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1.
Clin Cancer Res ; 27(2): 447-459, 2021 01 15.
Artículo en Inglés | MEDLINE | ID: mdl-33148674

RESUMEN

PURPOSE: Somatic mutations in phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA), which encodes the p110α catalytic subunit of PI3K, are found in multiple human cancers. While recurrent mutations in PIK3CA helical, regulatory, and kinase domains lead to constitutive PI3K pathway activation, other mutations remain uncharacterized. To further evaluate their clinical actionability, we designed a basket study for patients with PIK3CA-mutant cancers with the isoform-specific PI3K inhibitor taselisib. PATIENTS AND METHODS: Patients were enrolled on the basis of local PIK3CA mutation testing into one of 11 histology-specific cohorts and treated with taselisib at 6 or 4 mg daily until progression. Tumor DNA from baseline and progression (when available) was sequenced using a next-generation sequencing panel. Exploratory analyses correlating genomic alterations with treatment outcomes were performed. RESULTS: A total of 166 patients with PIK3CA-mutant cancers were enrolled. The confirmed response rate was 9%. Activity varied by tumor type and mutant allele, with confirmed responses observed in head and neck squamous (15.4%), cervical (10%), and other cancers, plus in tumors containing helical domain mutations. Genomic analyses identified mutations potentially associated with resistance to PI3K inhibition upfront (TP53 and PTEN) and postprogression through reactivation of the PI3K pathway (PTEN, STK11, and PIK3R1). Higher rates of dose modification occurred at higher doses of taselisib, indicating a narrow therapeutic index. CONCLUSIONS: Taselisib had limited activity in the tumor types tested and is no longer in development. This genome-driven study improves understanding of the activity, limitations, and resistance mechanisms of using PI3K inhibitors as monotherapy to target PIK3CA-mutant tumors.


Asunto(s)
Fosfatidilinositol 3-Quinasa Clase I/antagonistas & inhibidores , Imidazoles/uso terapéutico , Mutación , Neoplasias/tratamiento farmacológico , Oxazepinas/uso terapéutico , Adulto , Anciano , Anciano de 80 o más Años , Antineoplásicos/uso terapéutico , Fosfatidilinositol 3-Quinasa Clase I/genética , Fosfatidilinositol 3-Quinasa Clase I/metabolismo , Estudios de Cohortes , Femenino , Humanos , Masculino , Persona de Mediana Edad , Neoplasias/genética , Neoplasias/metabolismo , Supervivencia sin Progresión , Resultado del Tratamiento , Adulto Joven
2.
J Phys Chem B ; 124(46): 10507-10513, 2020 11 19.
Artículo en Inglés | MEDLINE | ID: mdl-33151069

RESUMEN

In this study, electron trapping phenomena in amorphous polymer electrets were studied using a solid-state electron affinity analysis by means of molecular dynamics simulations parametrized with ab initio calculations. Negatively charged amorphous systems of a cyclic transparent optical polymer (CYTOP) with different end groups were reproduced by molecular dynamics simulations parametrized by density functional theory analysis. Quantum mechanical calculations were performed for electron trapping sites to determine the electron affinity of an isolated molecule. The influence of the amorphous system surrounding the trapping site was considered by accounting for electrostatic interactions with surrounding molecules and multipole induction. A series of analyses were carried out to mimic the conformational diversity of the amorphous system. The calculated solid-state electron affinities were found to adopt a Gaussian-type distribution and were in good accordance with the experimental data for surface potential and thermally stimulated discharge spectra, indicating the reliability of the present analysis for predicting the charging performance of amorphous polymer electrets.

3.
Oncologist ; 24(9): 1153-1158, 2019 09.
Artículo en Inglés | MEDLINE | ID: mdl-30833486

RESUMEN

BACKGROUND: Mammalian target of rapamycin (mTOR) inhibitor-associated stomatitis (mIAS) is a frequent adverse event (AE) associated with mTOR inhibitor therapy and can impact treatment adherence. The objectives are to evaluate two steroid-based mouthrinses for preventing/ameliorating mIAS in patients with metastatic breast cancer (MBC) treated with everolimus. MATERIALS AND METHODS: This prospective, randomized phase II study enrolled 100 postmenopausal patients with hormone receptor-positive MBC within the US Oncology Network who were initiating therapy with an aromatase inhibitor + everolimus (AIE; 10 mg/day). Patients were randomized to prophylactic therapy with one of two oral rinses (Arm 1: Miracle Mouthwash [MMW] 480 mL recipe: 320 mL oral Benadryl [diphenhydramine; Johnson & Johnson, New Brunswick, NJ, USA], 2 g tetracycline, 80 mg hydrocortisone, 40 mL nystatin suspension, water; or Arm 2: prednisolone [P] 15 mg/5 mL oral solution, 1.8% alcohol). Patients were instructed to swish/expectorate 10 mL of the assigned rinse for 1-2 minutes four times daily starting with day 1 of AIE treatment, for the first 12 weeks. RESULTS: A total of 100 patients received treatment (49 MMW; 51 P). The incidence of stomatitis/oral AEs during the first 12 weeks was 35% (n = 17/49) and 37% (19/51) in the MMW and P arms, respectively. The incidence of grade 2 oral AEs was 14% (7/49) and 12% (6/51) with MMW or P, respectively. There were two grade 3 oral AEs (MMW arm) and no grade 4 events. There was one everolimus dose reduction (MMW) and six dose delays (four MMW, two P) and one dose reduction + delay (MMW) during the first 12 weeks of treatment. No patients stopped steroid mouthwash therapy because of rinse-related toxicity. CONCLUSION: Prophylactic use of steroid-containing oral rinses can prevent/ameliorate mIAS in patients with MBC treated with AIE. MMW + hydrocortisone is an affordable option, as is dexamethasone oral rinse. IMPLICATIONS FOR PRACTICE: This prospective phase-II study showed that two steroid-containing mouthrinses substantially reduced incidences of all-grade and grade ≥2 stomatitis and related oral adverse events (AEs), and the number of everolimus dose-delays and/or dose-reduction in metastatic breast cancer (MBC) patients receiving everolimus treatment plus an aromatase inhibitor. Both oral rinses were well tolerated and demonstrated similar efficacy. Prophylactic use of steroid mouth rinse provides a cost-effective option that substantially decreases the incidence and severity of mammalian target of rapamycin (mTOR) inhibitor-associated stomatitis and related oral AEs as well as the need for dose modification in MBC patients undergoing treatment with an mTOR inhibitor.


Asunto(s)
Neoplasias de la Mama/tratamiento farmacológico , Everolimus/efectos adversos , Hidrocortisona/administración & dosificación , Antisépticos Bucales/administración & dosificación , Prednisolona/administración & dosificación , Estomatitis/prevención & control , Serina-Treonina Quinasas TOR/antagonistas & inhibidores , Adulto , Anciano , Anciano de 80 o más Años , Antiinflamatorios/administración & dosificación , Antineoplásicos/efectos adversos , Antineoplásicos/uso terapéutico , Neoplasias de la Mama/patología , Everolimus/uso terapéutico , Femenino , Humanos , Persona de Mediana Edad , Estudios Prospectivos , Estomatitis/inducido químicamente , Estomatitis/tratamiento farmacológico , Estomatitis/patología
4.
Macromolecules ; 52(3): 968-981, 2019 Feb 12.
Artículo en Inglés | MEDLINE | ID: mdl-30792553

RESUMEN

We develop a generic coarse-grained model of soluble conjugated polymers, capable of describing their self-assembly into a lamellar mesophase. Polymer chains are described by a hindered-rotation model, where interaction centers represent entire repeat units, including side chains. We introduce soft anisotropic nonbonded interactions to mimic the potential of mean force between atomistic repeat units. The functional form of this potential reflects the symmetry of the molecular order in a lamellar mesophase. The model can generate both nematic and lamellar (sanidic smectic) molecular arrangements. We parametrize this model for a soluble conjugated polymer poly(3-hexylthiophene) (P3HT) and demonstrate that the simulated lamellar mesophase matches morphologies of low molecular weight P3HT, experimentally observed at elevated temperatures. A qualitative charge-transport model allows us to link local chain conformations and mesoscale order to charge transport. In particular, it shows how coarsening of lamellar domains and chain extension increase the charge carrier mobility. By modeling large systems and long chains, we can capture transport between lamellar layers, which is due to rare, but thermodynamically allowed, backbone bridges between neighboring layers.

5.
J Org Chem ; 83(6): 3265-3274, 2018 03 16.
Artículo en Inglés | MEDLINE | ID: mdl-29484888

RESUMEN

Facile synthesis of 5-fluoropyrazoles by direct fluorination of pyrazoles with N-fluorobenzenesulfonimide (NFSI) was elaborated. This approach was used to prepare the unsubstituted 5-fluoro-1 H-pyrazole, the known fungicide Penflufen, and many functionalized 5-fluoropyrazoles: building blocks for medicinal chemistry and agrochemistry.

6.
J Phys Chem Lett ; 8(17): 4155-4160, 2017 Sep 07.
Artículo en Inglés | MEDLINE | ID: mdl-28809493

RESUMEN

Molecular dynamics simulations are combined with solid-state NMR measurements to gain insight into the macroscopic structural composition of the π-conjugated polymer poly(2,5-bis(3-tetradecyl-thiophen-2-yl)thieno[3,2-b]thiophene) (PBTTT). The structural and dynamical properties, as established by the NMR analyses, were used to test the local structure of three constitutient mesophases with (i) crystalline backbones and side chains, (ii) lamellar backbones and disordered side chains, or (iii) amorphous backbones and side chains. The relative compositions of these mesophases were then determined from the deconvolution of the 1H and 13C solid-state NMR spectra and dynamic order parameters. Surprisingly, on the basis of molecular dynamics simulations, the powder composition consisted of only 28% of the completely crystalline mesophase, while 23% was lamellar with disordered side chains and 49% amorphous. The protocol presented in this work is a general approach and can be used for elucidating the relative compositions of mesophases in π-conjugated polymers.

7.
Clin Genitourin Cancer ; 11(2): 175-81, 2013 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-23228446

RESUMEN

BACKGROUND: Data support chemotherapy combined with antiangiogenic therapy in metastatic urothelial cancer (mUC) and muscle-invasive bladder cancer (MIBC). We investigated the efficacy and safety of gemcitabine, cisplatin, and sunitinib (GCS) in mUC and MIBC in parallel phase II trials. PATIENTS AND METHODS: Trial 1 enrolled 36 patients with mUC who were chemotherapy naive; trial 2 enrolled 9 patients with MIBC. The primary endpoints for trials 1 and 2 were response rate and pathologic complete response, respectively. GCS was given as first-line treatment for patients with mUC and as neoadjuvant therapy for patients with MIBC. The Simon minimax 2-stage design was used for an objective response rate in trial 1 and for the pathologic complete response rate in trial 2. RESULTS: The initial trial 1 GCS dose was gemcitabine 1000 mg/m(2) intravenously, days 1 and 8; cisplatin 70 mg/m(2) intravenously, day 1; and sunitinib 37.5 mg orally daily, days 1 to 14 of a 21-day cycle. These doses proved intolerable. The doses of gemcitabine and cisplatin were subsequently reduced to 800 and 60 mg/m(2), respectively, without an improvement in drug delivery, and the trial was closed. This lower-dose regimen was applied in trial 2, which was stopped early due to excess toxicity. Grade 3 to 4 hematologic toxicities occurred in 70% (23/33) of patients in trial 1 and 22% (2/9) of patients in trial 2. In trial 1, the response rate was 49% (95% CI, 31%-67%); in trial 2, the pathologic complete response was 22% (2/9). Due to early closure secondary to toxicity, the sample sizes of both trials were small. CONCLUSIONS: Delivery of GCS was hampered by excessive toxicity in both advanced and neoadjuvant settings.


Asunto(s)
Antineoplásicos/uso terapéutico , Carcinoma de Células Transicionales/tratamiento farmacológico , Carcinoma de Células Transicionales/secundario , Cisplatino/uso terapéutico , Desoxicitidina/análogos & derivados , Indoles/uso terapéutico , Pirroles/uso terapéutico , Neoplasias de la Vejiga Urinaria/tratamiento farmacológico , Adulto , Anciano , Anciano de 80 o más Años , Inhibidores de la Angiogénesis/efectos adversos , Inhibidores de la Angiogénesis/uso terapéutico , Antimetabolitos Antineoplásicos/efectos adversos , Antimetabolitos Antineoplásicos/uso terapéutico , Antineoplásicos/efectos adversos , Carcinoma de Células Transicionales/patología , Carcinoma de Células Transicionales/cirugía , Cisplatino/efectos adversos , Desoxicitidina/efectos adversos , Desoxicitidina/uso terapéutico , Femenino , Humanos , Indoles/efectos adversos , Masculino , Persona de Mediana Edad , Terapia Neoadyuvante , Invasividad Neoplásica , Pirroles/efectos adversos , Sunitinib , Tasa de Supervivencia , Neoplasias de la Vejiga Urinaria/mortalidad , Neoplasias de la Vejiga Urinaria/patología , Neoplasias de la Vejiga Urinaria/cirugía , Urotelio/patología , Gemcitabina
8.
Mol Ther ; 20(3): 679-86, 2012 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-22186789

RESUMEN

We performed a phase I trial of FANG vaccine, an autologous tumor-based product incorporating a plasmid encoding granulocyte-macrophage colony-stimulating factor (GMCSF) and a novel bifunctional short hairpin RNAi (bi-shRNAi) targeting furin convertase, thereby downregulating endogenous immunosuppressive transforming growth factors (TGF) ß1 and ß2. Patients with advanced cancer received up to 12 monthly intradermal injections of FANG vaccine (1 × 10(7) or 2.5 × 10(7) cells/ml injection). GMCSF, TGFß1, TGFß2, and furin proteins were quantified by enzyme-linked immunosorbent assay (ELISA). Safety and response were monitored. Vaccine manufacturing was successful in 42 of 46 patients of whom 27 received ≥1 vaccine. There were no treatment-related serious adverse events. Most common grade 1, 2 adverse events included local induration (n = 14) and local erythema (n = 11) at injection site. Post-transfection mean product expression GMCSF increased from 7.3 to 1,108 pg/10(6) cells/ml. Mean TGFß1 and ß2 effective target knockdown was 93.5 and 92.5% from baseline, respectively. Positive enzyme-linked immunospot (ELISPOT) response at month 4 was demonstrated in 9 of 18 patients serially assessed and correlated with survival duration from time of treatment (P = 0.025). Neither dose-adverse event nor dose-response relationship was noted. In conclusion, FANG vaccine was safe and elicited an immune response correlating with prolonged survival. Phase II assessment is justified.


Asunto(s)
Vacunas contra el Cáncer/uso terapéutico , Furina/genética , Factor Estimulante de Colonias de Granulocitos y Macrófagos/genética , Neoplasias/terapia , ARN Interferente Pequeño/uso terapéutico , Adulto , Anciano , Vacunas contra el Cáncer/administración & dosificación , Vacunas contra el Cáncer/efectos adversos , Femenino , Expresión Génica , Factor Estimulante de Colonias de Granulocitos y Macrófagos/inmunología , Humanos , Interferón gamma/biosíntesis , Leucocitos Mononucleares/inmunología , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Neoplasias/inmunología , Neoplasias/mortalidad , Neoplasias/patología , Análisis de Supervivencia , Transgenes , Resultado del Tratamiento
9.
J Clin Oncol ; 26(35): 5755-60, 2008 Dec 10.
Artículo en Inglés | MEDLINE | ID: mdl-19001323

RESUMEN

PURPOSE: Concurrent chemoradiotherapy is standard treatment for patients with inoperable stage III non-small-cell lung cancer (NSCLC). A phase II study by the Southwest Oncology Group using consolidation docetaxel after cisplatin (P), etoposide (E), and radiation (XRT) resulted in a median survival time (MST) of 26 months. This randomized phase III trial evaluated whether consolidation docetaxel was responsible for this improved survival. PATIENTS AND METHODS: Eligible patients had stage IIIA or IIIB NSCLC, baseline performance status of 0 to 1, forced expiratory volume in 1 second >or= 1 L, and less than 5% weight loss. Patients received P 50 mg/m(2) intravenously (IV) on days 1, 8, 29, and 36 and E 50 mg/m(2) IV on days 1-5 and 29-33 concurrently with chest XRT to 59.40 Gy. Patients who did not experience progression were randomly assigned to docetaxel 75 mg/m(2) IV every 21 days for three cycles versus observation. The primary end point was to compare overall survival (Kaplan-Meier analysis). RESULTS: On the basis of evidence of futility, a data and safety monitoring board recommended early termination after an analysis of the initial 203 patients. Patient characteristics (n = 203) were as follows: 34% female; median age, 63 years; 39.4% stage IIIA; and 60.6% stage IIIB. One hundred forty-seven (72.4%) of 203 patients were randomly assigned to docetaxel (n = 73) or observation (n = 74). Grade 3 to 5 toxicities during docetaxel included febrile neutropenia (10.9%) and pneumonitis (9.6%); 28.8% of patients were hospitalized during docetaxel (v 8.1% in observation arm), and 5.5% died as a result of docetaxel. The MST for all patients (n = 203) was 21.7 months; MST was 21.2 months for docetaxel arm compared with 23.2 months for observation arm (P = .883). CONCLUSION: Consolidation docetaxel after PE/XRT results in increased toxicities but does not further improve survival compared with PE/XRT alone in patients with stage III inoperable NSCLC.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/patología , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Carcinoma de Pulmón de Células no Pequeñas/mortalidad , Carcinoma de Pulmón de Células no Pequeñas/patología , Carcinoma de Pulmón de Células no Pequeñas/radioterapia , Quimioterapia Adyuvante , Cisplatino/administración & dosificación , Docetaxel , Etopósido/administración & dosificación , Femenino , Humanos , Estimación de Kaplan-Meier , Neoplasias Pulmonares/mortalidad , Neoplasias Pulmonares/radioterapia , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Radioterapia Adyuvante , Taxoides/administración & dosificación , Factores de Tiempo , Resultado del Tratamiento
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