RESUMEN
Few studies have reported the real-world use of both romiplostim and eltrombopag in immune thrombocytopenia (ITP). TRAIT was a retrospective observational study aimed to evaluate the platelet responses and adverse effects associated with the use of these thrombopoietin receptor agonists (TPO-RAs) in adult patients with ITP in the United Kingdom. Of 267 patients (median age at diagnosis, 48 years) with ITP (primary ITP [n = 218], secondary ITP [n = 49]) included in the study, 112 (42%) received eltrombopag and 155 (58%) received romiplostim as the first prescribed TPO-RA. A platelet count ≥30 × 109/L was achieved in 89% of patients with the first TPO-RA treatments, while 68% achieved a platelet count ≥100 × 109/L. Treatment-free response (TFR; platelet count ≥30 × 109/L, 3 months after discontinuing treatment) was achieved by 18% of the total patients. Overall, 61 patients (23%) switched TPO-RAs, most of whom achieved platelet counts ≥30 × 109/L with the second TPO-RA (23/25 who switched from eltrombopag to romiplostim [92%]; 28/36 who switched from romiplostim to eltrombopag [78%]). TFR was associated with secondary ITP, early TPO-RA initiation after diagnosis, the presence of comorbidity and no prior splenectomy or treatment with steroids or mycophenolate mofetil. Both TPO-RAs had similar efficacy and safety profiles to those reported in clinical studies.
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Benzoatos , Hidrazinas , Púrpura Trombocitopénica Idiopática , Pirazoles , Receptores Fc , Receptores de Trombopoyetina , Proteínas Recombinantes de Fusión , Trombopoyetina , Humanos , Receptores de Trombopoyetina/agonistas , Proteínas Recombinantes de Fusión/uso terapéutico , Proteínas Recombinantes de Fusión/efectos adversos , Proteínas Recombinantes de Fusión/administración & dosificación , Persona de Mediana Edad , Púrpura Trombocitopénica Idiopática/tratamiento farmacológico , Benzoatos/uso terapéutico , Benzoatos/efectos adversos , Masculino , Femenino , Pirazoles/uso terapéutico , Pirazoles/efectos adversos , Trombopoyetina/uso terapéutico , Trombopoyetina/efectos adversos , Hidrazinas/uso terapéutico , Hidrazinas/efectos adversos , Receptores Fc/uso terapéutico , Adulto , Reino Unido , Estudios Retrospectivos , Anciano , Recuento de Plaquetas , Resultado del Tratamiento , Anciano de 80 o más Años , Adulto Joven , AdolescenteRESUMEN
AIM: For people with haemophilia A (PwHA), bleeding in the joints leads to joint damage and haemophilia-related arthropathy, impacting range of motion and life expectancy. Existing guidelines for managing haemophilia A support healthcare professionals (HCPs) and PwHA in their efforts to preserve joint health. However, such guidance should be reviewed, considering emerging evidence and consensus as presented in this manuscript. METHODS: Fifteen HCPs experienced in the management of PwHA in the UK participated in a three-round Delphi panel. Consensus was defined at ≥70% of panellists agreeing or disagreeing for Likert-scale questions, and ≥70% selecting the same option for multiple- or single-choice questions. Questions not reaching consensus were revised for the next round. RESULTS: 26.8% (11/41), 44.8% (13/29) and 93.3% (14/15) of statements reached consensus in Rounds 1, 2 and 3, respectively. HCPs agreed that prophylaxis should be offered to patients with a baseline factor VIII (FVIII) level of ≤5 IU/dL and that, where there is no treatment burden, the aim of prophylaxis should be to achieve a trough FVIII level ≥15 IU/dL and maintain a longer period with FVIII levels of ≥20-30 IU/dL to provide better bleed protection. The aspirational goal for PwHA is to prevent all joint bleeds, which may be achieved by maintaining normalised (50-150 IU/dL) FVIII levels. CONCLUSION: The panel of experts were largely aligned on approaches to preserving joint health in PwHA, and this consensus may help guide HCPs.
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Hemofilia A , Humanos , Hemofilia A/tratamiento farmacológico , Factor VIII/uso terapéutico , Consenso , Hemartrosis/prevención & control , Hemorragia/prevención & control , Reino UnidoRESUMEN
INTRODUCTION: The UK National Haemophilia Database (NHD) collects data from all UK persons with haemophilia A with inhibitors (PwHA-I). It is well-placed to investigate patient selection, clinical outcomes, drug safety and other issues not addressed in clinical trials of emicizumab. AIMS: To determine safety, bleeding outcomes and early effects on joint health of emicizumab prophylaxis in a large, unselected cohort using national registry and patient reported Haemtrack (HT) data between 01 January 2018 and 30 September 2021. METHODS: Prospectively collected bleeding outcomes were analysed in people with ≥6 months emicizumab HT data and compared with previous treatment if available. Change in paired Haemophilia Joint Health Scores (HJHS) were analysed in a subgroup. Adverse events (AEs) reports were collected and adjudicated centrally. RESULTS: This analysis includes 117 PwHA-I. Mean annualised bleeding rate (ABR) was .32 (95% CI, .18; .39) over a median 42 months treatment with emicizumab. Within-person comparison (n = 74) demonstrated an 89% reduction in ABR after switching to emicizumab and an increase in zero treated bleed rate from 45 to 88% (p < .01). In a subgroup of 37 people, total HJHS improved in 36%, remained stable in 46% and deteriorated in 18%, with a median (IQR) within-person change of -2.0 (-9, 1.5) (p = .04). Three arterial thrombotic events were reported, two possibly drug related. Other AEs were generally non-severe and usually limited to early treatment, included cutaneous reactions (3.6%), headaches (1.4%), nausea (2.8%) and arthralgia (1.4%). CONCLUSIONS: Emicizumab prophylaxis is associated with sustained low bleeding rates and was generally well-tolerated in people with haemophilia A and inhibitors.
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Anticuerpos Biespecíficos , Hemofilia A , Humanos , Hemofilia A/complicaciones , Hemofilia A/tratamiento farmacológico , Estudios de Seguimiento , Anticuerpos Biespecíficos/efectos adversos , Hemorragia/complicaciones , Reino Unido , Factor VIII/uso terapéuticoRESUMEN
PURPOSE: To present a case of refractory full-thickness macular hole (FTMH), in which autologous platelet-rich plasma (aPRP) was used on two consecutive occasions, and associated with successful closure only after complete cessation of anti-platelet therapy. METHODS: Interventional case report. RESULTS: A 63-year-old male with Alport syndrome underwent pars plana vitrectomy with internal limiting membrane peeling and gas for a large FTMH. The patient was on systemic anti-platelet agents for coronary disease. Post-operatively, the FTMH remained open and repeated surgery, augmented with aPRP, was performed. Although a thick pre-retinal coagulum was evident on optical coherence tomography on day one post-surgery, the second surgery failed. Ultimately, successful aPRP-augmented surgical closure of the FTMH was achieved only after complete cessation of systemic anti-platelet agents. CONCLUSION: Appropriate management of anti-platelet therapy may be relevant when planning aPRP use, though further large-scale studies are needed to assess the precise effect of anti-platelet therapy on the efficacy of aPRP, and to confirm the potential role of aPRP in patients with Alport syndrome.
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Membrana Epirretinal , Nefritis Hereditaria , Perforaciones de la Retina , Masculino , Humanos , Persona de Mediana Edad , Perforaciones de la Retina/cirugía , Perforaciones de la Retina/complicaciones , Membrana Epirretinal/cirugía , Retina , Vitrectomía/métodos , Tomografía de Coherencia Óptica/métodos , Estudios RetrospectivosRESUMEN
BACKGROUND: FLT180a (verbrinacogene setparvovec) is a liver-directed adeno-associated virus (AAV) gene therapy that uses a synthetic capsid and a gain-of-function protein to normalize factor IX levels in patients with hemophilia B. METHODS: In this multicenter, open-label, phase 1-2 trial, we assessed the safety and efficacy of varying doses of FLT180a in patients with severe or moderately severe hemophilia B (factor IX level, ≤2% of normal value). All the patients received glucocorticoids with or without tacrolimus for immunosuppression to decrease the risk of vector-related immune responses. After 26 weeks, patients were enrolled in a long-term follow-up study. The primary end points were safety and efficacy, as assessed by factor IX levels at week 26. RESULTS: Ten patients received one of four FLT180a doses of vector genomes (vg) per kilogram of body weight: 3.84×1011 vg, 6.40×1011 vg, 8.32×1011 vg, or 1.28×1012 vg. After receiving the infusion, all the patients had dose-dependent increases in factor IX levels. At a median follow-up of 27.2 months (range, 19.1 to 42.4), sustained factor IX activity was observed in all the patients except one, who resumed factor IX prophylaxis. As of the data-cutoff date (September 20, 2021), five patients had normal factor IX levels (range, 51 to 78%), three patients had levels from 23 to 43%, and one had a level of 260%. Of the reported adverse events, approximately 10% were related to FLT180a and 24% to immunosuppression. Increases in liver aminotransferase levels were the most common FLT180a-related adverse events. Late increases in aminotransferase levels occurred in patients who had received prolonged tacrolimus beyond the glucocorticoid taper. A serious adverse event of arteriovenous fistula thrombosis occurred in the patient with high factor IX levels. CONCLUSIONS: Sustained factor IX levels in the normal range were observed with low doses of FLT180a but necessitated immunosuppression with glucocorticoids with or without tacrolimus. (Funded by Freeline Therapeutics; ClinicalTrials.gov numbers, NCT03369444 and NCT03641703; EudraCT numbers, 2017-000852-24 and 2017-005080-40.).
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Dependovirus , Terapia Genética , Glucocorticoides , Hemofilia B , Dependovirus/genética , Factor IX/análisis , Factor IX/genética , Estudios de Seguimiento , Terapia Genética/efectos adversos , Terapia Genética/métodos , Vectores Genéticos/uso terapéutico , Glucocorticoides/efectos adversos , Glucocorticoides/uso terapéutico , Hemofilia B/genética , Hemofilia B/metabolismo , Hemofilia B/terapia , Humanos , Inmunosupresores/efectos adversos , Inmunosupresores/uso terapéutico , Tacrolimus/efectos adversos , Tacrolimus/uso terapéutico , Transaminasas/análisisRESUMEN
BACKGROUND: Immune thrombocytopenia is a rare autoimmune disorder with associated bleeding risk and fatigue. Recommended first-line treatment for immune thrombocytopenia is high-dose glucocorticoids, but side effects, variable responses, and high relapse rates are serious drawbacks. METHODS: In this multicenter, open-label, randomized, controlled trial conducted in the United Kingdom, we assigned adult patients with immune thrombocytopenia, in a 1:1 ratio, to first-line treatment with a glucocorticoid only (standard care) or combined glucocorticoid and mycophenolate mofetil. The primary efficacy outcome was treatment failure, defined as a platelet count of less than 30×109 per liter and initiation of a second-line treatment, assessed in a time-to-event analysis. Secondary outcomes were response rates, side effects, occurrence of bleeding, patient-reported quality-of-life measures, and serious adverse events. RESULTS: A total of 120 patients with immune thrombocytopenia underwent randomization (52.4% male; mean age, 54 years [range 17 to 87]; mean platelet level, 7×109 per liter) and were followed for up to 2 years after beginning trial treatment. The mycophenolate mofetil group had fewer treatment failures than the glucocorticoid-only group (22% [13 of 59 patients] vs. 44% [27 of 61 patients]; hazard ratio, 0.41; range, 0.21 to 0.80; P = 0.008) and greater response (91.5% of patients having platelet counts greater than 100×109 per liter vs. 63.9%; P<0.001). We found no evidence of a difference between the groups in the occurrence of bleeding, rescue treatments, or treatment side effects, including infection. However, patients in the mycophenolate mofetil group reported worse quality-of-life outcomes regarding physical function and fatigue than those in the glucocorticoid-only group. CONCLUSIONS: The addition of mycophenolate mofetil to a glucocorticoid for first-line treatment of immune thrombocytopenia resulted in greater response and a lower risk of refractory or relapsed immune thrombocytopenia, but with somewhat decreased quality of life. (Funded by the U.K. National Institute for Health Research; FLIGHT ClinicalTrials.gov number, NCT03156452; EudraCT number, 2017-001171-23.).
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Glucocorticoides/uso terapéutico , Inmunosupresores/uso terapéutico , Ácido Micofenólico/uso terapéutico , Púrpura Trombocitopénica Idiopática/tratamiento farmacológico , Adolescente , Adulto , Anciano , Quimioterapia Combinada , Fatiga/inducido químicamente , Femenino , Glucocorticoides/efectos adversos , Hemorragia/etiología , Hemorragia/prevención & control , Humanos , Inmunosupresores/efectos adversos , Masculino , Persona de Mediana Edad , Ácido Micofenólico/efectos adversos , Recuento de Plaquetas , Púrpura Trombocitopénica Idiopática/complicaciones , Calidad de Vida , Adulto JovenRESUMEN
INTRODUCTION: In good risk patients (historic inhibitor peak < 200BU), the International Immune Tolerance Study demonstrated equal efficacy to induce tolerance between high (200iu/kg/day) and low dose (50iu/kg ×3 times/week) immune tolerance induction (ITI) regimens. However, the trial stopped early on account of the excessive bleed rate in the low dose ITI arm. METHODS: United Kingdom Haemophilia Centre Doctors' Organization (UKHCDO) Paediatric and Inhibitor working parties considered available ITI data alongside the bi-phenotypic antibody emicizumab (Hemlibra®) efficacy and safety data to develop a consensus guideline for the future UK ITI guideline. RESULTS: This revision of UKHCDO ITI guidance incorporates the recommendation to use emicizumab as a prophylaxis haemostatic agent to reduce bleeding rates and to facilitate low dose and reduced frequency of FVIII CFC for ITI in the majority of children. CONCLUSION: This consensus protocol will facilitate future evaluation of ITI outcomes in the evolving landscape of haemophilia therapeutics and ITI strategies.
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Hemofilia A , Niño , Factor VIII , Hemofilia A/tratamiento farmacológico , Hemorragia/prevención & control , Humanos , Tolerancia Inmunológica , Reino UnidoRESUMEN
The writing group produced the draft guideline, which was subsequently revised by consensus. Review of the manuscript was performed by the BSH Guidelines Committee Haemostasis and Thrombosis Taskforce, the BSH Guidelines Committee and the Haemostasis and Thrombosis sounding board of the BSH. It was also on the members section of the BSH website for comment. It has also been reviewed by members of the United Kingdom Haemophilia Centre Doctors' Organisation (UKHCDO) Advisory Board, Haemophilia Nurses Association (HNA), Haemophilia Chartered Physiotherapists Association (HCPA); these organisations do not necessarily approve or endorse the contents.
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Humanos , Preescolar , Niño , Adolescente , Adulto , Hemartrosis/prevención & control , Trastornos Hemorrágicos/tratamiento farmacológico , Hemostáticos/uso terapéutico , Trastornos Hemorrágicos/diagnósticoAsunto(s)
Púrpura Trombocitopénica Idiopática/diagnóstico , Púrpura Trombocitopénica Idiopática/tratamiento farmacológico , Manejo de la Enfermedad , Encuestas de Atención de la Salud , Humanos , Pautas de la Práctica en Medicina , Receptores de Trombopoyetina/agonistas , Receptores de Trombopoyetina/antagonistas & inhibidores , Reino UnidoRESUMEN
Current guidelines advocate using fixed-doses of oral vitamin K to reverse excessive anticoagulation in warfarinised patients who are either asymptomatic or have minor bleeds. Over-anticoagulated patients present with a wide range of International Normalised Ratio (INR) values and response to fixed doses of vitamin K varies. Consequently a significant proportion of patients remain outside their target INR after vitamin K administration, making them prone to either haemorrhage or thromboembolism. We compared the performance of a novel tailored vitamin K dosing regimen to that of a fixed-dose regimen with the primary measure being the proportion of over-anticoagulated patients returning to their target INR within 24 h. One hundred and eighty-one patients with an index INR > 6·0 (asymptomatic or with minor bleeding) were randomly allocated to receive oral administration of either a tailored dose (based upon index INR and body surface area) or a fixed-dose (1 or 2 mg) of vitamin K. A greater proportion of patients treated with the tailored dose returned to within target INR range compared to the fixed-dose regimen (68·9% vs. 52·8%; P = 0·026), whilst a smaller proportion of patients remained above target INR range (12·2% vs. 34·0%; P < 0·001). Individualised vitamin K dosing is more accurate than fixed-dose regimen in lowering INR to within target range in excessively anticoagulated patients.
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Anticoagulantes/efectos adversos , Antifibrinolíticos/administración & dosificación , Coagulación Sanguínea/efectos de los fármacos , Relación Normalizada Internacional , Vitamina K/administración & dosificación , Warfarina/efectos adversos , Administración Oral , Adulto , Anciano , Anciano de 80 o más Años , Relación Dosis-Respuesta a Droga , Esquema de Medicación , Femenino , Hemorragia/sangre , Hemorragia/inducido químicamente , Hemorragia/prevención & control , Humanos , Masculino , Persona de Mediana Edad , Tromboembolia/sangre , Tromboembolia/etiología , Tromboembolia/prevención & control , Resultado del Tratamiento , Adulto JovenAsunto(s)
Trastornos de la Coagulación Sanguínea/diagnóstico , Trastornos de la Coagulación Sanguínea/terapia , Inhibidores de Factor de Coagulación Sanguínea , Anciano , Anciano de 80 o más Años , Factor VIII/antagonistas & inhibidores , Humanos , Factor de von Willebrand/antagonistas & inhibidoresAsunto(s)
Factor IX/antagonistas & inhibidores , Factor VIII/antagonistas & inhibidores , Hemofilia A/inmunología , Hemofilia B/inmunología , Isoanticuerpos/inmunología , Factores de Coagulación Sanguínea/uso terapéutico , Pérdida de Sangre Quirúrgica/prevención & control , Ensayos Clínicos como Asunto , Análisis Mutacional de ADN , Desensibilización Inmunológica , Relación Dosis-Respuesta Inmunológica , Factor IX/genética , Factor IX/inmunología , Factor IX/uso terapéutico , Factor VIII/genética , Factor VIII/inmunología , Factor VIII/uso terapéutico , Factor VIIa/uso terapéutico , Femenino , Hemofilia A/genética , Hemofilia A/terapia , Hemofilia B/genética , Hemofilia B/terapia , Hemorragia/tratamiento farmacológico , Hemorragia/prevención & control , Humanos , Tolerancia Inmunológica , Pruebas Inmunológicas/métodos , Inmunosupresores/uso terapéutico , Isoanticuerpos/biosíntesis , Isoanticuerpos/sangre , Masculino , Proteínas Recombinantes/uso terapéutico , Factores de Riesgo , Medicina Estatal/organización & administración , Reino UnidoRESUMEN
Rozrolimupab, a recombinant mixture of 25 fully human RhD-specific monoclonal antibodies, represents a new class of recombinant human antibody mixtures. In a phase 1 or 2 dose escalation study, RhD(+) patients (61 subjects) with primary immune thrombocytopenia received a single intravenous dose of rozrolimupab ranging from 75 to 300 µg/kg. The primary outcome was the occurrence of adverse events. The principal secondary outcome was the effect on platelet levels 7 days after the treatment. The most common adverse events were headache and pyrexia, mostly mild, and reported in 20% and 13% of the patients, respectively, without dose relationship. Rozrolimupab caused an expected transient reduction of hemoglobin concentration in the majority of the patients. At the dose of 300 µg/kg platelet responses, defined as platelet count ≥ 30 × 10(9)/L and an increase in platelet count by > 20 × 10(9)/L from baseline were observed after 72 hours and persisted for at least 7 days in 8 of 13 patients (62%). Platelet responses were observed within 24 hours in 23% of patients and lasted for a median of 14 days. Rozrolimupab was well tolerated and elicited rapid platelet responses in patients with immune thrombocytopenia and may be a useful alternative to plasma-derived products. This trial is registered at www.clinicaltrials.gov as #NCT00718692.
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Anticuerpos Monoclonales/administración & dosificación , Inmunoglobulina G/administración & dosificación , Púrpura Trombocitopénica Idiopática/tratamiento farmacológico , Proteínas Recombinantes/administración & dosificación , Adulto , Anciano , Anticuerpos Monoclonales/efectos adversos , Anticuerpos Monoclonales/farmacocinética , Relación Dosis-Respuesta a Droga , Femenino , Humanos , Inmunoglobulina G/efectos adversos , Masculino , Persona de Mediana Edad , Proteínas Recombinantes/efectos adversos , Proteínas Recombinantes/farmacocinéticaRESUMEN
Vascular endothelial growth factor (VEGF) is involved in tumour angiogenesis, an important process for the growth and metastatic potential of solid tumours. Numerous studies have demonstrated up-regulation of VEGF at both mRNA and protein level in various tumours and a correlation with advanced stage and prognosis has been demonstrated in some cases. Limited information exists about its role in lymphoid malignancies and in particular, Hodgkin's disease. The present study examined the immunohistochemical expression of VEGF using the monoclonal antibody VG1 in a series of 61 cases of Hodgkin's disease, including both classical Hodgkin's disease and the nodular lymphocyte predominance variant, and correlated these results with microvessel density, using an anti-CD31 monoclonal antibody. In 41 cases (70.6%) of classical Hodgkin's disease and one of the three cases of nodular lymphocyte predominance Hodgkin's disease, the neoplastic Reed-Sternberg and Hodgkin cells expressed VEGF. The staining observed was cytoplasmic, either diffuse or with a focal paranuclear distribution. Macrophages were always positive, while reactive lymphocytes showed occasional positivity. A variable amount of strong extracellular staining was also observed in the tissue stroma and intravascular plasma staining was prominent. There was no statistically significant relationship between VEGF expression and the subtype of Hodgkin's disease or microvessel density. In vitro studies using the Reed-Sternberg cell lines L428 and KM-H2 were also performed in both normoxia and hypoxia and VEGF protein production was assessed by flow cytometry (FACS), immunoassay of cell culture supernatant, and RT-PCR. Analysis by FACS demonstrated a subset of cells in both cell lines reacting with VG1 and analysis of secreted VEGF (pg/ml per 1x10(6) cells) in cell culture supernatant confirmed the normoxic production in both cell lines and significant hypoxic induction (p<0.005). Additionally, both cell lines expressed VEGF mRNA, as demonstrated using the RT-PCR method. In conclusion, neoplastic cells express VEGF in Hodgkin's disease, as is the case in solid tumours, and this expression may be induced by hypoxia. The presence of VEGF in reactive macrophages and in the extracellular matrix might facilitate tumour progression.
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Factores de Crecimiento Endotelial/metabolismo , Enfermedad de Hodgkin/metabolismo , Linfocinas/metabolismo , Proteínas de Neoplasias/metabolismo , Neovascularización Patológica/metabolismo , Células de Reed-Sternberg/metabolismo , Línea Celular , Factores de Crecimiento Endotelial/genética , Enfermedad de Hodgkin/patología , Humanos , Linfocinas/genética , Proteínas de Neoplasias/genética , ARN Mensajero/genética , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Regulación hacia Arriba , Factor A de Crecimiento Endotelial Vascular , Factores de Crecimiento Endotelial VascularRESUMEN
PURPOSE: Hypoxia-inducible factors HIF1alpha and HIF2alpha (HIFalphas) regulate the expression of a variety of genes encoding proteins related to angiogenesis and to anaerobic metabolism of cells exposed to hypoxic stress. Their putative role as markers of clinically relevant hypoxia and, therefore, as predictors of response to chemoradiotherapy is herein examined. PATIENTS AND METHODS: Using immunohistochemistry, we assessed the expression of HIFalphas in normal head-neck mucosa and in 75 cancer specimens from patients with locally advanced squamous cell head-and-neck cancer (SCHNC), treated with concurrent carboplatin chemoradiotherapy. RESULTS: Head-and-neck mucosa from normal individuals did not show any HIF1alpha or HIF2alpha reactivity. SCHNC showed a varying expression of HIFalphas ranging through negative reactivity, to weak or focally strong cytoplasmic reactivity, or to strong diffuse cytoplasmic/nuclear reactivity. Fifty-two percent and 33% of cancer samples showed the latter expression pattern for HIF1alpha and HIF2alpha, respectively, and were considered to bear "high" HIF reactivity. Bone/cartilage involvement was more frequent in tumors with high HIF1alpha expression (p = 0.05). HIF1alpha and HIF2alpha overexpression were significantly associated with high microvessel density (p = 0.002 and 0.02, respectively) and with VEGF expression (p = 0.01 and 0.005, respectively). HIF1alpha was related to high thymidine phosphorylase expression (p = 0.03), whereas VEGF/KDR-activated tumor vasculature was significantly more frequent in HIF2alpha-overexpressing tumors (p = 0.02). High HIF1alpha and HIF2alpha were associated with incomplete response to chemoradiation (p = 0.007 and p = 0.02, respectively). In univariate analysis, high HIF1alpha and HIF2alpha expression were significantly associated with poor local relapse-free survival (p = 0.003 and 0.003, respectively) and with poor overall survival (p = 0.05 and 0.001, respectively). In multivariate models, HIF2alpha expression was an independent prognostic factor. In biopsies performed after the delivery of 20 Gy of radiotherapy, upregulation of HIFalphas was noted in some cases. CONCLUSIONS: It is concluded that the overexpression of HIFalphas in SCHNC is related to locally aggressive behavior, to intensification of angiogenesis, and to an important resistance to carboplatin chemoradiotherapy.
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Carcinoma de Células Escamosas/tratamiento farmacológico , Carcinoma de Células Escamosas/radioterapia , Neoplasias de Cabeza y Cuello/tratamiento farmacológico , Neoplasias de Cabeza y Cuello/radioterapia , Neovascularización Patológica , Transactivadores/biosíntesis , Factores de Transcripción/biosíntesis , Antineoplásicos/uso terapéutico , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico , Carboplatino/uso terapéutico , Carcinoma de Células Escamosas/metabolismo , Estudios de Casos y Controles , Estudios de Cohortes , Neoplasias de Cabeza y Cuello/metabolismo , Humanos , Hipoxia , Subunidad alfa del Factor 1 Inducible por Hipoxia , Inmunohistoquímica , Pronóstico , Factores de Tiempo , Regulación hacia ArribaRESUMEN
Tumor-associated macrophages (TAMs) produce angiogenic factors and in breast cancer are associated with high vascular grade and poor survival. TAMs preferentially migrate to hypoxic areas within tumors and strongly express hypoxia-inducible factor (HIF)-2 alpha. This study examined whether HIF-2 alpha was involved in TAM angiogenic activation by correlating its expression with tumor microvessel density as a marker of angiogenesis, and other tumor variables, in a series of human primary invasive breast carcinomas. A correlation was found between high TAM HIF-2 alpha and high tumor vascularity (P < 0.0001), as well as high tumor grade (P = 0.007). The relation of HIF-2 alpha expression to a recently described oxygen-dependent pathway of angiogenesis was also studied, and an inverse relationship was found between TAM HIF-2 alpha and tumor thymidine phosphorylase expression (P = 0.02). These results suggest that TAM HIF-2 signaling may be a useful target for future antiangiogenic strategies but show that tumors use both oxygen-dependent and oxygen deficiency-regulated pathways for angiogenesis. Thus, combined blockade of pathways and careful assessment of these pathways in trials are necessary.