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The past decade, it has become evident that circadian rhythms within metabolically active tissues are very important for physical health. However, although shift work has also been associated with an increased risk of fractures, circadian rhythmicity has not yet been extensively studied in bone. Here, we investigated which genes are rhythmically expressed in bone, and whether circadian disruption by shifts in light-dark cycle affects bone turnover and structure in mice. Our results demonstrate diurnal expression patterns of clock genes (Rev-erbα, Bmal1, Per1, Per2, Cry1, Clock), as well as genes involved in osteoclastogenesis, osteoclast proliferation and function (Rankl, Opg, Ctsk), and osteocyte function (c-Fos) in bone. Weekly alternating light-dark cycles disrupted rhythmic clock gene expression in bone and caused a reduction in plasma levels of procollagen type 1 amino-terminal propeptide (P1NP) and tartrate-resistant acidic phosphatase (TRAP), suggestive of a reduced bone turnover. These effects coincided with an altered trabecular bone structure and increased cortical mineralization after 15 weeks of light-dark cycles, which may negatively affect bone strength in the long term. Collectively, these results show that a physiological circadian rhythm is important to maintain bone health, which stresses the importance of further investigating the association between shift work and skeletal disorders.
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Densidade Óssea , Osso e Ossos/fisiologia , Ritmo Circadiano , Regulação da Expressão Gênica , Luz , Fatores de Transcrição ARNTL/metabolismo , Animais , Comportamento Animal , Proteínas CLOCK/metabolismo , Catepsina K/metabolismo , Relógios Circadianos , Criptocromos/metabolismo , Feminino , Lipídeos/química , Camundongos , Membro 1 do Grupo D da Subfamília 1 de Receptores Nucleares/metabolismo , Osteogênese , Osteoprotegerina/metabolismo , Proteínas Circadianas Period/metabolismo , Fotoperíodo , Proteínas Proto-Oncogênicas c-fos/metabolismo , Ligante RANK/metabolismo , Microtomografia por Raio-XRESUMO
BACKGROUND: In patients with persistent symptoms of meralgia paresthetica, a neurectomy of the lateral femoral cutaneous nerve (LFCN) can be performed to alleviate pain symptoms. The neurectomy procedure can be performed either as a primary procedure or after failure of a previously performed neurolysis or decompression of the LFNC (secondary neurectomy). The goal of the present study was to quantify the histopathologic changes inside the LFCN obtained from patients with persistent symptoms of meralgia paresthetica, and specifically to compare to what extend these changes are present after primary versus secondary neurectomy. METHODS: A total of 39 consecutive cases were analyzed microscopically: in 29 cases, the neurectomy had been performed as primary procedure, in 10 cases, after failed neurolysis. Intraneural changes were quantified for the (1) thickening of perineurium, (2) deposition of mucoid, and (3) percentage of collagen. Analysis was performed at three levels: proximal to, at, and distal to the previous site of compression. In addition, correlations were investigated for the duration of symptoms and the body mass index (BMI) of the patient. RESULTS: Intraneural changes were found consistently in all cases. There was no significant difference for the primary and secondary neurectomy groups. There was also no relation with the previous site of compression. There was a weak correlation between the occurrence of intraneural changes and the duration of symptoms, although this difference was not statistically significant. CONCLUSIONS: Histopathological changes in this study were found in all patients with persistent symptoms of meralgia paresthetica regardless of a previously performed neurolysis procedure. This finding suggests that the intraneural changes that occur in persistent meralgia paresthetica are largely irreversible and support the surgical strategy of neurectomy as an alternative to neurolysis, also for primary surgical treatment and not only after failure of neurolysis.
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Nervo Femoral/patologia , Neuropatia Femoral/patologia , Adulto , Colágeno/metabolismo , Descompressão Cirúrgica , Feminino , Nervo Femoral/metabolismo , Nervo Femoral/cirurgia , Neuropatia Femoral/metabolismo , Neuropatia Femoral/cirurgia , Humanos , Masculino , Pessoa de Meia-Idade , Muco/metabolismoRESUMO
BACKGROUND: We performed a phase I modified 3 + 3 dose escalation study to evaluate the safety and activity of bevacizumab plus gemcitabine and nab-paclitaxel in patients with advanced solid tumours. METHODS: Patients were given fixed dose gemcitabine plus increasing doses of nab-paclitaxel and bevacizumab. Toxicity, response, and association with VEGF polymorphism was analysed. RESULTS: The study enrolled 110 patients who had undergone a median of 3 prior lines of therapy. The median age was 60 years (range, 17-85 years), and 55 patients (50%) had gemcitabine-refractory disease. We observed 3 dose-limiting toxicities during dose escalation and 3 DLTs in expansion cohorts. Dose escalation to 150 mg/m2 nab-paclitaxel and 15 mg/kg bevacizumab with 1000 mg/m2 of gemcitabine was well tolerated with no MTD. One patient with gemcitabine-refractory peritoneal papillary carcinoma had a complete response, 13 patients (13%) had partial responses, and 54 patients (52%) had stable disease ≥12 weeks. Exploratory VEGF single nucleotide polymorphism (SNP) analysis was performed on 13 patients. CONCLUSIONS: The combination of gemcitabine, nab-paclitaxel, and bevacizumab is safe, well-tolerated, and has activity in advanced malignancies, including gemcitabine-refractory tumours. Based on this study, the recommended phase 2 dose is gemcitabine 1000 mg/m2, nab-paclitaxel 125 mg/m2, and bevacizumab 15 mg/kg. VEGF polymorphism data should be evaluated in future bevacizumab-based trials.
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Albuminas/administração & dosagem , Bevacizumab/administração & dosagem , Desoxicitidina/análogos & derivados , Neoplasias/tratamento farmacológico , Paclitaxel/administração & dosagem , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Albuminas/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Bevacizumab/efeitos adversos , Desoxicitidina/administração & dosagem , Desoxicitidina/efeitos adversos , Esquema de Medicação , Feminino , Humanos , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Neoplasias/genética , Paclitaxel/efeitos adversos , Polimorfismo Genético , Resultado do Tratamento , Fator A de Crescimento do Endotélio Vascular/genética , Adulto Jovem , GencitabinaRESUMO
Background Both MET and c-SRC are important mediators of cancer progression and there is cross talk between the two molecules. Preclinical studies have demonstrated combination of MET and c-SRC inhibitors is effective in multiple cancer types. Methods We analyzed the safety and efficacy of administering a c-SRC inhibitor (dasatinib) in combination with a MET inhibitor (crizotinib) in a two-arm concurrent phase I study. Arm A consisted of crizotinib fixed at 250 mg twice per day with escalation of dasatinib. Arm B consisted of dasatinib fixed at 140 mg daily with escalation of crizotinib. Endpoints included dose-limiting toxicities (DLTs), recommended phase II dose (RP2D), and response (RECIST 1.1). Results We enrolled 61 patients (arm A: 31, arm B: 30). The most common cancers were sarcoma (21%) and prostate cancer (16%). In Arm A, at dose level 2 (DL2), 40% (2/5) experienced DLTs. In the expanded DL1, 21% (4/19) experienced DLTs (all grade 3). In Arm B, at DL2, 50% (2/4) experienced DLTs. In the expanded DL1, 22% (4/18) experienced DLTs (all grade 3). RP2D was determined to be arm A, DL1 (250 mg crizotinib orally twice per day plus 50 mg dasatinib orally daily). Partial response (N = 1) and stable disease for ≥6 months (N = 3) were seen. Conclusions The combination of crizotinib and dasatinib is safe to administer but tolerability is limited given the high rate of adverse events. Responses and durable stable disease were limited. Further precision therapy approach using this specific combination may be difficult given the toxicity.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Crizotinibe/uso terapêutico , Dasatinibe/uso terapêutico , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Inibidores de Proteínas Quinases/uso terapêutico , Adulto , Idoso , Antineoplásicos/efeitos adversos , Antineoplásicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Crizotinibe/efeitos adversos , Dasatinibe/efeitos adversos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Inibidores de Proteínas Quinases/efeitos adversos , Resultado do TratamentoRESUMO
BACKGROUND: Liver metastases are associated with a poor prognosis. We investigated the use of hepatic arterial infusion (HAI) of irinotecan combination therapy in patients with liver metastases. PATIENTS AND METHODS: Patients with histologically confirmed advanced cancer with liver metastases that was refractory to standard therapy were eligible. A standard "3 + 3" phase I study design was used to determine the dose-limiting toxicity (DLT) and the maximum tolerated dose (MTD). Three cohorts were evaluated: HAI of irinotecan with systemic intravenous (IV) (a) bevacizumab, (b) oxaliplatin and bevacizumab, or (c) bevacizumab and cetuximab. RESULTS: From October 2009 through December 2013, 98 patients with various tumor types were enrolled (median age, 62 years, range, 34-85; and median number of prior therapies, 4, range, 1-11). In cohorts A and C, dose escalation continued until the highest dose level-considered the MTD-was reached. In cohort B, dose escalation continued until dose level 3, and dose level 2 was considered the MTD. Rates of grade 3/4 adverse events were as follows: diarrhea, 8 %; fatigue, 4 %; neutropenia, 4 %; thrombocytopenia, 2 %; and skin rash, 2 %. Seventy-seven patients were evaluable for response. Partial response was noted in 5 (6.5 %) patients (neuroendocrine cancer, n = 2; CRC, n = 2; NSCLC, n = 1); and stable disease ≥ 6 months in 17 (22.1 %) patients (CRC, n = 13; breast, n = 1; neuroendocrine, n = 1; NSCLC, n = 1; pancreatic, n = 1). CONCLUSIONS: HAI irinotecan in combination with bevacizumab; oxaliplatin plus bevacizumab; or cetuximab plus bevacizumab was safe and may be a treatment option for selected patients with advanced cancer and liver involvement.
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Antineoplásicos Fitogênicos/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Bevacizumab/administração & dosagem , Camptotecina/análogos & derivados , Cetuximab/administração & dosagem , Neoplasias Hepáticas/tratamento farmacológico , Compostos Organoplatínicos/administração & dosagem , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos Fitogênicos/efeitos adversos , Antineoplásicos Fitogênicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Bevacizumab/efeitos adversos , Bevacizumab/uso terapêutico , Camptotecina/administração & dosagem , Camptotecina/efeitos adversos , Camptotecina/uso terapêutico , Cetuximab/efeitos adversos , Cetuximab/uso terapêutico , Feminino , Artéria Hepática , Humanos , Infusões Intra-Arteriais , Infusões Intravenosas , Irinotecano , Neoplasias Hepáticas/secundário , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Compostos Organoplatínicos/efeitos adversos , Compostos Organoplatínicos/uso terapêutico , OxaliplatinaRESUMO
PURPOSE: Combining agents that block both the VEGF and PI3K/AKT/mTOR pathways may be synergistic. We explored a novel dosing schedule to assess safety, toxicity and activity in patients with advanced solid tumors. PATIENTS AND METHODS: Patients with refractory solid tumors were enrolled in a modified 3 + 3 Phase I dose escalation study to determine dose limiting toxicities (DLTs) and the maximum tolerated dose (MTD) of a combination of everolimus (mTOR inhibitor) and pazopanib (tyrosine kinase inhibitor with anti-VEGF activity). An expansion cohort selected for patients with molecular alterations in the PI3K/AKT/mTOR pathway. RESULTS: Sixty-two patients were enrolled; median age was 60 years; 29 were women. The MTD was pazopanib 600 mg every other day (QOD) alternating with everolimus 10 mg PO QOD. DLTs were grade 3 thrombocytopenia and creatinine elevation. Most common toxicities of any grade were thrombocytopenia, transaminitis, leukopenia/neutropenia and lipid abnormalities. Among 52 patients evaluable for response, the clinical benefit rate (CBR) was 27 % (14/52) including four partial responses (PR), and 10 stable disease (SD) ≥6 months. 26 of 45 patients evaluated for molecular alterations had at least one alteration in the PI3K/AKT/mTOR pathway. CBR in patients with a matched alteration was 27 % (7/26) versus 26 % (5/19) for patients without an alteration (p = 0.764). However, 64% of those with CBR and molecular testing done for alteration in the PI3K/AKT/mTOR pathway were positive. CONCLUSION: Combination treatment with pazopanib and everolimus was well tolerated and demonstrated activity in solid tumors. Further exploration of this combination and molecular correlation with treatment outcomes is warranted.
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Resistencia a Medicamentos Antineoplásicos , Everolimo/uso terapêutico , Mutação/genética , Neoplasias/tratamento farmacológico , PTEN Fosfo-Hidrolase/metabolismo , Fosfatidilinositol 3-Quinases/genética , Pirimidinas/uso terapêutico , Sulfonamidas/uso terapêutico , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Relação Dose-Resposta a Droga , Everolimo/efeitos adversos , Feminino , Humanos , Indazóis , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Neoplasias/patologia , Pirimidinas/efeitos adversos , Sulfonamidas/efeitos adversos , Resultado do Tratamento , Adulto JovemRESUMO
PURPOSE: Aberrant alterations of ERBB receptor tyrosine kinases lead to tumorigenesis. Single agent therapy targeting EGFR or HER2 has shown clinical successes, but drug resistance often develops due to aberrant or compensatory mechanisms. Herein, we sought to determine the feasibility and safety of neratinib and trametinib in patients with EGFR mutation/amplification, HER2 mutation/amplification, HER3/4 mutation and KRAS mutation. METHODS: Patients with actionable somatic mutations or amplifications in ERBB genes or actionable KRAS mutations were enrolled to receive neratinib and trametinib in this phase I dose escalation trial. The primary endpoint was determination of the maximum tolerated dose (MTD) and dose-limiting toxicity (DLT). Secondary endpoints included pharmacokinetic analysis and preliminary anti-tumor efficacy. RESULTS: Twenty patients were enrolled with a median age of 50.5 years and a median of 3 lines of prior therapy. Grade 3 treatment-related toxicities included: diarrhea (25%), vomiting (10%), nausea (5%), fatigue (5%) and malaise (5%). The MTD was dose level (DL) minus 1 (neratinib 160 mg daily with trametinib 1 mg, 5 days on and 2 days off) given 2 DLTs of grade 3 diarrhea in DL1 (neratinib 160 mg daily with trametinib 1 mg daily). The treatment-related toxicities of DL1 included: diarrhea (100%), nausea (55.6%) and rash (55.6%). Pharmacokinetic data showed trametinib clearance was significantly reduced leading to high drug exposures of trametinib. Two patients achieved stable disease (SD) ≥ 4 months. CONCLUSION: Neratinib and trametinib combination was toxic and had limited clinical efficacy. This may be due to suboptimal drug dosing given drug-drug interactions. TRIAL REGISTRATION ID: NCT03065387.
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Neoplasias , Proteínas Proto-Oncogênicas p21(ras) , Humanos , Pessoa de Meia-Idade , Proteínas Proto-Oncogênicas p21(ras)/genética , Protocolos de Quimioterapia Combinada Antineoplásica , Neoplasias/tratamento farmacológico , Inibidores de Proteínas Quinases/efeitos adversos , Genes erbB , Mutação , Receptores ErbB/genética , Náusea/tratamento farmacológico , Diarreia/tratamento farmacológico , Quinases de Proteína Quinase Ativadas por Mitógeno , Receptor ErbB-2/genética , Receptor ErbB-2/metabolismoRESUMO
BACKGROUND/AIMS: We conducted a phase I trial of IP oxaliplatin and paclitaxel with IV paclitaxel and bevacizumab in patients with peritoneal carcinomatosis. METHODOLOGY: Patients received IV bevacizumab (2.5mg/kg) over 1 hour (day 1), then IV paclitaxel (110 mg/m2) 24-hr-infusion (day 1) and IP oxaliplatin (25-40 mg/m2) (day 2), and IP paclitaxel (30-60 mg/m2) (day 8 from cycle 2 onwards). A '3+3' design was used. RESULTS: Nineteen patients were treated (median age 60 years; 10 women, 9 men; median number of prior therapies 3). Primary tumors were colorectal (n=9), signet ring carcinoma (n=2), gastric (n=2), ovarian (n=2) and others (n=4). The maximum tolerated doses (MTD) of IP oxaliplatin and IP paclitaxel were 25mg/m2 and 60 mg/ m2, respectively. Nine (47%) patients reported no toxicities >grade 2. Two patients receiving IP oxaliplatin 40 mg/m2 and IP paclitaxel 60 mg/m2 had dose limiting toxicities (DLT) of grade 3 diarrhea/dehydration and febrile neutropenia. Toxicities included abdominal pain (n=14), nausea (n=10) and constipation (n=7). Of 12 patients restaged at 2 months, 7 (58%) had stable disease (SD) including 2 (17%) who had SD for >4 months. CONCLUSIONS: IP paclitaxel and IP oxaliplatin can be given safely at 60 mg/m2 and 25mg/m2, respectively.
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Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Neoplasias Peritoneais/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais Humanizados/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Bevacizumab , Feminino , Humanos , Infusões Intravenosas , Injeções Intraperitoneais , Masculino , Pessoa de Meia-Idade , Compostos Organoplatínicos/administração & dosagem , Compostos Organoplatínicos/efeitos adversos , Oxaliplatina , Paclitaxel/administração & dosagem , Paclitaxel/efeitos adversos , Neoplasias Peritoneais/mortalidadeRESUMO
Intrahepatic cholangiocarcinoma is a rare malignancy, which is rich in actionable alterations. Genomic aberrations in the mitogen-activated protein kinase (MAPK) pathway are common, and BRAF exon 15 p.V600E mutations are present in 5-7% of biliary tract cancers (BTC). Dual inhibition of BRAF and MEK has been established for BRAF-mutated melanoma and lung cancer, and recent basket trials have shown efficacy of this combination in BRAF V600E-mutant BTCs. Here, we report on a patient with BRAF exon 15 p.V600E mutant metastatic intrahepatic cholangiocarcinoma who was started on BRAF and MEK inhibition with vemurafenib and combimetinib. Shortly thereafter, he developed debilitating myositis, which was refractory to corticosteroids, requiring therapeutic plasma exchange and intravenous immunoglobulin. We also review BRAF as a target in BTCs, relevant clinical trials, and adverse events associated with BRAF and MEK inhibition.
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PURPOSE: As hypoxia can mediate resistance to immunotherapy, we investigated the safety, tolerability, and efficacy of combining evofosfamide, a prodrug that alleviates hypoxia, with ipilimumab, an immune checkpoint inhibitor, in immunologically "cold" cancers, which are intrinsically insensitive to immunotherapy, as well as in "hot/warm" metastatic cancers that are, atypical of such cancers, resistant to immunotherapy. PATIENTS AND METHODS: In a phase I, 3+3 dose-escalation trial (NCT03098160), evofosfamide (400-640 mg/m2) and ipilimumab (3 mg/kg) were administered in four 3-week cycles. The former was administered on days 1 and 8 of cycles 1-2, while the latter was administered on day 8 of cycles 1-4. Response was assessed using immune-related RECIST and retreatment was allowed, if deemed beneficial, after completion of cycle 4 or at progression. RESULTS: Twenty-two patients were enrolled, of whom 21 were evaluable, encompassing castration-resistant prostate cancer (n = 11), pancreatic cancer (n = 7), immunotherapy-resistant melanoma (n = 2), and human papillomavirus-negative head and neck cancer (n = 1). Drug-related hematologic toxicities, rash, fever, nausea, vomiting, and elevation of liver enzymes were observed in > 10% of patients. The most common drug-related grade 3 adverse event was alanine aminotransferase elevation (33.3%). Two patients discontinued ipilimumab and 4 required evofosfamide deescalation due to toxicity. Of 18 patients with measurable disease at baseline, 3 (16.7%) achieved partial response and 12 (66.7%) achieved stable disease. The best responses were observed at 560 mg/m2 evofosfamide. Preexisting immune gene signatures predicted response to therapy, while hypermetabolic tumors predicted progression. Responders also showed improved peripheral T-cell proliferation and increased intratumoral T-cell infiltration into hypoxia. CONCLUSIONS: No new or unexpected safety signals were observed from combining evofosfamide and ipilimumab, and evidence of therapeutic activity was noted.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Ipilimumab/administração & dosagem , Melanoma/tratamento farmacológico , Nitroimidazóis/administração & dosagem , Neoplasias Pancreáticas/tratamento farmacológico , Mostardas de Fosforamida/administração & dosagem , Neoplasias da Próstata/tratamento farmacológico , Carcinoma de Células Escamosas de Cabeça e Pescoço/tratamento farmacológico , Idoso , Feminino , Humanos , Ipilimumab/efeitos adversos , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Nitroimidazóis/efeitos adversos , Mostardas de Fosforamida/efeitos adversos , Segurança , Resultado do TratamentoRESUMO
BACKGROUND: Imatinib mesylate can induce rapid tumor regression, increase tumor antigen presentation, and inhibit tumor immunosuppressive mechanisms. CTLA-4 blockade and imatinib synergize in mouse models to reduce tumor volume via intratumoral accumulation of CD8+ T cells. We hypothesized that imatinib combined with ipilimumab would be tolerable and may synergize in patients with advanced cancer. METHODS: Primary objective of the dose-escalation study (3 + 3 design) was to establish the maximum tolerated dose (MTD) and recommended phase II dose. Secondary objectives included evaluation of antitumor activity of the combination based on KIT mutation status and the capacity of tumor-associated immune biomarkers to predict response. RESULTS: The primary objective to establish the maximum tolerated dose (MTD) was achieved, and the recommended phase II doses are ipilimumab at 3 mg/kg every 3 weeks and imatinib 400 mg twice daily. Of the 35 patients treated in the escalation and GIST expansion, none experienced dose-limiting toxicities. The most common grade 1/2-related adverse events (AEs) were fatigue (66%), nausea (57%), anorexia, vomiting (each 31%), edema (29%), and anemia, diarrhea, and rash (each 23%). Grade 3 AEs occurred in 6 patients (17%) and included fatigue, anemia, fever, rash, and vomiting. There were no grade 4 AEs. In general, the combination was well tolerated. Among all patients, 2 responses were seen: 1 partial response (GIST) and 1 partial response (melanoma). Stable disease was seen in 6 patients lasting an average of 6 months. The melanoma responder was KIT mutated and the GIST responder was wild-type. CONCLUSIONS: Our findings suggest that this combination of a targeted agent with checkpoint blockade is safe across multiple tumor types. Low activity with no clear signal for synergy was observed in escalation or GIST expansion cohorts. Assessment of antitumor activity of this combination in the KIT-mutant melanoma population is being evaluated. TRIAL REGISTRATION: Clinicaltrials.gov NCT01738139, registered 28 November 2012.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Mesilato de Imatinib/uso terapêutico , Ipilimumab/uso terapêutico , Neoplasias/tratamento farmacológico , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Feminino , Humanos , Mesilato de Imatinib/administração & dosagem , Mesilato de Imatinib/farmacologia , Ipilimumab/administração & dosagem , Ipilimumab/farmacologia , Masculino , Pessoa de Meia-Idade , Neoplasias/patologia , Adulto JovemRESUMO
BACKGROUND: Liver metastases in patients with cancer are associated with poor survival. We hypothesized that hepatic arterial infusion (HAI) of oxaliplatin combination therapy would have antitumor activity in these patients. PATIENTS AND METHODS: Patients with advanced cancer and predominant liver metastases were treated on a phase I study of HAI oxaliplatin in combination with systemic bevacizumab, with or without HAI or systemic fluorouracil and/or leucovorin and/or cetuximab. Patients were divided into two treatment arms according to KRAS mutational status and physician choice. A "3 + 3" design was used. RESULTS: Among 76 patients (median age 61 years; 34 women; median number of prior therapies 4), the most common cancer was colorectal (CRC) (n = 58). Overall, the only dose-limiting toxicity was Grade 3 diarrhea (n = 2). The most common treatment-related toxicities were hypertension (n = 40), nausea (n = 29), fatigue (n = 28), and transaminitis (n = 26). Of 76 patients, one (1 %) had a complete response (CR), 12 (16 %) had a partial response (PR), and 12 (16 %) had SD for ≥ 6 months (total CR/PR/SD ≥ 6 months 25/76 = 33 %). In CRC (n = 58), total CR/PR/SD ≥ 6 months was 31 % (n = 18). Both patients with pancreatic neuroendocrine tumors achieved a PR (24+ months) and a CR (6+ months). Time to treatment failure (TTF) on the current regimen was 3.5 versus 2.8 months on patients' prior systemic treatment (p = 0.37). CONCLUSIONS: HAI oxaliplatin combination therapy with 5-fluorouracil, leucovorin, bevacizumab, and/or cetuximab was well tolerated and had antitumor activity in selected heavily pretreated patients with predominant liver disease.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/secundário , Compostos Organoplatínicos/administração & dosagem , Compostos Organoplatínicos/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Feminino , Artéria Hepática , Humanos , Infusões Intra-Arteriais , Neoplasias Hepáticas/mortalidade , Masculino , Pessoa de Meia-Idade , Compostos Organoplatínicos/efeitos adversos , OxaliplatinaRESUMO
PURPOSE: This pilot clinical trial explored the feasibility, safety, and efficacy of regional hepatic therapy combined with systemic anticancer agents in patients with refractory solid tumors and extensive unresectable liver involvement, including those with compromised hepatic function. PATIENTS AND METHODS: Six patients with colorectal (N = 3), ovarian (N = 2), and hepatocellular carcinoma (N = 1) received intra-arterial hepatic oxaliplatin followed by intravenous 5-fluorouracil, leucovorin, and bevacizumab every 2 weeks until disease progression. All had extensive liver metastases; four had elevated baseline serum total bilirubin. Median total bilirubin was 2.8 mg/dL (range, 0.2-5.2 mg/dL). Median Child-Pugh score was 7 (range, 5-10). RESULTS: Thirty treatments were delivered (2-7 per patient). Median age of patients was 57 years (range, 25-69 years). Three patients (1 with colorectal, 1 with hepatocellular, and 1 with ovarian cancer) attained partial responses. Two had failed previous oxaliplatin and cisplatin treatment. Some with elevated bilirubin at baseline had a significant drop in bilirubin with treatment (bilirubin 5.2 â 1 mg/dL, 4.8 â 1.1 mg/dL, and 5.2 â 1.8 mg/dL). The regimen was generally well tolerated; the most common side effects were grade 1 fatigue, anorexia, and/or hypertension. One patient died of enzyme-linked, immunoassay-confirmed, heparin-induced thrombocytopenia during the sixth cycle of therapy. CONCLUSION: At doses tested, this regimen was safe and demonstrated antitumor activity in patients with advanced refractory malignancies involving the liver, including those with hepatic insufficiency. Further study is warranted.
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Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Neoplasias Colorretais/tratamento farmacológico , Resistencia a Medicamentos Antineoplásicos , Artéria Hepática , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Ovarianas/tratamento farmacológico , Adulto , Idoso , Anticorpos Monoclonais/administração & dosagem , Anticorpos Monoclonais Humanizados , Bevacizumab , Neoplasias Colorretais/patologia , Feminino , Fluoruracila/administração & dosagem , Humanos , Infusões Intra-Arteriais , Leucovorina/administração & dosagem , Neoplasias Hepáticas/secundário , Masculino , Pessoa de Meia-Idade , Compostos Organoplatínicos/administração & dosagem , Neoplasias Ovarianas/patologia , Oxaliplatina , Projetos Piloto , Terapia de Salvação , Taxa de Sobrevida , Tomografia Computadorizada por Raios X , Resultado do TratamentoRESUMO
OBJECTIVE: To assess whether the addition of a brief course of intravenous corticosteroids reduces the incidence of infusion-related adverse events associated with gemtuzumab ozogamicin (GO) administration. METHODS: One hundred forty-three sequential patients received GO-based therapy for refractory myeloid leukemias: 110 patients received the standard regimen of acetaminophen 650 mg orally with diphenhydramine 50 mg intravenously and 33 patients received the same premedications with methylprednisolone sodium succinate 50 mg intravenous piggyback (IVPB) prior to infusion and repeated 1 hour into the infusion. RESULTS: Of 110 patients who received GO with standard premedications alone, 32 (29%) had grade 2 or above infusion-related adverse events. In 33 patients who received these premedications with methylprednisolone 50 mg IVPB prior to infusion and repeated 1 hour into the infusion, only 1 (3%) experienced any infusion-related adverse events (p = 0.0009, 95% CI 0.16 to 0.36). There was no significant difference between the patient cohorts in terms of hepatotoxicity, rate of development of hepatic venoocclusive disease, response rates, or infectious complications. CONCLUSIONS: A brief course of intravenous corticosteroids significantly reduces the incidence of GO infusion-related adverse events.
Assuntos
Aminoglicosídeos , Antibacterianos/efeitos adversos , Anti-Inflamatórios/uso terapêutico , Anticorpos Monoclonais/efeitos adversos , Imunotoxinas/efeitos adversos , Leucemia Mieloide Aguda/tratamento farmacológico , Hemissuccinato de Metilprednisolona/uso terapêutico , Acetaminofen/efeitos adversos , Acetaminofen/uso terapêutico , Adulto , Analgésicos não Narcóticos/efeitos adversos , Analgésicos não Narcóticos/uso terapêutico , Antibacterianos/administração & dosagem , Anti-Inflamatórios/administração & dosagem , Anticorpos Monoclonais/administração & dosagem , Anticorpos Monoclonais Humanizados , Fibrilação Atrial/induzido quimicamente , Fibrilação Atrial/prevenção & controle , Calafrios/induzido quimicamente , Calafrios/prevenção & controle , Dispneia/induzido quimicamente , Dispneia/prevenção & controle , Eritema/induzido quimicamente , Eritema/prevenção & controle , Febre/induzido quimicamente , Febre/prevenção & controle , Gemtuzumab , Hepatopatia Veno-Oclusiva/induzido quimicamente , Hepatopatia Veno-Oclusiva/prevenção & controle , Humanos , Hipertensão/induzido quimicamente , Hipertensão/prevenção & controle , Hipotensão/induzido quimicamente , Hipotensão/prevenção & controle , Imunotoxinas/administração & dosagem , Infusões Intravenosas , Hemissuccinato de Metilprednisolona/administração & dosagem , Dor/induzido quimicamente , Dor/prevenção & controle , Rabdomiólise/induzido quimicamente , Rabdomiólise/prevenção & controle , Vômito/induzido quimicamente , Vômito/prevenção & controleRESUMO
BACKGROUND: Systemic fungal infections remain the leading cause of mortality in patients with newly diagnosed acute myelogenous leukemia (AML) and high-risk myelodysplastic syndrome (MDS). The objective of the current study was to determine whether intravenous itraconazole (i.v. ITRA) reduced the incidence of probable/proven fungal infections in this group of patients, and compare the results with those of a historic control group treated with fluconazole plus itraconazole capsules (F+I). METHODS: Patients with AML and high-risk MDS who underwent induction chemotherapy received 200 mg of i.v. itraconazole over 60 minutes every 12 hours during the first 2 days followed by 200 mg given i.v. once daily. RESULTS: One hundred patients were enrolled, 96 of whom were evaluable. Approximately 48% of the patients in the group of patients treated with i.v. ITRA as well as in the F+I group completed prophylaxis. Nine patients (9%) in the study group developed either proven/probable fungal infections (Candida glabrata in 5 patients, C. tropicalis in 1 patient, C krusei in 1 patient, and Fusarium in 2 patients) compared with 3 patients (4%) with proven fungal infection in the historic control group (C. tropicalis in 1 patient and Aspergillus in 2 patients). There were no significant differences noted between the two groups with regard to the percentage of patients who developed proven/probable or possible fungal infection as well as with regard to survival. These results also were obtained after adjusting for relevant prognostic factors (creatinine and bilirubin). The most common toxicity encountered with the use of i.v. ITRA was NCI Grade 3-4 hyperbilirubinemia (6%). CONCLUSIONS: Despite its theoretic advantages, the authors found no evidence that i.v. ITRA is superior to itraconazole capsules, at least when the latter is combined with fluconazole.
Assuntos
Fungemia/prevenção & controle , Itraconazol/administração & dosagem , Leucemia Mieloide Aguda/tratamento farmacológico , Síndromes Mielodisplásicas/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Análise de Variância , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Relação Dose-Resposta a Droga , Esquema de Medicação , Feminino , Fungemia/tratamento farmacológico , Humanos , Infusões Intravenosas , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/mortalidade , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Síndromes Mielodisplásicas/diagnóstico , Síndromes Mielodisplásicas/mortalidade , Prevenção Primária/métodos , Probabilidade , Prognóstico , Modelos de Riscos Proporcionais , Estudos Prospectivos , Indução de Remissão , Medição de Risco , Análise de Sobrevida , Resultado do TratamentoRESUMO
BACKGROUND: The optimal antifungal prophylactic regimen for patients with acute myelogenous leukemia (AML) or high-risk myelodysplastic syndrome (MDS) undergoing induction chemotherapy has yet to be identified. A prospective historical control study evaluated the efficacy and safety of amphotericin B lipid complex (ABLC) in this patient population. METHODS: Newly diagnosed patients with AML or high-risk MDS who were undergoing induction chemotherapy received prophylactic ABLC 2.5 mg/kg intravenously 3 times weekly. This treatment group was compared with a historical control group that had similar baseline characteristics and received prophylactic liposomal amphotericin B (L-AmB) 3 mg/kg 3 times weekly. The primary endpoint was the incidence of documented or suspected fungal infections during and up to 4 weeks after cessation of prophylaxis. Reported adverse events were used to assess tolerability. RESULTS: The overall efficacy of antifungal prophylaxis was similar in patients who received ABLC and patients who received L-AmB (P=0.95). Among 131 ABLC-treated patients and 70 L-AmB-treated patients who were assessed for efficacy and safety, 49% of patients in each group completed therapy without developing a documented or suspected fungal infection. Documented fungal infections occurred in 5% of ABLC-treated patients and in 4% of L-AmB-treated patients. Alternative antifungal strategies were required because of persistent fever or pneumonia of unknown pathogen in 28% and 32% of ABLC-treated and L-AmB-treated patients, respectively. Grade 3 and 4 adverse events, therapy discontinuations due to adverse events, and survival rates also were similar between treatment groups. CONCLUSIONS: ABLC and L-AmB appeared to have similar efficacy and were tolerated well as antifungal prophylaxis in patients with AML and high-risk MDS who were undergoing induction chemotherapy.