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BACKGROUND: The current study represents a subset analysis of quality-of-life (QOL) outcomes among patients treated on a phase 2 trial of de-escalated chemoradiation for human papillomavirus (HPV)-associated oropharyngeal cancer. METHODS: Eligibility included newly diagnosed, (American Joint Committee on Cancer, 7th edition) stage III or IV oropharyngeal squamous cell carcinoma, p16 positivity, age ≥ 18 years, and a Zubrod performance status of 0 to 1. Treatment was induction paclitaxel at a dose of 175 mg/m2 and carboplatin at an area under the curve of 6 for 2 cycles followed by response-adapted, dose-reduced radiation of 54 Gy or 60 Gy with weekly concurrent paclitaxel at a dose of 30 mg/m2 . The University of Washington Quality of Life (UW-QOL) and the Functional Assessment of Cancer Therapy-Head and Neck questionnaires were used to assess patient-reported QOL as a secondary endpoint. RESULTS: A total of 45 patients were registered, 40 of whom completed QOL surveys and were evaluable. Nadirs for overall UW-QOL and Functional Assessment of Cancer Therapy-Head and Neck scores were reached at 4 weeks after treatment but returned to baseline at 3 months. Nearly all functional indices returned to baseline levels by 6 to 9 months. The mean overall UW-QOL score was 71.6 at baseline compared with 70.8, 73.0, 83.3, and 81.1, respectively, at 3 months, 6 months, 1 year, and 2 years after therapy. The percentage of patients rating their overall QOL as "very good" or "outstanding" at 6 months, 1 year, and 2 years using the UW-QOL was 50%, 77%, and 84%, respectively. CONCLUSIONS: This de-escalation regimen achieved QOL outcomes that were favorable compared with historical controls. These results serve as powerful evidence that ongoing de-escalation efforts lead to tangible gains in function and QOL. Cancer 2018;124:521-9. © 2017 American Cancer Society.
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Quimioradioterapia , Neoplasias Orofaríngeas/terapia , Papillomaviridae/aislamiento & purificación , Medición de Resultados Informados por el Paciente , Calidad de Vida , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Neoplasias Orofaríngeas/psicología , Neoplasias Orofaríngeas/virologíaRESUMEN
BACKGROUND: Head and neck cancers positive for human papillomavirus (HPV) are exquisitely radiosensitive. We investigated whether chemoradiotherapy with reduced-dose radiation would maintain survival outcomes while improving tolerability for patients with HPV-positive oropharyngeal carcinoma. METHODS: We did a single-arm, phase 2 trial at two academic hospitals in the USA, enrolling patients with newly diagnosed, biopsy-proven stage III or IV squamous-cell carcinoma of the oropharynx, positive for HPV by p16 testing, and with Zubrod performance status scores of 0 or 1. Patients received two cycles of induction chemotherapy with 175 mg/m2 paclitaxel and carboplatin (target area under the curve of 6) given 21 days apart, followed by intensity-modulated radiotherapy with daily image guidance plus 30 mg/m2 paclitaxel per week concomitantly. Complete or partial responders to induction chemotherapy received 54 Gy in 27 fractions, and those with less than partial or no responses received 60 Gy in 30 fractions. The primary endpoint was progression-free survival at 2 years, assessed in all eligible patients who completed protocol treatment. This study is registered with ClinicalTrials.gov, numbers NCT02048020 and NCT01716195. FINDINGS: Between Oct 4, 2012, and March 3, 2015, 45 patients were enrolled with a median age of 60 years (IQR 54-67). One patient did not receive treatment and 44 were included in the analysis. 24 (55%) patients with complete or partial responses to induction chemotherapy received 54 Gy radiation, and 20 (45%) with less than partial responses received 60 Gy. Median follow-up was 30 months (IQR 26-37). Three (7%) patients had locoregional recurrence and one (2%) had distant metastasis; 2-year progression-free survival was 92% (95% CI 77-97). 26 (39%) of 44 patients had grade 3 adverse events, but no grade 4 events were reported. The most common grade 3 events during induction chemotherapy were leucopenia (17 [39%]) and neutropenia (five [11%]), and during chemoradiotherapy were dysphagia (four [9%]) and mucositis (four [9%]). One (2%) of 44 patients was dependent on a gastrostomy tube at 3 months and none was dependent 6 months after treatment. INTERPRETATION: Chemoradiotherapy with radiation doses reduced by 15-20% was associated with high progression-free survival and an improved toxicity profile compared with historical regimens using standard doses. Radiotherapy de-escalation has the potential to improve the therapeutic ratio and long-term function for these patients. FUNDING: University of California.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Carcinoma de Células Escamosas/radioterapia , Papillomavirus Humano 16 , Recurrencia Local de Neoplasia , Neoplasias Orofaríngeas/radioterapia , Infecciones por Papillomavirus/complicaciones , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Carboplatino/administración & dosificación , Carcinoma de Células Escamosas/tratamiento farmacológico , Carcinoma de Células Escamosas/secundario , Carcinoma de Células Escamosas/virología , Quimioradioterapia/efectos adversos , Trastornos de Deglución/etiología , Supervivencia sin Enfermedad , Estudios de Seguimiento , Humanos , Quimioterapia de Inducción/efectos adversos , Leucopenia/inducido químicamente , Masculino , Persona de Mediana Edad , Mucositis/etiología , Metástasis de la Neoplasia , Recurrencia Local de Neoplasia/diagnóstico , Estadificación de Neoplasias , Neutropenia/inducido químicamente , Neoplasias Orofaríngeas/tratamiento farmacológico , Neoplasias Orofaríngeas/patología , Neoplasias Orofaríngeas/virología , Paclitaxel/administración & dosificación , Infecciones por Papillomavirus/virología , Dosificación Radioterapéutica , Criterios de Evaluación de Respuesta en Tumores Sólidos , Tasa de SupervivenciaAsunto(s)
Indoles/uso terapéutico , Proteínas Proto-Oncogénicas B-raf/antagonistas & inhibidores , Sulfonamidas/uso terapéutico , Neoplasias de la Tiroides/tratamiento farmacológico , Humanos , Masculino , Persona de Mediana Edad , Mutación , Proteínas Proto-Oncogénicas B-raf/genética , Carcinoma Anaplásico de Tiroides , VemurafenibRESUMEN
"Spontaneous" heparin-induced thrombocytopenia is a rare and virulent form of heparin-induced thrombocytopenia that occurs in the absence of exposure to any drug of the heparin class of anticoagulants. Most reported cases have occurred after knee replacement surgery. Herein we report 2 additional cases following total knee replacement. Clinical suspicion and immediate initiation of appropriate nonheparin anticoagulation are essential to avoid potentially devastating thrombotic complications.
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In the present case report, we describe the management of severe coronary artery disease in a patient with Glanzmann thrombasthenia. To the best of our knowledge, there are no established guidelines for revascularization in this setting, and we pose novel discussion points regarding the nuanced care of this patient. (Level of Difficulty: Intermediate.).
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Adrenoleucodistrofia/tratamiento farmacológico , Inhibidores Enzimáticos/efectos adversos , Ácidos Erucicos/efectos adversos , Hematínicos/administración & dosificación , Receptores Fc/administración & dosificación , Proteínas Recombinantes de Fusión/administración & dosificación , Trombocitopenia/inducido químicamente , Trombopoyetina/administración & dosificación , Administración Cutánea , Anciano , Humanos , Masculino , Trombocitopenia/prevención & controlRESUMEN
The U.S. Food and Drug Administration modified warfarin labeling in 2007 to suggest, but not mandate, pharmacogenetic testing. Genetic analysis is now commercially available. However, results predict only one third of all dosing variation, the value of testing in reducing bleeding and thrombosis rates remains unproved, and cost-effectiveness is not established. Careful consideration of clinical factors that influence dosing, conscientious prothrombin time monitoring, and sage dosage adjustment remain paramount in warfarin management. Further study is required before routine warfarin pharmacogenetic testing can be recommended.
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Anticoagulantes/administración & dosificación , Hidrocarburo de Aril Hidroxilasas/genética , Oxigenasas de Función Mixta/genética , Análisis por Matrices de Proteínas/economía , Warfarina/administración & dosificación , Anticoagulantes/efectos adversos , Anticoagulantes/metabolismo , Análisis Costo-Beneficio , Citocromo P-450 CYP2C9 , Hemorragia/genética , Hemorragia/prevención & control , Humanos , Polimorfismo de Nucleótido Simple , Etiquetado de Productos , Trombosis/genética , Trombosis/prevención & control , Estados Unidos , United States Food and Drug Administration , Vitamina K Epóxido Reductasas , Warfarina/efectos adversos , Warfarina/metabolismoRESUMEN
Systemic lupus erythematosus may present with several distinct autoimmune phenomena simultaneously. We report a patient presenting with three serious hematologic disorders: thrombotic thrombocytopenic purpura, catastrophic antiphospholipid syndrome, and warm-type IgG red cell autoantibodies. The case is an example of the complex clinical nature of lupus and the importance of accurately identifying individual complications in order to optimize management.
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OBJECTIVE: The objective of our study was to describe survival outcome in 124 patients with unresectable hepatocellular carcinoma treated with triple-drug transcatheter arterial chemoembolization (TACE) using doxorubicin, cisplatin, and mitomycin C using a standardized regimen. MATERIALS AND METHODS: One hundred twenty-four patients underwent TACE using a standardized triple-drug regimen. Embolization was performed using subselective coaxial embolization technique. Fifty-six patients (group 1) received triple-drug TACE in conjunction with a nonpermanent embolic agent, microfibrillar collagen (Avitene), and 68 patients (group 2) had triple-drug TACE with a permanent embolic agent, Embosphere Microspheres. RESULTS: Twenty-eight patients underwent liver transplantation after TACE, and survival in these patients was significantly longer than those who did not receive a transplant (p < or = 0.001). The mean survival for the no-transplant group (n = 96) was longer in patients with Child-Pugh class A cirrhosis than in those with Child-Pugh class B cirrhosis (30.3 +/- 2.92 [standard error] vs 11.6 +/- 2.84 months, respectively; p < 0.001), in those with Okuda stage I versus stage II disease (31.4 +/- 3.03 vs 17.4 +/- 3.16 months; p = 0.002), and in those with a pre-TACE bilirubin level of less than 2.5 mg/dL (42.75 micromol/L; 28.3 +/- 2.75 vs 13.2 +/- 3.83 months; p = 0.007). Improved survival was seen in the no-transplant patients receiving TACE with the permanent embolic agent (group 2) than in those receiving TACE with the nonpermanent agent (group 1) out to 30 months (p = 0.002). Complications occurred in 16 patients (12.9%). The 30-day mortality was 2.4%. CONCLUSION: Patients with hepatocellular carcinoma who underwent triple-drug TACE followed by liver transplantation showed the longest survival. Patients who did not receive a transplant and were treated with triple-drug TACE with a permanent embolic agent showed longer survival to 30 months after TACE than those receiving a nonpermanent embolic agent.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Carcinoma Hepatocelular/terapia , Quimioembolización Terapéutica/métodos , Neoplasias Hepáticas/terapia , Resinas Acrílicas/administración & dosificación , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Angiografía de Substracción Digital , Cisplatino/administración & dosificación , Colágeno/administración & dosificación , Terapia Combinada , Doxorrubicina/administración & dosificación , Femenino , Gelatina/administración & dosificación , Humanos , Pruebas de Función Hepática , Trasplante de Hígado , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Mitomicina/administración & dosificación , Modelos de Riesgos Proporcionales , Estadísticas no Paramétricas , Tomografía Computarizada por Rayos X , Resultado del TratamientoRESUMEN
Glycoprotein (GP) IIb/IIIa inhibitors including abciximab, eptifibatide and tirofiban have been studied extensively as short-term adjuncts to short-term heparin and indefinite aspirin in patients with acute coronary syndrome or undergoing percutaneous coronary interventions on native vessels. The drugs provide a small advantage in the composite endpoint of death, myocardial infarction, and need for revascularization at 30 days (1-2% of treated patients) at the expense of an increase in major and potentially fatal bleeding complications (1% of treated patients over heparin plus aspirin alone). Highest-risk patients appear to benefit the most; clopidogrel should also be considered in these patients. Patients undergoing percutaneous interventions on bypass grafts do not benefit. Whether one GP IIb/IIIa inhibitor is superior to another is incompletely clarified. Abciximab causes severe immune-mediated thrombocytopenia (<20,000/microl) in 0.7% of cases; this is more often than eptifibatide or tirofiban (0.2%). Pseudothrombocytopenia should be differentiated. Effective use of GP IIb/IIIa inhibitors for acute coronary syndrome and percutaneous coronary interventions requires discerning clinical judgment. The value of GP IIb/IIIa inhibitors is not established in other forms of vascular disease.
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Inhibidores de Agregación Plaquetaria/uso terapéutico , Complejo GPIIb-IIIa de Glicoproteína Plaquetaria/antagonistas & inhibidores , Enfermedades Cardiovasculares/complicaciones , Enfermedades Cardiovasculares/tratamiento farmacológico , Enfermedades Cardiovasculares/mortalidad , Hemorragia/inducido químicamente , Humanos , Inhibidores de Agregación Plaquetaria/efectos adversos , Inhibidores de Agregación Plaquetaria/economía , Trombocitopenia/inducido químicamente , Resultado del TratamientoRESUMEN
Thromboembolic disorders are a major cause of morbidity and mortality. As knowledge of the complex interactions between the vessel wall, platelets and coagulation and fibrinolytic enzyme systems increases, new avenues for more effective and safer therapies become evident. In this review, we discuss mechanisms of hemostasis in relation to antithrombotic agents and results of clinical trials using these drugs.
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Fibrinolíticos/farmacología , Hemostasis/efectos de los fármacos , Factores de Coagulación Sanguínea/antagonistas & inhibidores , Fibrinolíticos/uso terapéutico , Humanos , Inhibidores de Agregación PlaquetariaRESUMEN
OBJECTIVE: To review the clinical features and pathophysiologic mechanisms of the thrombotic microangiopathies (TMAs) including acquired and congenital thrombotic thrombocytopenic purpura (TTP), Shiga toxin-induced and atypical (non-Shiga toxin-induced) hemolytic uremic syndrome (HUS), and the TMAs associated with pregnancy, drugs, and organ transplantation. METHODS: PubMed Medline was used to identify articles published from 2000 to July 2013 using the following key words: thrombotic thrombocytopenic purpura, hemolytic uremic syndrome, Shiga toxin, ADAMTS13, and eculizumab. Articles in languages other than English, papers available in abstract form only, and nearly all single case reports were excluded. Small series, reports from registries and study groups, reviews, guidelines, and articles concerning pathophysiology and therapy were preferentially considered. RESULTS: Impaired post-secretion processing of unusually large von Willebrand multimers due to deficiency of ADAMTS13 (IgG antibodies or congenital), dysregulation of the alternative complement pathway (mutations and/or specific antibodies), and endothelial injury are pathophysiologic mechanisms involved in the TMAs. Acquired and congenital TTP are due primarily to severe ADAMTS13 deficiency, atypical HUS is commonly associated with complement dysregulation, and Shiga toxin, drugs, immune complexes, and others likely damage endothelium. However, there is considerable mechanistic overlap, and the TMAs often have multifactorial causation. Plasma procedures, complement pathway inhibition, immunosuppression, and general supportive care are the principal therapies. CONCLUSIONS: The TMAs are very important conditions because of their associated organ damage and mortality rates. Prompt recognition and categorization by both clinical presentation and pathophysiologic mechanisms should become routine as they are crucial to an optimal treatment plan. Treatment advances have substantially reduced the morbidity of these disorders. Investigational therapies are promising.
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Síndrome Hemolítico-Urémico/metabolismo , Púrpura Trombocitopénica Trombótica/metabolismo , Proteínas ADAM/inmunología , Proteína ADAMTS13 , Anticuerpos Monoclonales Humanizados/uso terapéutico , Síndrome Hemolítico Urémico Atípico/metabolismo , Síndrome Hemolítico Urémico Atípico/terapia , Síndrome Hemolítico-Urémico/inmunología , Síndrome Hemolítico-Urémico/terapia , Humanos , Púrpura Trombocitopénica Trombótica/inmunología , Púrpura Trombocitopénica Trombótica/terapia , Toxina Shiga/inmunología , Microangiopatías Trombóticas/inmunología , Microangiopatías Trombóticas/metabolismo , Microangiopatías Trombóticas/terapiaRESUMEN
Factor XI deficiency, an injury-related bleeding disorder, is rare worldwide but common in Jews in whom 2 mutations, Glu117Stop (type II) and Phe283Leu (type III), prevail. Mean factor XI activities in homozygotes for Glu117Stop and for Phe283Leu are 1 and 10 U/dL, respectively. Inhibitors to factor XI in patients with severe factor XI deficiency have been reported in a small number of instances. This study was undertaken to determine the prevalence of acquired inhibitors against factor XI in patients with severe factor XI deficiency, discern whether these inhibitors are related to specific mutations, and characterize their activity. Clinical information was obtained from unrelated patients with severe factor XI deficiency, and blood was analyzed for factor XI activity, inhibitor to factor XI, and causative mutations. Immunoglobulin G purified from patients with an inhibitory activity was tested for binding to factor XI, effects on activation of factor XI by factor XIIa and thrombin, and activation of factor IX by exogenous factor XIa. Of 118 Israeli patients, 7 had an inhibitor; all belonged to a subgroup of 21 homozygotes for Glu117Stop who had a history of plasma replacement therapy. Three additional patients with inhibitors from the United Kingdom and the United States also had this genotype and were exposed to plasma. The inhibitors affected factor XI activation by thrombin or factor XIIa, and activation of factor IX by factor XIa. The results imply that patients with a very low factor XI level are susceptible to development of an inhibitor following plasma replacement.