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1.
JCI Insight ; 2021 Feb 11.
Artigo em Inglês | MEDLINE | ID: mdl-33571168

RESUMO

We are reporting on a phase IIa study which aimed to determine the intubation rate, survival, viral clearance, and the development of endogenous antibodies in patients with COVID-19 pneumonia treated with convalescent plasma (CCP) containing high levels of neutralizing anti-SARS-CoV-2 antibodies. All 51 treated patients had COVID-19 pneumonia by radiographic and laboratory evaluation. Fresh or frozen CCP from donors with high titers of neutralizing antibodies was administered. The non-mechanically ventilated patients (n=36) had an intubation rate of 13.9% and a day-30 survival of 88.9%. The overall survival for a comparative group based on network data was 72.5% (1625/2241). Patients had rates of negative nasopharyngeal swab on day +10 and +30 of 43.8% and 73% respectively. Patients mechanically ventilated had a day-30 mortality of 46.7%; the mortality for a comparative group based on network data was 71% (369/520). All evaluable patients were found to have neutralizing antibodies on day +3 (n=47), and all but 1 had antibodies on day +30 and +60. The only adverse event was a mild rash. We are concluding that in this study of patients with COVID-19 pneumonia, CCP was safe and conferred transfer of antibodies while preserving endogenous immune response.

2.
Sci Rep ; 11(1): 4389, 2021 02 23.
Artigo em Inglês | MEDLINE | ID: mdl-33623090

RESUMO

New Jersey was an early epicenter for the COVID-19 pandemic in the United States, yet information on hospitalized COVID-19 patients from this area is scarce. This study aimed to provide data on demographics and clinical features of a hospitalized patient population who were confirmed with infection by our in-house (CDI) real-time reverse-transcription polymerase chain reaction (RT-PCR) test. We included consecutive patients who were admitted to Hackensack Meridian Health system hospitals with laboratory-confirmed diagnoses of COVID-19 at Hackensack University Medical Center by the CDI virus test between March 12, 2020, and April 8, 2020. Clinical data and viral testing results were collected and analyzed for characteristics associated with outcomes, as well as the correlation with viral load. A total of 722 patients were included in the study, with a median age of 63 (interquartile range (IQR), 51-75) and 272 (37.7%) females. Mortality of this case series was 25.8%, with a statistically significant linear increase observed from age 40 to ≥ 80 by 10-year intervals. Viral load, as indicated by the cycle of threshold (Ct) values from the RT-PCR test, was significantly higher in the oldest patient group (≥ 80), and inversely correlated with survival. This is the first report to describe the clinical characteristics and outcomes in a large hospitalized COVID-19 patient series from New Jersey. Findings from this study are valuable to the ongoing response of both nationwide healthcare networks and the medical research community.

3.
J Clin Pediatr Dent ; 44(6): 451-458, 2020 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-33378466

RESUMO

OBJECTIVE: The surface roughness of various orthodontic materials could affect biofilm formation and friction. The purpose of this study was to examine the surface roughness and chemical composition of the slots and wings of several ceramic self-ligating brackets. STUDY DESIGN: Four types of ceramic self-ligating brackets were separated into experimental groups (DC, EC, IC, and QK) while a metal self-ligating bracket (EM) was used as the control group. Atomic force microscopy and energy-dispersive x-ray spectroscope were used to examine the surface roughness and chemical composition of each bracket slot and wing. RESULTS: The control group was made of ferrum and chrome while all the experimental groups were comprised of aluminum and oxide. There was a statistically significant difference in the roughness average (Sa) among the various self-ligating brackets (p< 0.001 in slots and p<0.01 in the wing). The slots in the EC group had the lowest Sa, followed by the DC, IC, control, and QK groups. The wings in the IC group had the lowest Sa, followed by the EC, DC, control, and QK groups. CONCLUSIONS: There is a significant difference in the surface roughness of the slots and wings among several types of ceramic self-ligating brackets.


Assuntos
Braquetes Ortodônticos , Biofilmes , Cerâmica , Ligas Dentárias , Fricção , Humanos , Teste de Materiais , Desenho de Aparelho Ortodôntico , Fios Ortodônticos , Aço Inoxidável , Propriedades de Superfície
4.
J Oncol Pharm Pract ; : 1078155220967440, 2020 Oct 27.
Artigo em Inglês | MEDLINE | ID: mdl-33106104

RESUMO

INTRODUCTION: Ibrutinib is a small molecule inhibitor of Bruton's tyrosine kinase indicated for the treatment of a variety of B-cell malignancies including chronic lymphocytic leukemia, mantle cell lymphoma, marginal zone lymphoma, and Waldenstrom's macroglobulinemia. These indolent hematologic malignancies are considered diseases of the elderly, a population that may have dysphagia leading to difficulty swallowing tablets and capsules. Ibrutinib is currently not available in a liquid oral dosage form. We report the utilization and clinical outcomes associated with alternative administration of ibrutinib capsules in a patient with chronic lymphocytic leukemia and significant dysphagia. CASE REPORT: An 86-year old female requiring chronic lymphocytic leukemia-directed therapy due to a rising absolute lymphocyte count and worsening, transfusion-dependent anemia with a past medical history of dementia and dysphagia, was initiated on ibrutinib. MANAGEMENT & OUTCOME: Due to the patient's significant inability to swallow, ibrutinib capsules were administered via an alternative method by opening them and sprinkling onto soft food or applesauce. With ibrutinib therapy, the patient has had a significant clinical response in her chronic lymphocytic leukemia as evidenced by her decreased absolute lymphocyte count and achieving transfusion independence with improvements in hemoglobin. DISCUSSION: Ibrutinib administration via this alternative method resulted in an initial clinical response in the treatment of our patient's chronic lymphocytic leukemia as evidenced by a decreasing absolute lymphocyte count and improved anemia that achieved transfusion independence. The patient has maintained this response to therapy after approximately 1 year at the time of manuscript preparation.

5.
Sci Adv ; 6(27): eaba8564, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32923587

RESUMO

Activation of the innate immune system and natural killer (NK) cells has been a key effort in cancer immunotherapy research. Here, we report a nanoparticle-based trispecific NK cell engager (nano-TriNKE) platform that can target epidermal growth factor receptor (EGFR)-overexpressing tumors and promote the recruitment and activation of NK cells to eradicate these cancer cells. Moreover, the nanoengagers can deliver cytotoxic chemotherapeutics to further improve their therapeutic efficacy. We have demonstrated that effective NK cell activation can be achieved by the spatiotemporal coactivation of CD16 and 4-1BB stimulatory molecules on NK cells with nanoengagers, and the nanoengagers are more effective than free antibodies. We also show that biological targeting, either through radiotherapy or EGFR, is critical to the therapeutic effects of nanoengagers. Last, EGFR-targeted nanoengagers can augment both NK-activating agents and chemotherapy (epirubicin) as highly effective anticancer agents, providing robust chemoimmunotherapy.

6.
Biosens Bioelectron ; 169: 112572, 2020 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-32916610

RESUMO

Convalescent serum with a high abundance of neutralization IgG is a promising therapeutic agent for rescuing COVID-19 patients in the critical stage. Knowing the concentration of SARS-CoV-2 S1-specific IgG is crucial in selecting appropriate convalescent serum donors. Here, we present a portable microfluidic ELISA technology for rapid (15 min), quantitative, and sensitive detection of anti-SARS-CoV-2 S1 IgG in human serum with only 8 µL sample volume. We first identified a humanized monoclonal IgG that has a high binding affinity and a relatively high specificity towards SARS-CoV-2 S1 protein, which can subsequently serve as the calibration standard of anti-SARS-CoV-2 S1 IgG in serological analyses. We then measured the abundance of anti-SARS-CoV-2 S1 IgG in 16 convalescent COVID-19 patients. Due to the availability of the calibration standard and the large dynamic range of our assay, we were able to identify "qualified donors" for convalescent serum therapy with only one fixed dilution factor (200 ×). Finally, we demonstrated that our technology can sensitively detect SARS-CoV-2 antigens (S1 and N proteins) with pg/mL level sensitivities in 40 min. Overall, our technology can greatly facilitate rapid, sensitive, and quantitative analysis of COVID-19 related markers for therapeutic, diagnostic, epidemiologic, and prognostic purposes.


Assuntos
Anticorpos Antivirais/sangue , Betacoronavirus/imunologia , Infecções por Coronavirus/virologia , Ensaio de Imunoadsorção Enzimática/instrumentação , Imunoglobulina G/sangue , Técnicas Analíticas Microfluídicas/instrumentação , Pneumonia Viral/virologia , Adolescente , Adulto , Anticorpos Antivirais/imunologia , Antígenos Virais/sangue , Antígenos Virais/imunologia , Técnicas Biossensoriais/economia , Técnicas Biossensoriais/instrumentação , Infecções por Coronavirus/terapia , Ensaio de Imunoadsorção Enzimática/economia , Desenho de Equipamento , Humanos , Imunização Passiva , Imunoglobulina G/imunologia , Limite de Detecção , Medições Luminescentes/economia , Medições Luminescentes/instrumentação , Técnicas Analíticas Microfluídicas/economia , Pessoa de Meia-Idade , Pandemias , Pneumonia Viral/terapia , Fatores de Tempo , Adulto Jovem
7.
ACS Infect Dis ; 6(9): 2431-2440, 2020 09 11.
Artigo em Inglês | MEDLINE | ID: mdl-32786275

RESUMO

Semisynthetic rifamycin derivatives such as rifampicin (Rif) are first line treatments for tuberculosis and other bacterial infections. Historically, synthetic modifications made to the C-3/C-4 region of the rifamycin naphthalene core, like those seen in Rif, have yielded the biggest improvements in pharmacological properties. However, modifications found in natural product rifamycin congeners occur at other positions in the structure. The kanglemycins (Kangs) are a family of rifamycin congeners with a unique collection of natural modifications including a dimethylsuccinic acid appended to their polyketide backbone. These modifications confer activity against the single most common clinically relevant Rif resistance (RifR) mutation in the antibiotic's target, the bacterial RNA polymerase (RNAP). Here we evaluate the in vivo efficacy of Kang A, the parent compound in the Kang family, in a murine model of bacterial peritonitis/sepsis. We then set out to improve its potency by combining its natural tailoring modifications with semisynthetic derivatizations at either its acid moiety or in the C-3/C-4 region. A collection of C-3/C-4 benzoxazino Kang derivatives exhibit improved activity against wild-type bacteria, and acquire activity against the second most common clinically relevant RifR mutation. The semisynthetic analogue 3'-hydroxy-5'-[4-isobutyl-1-piperazinyl] benzoxazino Kang A (Kang KZ) protected mice against infection with either Rif sensitive MRSA or a highly virulent RifR Staphylococcus  aureus strain in a neutropenic peritonitis/sepsis model and led to reduced bacterial burdens. The compounds generated in this study may represent promising candidates for treating RifR infections.

8.
J Clin Oncol ; 38(26): 3003-3011, 2020 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-32658627

RESUMO

PURPOSE: Diffuse large B-cell lymphoma (DLBCL) presents as a limited-stage disease in 25% to 30% of patients, with better overall survival (OS) than that for advanced-stage disease but with continuous relapse regardless of treatment approach. The preferred treatment is abbreviated rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) and radiation therapy. On the basis of promising results of positron emission tomography (PET)-directed treatment approaches, we designed a National Clinical Trials Network (NCTN) study to improve outcomes and decrease toxicity. METHODS: Patients with nonbulky (< 10 cm) stage I/II untreated DLBCL received 3 cycles of standard R-CHOP therapy and underwent a centrally reviewed interim PET/computed tomography scan (iPET). Those with a negative iPET proceeded with 1 additional cycle of R-CHOP, whereas those with a positive iPET received involved field radiation therapy followed by ibritumomab tiuxetan radioimmunotherapy. RESULTS: Of 158 patients enrolled, 132 were eligible and 128 underwent iPET, which was positive in 14 (11%) of the patients. With a median follow-up of 4.92 years (range, 1.1-7.7 years), only 6 patients progressed and 3 died as a result of lymphoma. Eleven patients died as a result of nonlymphoma causes at a median age of 80 years. The 5-year progression-free survival estimate was 87% (95% CI, 79% to 92%) and the OS estimate was 89% (95% CI, 82% to 94%), with iPET-positive and iPET-negative patients having similar outcomes. CONCLUSION: To our knowledge, S1001 is the largest prospective study in the United States of limited-stage DLBCL in the rituximab era, with the best NCTN results in this disease subset. With PET-directed therapy, 89% of the patients with a negative iPET received R-CHOP × 4, and only 11% had a positive iPET and required radiation, with both groups having excellent outcomes. The trial establishes R-CHOP × 4 alone as the new standard approach to limited-stage disease for the absolute majority of patients.

9.
J Clin Oncol ; 38(32): 3794-3804, 2020 Nov 10.
Artigo em Inglês | MEDLINE | ID: mdl-32701411

RESUMO

PURPOSE: Chimeric antigen receptor (CAR) T-cell therapy of B-cell malignancies has proved to be effective. We show how the same approach of CAR T cells specific for CD30 (CD30.CAR-Ts) can be used to treat Hodgkin lymphoma (HL). METHODS: We conducted 2 parallel phase I/II studies (ClinicalTrials.gov identifiers: NCT02690545 and NCT02917083) at 2 independent centers involving patients with relapsed or refractory HL and administered CD30.CAR-Ts after lymphodepletion with either bendamustine alone, bendamustine and fludarabine, or cyclophosphamide and fludarabine. The primary end point was safety. RESULTS: Forty-one patients received CD30.CAR-Ts. Treated patients had a median of 7 prior lines of therapy (range, 2-23), including brentuximab vedotin, checkpoint inhibitors, and autologous or allogeneic stem cell transplantation. The most common toxicities were grade 3 or higher hematologic adverse events. Cytokine release syndrome was observed in 10 patients, all of which were grade 1. No neurologic toxicity was observed. The overall response rate in the 32 patients with active disease who received fludarabine-based lymphodepletion was 72%, including 19 patients (59%) with complete response. With a median follow-up of 533 days, the 1-year progression-free survival and overall survival for all evaluable patients were 36% (95% CI, 21% to 51%) and 94% (95% CI, 79% to 99%), respectively. CAR-T cell expansion in vivo was cell dose dependent. CONCLUSION: Heavily pretreated patients with relapsed or refractory HL who received fludarabine-based lymphodepletion followed by CD30.CAR-Ts had a high rate of durable responses with an excellent safety profile, highlighting the feasibility of extending CAR-T cell therapies beyond canonical B-cell malignancies.

10.
J Am Med Dir Assoc ; 21(12): 1937-1943.e2, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-32553489

RESUMO

OBJECTIVE: Determine the prevalence of methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant Enterococcus spp. (VRE), extended-spectrum beta-lactamase producing organisms (ESBLs), and carbapenem-resistant Enterobacteriaceae (CRE) among residents and in the environment of nursing homes (NHs). DESIGN: Point prevalence sampling of residents and environmental sampling of high-touch objects in resident rooms and common areas. SETTING: Twenty-eight NHs in Southern California from 2016 to 2017. PARTICIPANTS: NH participants in Project PROTECT, a cluster-randomized trial of enhanced bathing and decolonization vs routine care. METHODS: Fifty residents were randomly sampled per NH. Twenty objects were sampled, including 5 common room objects plus 5 objects in each of 3 rooms (ambulatory, total care, and dementia care residents). RESULTS: A total of 2797 swabs were obtained from 1400 residents in 28 NHs. Median prevalence of multidrug-resistant organism (MDRO) carriage per NH was 50% (range: 24%-70%). Median prevalence of specific MDROs were as follows: MRSA, 36% (range: 20%-54%); ESBL, 16% (range: 2%-34%); VRE, 5% (range: 0%-30%); and CRE, 0% (range: 0%-8%). A median of 45% of residents (range: 24%-67%) harbored an MDRO without a known MDRO history. Environmental MDRO contamination was found in 74% of resident rooms and 93% of common areas. CONCLUSIONS AND IMPLICATIONS: In more than half of the NHs, more than 50% of residents were colonized with MDROs of clinical and public health significance, most commonly MRSA and ESBL. Additionally, the vast majority of resident rooms and common areas were MDRO contaminated. The unknown submerged portion of the iceberg of MDRO carriers in NHs may warrant changes to infection prevention and control practices, particularly high-fidelity adoption of universal strategies such as hand hygiene, environmental cleaning, and decolonization.

11.
Am J Ophthalmol Case Rep ; 19: 100765, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32548334

RESUMO

Purpose: To report a case of conjunctivitis due to Mycobacterium abscessus in the setting of keratoconjunctivitis sicca due to Sjögren's syndrome in the absence of other known risk factors such as surgery, trauma or immunosuppressive therapy. Observations: A 61-year-old woman with a history of keratoconjunctivitis sicca secondary to Sjögren's syndrome presented with dryness, irritation, redness, and discharge in her left eye for 2 months. She was diagnosed with chronic conjunctivitis and began a regimen of moxifloxacin and an ocular ointment of dexamethasone, neomycin, and polymyxin with no improvement of symptoms. Concurrent cultures grew Mycobacterium abscessus and the patient began treatment with amikacin drops, oral clarithromycin and intravenous imipenem, followed by amikacin drops, oral clarithromycin, and oral clofazimine, but her course was complicated by a perforated corneal ulcer that required a corneal patch graft. The patient eventually recovered despite persistent colonization. Conclusions/importance: We present a case of Mycobacterium abscessus conjunctivitis in a patient with keratoconjunctivitis sicca secondary to Sjögren's syndrome without previous history of surgery, trauma, or other known risk factors. Because of low suspicion and clinician awareness, ocular nontuberculous mycobacteria (NTM) infection may have a delayed diagnosis and treatment. Clinicians should consider NTM in the differential diagnosis in patients with autoimmune disease such as Sjögren's syndrome. Treatment may be lengthy, requiring topical and systemic antibiotics and is often complicated due to resistance.

12.
Blood Adv ; 4(11): 2548-2555, 2020 06 09.
Artigo em Inglês | MEDLINE | ID: mdl-32516414

RESUMO

Approximately 90% of limited-stage Hodgkin lymphoma (HL) patients are projected to be cured with standard therapy, but many do not live their expected life span because of late treatment-related complications. New treatment paradigms are needed to reduce the use of radiation therapy (RT) as well as conventional chemotherapy drugs while improving upon current standard-of-care survival outcomes. In this phase 2 multicenter study, patients with non-bulky limited-stage HL received doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) followed by brentuximab vedotin (BV) consolidation. Forty-one patients were enrolled, and patient characteristics included median age of 29 years (range, 19 to 67 years), 58% were female, 45% had unfavorable disease, and 98% had stage II disease. Based on positron emission tomography (PET)-based risk stratification, patients received 2 to 6 cycles of ABVD followed by 6 cycles of BV. After ABVD followed by BV, 95% of evaluable patients (37 out of 39; 95% confidence interval [CI], 83%-99%) achieved PET-negative status. In the intent-to-treat patient population, the estimated 3-year progression-free survival (PFS) rate was 92%, and the overall survival (OS) rate was 97%, with a median follow-up of 47 months. All 37 patients who achieved negative PET status after BV consolidation effectively avoided RT and remain in remission with estimated 3-year PFS and OS rates of 100%. In conclusion, BV demonstrates encouraging clinical activity when it follows ABVD therapy in limited-stage HL. Early incorporation of BV may reduce the use of RT as well as conventional chemotherapy drugs while achieving favorable survival outcomes in risk-stratified patients with non-bulky limited-stage HL. This trial was registered at www.clinicaltrials.gov as #NCT01578967.

13.
BMC Gastroenterol ; 20(1): 141, 2020 May 08.
Artigo em Inglês | MEDLINE | ID: mdl-32384881

RESUMO

BACKGROUND: Histoplasma capsulatum is the most common endemic mycosis in the United States and frequently presents as an opportunistic infection in immunocompromised hosts. Though liver involvement is common in disseminated histoplasmosis, primary gastrointestinal histoplasmosis of the liver in absence of lung involvement is rare. Similarly, cholestatic granulomatous hepatitis in liver histoplasmosis is rarely seen. CASE PRESENTATION: We present a rare case of primary gastrointestinal histoplasmosis manifesting with acute granulomatous hepatitis and cholestasis in a 48-year-old female with psoriatic arthritis, receiving methotrexate and infliximab. The epidemiology, risk factors, clinical presentation, diagnosis, and treatment of histoplasmosis is discussed. Furthermore, we review the published cases of biopsy-proven disseminated histoplasmosis with cholestatic jaundice to highlight histoplasmosis involvement in the liver. CONCLUSION: Histoplasmosis should be considered in immunosuppressed patients with fever, chills, abdominal pain and cholestasis with progressive jaundice, particularly in subjects without evidence of biliary obstruction. Future studies are needed to accurately assess the risk of this fungal infection, specifically in patients on immunomodulatory therapy for autoimmune disease.

14.
Sci Adv ; 6(14): eaaz9798, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32270047

RESUMO

Overactivation of the PI3K/mTOR signaling has been identified in non-Hodgkin's lymphoma. BEZ235 is an effective dual PI3K/mTOR inhibitor, but it was withdrawn from early-phase clinical trials owing to poor solubility and on-target/off-tumor toxicity. Here, we developed a nanoparticle (NP)-based pretargeted system for the therapeutic delivery of BEZ235 to CD20- and HLA-DR-expressing lymphoma cells for targeted therapy. The pretargeted system is composed of dibenzocyclooctyne-functionalized anti-CD20 and anti-Lym1 antibodies as the tumor-targeting components and azide-functionalized BEZ235-encapsulated NPs as the effector drug carrier. Using lymphoma cell lines with different CD20 and HLA-DR antigen densities as examples, we demonstrate that the dual antibody pretargeted strategy effectively raises the number of NPs retained on the target tumor cells and improves the in vitro and in vivo antitumor activity of BEZ235 through the inhibition of the PI3K/mTOR pathway. Our data demonstrate that the NP-based pretargeted system improves the therapeutic window of small-molecule kinase inhibitor.

15.
Cell Chem Biol ; 27(5): 560-570.e10, 2020 05 21.
Artigo em Inglês | MEDLINE | ID: mdl-32197094

RESUMO

Published Mycobacterium tuberculosis ß-ketoacyl-ACP synthase KasA inhibitors lack sufficient potency and/or pharmacokinetic properties. A structure-based approach was used to optimize existing KasA inhibitor DG167. This afforded indazole JSF-3285 with a 30-fold increase in mouse plasma exposure. Biochemical, genetic, and X-ray studies confirmed JSF-3285 targets KasA. JSF-3285 offers substantial activity in an acute mouse model of infection and in the corresponding chronic infection model, with efficacious reductions in colony-forming units at doses as low as 5 mg/kg once daily orally and improvement of the efficacy of front-line drugs isoniazid or rifampicin. JSF-3285 is a promising preclinical candidate for tuberculosis.

17.
Perm J ; 242020.
Artigo em Inglês | MEDLINE | ID: mdl-31905331

RESUMO

CONTEXT: Current guidelines recommend a nonfluoroquinolone agent as first-line treatment of acute uncomplicated cystitis (AUC) because of concerns of antimicrobial resistance and adverse effects. OBJECTIVE: To test whether a multifaceted intervention involving education and feedback reduced primary care practitioners' ciprofloxacin prescriptions for AUC therapy. DESIGN: Primary care practitioners at 3 medical offices participated: 65 in the intervention group and 51 in the control group. Intervention group participants received an educational lecture and emailed summary of antimicrobial guidelines, their AUC prescriptions were audited, and feedback was provided on inappropriate antibiotic choices. Prescriptions at AUC encounters were tracked during baseline, intervention, and postintervention periods. MAIN OUTCOME MEASURES: Proportion of AUC encounters at which ciprofloxacin was prescribed vs recommended first-line antibiotics. RESULTS: Intervention group participants had 5262 eligible AUC encounters, and control group participants had 5473. At baseline, ciprofloxacin was prescribed at 29.7% and 33.7% of eligible AUC encounters in the intervention and control groups, respectively (p = 0.003). After intervention, ciprofloxacin was prescribed at 10.8% of eligible AUC encounters in the intervention group and 34.3% in the control (p < 0.001). Adjusted odds ratios of ciprofloxacin prescription for AUC therapy were significantly lower in the intervention group during postintervention and intervention periods vs baseline (0.29, 95% confidence interval = 0.20-0.44, p < 0.001 and 0.80, 95% confidence interval = 0.66-0.97, p = 0.03). Adjusted odds ratios did not change over time in the controls. CONCLUSION: Educating primary care practitioners and conducting audit and feedback reduced their prescriptions of ciprofloxacin for AUC therapy.

18.
Acta Haematol ; 143(1): 40-50, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31315113

RESUMO

BACKGROUND: Outcomes for patients with peripheral T-cell lymphoma (PTCL) who fail to achieve complete response (CR) or relapse after front-line therapy are poor with lack of prospective outcomes data. OBJECTIVES: COMPLETE is a prospective registry of 499 patients enrolled at academic and community sites in the United States detailing patient demographics, treatment and outcomes for patients with aggressive T cell lymphomas. We report results for patients with primary refractory and relapsed disease. METHODS: Primary refractory disease was defined as an evaluable best response to initial treatment (induction ± maintenance or consolidation/transplant) other than CR, and included a partial response, progressive disease, or no response/stable disease. Relapsed disease was defined as an evaluable best response to initial treatment of CR, followed by disease progression at a later date, irrespective of time to progression. Patients were included in the analysis if initial treatment began within 30 days of enrollment and treatment duration was ≥4 days. RESULTS: Of 420 evaluable patients, 97 met the definition for primary refractory and 58 with relapsed disease. In the second-line setting, relapsed patients received single-agent therapies more often than refractory patients (52 vs. 28%; p = 0.01) and were more likely to receive single-agent regimens (74 vs. 53%; p = 0.03). The objective response rate to second-line therapy was higher in relapsed patients (61 vs. 40%; p = 0.04) as was the proportion achieving a CR (41 vs. 14%; p = 0.002). Further, relapsed patients had longer overall survival (OS) compared to refractory patients, with a median OS of 29.1 versus 12.3 months. CONCLUSIONS: Despite the availability of newer active single agents, refractory patients were less likely to receive these therapies and continue to have inferior outcomes compared to those with relapsed disease. PTCL in the real world remains an unmet medical need, and improvements in front-line therapies are needed.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Linfoma de Células T Periférico/tratamento farmacológico , Idoso , Feminino , Humanos , Estimativa de Kaplan-Meier , Linfoma de Células T Periférico/mortalidade , Masculino , Pessoa de Meia-Idade , Intervalo Livre de Progressão , Recidiva , Sistema de Registros , Falha de Tratamento
19.
Ann Pharmacother ; 54(4): 371-379, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-31648540

RESUMO

Objective: To review the pharmacology, pharmacokinetics, efficacy, safety, dosing, and administration of mogamulizumab for the treatment of T-cell lymphomas. Data Sources: A literature search of PubMed (1966 to September 2019) was conducted using the keywords mogamulizumab, KW-0761, and lymphoma. Data were also obtained from package inserts and meeting abstracts. Study Selection and Data Extraction: All relevant published articles, package inserts, and unpublished meeting abstracts on mogamulizumab for the treatment of T-cell lymphomas were reviewed. Data Synthesis: Mogamulizumab is an anti-CC chemokine receptor 4 (CCR4) monoclonal antibody that has demonstrated activity in various T-cell lymphomas. It was approved by the US Food and Drug Administration (FDA) for the treatment of adult patients with relapsed or refractory mycosis fungoides (MF) or Sézary syndrome (SS) who have been treated with at least 1 prior line of therapy. Mogamulizumab demonstrated significant improvement in progression-free survival compared with vorinostat in patients with relapsed or refractory MF or SS. Serious adverse events associated with mogamulizumab include infusion-related reactions, cutaneous drug eruption, and autoimmune complications. Mogamulizumab administration in the preallogeneic hematopoietic stem cell transplant setting can increase the risk for severe posttransplant graft-versus-host disease. Relevance to Patient Care and Clinical Practice: Mogamulizumab is a first-in-class CCR4 inhibitor, providing a new option in the treatment of relapsed or refractory cutaneous T-cell lymphomas. Although not currently FDA approved for this indication, mogamulizumab may have some utility for the treatment of relapsed adult T-cell leukemia/lymphoma. Conclusion: The recent approval of mogamulizumab represents an important addition to the armamentarium of pharmacotherapies for T-cell lymphomas.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Antineoplásicos/uso terapêutico , Linfoma de Células T/tratamento farmacológico , Receptores CCR4/antagonistas & inibidores , Adulto , Anticorpos Monoclonais Humanizados/administração & dosagem , Anticorpos Monoclonais Humanizados/efeitos adversos , Anticorpos Monoclonais Humanizados/farmacocinética , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Antineoplásicos/farmacocinética , Erupção por Droga/etiologia , Humanos , Leucemia-Linfoma de Células T do Adulto/tratamento farmacológico , Linfoma de Células T/complicações , Linfoma de Células T/patologia , Linfoma Cutâneo de Células T/tratamento farmacológico , Pessoa de Meia-Idade , Receptores CCR4/imunologia , Recidiva , Neoplasias Cutâneas/tratamento farmacológico
20.
Cell Chem Biol ; 27(2): 172-185.e11, 2020 02 20.
Artigo em Inglês | MEDLINE | ID: mdl-31711854

RESUMO

The triazine antitubercular JSF-2019 was of interest due to its in vitro efficacy and the nitro group shared with the clinically relevant delamanid and pretomanid. JSF-2019 undergoes activation requiring F420H2 and one or more nitroreductases in addition to Ddn. An intrabacterial drug metabolism (IBDM) platform was leveraged to demonstrate the system kinetics, evidencing formation of NO⋅ and a des-nitro metabolite. Structure-activity relationship studies focused on improving the solubility and mouse pharmacokinetic profile of JSF-2019 and culminated in JSF-2513, relying on the key introduction of a morpholine. Mechanistic studies with JSF-2019, JSF-2513, and other triazines stressed the significance of achieving potent in vitro efficacy via release of intrabacterial NO⋅ along with inhibition of InhA and, more generally, the FAS-II pathway. This study highlights the importance of probing IBDM and its potential to clarify mechanism of action, which in this case is a combination of NO⋅ release and InhA inhibition.

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