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1.
Clin Cancer Res ; 29(17): 3301-3312, 2023 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-37364001

RESUMO

PURPOSE: Novel targeted and immunotherapies have improved outcomes in relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL), but toxicities limit widespread use. The selective Bruton tyrosine kinase (BTK) inhibitor acalabrutinib has activity in patients with R/R DLBCL but durable responses are uncommon. STAT3 inhibition has demonstrated clinical activity in DLBCL. PATIENTS AND METHODS: Final results of the phase I study of acalabrutinib plus STAT3 inhibitor (danvatirsen; AZD9150) in patients with R/R DLBCL are reported. Danvatirsen 200 mg intravenous infusion [Days 1, 3, 5 (Cycle 1); weekly infusions starting Day 8, Cycle 1] was administered in combination with oral acalabrutinib 100 mg twice daily until progressive disease (PD) or unacceptable toxicity. Primary endpoints were safety and tolerability. Secondary endpoints included efficacy, pharmacokinetics, and immunogenicity. RESULTS: Seventeen patients received combination treatment. One dose-limiting toxicity (Grade 3 liver transaminase) occurred in 1 patient. The most common reason for treatment discontinuation was PD (65%). In evaluable patients (n = 17), objective response rate was 24%; median duration of response was 1.9 months. All responders with available DLBCL cell-of-origin data were either activated B-cell or nongerminal center B-cell like subtype. Genetic subtype did not correlate with response. Baseline and longitudinal plasma cell-free DNA (cfDNA) concentrations were mostly higher in nonresponding patients. cfDNA changes were generally concordant with imaging. Pretreatment circulating B-cell levels were higher in responders versus nonresponders. CONCLUSIONS: Targeting both STAT3 and BTK in combination is safe and tolerable but efficacy is limited in R/R DLBCL. Results support evaluation of circulating tumor DNA as a biomarker for clinical response.


Assuntos
DNA Tumoral Circulante , Linfoma Difuso de Grandes Células B , Linfoma não Hodgkin , Humanos , DNA Tumoral Circulante/genética , Recidiva Local de Neoplasia/tratamento farmacológico , Linfoma não Hodgkin/tratamento farmacológico , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Linfoma Difuso de Grandes Células B/genética , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Biomarcadores
2.
Gastrointest Cancer Res ; 4(4): 128-34, 2011 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-22368736

RESUMO

BACKGROUND: Facilitation of margin-negative resection is the goal of neoadjuvant therapy regimens used in the treatment of borderline-resectable pancreatic cancer patients. Multiple treatment approaches have shown efficacy in this setting, including neoadjuvant GTX (gemcitabine [Gemzar], docetaxel [Taxotere], and capecitabine [Xeloda]) and radiotherapy (RT). Three-dimensional tumor response may be a more accurate method of assessment compared to traditional 1- and 2-dimensional techniques. We compared these 3 methods in a series of patients who underwent neoadjuvant GTX-RT and surgical resection. MATERIALS AND METHODS: This retrospective review included borderline-resectable pancreatic cancer patients treated with neoadjuvant GTX followed by 5-FU chemoradiotherapy with the intent of downstaging to resectability. Tumor was contoured on computed tomography (CT) scans obtained at the following time points: (A) initial staging, (B) CT simulation, and (C) restaging. These contours were used to determine tumor response according to WHO, RECIST, and volumetric criteria. RESULTS: Fourteen patients all experienced a measurable decrease in tumor volume following neoadjuvant therapy and were deemed suitable for at least surgical exploration. Radiotherapy was delivered to a median 50 Gy (range, 45-52 Gy) in 1.8-2.0 Gy fractions via 3-D conformal (21%) or IMRT (79%). The median percent volume changes before and after CT simulation were -3.4% and -52.6%, respectively. The overall median percent change was -54.5%. The corresponding absolute volume changes were -0.42 cm(3) (range, 9.12 to -12.47), -5.31 cm(3) (range, 2.06 to -15.93), and -6.72 cm(3) (range, 0.53 to -15.47), respectively. Response according to WHO, RECIST, and volumetric methods was identical with the exception of 1 patient. CONCLUSION: This is the first study to quantify volumetric tumor change objectively as a result of neoadjuvant chemoradiotherapy for the treatment of borderline resectable pancreatic cancer. Our data suggest that tumor response to neoadjuvant therapy is essentially equivalent between 1-, 2-, and 3-dimensional assessment methods.

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