuntos
Antineoplásicos Alquilantes/efeitos adversos , Erros de Diagnóstico , Hiperpigmentação/induzido quimicamente , Intertrigo/diagnóstico , Síndrome de Stevens-Johnson/diagnóstico , Tiotepa/efeitos adversos , Idoso , Humanos , Hiperpigmentação/diagnóstico , Hiperpigmentação/patologia , Intertrigo/induzido quimicamente , Intertrigo/patologia , Linfoma Difuso de Grandes Células B/complicações , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Masculino , Estomatite/induzido quimicamente
2.
Med Oncol ; 37(6): 51, 2020 Apr 24.
Artigo em Inglês | MEDLINE | ID: mdl-32333196

RESUMO

As we know more about the clinical and laboratory features of COVID-19, which is now accepted as a pandemic, many questions have been raised about how to manage and monitor the treatment of cancer patients. It was determined that the incidence of lymphopenia increased in COVID-19 and there was a significant relationship between lymphopenia and mortality. This can be thought of as an unresponsive problem in how to maintain anti-cancer drugs that cause lymphopenia. This article was written for a hypothetical approach in cancer patients diagnosed with COVID-19 in order to be an idea of collecting data for treatment with anti-cancer drugs that cause lymphopenia.


Assuntos
Antineoplásicos Alquilantes/efeitos adversos , Betacoronavirus , Infecções por Coronavirus , Linfopenia , Neoplasias , Pandemias , Pneumonia Viral , Temozolomida/efeitos adversos , Antineoplásicos Alquilantes/uso terapêutico , Infecções por Coronavirus/complicações , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/mortalidade , Humanos , Fatores Imunológicos/efeitos adversos , Fatores Imunológicos/uso terapêutico , Linfopenia/induzido quimicamente , Linfopenia/mortalidade , Neoplasias/complicações , Neoplasias/tratamento farmacológico , Pneumonia Viral/complicações , Pneumonia Viral/imunologia , Pneumonia Viral/mortalidade , Temozolomida/uso terapêutico
3.
Lancet Haematol ; 7(5): e395-e407, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32213344

RESUMO

BACKGROUND: Multiple myeloma is an incurable haematological malignancy, representing over 10% of haematological cancers in the USA. We did a phase 1-2 study of melflufen and dexamethasone in patients with relapsed and refractory multiple myeloma to determine the maximum tolerated dose of melflufen and to investigate its safety and efficacy. METHODS: We did a multicentre, international, dose-confirmation and dose-expansion, open-label, phase 1-2 study in seven centres in the USA and Europe. Eligible patients were aged 18 years or older, had relapsed and refractory multiple myeloma, had received two or more previous lines of therapy (including lenalidomide and bortezomib), were refractory to their last line of therapy, and had an Eastern Cooperative Oncology Group performance status of 2 or less. In phase 1, patients received an intravenous infusion of melflufen at 15 mg, 25 mg, 40 mg, or 55 mg for 30 min on day 1 in 21-day cycles plus oral dexamethasone 40 mg weekly and did not receive melflufen as a single agent. Melflufen was also tested in a single-agent cohort late in phase 2 in a small number of patients at the maximum tolerated dose identified in phase 1. In phase 2, patients were enrolled at the maximum tolerated dose in the melflufen plus dexamethasone in the combination cohort.. The phase 1 primary objective was to determine the maximum tolerated dose. The phase 2 primary objective was to evaluate overall response rate and clinical benefit rate. This primary analysis was done per protocol, in the all-treated and efficacy-evaluable population (defined as patients who received at least two doses of melflufen and who had a response assessment after baseline). The single-agent melflufen cohort was closed on October 6, 2016, as per the recommendation by the data safety monitoring committee on the basis of interim data suggesting greater activity in the melflufen plus dexamethasone cohort. The study is completed but survival follow-up is ongoing. This study is registered with ClinicalTrials.gov, NCT01897714. FINDINGS: Patients were enrolled between July 4, 2013, and Dec 31, 2016: 23 patients in phase 1 and 58 in phase 2, including six patients from phase 1 treated at the maximum tolerated dose of melflufen 40 mg plus weekly dexamethasone. In phase 2, 45 patients were given a combination of melflufen plus dexamethasone and 13 patients were given single-agent melflufen. In phase 1, the established maximum tolerated dose was 40 mg of melflufen in combination with dexamethasone. No dose-limiting toxicities were observed in the first three dose cohorts (15 mg, 25 mg, and 40 mg). The highest dose cohort tested (55 mg) exceeded the maximum tolerated dose because four of six patients experienced grade 4 neutropenia with grade 4 thrombocytopenia also occurring in three of these patients; therefore, the planned highest dose of 70 mg was not tested. In phase 2, patients treated with combination therapy achieved an overall response rate of 31% (14 of 45 patients; 95% CI 18-47) and clinical benefit rate of 49% (22 of 45; 34-64) in the all-treated population, and 41% (14 of 34; 25-59) and 65% (22 of 34; 47-80) in the efficacy-evaluable population. In the phase 2 single-agent cohort, the overall response rate was 8% (one of 13 patients; 0·2-36·0) and the clinical benefit rate was 23% (three of 13; 5-54). Among the 45 patients given melflufen plus dexamethasone during phase 2, the most common grade 3-4 adverse events were clinically manageable thrombocytopenia (28 [62%] patients) and neutropenia (26 [58%]), and non-haematological toxicity was infrequent. 24 serious adverse events were reported in 17 (38%) of 45 patients, most commonly pneumonia (five [11%]). The most common grade 3-4 adverse events that occurred in the phase 2 single-agent cohort of 13 patients were neutropenia (nine [69%]) and thrombocytopenia (eight [62%]). Nine patients experienced serious adverse events in the single-agent cohort, most commonly thrombocytopenia (two [15%]). There were three deaths from adverse events within 30 days of treatment that were possibly related to treatment: one in the 25 mg cohort in phase 1 (due to bacteraemia) and two in the phase 2 combination cohort (one due to neutropenic sepsis and one due to Escherichia coli sepsis), each in the setting of progressive disease. INTERPRETATION: These data show that melflufen is active in patients with relapsed and refractory multiple myeloma and tolerable in most patients. These results show the feasibility of this regimen and support the initiation of additional clinical studies of melflufen in multiple myeloma, both in combination with dexamethasone as well as in triplet regimens with additional classes of drugs. FUNDING: Oncopeptides AB.


Assuntos
Antineoplásicos Alquilantes/uso terapêutico , Antineoplásicos Hormonais/uso terapêutico , Dexametasona/uso terapêutico , Melfalan/análogos & derivados , Mieloma Múltiplo/tratamento farmacológico , Fenilalanina/análogos & derivados , Idoso , Antineoplásicos Alquilantes/administração & dosagem , Antineoplásicos Alquilantes/efeitos adversos , Antineoplásicos Hormonais/administração & dosagem , Antineoplásicos Hormonais/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Dexametasona/administração & dosagem , Dexametasona/efeitos adversos , Intervalo Livre de Doença , Feminino , Humanos , Estimativa de Kaplan-Meier , Masculino , Dose Máxima Tolerável , Melfalan/administração & dosagem , Melfalan/efeitos adversos , Melfalan/uso terapêutico , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/tratamento farmacológico , Fenilalanina/administração & dosagem , Fenilalanina/efeitos adversos , Fenilalanina/uso terapêutico
5.
Neurology ; 93(19): e1799-e1806, 2019 11 05.
Artigo em Inglês | MEDLINE | ID: mdl-31586022

RESUMO

OBJECTIVE: To determine the efficacy of the thrombopoietin receptor agonist romiplostim for the prevention of temozolomide-induced thrombocytopenia in newly diagnosed glioblastoma. METHODS: In the PLATUM phase II open-label, multicenter, single-arm trial, patients diagnosed with Common Terminology Criteria for Adverse Events grade 3 or 4 thrombocytopenia during chemoradiotherapy received weekly subcutaneous romiplostim injections. PLATUM aimed at demonstrating that the percentage of thrombocytopenic patients treated with romiplostim able to complete 6 cycles of maintenance temozolomide chemotherapy exceeded 10% (p0 = 0.10; pA = 0.35). Using type I error equal to 0.05% and 95% power, 31 patients had to be recruited. According to a Fleming 2-step design with a preplanned interim analysis after recruitment of 20 patients (step 1), the trial was terminated early for success. RESULTS: Twenty patients were enrolled in step 1. Median age was 61 years (range 33-73). Twelve patients received 6 temozolomide cycles, corresponding to a success rate of 60% (95% confidence interval 36%-81%). Four patients discontinued temozolomide because they did not respond to romiplostim, 2 for progression, and 2 for adverse events unrelated to romiplostim. CONCLUSION: The thrombopoietin receptor agonist romiplostim improves exposure to chemotherapy in patients with glioblastoma experiencing temozolomide-induced thrombocytopenia. CLINICALTRIALSGOV IDENTIFIER: NCT02227576. CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence that for patients with glioblastoma and thrombocytopenia, romiplostim is effective for the secondary prophylaxis of temozolomide-induced thrombocytopenia.


Assuntos
Antineoplásicos Alquilantes/efeitos adversos , Neoplasias Encefálicas/terapia , Glioblastoma/terapia , Receptores Fc/uso terapêutico , Proteínas Recombinantes de Fusão/uso terapêutico , Temozolomida/efeitos adversos , Trombocitopenia/prevenção & controle , Trombopoetina/uso terapêutico , Adulto , Idoso , Quimiorradioterapia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Receptores de Trombopoetina/agonistas , Trombocitopenia/induzido quimicamente , Trombocitopenia/tratamento farmacológico
6.
BMC Infect Dis ; 19(1): 881, 2019 Oct 22.
Artigo em Inglês | MEDLINE | ID: mdl-31640581

RESUMO

BACKGROUND: Bendamustine, used for the treatment of indolent B-cell non-Hodgkin lymphoma and chronic lymphocytic leukemia, is known to cause prolonged myelosuppression and lymphocytopenia and has been associated with the risk of developing serious and fatal infections. While reports of localized CMV infections in asymptomatic patients exist, disseminated CMV disease has not been described. CASE PRESENTATION: We report the first case of disseminated CMV infection in a 75-year-old male diagnosed with lymphoplasmacytic lymphoma/Waldenström macroglobulinemia with massive bone marrow infiltration. Despite 6-cycle R-bendamustine chemotherapy resulted in a good partial response, the patient developed persistent fever and severe weight loss. Analysis of cerebrospinal fluid and peripheral blood revealed the presence of CMV-DNA, while the fundus oculi examination revealed bilateral CMV retinitis. Treatment with induction and maintenance drugs was complicated by neutropenia and deterioration of renal function with electrolyte imbalance. From an immunological standpoint, we observed a profound imbalances in phenotype and function of B- and T-cell subsets, with a high proportion of circulating total, activated CD69+ and CD80+ B-cells, a low γ/δ T-cell frequency with a high proportion of CD69- and CD38-expressing cells, and hyperactivated/exhausted CD4+ and CD8+ T-cell phenotypes unable to face CMV challenge. CONCLUSIONS: We hereby describe a severe form of disseminated CMV disease after R-bendamustine treatment. Our observations strongly support the careful clinical monitoring of CMV reactivation/infection in oncologic patients undergoing this therapeutic regimen.


Assuntos
Cloridrato de Bendamustina/efeitos adversos , Infecções por Citomegalovirus/induzido quimicamente , Idoso , Antineoplásicos Alquilantes/efeitos adversos , Antivirais/uso terapêutico , Linfócitos B/efeitos dos fármacos , Linfócitos B/imunologia , Linfócitos T CD8-Positivos/imunologia , Infecções por Citomegalovirus/tratamento farmacológico , Infecções por Citomegalovirus/imunologia , Retinite por Citomegalovirus/induzido quimicamente , Retinite por Citomegalovirus/tratamento farmacológico , Retinite por Citomegalovirus/imunologia , Humanos , Masculino , Subpopulações de Linfócitos T/efeitos dos fármacos , Subpopulações de Linfócitos T/imunologia , Valganciclovir/uso terapêutico , Macroglobulinemia de Waldenstrom/tratamento farmacológico
7.
In Vivo ; 33(5): 1609-1614, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31471412

RESUMO

BACKGROUND/AIM: Trabectedin is a synthetic antineoplastic agent approved for advanced soft tissue sarcoma (STS) in Japan. The aim of this study was to evaluate the efficacy and safety of the Japan-approved dose of trabectedin for advanced STS. PATIENTS AND METHODS: We retrospectively reviewed 38 patients with advanced STS who received salvage chemotherapy with trabectedin. RESULTS: The overall response and disease control rates were 16% (5 patients) and 67% (20 patients), respectively. The median progression-free and overall survival were 7.3 and 17.8 months, respectively. There were no significant differences between patients with liposarcoma or leiomyosarcoma and those without, or between patients with TRS and those without. The most common grade 3-4 AEs were elevated transaminases and neutropenia. CONCLUSION: Trabectedin 1.2 mg/m2, as the approved dose in Japan, showed similar efficacy to the dose of 1.5 mg/m2 used in Western countries. Trabectedin could be an option for advanced STS in Japan, regardless of histological subtype.


Assuntos
Antineoplásicos Alquilantes/uso terapêutico , Sarcoma/tratamento farmacológico , Trabectedina/uso terapêutico , Adulto , Idoso , Antineoplásicos Alquilantes/administração & dosagem , Antineoplásicos Alquilantes/efeitos adversos , Biomarcadores Tumorais , Progressão da Doença , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Retrospectivos , Terapia de Salvação , Sarcoma/diagnóstico , Sarcoma/etiologia , Sarcoma/mortalidade , Trabectedina/administração & dosagem , Trabectedina/efeitos adversos , Resultado do Tratamento , Adulto Jovem
8.
Mol Carcinog ; 58(12): 2327-2339, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31544312

RESUMO

Autologous stem cell transplant (ASCT) with high-dose melphalan (HDM) is the standard treatment for fit multiple myeloma (MM) patients. It is generally believed that some DNA repair proteins impact the activity to repair melphalan-induced DNA damage, thus potentially contributing to the patient's clinical response. However, knowledge of these proteins is limited. In the current study, we investigated the roles of XRCC1, a protein involved in base excision repair and single-strand break repair, in melphalan response in MM cells. Small interfering RNA knockdown of XRCC1 significantly increased the accumulation of melphalan-induced DNA damage in MM cells and sensitized them to melphalan treatment, indicating that genetic variation in XRCC1 may impact response to melphalan treatment. We then evaluated the association between an XRCC1 variant with reduced activity, rs25487 (R399Q), and clinical outcomes of 108 MM patients with melphalan therapy. Our results showed that XRCC1 rs25487 was associated with prolonged progression-free survival (PFS) in MM patients. The adjusted hazard ratio for PFS between patients carrying rs25487 AA/AG and GG was 0.42 (95% confidence interval: 0.25, 0.84, P = .014). Taken together, these results indicate that XRCC1 is involved in the repair of melphalan-induced DNA damage and XRCC1 rs25487 variant with impaired DNA repair function influences the clinical responses of HDM in MM patients.


Assuntos
Reparo do DNA , Transplante de Células-Tronco Hematopoéticas/métodos , Melfalan/uso terapêutico , Mieloma Múltiplo/terapia , Proteína 1 Complementadora Cruzada de Reparo de Raio-X/metabolismo , Idoso , Antineoplásicos Alquilantes/efeitos adversos , Antineoplásicos Alquilantes/uso terapêutico , Quebras de DNA de Cadeia Simples/efeitos dos fármacos , Dano ao DNA , Relação Dose-Resposta a Droga , Feminino , Humanos , Estimativa de Kaplan-Meier , Masculino , Melfalan/efeitos adversos , Pessoa de Meia-Idade , Mieloma Múltiplo/genética , Mieloma Múltiplo/metabolismo , Polimorfismo de Nucleotídeo Único , Intervalo Livre de Progressão , Interferência de RNA , Transplante Autólogo , Proteína 1 Complementadora Cruzada de Reparo de Raio-X/genética
9.
J Clin Neurosci ; 68: 39-44, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31399318

RESUMO

The standard medical care of glioblastoma (GBM) patients with good performance status is based on focal brain radiotherapy (40-60 Gy) with concurrent temozolomide (TMZ) followed by adjuvant TMZ. Newly diagnosed multifocal and/or multicentric GBM (M/M GBM) cases are usually treated with TMZ alone: whole brain chemoradiotherapy (CRT) is avoided for safety reasons. To our knowledge, no study has investigated the safety and efficacy of whole-brain radiotherapy (WBRT) with concurrent TMZ in M/M GBM patients. This retrospective study sought to assess the role of WBRT associated with concurrent TMZ followed by TMZ alone in this population. Eleven patients with pathologically proven M/M GBM (≥3 lobes) were treated with WBRT between April 2009 and September 2017. The median age was 50 years [34-74]. The median dose of radiotherapy was 45 Gy at 1.8 Gy per fraction over 37 days [29-41], with concurrent daily TMZ at the dose of 75 mg/m2. This treatment was followed by adjuvant monthly TMZ (150 mg/m2-D1-D5). All pathology slides and radiology images were reviewed. The median overall and progression-free survival times for all patients were 10 months [4-25] and 5 months [3-21], respectively. There was no grade 3-4 toxicity due to radiotherapy. One patient stopped the TMZ during the radiochemotherapy period and 9 patients received adjuvant TMZ with a median number of 5 cycles [2-8]. Our study supports the safety and the efficacy of WBRT with TMZ in newly diagnosed M/M GBM. Larger prospective studies are needed to support our results.


Assuntos
Antineoplásicos Alquilantes/administração & dosagem , Neoplasias Encefálicas/terapia , Quimiorradioterapia/métodos , Irradiação Craniana/métodos , Glioblastoma/terapia , Temozolomida/administração & dosagem , Adulto , Idoso , Antineoplásicos Alquilantes/efeitos adversos , Neoplasias Encefálicas/patologia , Quimiorradioterapia/efeitos adversos , Irradiação Craniana/efeitos adversos , Feminino , Glioblastoma/mortalidade , Glioblastoma/patologia , Humanos , Pessoa de Meia-Idade , Estudos Retrospectivos , Temozolomida/efeitos adversos
10.
Int J Radiat Oncol Biol Phys ; 105(5): 1106-1112, 2019 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-31461674

RESUMO

PURPOSE: Malignant transformation (MT) of adult grade 2 glioma (low-grade glioma [LGG]) is associated with adverse survival. We sought to describe the incidence, outcomes, and risk factors for MT of molecularly classified LGG. METHODS AND MATERIALS: We reviewed a single-institutional database of adults who received a diagnosis of LGG with data allowing for molecular classification from 1980 to 2018 to evaluate time to MT and its associated risk factors. MT was defined as pathologic confirmation of grade 3-4 glioma and/or imaging characteristics consistent with MT by multidisciplinary consensus. RESULTS: Among the included 486 adults with molecularly classified LGG, median age was 39 years (range, 18-78), median tumor size was 3.9 cm (range, 0.3-13.0), and 262 (54%) were male. Molecular classification was IDHmut1p/19qcodel in 169 (35%), IDHmut1p/19qintact in 125 (26%), and IDHwt in 192 (40%) patients. Adjuvant management was observation in 246 (51%) patients, temozolomide alone in 82 (16%), radiation therapy alone in 63 (13%), and radiation therapy concurrent with temozolomide in 81 (17%). Temozolomide monotherapy was more likely to be given to IDHmut1p/19qcodel patients (P < .001). Median follow-up was 5.3 years. MT occurred in 84 (17%) patients, with a 5-year freedom from MT of 86% (95% confidence interval [CI], 82%-90%). Median overall survival after MT was 2.4 years (95% CI, 1.5-3.3) and was associated with molecular classification (P = .03) and grade at MT (P < .001). Factors associated with MT were male sex (hazard ratio [HR], 2.1; 95% CI, 1.2-3.6; P = .009), tumor size ≥5 cm (HR, 3.5; 95% CI, 2.0-6.2; P < .001), IDHmut1p/19qintact (HR, 2.7; 95% CI, 1.3-5.6; P = .009) or IDHwt classification (HR, 5.5; 95% CI, 2.5-11.8; P < .001), and adjuvant temozolomide monotherapy (HR, 3.8; 95% CI, 1.4-10.3; P = .008). CONCLUSIONS: MT of LGG has a poor prognosis associated with unfavorable molecular groups. Analysis of our large cohort identified adjuvant temozolomide monotherapy as the only modifiable risk factor for MT and provides the first clinical evidence of temozolomide-associated MT among molecularly classified adult LGG. This novel finding supplements our understanding of temozolomide-induced hypermutation and informs precision management of LGG.


Assuntos
Neoplasias Encefálicas/patologia , Transformação Celular Neoplásica/patologia , Glioma/patologia , Adulto , Idoso , Antineoplásicos Alquilantes/efeitos adversos , Antineoplásicos Alquilantes/uso terapêutico , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/mortalidade , Neoplasias Encefálicas/terapia , Transformação Celular Neoplásica/induzido quimicamente , Transformação Celular Neoplásica/genética , Quimiorradioterapia/métodos , Quimioterapia Adjuvante , Feminino , Glioma/genética , Glioma/mortalidade , Glioma/terapia , Humanos , Isocitrato Desidrogenase/genética , Masculino , Pessoa de Meia-Idade , Mutação , Fatores Sexuais , Temozolomida/efeitos adversos , Temozolomida/uso terapêutico , Carga Tumoral , Conduta Expectante
11.
Environ Sci Pollut Res Int ; 26(26): 26664-26673, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31292874

RESUMO

Cyclophosphamide (CYP) is a common anticancer drug used in the treatment of various malignancies. Naringin (NG) is a natural bioflavonoid that have been reported to have many medicinal and pharmacological properties. Acetylcholinesterase (AChE), butyrylcholinesterase (BChE), carbonic anhydrase (CA), α-glycosidase (α-Gly), and aldose reductase (AR) enzymes are the essential biological molecules needed for metabolic processes in all living cells. In the present study, the aim was to investigate the effect of NG against CYP-induced liver, brain, kidney, heart, and testis toxicities on some metabolic enzyme activities such as AChE, BChE, CA, α-Gly, and AR. Thirty-five male Wistar rats were randomly divided into five groups with each group consisting of seven rats. The rats were subjected to oral treatment of NG (50 and 100 mg/kg body weight) for 7 days before administering a single dose of CYP (200 mg/kg body weight, i.p) on the seventh day. Treatment with NG in all tissues regulated these enzyme activities in CYP-induced rats. The results of this study showed that NG regulates abnormal increases and decreases in CYP-induced metabolic enzyme activities in all tissues.


Assuntos
Antineoplásicos Alquilantes/farmacologia , Ciclofosfamida/antagonistas & inibidores , Flavanonas/farmacologia , Acetilcolinesterase/metabolismo , Aldeído Redutase/metabolismo , Animais , Antineoplásicos Alquilantes/efeitos adversos , Encéfalo/efeitos dos fármacos , Encéfalo/enzimologia , Butirilcolinesterase/metabolismo , Anidrases Carbônicas/metabolismo , Ciclofosfamida/efeitos adversos , Coração/efeitos dos fármacos , Rim/efeitos dos fármacos , Rim/enzimologia , Fígado/efeitos dos fármacos , Fígado/enzimologia , Masculino , Miocárdio , Substâncias Protetoras/farmacologia , Ratos , Ratos Wistar , Testículo/efeitos dos fármacos , Testículo/enzimologia
12.
Food Funct ; 10(8): 4998-5007, 2019 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-31355400

RESUMO

Grifola Frondosa, the king of mushrooms, is one of the most valued traditional medicines and has been used as a health food for a long time in China, Japan, and other Asian countries. The present study was designed to evaluate the immune-modulating effects of water-soluble polysaccharides from the Grifola Frondosa fruiting body (GFP) by using mouse peritoneal macrophage and cytoxan (CTX) induced immunosuppression models. Compared with CTX-induced immunosuppressive mice, the spleen and thymus indexes in mice with GFP orally administrated were significantly increased, body weight loss was alleviated, and the natural killer (NK) cytotoxicity and the proliferative activities of lymphocytes were elevated. Furthermore, levels of interleukin-2 (IL-2), interferon-6 (IL-6) and tumor necrosis factor-α (TNF-α) were notably reduced by CTX, while GFP abolished these effects. GFP also effectively increased total antioxidant capacity and superoxidase dismutase, catalase and glutathione peroxidase activities, and inhibited an increase in the malondialdehyde level. Histopathological analysis of spleens revealed the protective effect of GFP against CTX-induced immunosuppression. Western blotting results showed that GFP possessed immunomodulatory activity by up-regulating transcription factors (p-JAK2/JAK2, p-STAT3/STAT3 and SOCS3) in JAK2/STAT3/SOCS signaling pathways. This study suggested that GFP may provide an alternative strategy for lessening chemotherapy-induced immunosuppression.


Assuntos
Antineoplásicos Alquilantes/efeitos adversos , Ciclofosfamida/efeitos adversos , Grifola/química , Doenças do Sistema Imunitário/tratamento farmacológico , Janus Quinase 2/imunologia , Polissacarídeos/administração & dosagem , Substâncias Protetoras/administração & dosagem , Fator de Transcrição STAT3/imunologia , Proteína 3 Supressora da Sinalização de Citocinas/imunologia , Animais , Feminino , Humanos , Doenças do Sistema Imunitário/etiologia , Doenças do Sistema Imunitário/genética , Doenças do Sistema Imunitário/imunologia , Imunossupressão , Interleucina-2/genética , Interleucina-2/imunologia , Janus Quinase 2/genética , Células Matadoras Naturais/efeitos dos fármacos , Células Matadoras Naturais/imunologia , Camundongos , Camundongos Endogâmicos BALB C , Fator de Transcrição STAT3/genética , Transdução de Sinais/efeitos dos fármacos , Proteína 3 Supressora da Sinalização de Citocinas/genética
13.
BMJ Case Rep ; 12(6)2019 Jun 29.
Artigo em Inglês | MEDLINE | ID: mdl-31256047

RESUMO

Glioblastoma multiforme is an astrocyte-derived tumour representing the most aggressive primary brain malignancy. The median overall survival is 10-12 months, but it drops to 3-8.5 months for the cohort with more than 65 years old, which account to half of all patients. Initial management in this patient population aims to balance overall patient survival and quality of life with the inherent risks of treatment intervention, which include maximal safe tumour resection, radiation and temozolomide (TMZ) chemotherapy. This is accomplished through risk stratification as a function of patient age, functional status, comorbidities, tumour location and methylguanine methyltransferase promoter methylation status. We describe the care of a patient with prolonged febrile neutropaenia, with a rare but fatal complication from TMZ-induced idiosyncratic reaction, leading to aplastic anaemia and a provoking diagnosis of low-grade B-cell non-Hodgkin's lymphoma.


Assuntos
Anemia Aplástica/induzido quimicamente , Antineoplásicos Alquilantes/efeitos adversos , Neoplasias Encefálicas/complicações , Glioblastoma/complicações , Linfoma não Hodgkin/complicações , Temozolomida/efeitos adversos , Idoso de 80 Anos ou mais , Encéfalo , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/patologia , Evolução Fatal , Glioblastoma/tratamento farmacológico , Glioblastoma/patologia , Humanos , Achados Incidentais , Masculino
14.
BMJ Case Rep ; 12(5)2019 May 31.
Artigo em Inglês | MEDLINE | ID: mdl-31154345

RESUMO

Glioblastoma multiforme (GBM) is an aggressive tumour that can lead to lymphopaenia. Its standard treatment involves temozolomide (TMZ) chemotherapy with radiation, often with addition of corticosteroids for symptomatic management. Although TMZ is also immunosuppressive, patients receiving TMZ rarely develop disseminated opportunistic infections. Here, we report the case of a patient with GBM receiving TMZ, radiotherapy and corticosteroids, who develops an incidental new brain lesion that is found to be disseminated Aspergillus within a new GBM tumour site. The patient received successful early treatment of her central nervous system aspergillosis. This case illustrates the profound immunosuppressive potential of GBM in conjunction with TMZ and corticosteroids, which can lead to high-morbidity opportunistic infections concurrently with tumour progression. Future research is needed to elucidate GBM, TMZ and corticosteroids' compound immune effects and guide management that strikes a balance between treating high-morbidity infections and continuing with immunosuppressive chemotherapy.


Assuntos
Antineoplásicos Alquilantes/uso terapêutico , Aspergilose/diagnóstico , Abscesso Encefálico/diagnóstico , Neoplasias Encefálicas/terapia , Lobo Frontal , Glioblastoma/terapia , Temozolomida/uso terapêutico , Antineoplásicos Alquilantes/administração & dosagem , Antineoplásicos Alquilantes/efeitos adversos , Aspergilose/diagnóstico por imagem , Aspergilose/etiologia , Abscesso Encefálico/diagnóstico por imagem , Abscesso Encefálico/etiologia , Neoplasias Encefálicas/patologia , Terapia Combinada , Diagnóstico Diferencial , Feminino , Glioblastoma/patologia , Humanos , Imagem por Ressonância Magnética , Pessoa de Meia-Idade , Temozolomida/administração & dosagem , Temozolomida/efeitos adversos
15.
J Med Food ; 22(9): 896-906, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31216204

RESUMO

The present study investigated the immunomodulatory activity and associated mechanisms of heat-treated Lactobacillus plantarum LM1004 (HT-LM1004) in a cyclophosphamide (CTX)-induced mouse model of immunosuppression. HT-LM1004 induced phagocytic activity and nitric oxide production in RAW264.7 macrophages and stimulated the release of tumor necrosis factor (TNF)-α, interferon (IFN)-γ, interleukin (IL)-2, and IL-12p70. In mice with CTX-induced immunosuppression, oral HT-LM1004 administration restored thymus and spleen indices, including spleen weight. Consistent with the in vitro results, HT-LM1004 increased TNF-α, IFN-γ, IL-2, and IL-12p70 levels in mice after 14 days of treatment and enhanced the natural killer (NK) cell activity of splenocytes from mice with CTX-induced immunosuppression against YAC-1 lymphoma cells. The method of HT-LM1004 generation influenced this activity: L. plantarum LM1004 grown in a membrane bioreactor, which reduced the size of the cells to <1.0 µm through physical stress (micronization), promoted NK cell cytotoxicity to a greater extent than LM1004 subjected to heat treatment alone. These findings indicate that HT-LM1004 without or with micronization can reverse CTX-induced immunosuppression without adverse side effects by potentiating NK cell function.


Assuntos
Antineoplásicos Alquilantes/efeitos adversos , Ciclofosfamida/efeitos adversos , Fatores Imunológicos/administração & dosagem , Imunomodulação/efeitos dos fármacos , Lactobacillus plantarum/química , Probióticos/administração & dosagem , Animais , Antineoplásicos Alquilantes/administração & dosagem , Ciclofosfamida/administração & dosagem , Feminino , Temperatura Alta , Imunossupressão , Interferon gama/genética , Interferon gama/imunologia , Interleucina-12/genética , Interleucina-12/imunologia , Interleucina-2/genética , Interleucina-2/imunologia , Células Matadoras Naturais/efeitos dos fármacos , Células Matadoras Naturais/imunologia , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Camundongos , Camundongos Endogâmicos BALB C , Fagocitose/efeitos dos fármacos , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/imunologia
16.
J Assist Reprod Genet ; 36(9): 1793-1803, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31250176

RESUMO

PURPOSE: To determine whether pharmacological administration of recombinant human anti-Mullerian hormone (rAMH) protects the ovarian reserve and preserves fertility without interfering with anti-tumoural cytotoxic action of chemotherapy. METHODS: Intraperitoneal delivery of rAMH and ovarian post-receptor activity were assessed with immunohistochemistry and western blot. Differential follicle counts and reproductive outcomes were assessed after cyclophosphamide (Cy) administration, with/without concurrent administration of rAMH. Interference of rAMH with Cy chemotoxicity was assessed on a human breast cancer cell line and an in vivo mouse model of human leukaemia. RESULTS: rAMH reached the ovary after intraperitoneal injection and demonstrated post-receptor bioactivity. Cy administration in mice caused primordial follicle activation, as shown by a decrease in primordial follicle population accompanied by an increase in early growing follicles and granulosa cell proliferation. Co-administration of rAMH reduced follicle activation, thereby protecting the primordial follicle reserve, and improving long-term fertility and reproductive outcomes. rAMH co-administration did not interfere with the cytotoxic actions of Cy in vitro on breast cancer cell line or in vivo in a model of human leukaemia. CONCLUSION: This study demonstrates that rAMH is bioactive in the ovary for a limited time, and that pharmacological administration of rAMH during chemotherapy treatment reduces follicle activation and primordial follicle loss and significantly improves reproductive outcomes in a mouse model, and does not interfere with the therapeutic actions of the treatment. Further investigation is necessary to determine whether it has similar protective effects in the human ovary.


Assuntos
Hormônio Antimülleriano/farmacologia , Ciclofosfamida/farmacologia , Preservação da Fertilidade/métodos , Reserva Ovariana/efeitos dos fármacos , Animais , Hormônio Antimülleriano/genética , Antineoplásicos Alquilantes/efeitos adversos , Antineoplásicos Alquilantes/farmacologia , Linhagem Celular Tumoral , Ciclofosfamida/efeitos adversos , Feminino , Humanos , Leucemia Experimental/tratamento farmacológico , Masculino , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos NOD , Folículo Ovariano/efeitos dos fármacos , Folículo Ovariano/patologia , Reserva Ovariana/fisiologia , Gravidez , Taxa de Gravidez , Proteínas Recombinantes/genética , Proteínas Recombinantes/farmacologia
18.
Vet Clin Pathol ; 48(2): 255-258, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31062418

RESUMO

A 9-year-old mixed breed 13 kg spayed female dog was presented for evaluation of two masses in the right abdominal mammary gland region. Surgery was conducted to excise the masses. A grade I complex mammary gland carcinoma and high grade (grade III) mast cell tumor with an inguinal lymph node metastasis were diagnosed. Forty-seven days after the surgical procedure, the mast cell tumor relapsed, and neoadjuvant treatment with lomustine (81 mg/m2 ) was prescribed. Thirteen days from initiation of lomustine therapy, the dog was re-presented to the hospital with bloody diarrhea, hematemesis, epistaxis, an elevated rectal temperature, depression, severe dehydration, and marked dyspnea. The CBC showed severe thrombocytopenia and leukopenia. According to the owner, lomustine (45mg per os [PO]) was mistakenly administered daily for 10 consecutive days (total dose, 810 mg/m2 ). The dog died and a necropsy was performed. The main gross lesions consisted of severe multifocal hemorrhages in multiple organs, especially in the digestive system. Histopathologic evaluation revealed disseminated hemorrhages, as well as marked bone marrow aplasia. This report describes the clinical, hematologic, gross, and histologic findings in a fatal case of lomustine overdose in a dog.


Assuntos
Antineoplásicos Alquilantes/efeitos adversos , Carcinoma/tratamento farmacológico , Doenças do Cão/diagnóstico , Transtornos Hemorrágicos/veterinária , Leucopenia/veterinária , Lomustina/efeitos adversos , Trombocitopenia/veterinária , Animais , Antineoplásicos Alquilantes/administração & dosagem , Medula Óssea/patologia , Doenças do Cão/sangue , Doenças do Cão/patologia , Cães , Evolução Fatal , Feminino , Transtornos Hemorrágicos/sangue , Transtornos Hemorrágicos/diagnóstico , Transtornos Hemorrágicos/patologia , Lomustina/administração & dosagem , Metástase Linfática , Glândulas Mamárias Animais/patologia
19.
J Neurosurg Sci ; 63(3): 286-291, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31096725

RESUMO

BACKGROUND: Glioblastoma multiforme (GBM) is an extremely challenging neurological disease for which the development of more effective therapeutic options and of adjuvant/complementary treatment is needed. We investigated the effects of an innovative phytosome-based delivery form of boswellic acids extract (Monoselect AKBA™) on radiochemotherapy-induced cerebral edema in patients with primary GBM. METHODS: Patients with de novo GBM treated with surgery, radiotherapy and chemotherapy with temozolomide were enrolled in this longitudinal study and received boswellia-based product 4500 mg/die for a maximum of 34 weeks. Cerebral edema was assessed at 4, 12, 22 and 34 weeks post-surgery, together with steroids consumption and patients' psychological status. RESULTS: A total of 20 patients were included in the study. The percentage of patients with reduced edema was constant during the study, while the percentage of those with reduced or stable edema tended to increase over time. Of note, two patients achieved a considerable reduction in brain edema, which led to a more favorable and beneficial surgical resection. In addition, a good percentage of patients assumed a stable/reduced steroids dose or were dexamethasone free during the study. Lastly, patients' QoL and psychological state were maintained throughout the study. CONCLUSIONS: Complementary treatment with Monoselect AKBA™ might exert a beneficial effect in reducing radiochemotherapy-induced cerebral edema, thanks to the anti-inflammatory properties of the boswellia serrata extract. The reduction in brain edema might diminish dexamethasone assumption, thus minimizing steroids-induced side effects, and in few cases may allow a complete surgical excision of the tumor mass.


Assuntos
Anti-Inflamatórios não Esteroides/administração & dosagem , Edema Encefálico/tratamento farmacológico , Neoplasias Encefálicas/terapia , Quimiorradioterapia/efeitos adversos , Glioblastoma/terapia , Triterpenos/administração & dosagem , Adulto , Idoso , Antineoplásicos Alquilantes/efeitos adversos , Edema Encefálico/etiologia , Formas de Dosagem , Feminino , Humanos , Lecitinas , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Projetos Piloto , Temozolomida/efeitos adversos
20.
Dev Period Med ; 23(1): 39-44, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30954980

RESUMO

OBJECTIVE: Background: Patients with Ewing sarcoma have a dismal outcome. Maintenance treatment with trofosfamide has been proposed as an effective regimen for some paediatric malignancies. Aim: We sought to evaluate the schedule of trofosfamide for patients with high-risk primary bone Ewing sarcoma. PATIENTS AND METHODS: Materials and methods: Fifteen patients with primary bone Ewing sarcoma received treatment with trofosfamide (150 mg/m2 p.o. days 1-10) every 28 days. All patients had standard tumour imaging and laboratory evaluation. All toxicities were documented. RESULTS: Results: A total of 90 cycles (median 5 cycles/patient) were administered. A complete response was maintained in nine patients, while six patients had disease progression during treatment. Median time to progression was 1.9 months (range 1.8 to 4.6). Eleven patients (73.3%) are alive including nine with no evidence of disease with a median follow-up of 3.9 years (range 1.4 to 7.6). All patients with active disease at the start of the trofosfamide treatment died. There were no significant toxicities. CONCLUSION: Conclusions: Treatment with trofosfamide is well-tolerated and could have a role to maintain response in patients with primary bone Ewing sarcoma. Further studies are needed to better define the use of this regimen in the upfront management of those patients.


Assuntos
Neoplasias Ósseas/tratamento farmacológico , Ciclofosfamida/análogos & derivados , Sarcoma de Ewing/tratamento farmacológico , Adolescente , Antineoplásicos Alquilantes/efeitos adversos , Antineoplásicos Alquilantes/uso terapêutico , Neoplasias Ósseas/diagnóstico , Neoplasias Ósseas/diagnóstico por imagem , Criança , Pré-Escolar , Ciclofosfamida/efeitos adversos , Ciclofosfamida/uso terapêutico , Feminino , Humanos , Masculino , Sarcoma de Ewing/diagnóstico , Sarcoma de Ewing/diagnóstico por imagem , Resultado do Tratamento , Adulto Jovem
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