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BACKGROUND: Music therapy interventions with informal carers of individuals with life-threatening illness at pre- and post-bereavement is an increasingly important clinical area. This systematic review is the first to synthesise and critically evaluate the international evidence associated with music therapy with adult informal carers pre- and post-bereavement. Specifically, the objectives were: i) to describe the characteristics and effectiveness of music therapy interventions which aim to improve health-related outcomes for adult informal carers of adults with life-threatening illness (pre- and post-bereavement), and ii) to describe the experience of music therapy for adult informal carers of adults with life-threatening illness (pre- and post-bereavement). METHODS: Eligibility: adult informal carers of adults at end of life or bereaved; music therapy interventions for improving health-related outcomes; qualitative; mixed-method; and quantitative studies including comparators of any other intervention; published in English from 1998 onwards. Six databases were searched up to July 2022. A JBI mixed-methods systematic review approach was followed throughout, including quality appraisal, data extraction and a convergent segregated approach to synthesis and integration. RESULTS: A total of 34 studies were included, published between 2003 and 2022. Most were conducted in North America (n = 13), Australia (n = 10), or Europe (n = 8). No studies were conducted in low- and middle-income countries or in the UK. The majority were qualitative (n = 17), followed by quasi-experimental (n = 8), mixed-methods (n = 7) and two RCTs. The majority focused on carers of individuals with dementia (n = 21) or advanced cancer (n = 7). Seventeen studies were purely quantitative or included a quantitative component. During meta-synthesis, findings were aligned to core outcomes for evaluating bereavement interventions in palliative care and previously identified risk factors for complicated grief. Commonly targeted outcomes in quantitative studies included quality of life and mental wellbeing, showing equivocal effectiveness of music therapy with significant and non-significant results. Twenty-two studies either purely qualitative or with a qualitative component underwent meta synthesis and suggested a diverse range of improved pre- and post-bereavement outcomes for informal carers across all core outcomes, and across all risk and protective factors, including psychological, spiritual, emotional, and social outcomes. CONCLUSIONS: Qualitative studies provide moderate to strong evidence for improved health-related outcomes for adult informal carers of adults with life-threatening illness pre-bereavement. Limited studies including those bereaved negates conclusions for the bereavement phase. Comparisons and explanations for effectiveness across quantitative and qualitative studies are equivocal, with a high risk of bias and small samples in the limited number of quantitative studies, demonstrating a need for high-quality RCTs. SYSTEMATIC REVIEW PRE-REGISTRATION: PROSPERO [CRD42021244859].
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Cuidadores , Musicoterapia , Humanos , Musicoterapia/métodos , Musicoterapia/normas , Cuidadores/psicología , Aflicción , Adulto , Calidad de Vida/psicologíaRESUMEN
Here we report the discovery of MED6-189, a new analogue of the kalihinol family of isocyanoterpene (ICT) natural products. MED6-189 is effective against drug-sensitive and -resistant P. falciparum strains blocking both intraerythrocytic asexual replication and sexual differentiation. This compound was also effective against P. knowlesi and P. cynomolgi. In vivo efficacy studies using a humanized mouse model of malaria confirms strong efficacy of the compound in animals with no apparent hemolytic activity or apparent toxicity. Complementary chemical biology, molecular biology, genomics and cell biological analyses revealed that MED6-189 primarily targets the parasite apicoplast and acts by inhibiting lipid biogenesis and cellular trafficking. Genetic analyses in P. falciparum revealed that a mutation in PfSec13, which encodes a component of the parasite secretory machinery, reduced susceptibility to the drug. The high potency of MED6-189 in vitro and in vivo, its broad range of efficacy, excellent therapeutic profile, and unique mode of action make it an excellent addition to the antimalarial drug pipeline.
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PURPOSE: Interferon alfa-2b (IFN alpha-2b) exhibits antitumor activity in metastatic melanoma and on this basis has been evaluated as an adjuvant therapy following surgery for deep primary (T4) or regionally metastatic (N1) melanoma. METHODS: A randomized controlled study of IFN alpha-2b (Schering-Plough, Kenilworth, NJ) administered at maximum-tolerated doses of 20 MU/m2/d intravenously (i.v.) for 1 month and 10 MU/m2 three times per week subcutaneously (SC) for 48 weeks versus observation, was conducted by the Eastern Cooperative Oncology Group (ECOG) in 287 patients. RESULTS: A significant prolongation of relapse-free survival (P = .0023, one-sided) and prolongation of overall survival (P = .0237, one-sided) was observed with IFN alpha-2b therapy in this trial, which is now mature with a median follow-up time of 6.9 years. The impact of treatment on relapse rate is most pronounced early during the treatment interval. The overall benefit of treatment in this trial was analyzed stratified by tumor burden and the presence or absence of microscopic nonpalpable and palpable regional lymph node metastasis. The benefit of therapy with IFN alpha-2b was greatest among node-positive strata. Toxicity of IFN alpha-2b required dose modification in the majority of patients, but treatment at > or = 80% of the scheduled dose was feasible in the majority of patients through the IV phase of treatment, and for more than 3 months of SC maintenance therapy. Discontinuation of treatment due to toxicity was infrequent after the fourth month of therapy. CONCLUSION: IFN alpha-2b prolongs the relapse-free interval and overall survival of high-risk resected melanoma patients. The increment in median disease-free survival (from 1 to 1.7 years) and overall survival (from 2.8 to 3.8 years) that results from this therapy is associated with a 42% improvement in the fraction of patients who are continuously disease-free after treatment with IFN (from 26% to 37%) in comparison to observation. IFN alpha-2b is the first agent to show a significant benefit in relapse-free and overall survival of high-risk melanoma patients in a randomized controlled trial.
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Melanoma , Proteínas Proto-Oncogénicas B-raf , Humanos , Indazoles , Paclitaxel , Piridonas , Pirimidinas , Pirimidinonas , SulfonamidasAsunto(s)
Ansiedad/diagnóstico , Tamizaje Masivo/psicología , Melanoma/diagnóstico , Neoplasias Cutáneas/diagnóstico , Estrés Psicológico/diagnóstico , Adulto , Ansiedad/psicología , Biopsia/psicología , Estudios Transversales , Humanos , Melanoma/patología , Melanoma/psicología , Psicometría , Piel/patología , Neoplasias Cutáneas/patología , Neoplasias Cutáneas/psicología , Estrés Psicológico/psicología , Encuestas y Cuestionarios/estadística & datos numéricosRESUMEN
The resistance of melanoma to current treatment modalities represents a major obstacle for durable therapeutic response, and thus the elucidation of mechanisms of resistance is urgently needed. The crucial functions of activating transcription factor-2 (ATF2) in the development and therapeutic resistance of melanoma have been previously reported, although the precise underlying mechanisms remain unclear. Here, we report a protein kinase C-É (PKCÉ)- and ATF2-mediated mechanism that facilitates resistance by transcriptionally repressing the expression of interferon-ß1 (IFNß1) and downstream type-I IFN signaling that is otherwise induced upon exposure to chemotherapy. Treatment of early-stage melanomas expressing low levels of PKCÉ with chemotherapies relieves ATF2-mediated transcriptional repression of IFNß1, resulting in impaired S-phase progression, a senescence-like phenotype and increased cell death. This response is lost in late-stage metastatic melanomas expressing high levels of PKCÉ. Notably, nuclear ATF2 and low expression of IFNß1 in melanoma tumor samples correlates with poor patient responsiveness to biochemotherapy or neoadjuvant IFN-α2a. Conversely, cytosolic ATF2 and induction of IFNß1 coincides with therapeutic responsiveness. Collectively, we identify an IFNß1-dependent, cell-autonomous mechanism that contributes to the therapeutic resistance of melanoma via the PKCÉ-ATF2 regulatory axis.
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Factor de Transcripción Activador 2/metabolismo , Resistencia a Antineoplásicos , Interferón beta/genética , Melanoma/genética , Línea Celular Tumoral , Núcleo Celular/metabolismo , Regulación hacia Abajo , Humanos , Melanoma/tratamiento farmacológico , Melanoma/metabolismo , Melanoma/patología , Regiones Promotoras Genéticas , Proteína Quinasa C-epsilon/metabolismo , Transducción de Señal , Transcripción GenéticaRESUMEN
BACKGROUND: Temozolomide (TMZ) is widely used for chemotherapy of metastatic melanoma. We hypothesized that epigenetic modulators will reverse chemotherapy resistance, and in this article, we report studies that sought to determine the recommended phase 2 dose (RP2D), safety, and efficacy of decitabine (DAC) combined with TMZ. PATIENTS AND METHODS: In phase I, DAC was given at two dose levels: 0.075 and 0.15 mg/kg intravenously daily × 5 days/week for 2 weeks, TMZ orally 75 mg/m(2) qd for weeks 2-5 of a 6-week cycle. The phase II portion used a two-stage Simon design with a primary end point of objective response rate (ORR). RESULTS: The RP2D is DAC 0.15 mg/kg and TMZ 75 mg/m(2). The phase II portion enrolled 35 patients, 88% had M1c disease; 42% had history of brain metastases. The best responses were 2 complete response (CR), 4 partial response (PR), 14 stable disease (SD), and 13 progressive disease (PD); 18% ORR and 61% clinical benefit rate (CR + PR + SD). The median overall survival (OS) was 12.4 months; the 1-year OS rate was 56%. Grade 3/4 neutropenia was common but lasted >7 days in six patients. CONCLUSIONS: The combination of DAC and TMZ is safe, leads to 18% ORR and 12.4-month median OS, suggesting possible superiority over the historical 1-year OS rate, and warrants further evaluation in a randomized setting.
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Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Azacitidina/análogos & derivados , Dacarbazina/análogos & derivados , Melanoma/tratamiento farmacológico , Neoplasias Cutáneas/tratamiento farmacológico , Adulto , Anciano , Antineoplásicos/administración & dosificación , Antineoplásicos/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/antagonistas & inhibidores , Azacitidina/administración & dosificación , Azacitidina/efectos adversos , Azacitidina/farmacocinética , Dacarbazina/administración & dosificación , Dacarbazina/farmacocinética , Decitabina , Supervivencia sin Enfermedad , Esquema de Medicación , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/inducido químicamente , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/patología , Femenino , Humanos , Masculino , Melanoma/patología , Persona de Mediana Edad , Metástasis de la Neoplasia/tratamiento farmacológico , Metástasis de la Neoplasia/patología , Estadificación de Neoplasias , Neoplasias Cutáneas/patología , TemozolomidaRESUMEN
BACKGROUND: The DNA repair protein O6-methylguanine-DNA methyltransferase (MGMT) reverses the O6-methylguanine (O6-meG) lesion induced by dacarbazine. Depletion of MGMT can be achieved using O6-meG pseudosubstrates. Herein, we report the first phase I experience of the novel O6-meG pseudosubstrate lomeguatrib, combined with dacarbazine. METHODS: This is a phase I dose-escalation study to determine the maximum tolerated dose and recommended phase II dose (RP2D) of lomeguatrib combined with a single dose of dacarbazine on a 21-day schedule. RESULTS: The vast majority of the 41 patients enrolled had metastatic melanoma (36/41) and most had no previous chemotherapy (30/41). The most frequent non-hematological adverse events (AEs) were nausea (52%), and fatigue (42%). The most frequent AEs of grade 3-4 severity were neutropaenia (42%), leukopaenia (17%), and thrombocytopaenia (12%). Only 1 patient had a partial response and 10 patients had stable disease. CONCLUSION: The RP2D of lomeguatrib was 40 mg orally twice daily for 10 days combined with 400 mg m(-2) of dacarbazine IV on day 2. Oral administration of lomeguatrib substantially increases the haematological toxicity of dacarbazine consistent with experience with other O6-meG pseudosubstrates.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Dacarbazina/administración & dosificación , Melanoma/tratamiento farmacológico , Neoplasias/tratamiento farmacológico , O(6)-Metilguanina-ADN Metiltransferasa/antagonistas & inhibidores , Purinas/administración & dosificación , Adulto , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Esquema de Medicación , Femenino , Humanos , Masculino , Persona de Mediana EdadRESUMEN
Salmonellosis has been reported as an important cause of mortality of garden birds in several countries, including Norway and Scotland. We investigated the frequency of the disease in garden birds submitted for postmortem examination by members of the public in England and Wales between 1993 and 2003, inclusive. We found salmonellosis to be the most frequent cause of death due to infectious disease in the garden birds submitted. This disease was confirmed in 7 of the 45 bird species that were examined postmortem, with the greenfinch (Carduelis chloris) and the house sparrow (Passer domesticus) most frequently affected. Salmonella Typhimurium definitive phage type (DT) 40, DT56 variant(v), and DT160 accounted for the majority of isolates. Salmonellosis incidents chiefly occurred in the English Midlands, the English/Welsh border region, and southern England. Variation in the temporal and spatial distribution of the phage types occurred over the study period. While birds were examined throughout the year, there was a marked winter seasonality in salmonellosis. A significant sex bias was observed in affected greenfinches, with males more frequently diagnosed with salmonellosis than females. No sex bias was observed for other affected species. Further research is required to determine if salmonellosis is an important constraint to the populations of affected species and if disease outbreaks are driven by human factors, such as provisioning.
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Passeriformes/microbiología , Salmonelosis Animal/epidemiología , Salmonelosis Animal/microbiología , Fagos de Salmonella/aislamiento & purificación , Salmonella typhimurium/aislamiento & purificación , Animales , Autopsia , Aves , Brotes de Enfermedades , Inglaterra/epidemiología , Femenino , Geografía , Masculino , Factores de Riesgo , Salmonelosis Animal/mortalidad , Estaciones del Año , Gales/epidemiologíaRESUMEN
Although patients diagnosed with melanoma of = 1.00 mm thickness have a relatively good cure rate, the prognosis for patients with locally advanced and metastatic melanoma is grave. The discovery of new and effective therapies for this disease depends in large part on molecular studies that will resolve why advanced-stage melanoma is refractory to conventional chemotherapy and radiation therapy. To identify genes that have important functions in advanced-stage melanomas, in particular, in melanoma-infiltrated lymph nodes, which are not well characterized at the molecular level, we generated a LongSAGE library from a melanoma-positive lymph node, and subjected melanoma-infiltrated lymph nodes to protein expression profiling. The data document that the molecular signature of melanoma, which has spread to regional lymph nodes, is very similar to the molecular signature of primary melanomas. Equally important, we provide evidence that the ubiquitin-conjugating enzyme, Ubc9, is expressed at high levels in melanoma-positive lymph nodes, and that it plays a crucial role in preventing advanced-stage melanomas from undergoing chemotherapy-induced apoptosis.
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Anticuerpos Antineoplásicos , Antígenos de Neoplasias/biosíntesis , Ganglios Linfáticos/inmunología , Ganglios Linfáticos/patología , Melanoma/enzimología , Melanoma/patología , Análisis por Matrices de Proteínas , Enzimas Ubiquitina-Conjugadoras/inmunología , Antígenos de Neoplasias/genética , Apoptosis/efectos de los fármacos , Apoptosis/inmunología , Resistencia a Antineoplásicos , Humanos , Melanoma/diagnóstico , Melanoma/tratamiento farmacológico , Invasividad Neoplásica , Estadificación de Neoplasias , Biblioteca de Péptidos , Células Tumorales Cultivadas , Enzimas Ubiquitina-Conjugadoras/análisis , Enzimas Ubiquitina-Conjugadoras/biosíntesis , Enzimas Ubiquitina-Conjugadoras/genéticaRESUMEN
Although CD4(+) Type-1T helper (Th1) cells secreting interferon-gamma (IFN-gamma) appear to play an essential role in promoting durable antitumor immunity, we have previously shown that patients with cancer exhibit dysfunctional Th1-type responses against epitopes derived from tumor antigens, such as MAGE-A6. Here, we engineered human dendritic cells (DCs) to secrete high levels of the IFN-gamma-inducing cytokines, interleukin (IL)-12p70 and IL-18, via recombinant adenoviral infection to generate an in vitro stimulus capable of promoting previously deficient patient Th1-type responses. Dendritic cells co-infected with Ad.IL-12 and Ad.IL-18 (DC.IL-12/18) were more effective at stimulating MAGE-A6-specific Th1-type CD4(+) T-cell responses than DCs infected with either of the cytokine vectors alone, control Ad.Psi5 virus or uninfected DCs. Furthermore, we show that DC.IL-12/18 loaded with recombinant MAGE-A6 protein (rMAGE) and used as in vitro stimulators promote Th1-type immunity that is frequently directed against multiple MAGE-A6-derived epitopes. The superiority of DC.IL-12/18-based stimulations in melanoma patients was independent of disease stage or current disease status. Based on these results, we believe this modality may prove clinically useful as a vaccine platform to promote the recovery of tumor antigen-specific, Th1-type CD4(+) T-cell responses in patients with cancer.
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Antígenos de Neoplasias/genética , Células Dendríticas/inmunología , Interleucina-12 , Interleucina-18 , Melanoma/terapia , Proteínas de Neoplasias/genética , Neoplasias Cutáneas/terapia , Adenoviridae , Linfocitos T CD4-Positivos/inmunología , Vacunas contra el Cáncer , Vectores Genéticos , Humanos , Técnicas In Vitro , Interleucina-12/genética , Interleucina-18/genética , Melanoma/inmunología , Proteínas Recombinantes , Neoplasias Cutáneas/inmunología , Células TH1Asunto(s)
Enfermedades de las Aves/mortalidad , Cardiobacteriaceae/patogenicidad , Infecciones por Bacterias Gramnegativas/veterinaria , Passeriformes , Animales , Enfermedades de las Aves/microbiología , Inglaterra/epidemiología , Femenino , Infecciones por Bacterias Gramnegativas/microbiología , Infecciones por Bacterias Gramnegativas/mortalidad , Incidencia , Masculino , Gales/epidemiologíaRESUMEN
BACKGROUND: Biopsy of the central nervous system (CNS) has been reported previously using relatively large-caliber (12-17-gauge) biopsy instruments with or without stereotactic guidance. In this series, fine-needle aspiration biopsies (FNABs) were performed using a smaller diameter needle to evaluate mass lesions of the CNS. METHODS: One hundred thirty FNABs were performed freehand under computed tomography (CT) guidance without stereotactic instrumentation guidance using a 22-gauge needle. RESULTS: A definitive diagnosis was rendered in 97 of 130 FNABs (75%), including glioblastoma multiforme (GBM) (n = 33 biopsies); anaplastic astrocytoma (n = 14 biopsies); metastatic carcinoma (n = 13 biopsies); low-grade astrocytoma (LGA) (n = 10 biopsies); lymphoma (n = 7 biopsies); oligodendroglioma (n = 5 biopsies); reactive gliosis (n = 2 biopsies); and abscess (n = 13 biopsies), with the infectious agent identified in 7 of 13 biopsies. Immunohistochemistry was employed in 51 biopsies to assist in determining either the cell type or the infectious agent. Indefinite diagnoses were rendered in 33 patients (25%), including LGA versus gliosis (n = 8 patients), necrosis and/or inflammation (n = 3 patients), nondiagnostic material (n = 17 patients), suspicious for lymphoma (n = 2 patients), suspicious for GBM (n = 2 patients), and high-grade neoplasm not otherwise classified (n = 1 patient). There was no morbidity or mortality attributed to the procedure. CONCLUSIONS: FNAB of CNS mass lesions established a diagnosis based on cytologic interpretation in 75% of biopsies without morbidity or mortality. Because morbidity and mortality rates in CT-guided biopsies utilizing stereotactic techniques with large-caliber needles have been reported as high as 14% and 4.7%, respectively, freehand FNAB under CT guidance may be a preferred initial method for evaluating mass lesions of the CNS.
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Biopsia con Aguja/métodos , Neoplasias Encefálicas/patología , Técnicas Estereotáxicas , Tomografía Computarizada por Rayos X/métodos , Adulto , Anciano , Encefalopatías/patología , Estudios de Cohortes , Medios de Contraste , Diagnóstico Diferencial , Femenino , Tecnología de Fibra Óptica , Humanos , Inmunohistoquímica , Masculino , Persona de Mediana Edad , Intensificación de Imagen Radiográfica , Estudios Retrospectivos , Sensibilidad y Especificidad , Tomografía Computarizada por Rayos X/instrumentaciónRESUMEN
PURPOSE: To correlate the presence of extracapsular spread (ECS) of regional nodal metastases, and micrometastasis near the primary tumor, with disease outcome in the intergroup study E1690 in relation to the impact of recombinant interferon-alfa (rIFN alpha)-2b. PATIENTS AND METHODS: E1690 included 642 patients with American Joint Committee on Cancer stage IIB or III cutaneous melanoma. Patients were randomized into high- and low-dose rIFN alpha-2b treatment arms and an observation arm. Pathologic slides were reviewed for selected parameters from at least half of the subjects in all three arms. Evaluation of the primary tumor included notations regarding ulceration, mitotic activity, thickness, microscopic satellites (MS), and nodal ECS on a standardized pathology form. These data were collated in relation to relapse-free survival (RFS) and overall survival (OS) at 50 months' follow-up and studied using Cox regression analysis. RESULTS: Ulceration, mitotic activity, thickness, and size of tumor-bearing lymph nodes did not show a statistically significant correlation with either OS or RFS across all treatment arms. The presence of MS was correlated with RFS (P =.0008) and OS (P =.05). ECS correlated with RFS (hazard ratio = 1.44, P =.032) but not OS (P =.11). CONCLUSION: The presence of MS (in 6% [18 of 308 patients]) had a significant adverse impact on both RFS (P =.0008) and OS (P =.053). Ulceration, mitotic activity, thickness, and number of positive lymph nodes had no significant effect on OS in this subset study (univariate or multivariate Cox analysis). The presence of ECS in lymph nodes had a significant adverse effect on RFS (P =.032) but not on OS.
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Antineoplásicos/uso terapéutico , Interferón-alfa/uso terapéutico , Melanoma/tratamiento farmacológico , Melanoma/patología , Humanos , Interferón alfa-2 , Metástasis Linfática , Índice Mitótico , Estadificación de Neoplasias , Proteínas Recombinantes , Neoplasias Cutáneas/tratamiento farmacológico , Neoplasias Cutáneas/patología , Análisis de Supervivencia , ÚlceraRESUMEN
A 3-year-old girl with acute lymphocytic leukemia (ALL) in remission developed lower extremity paraparesis and areflexia 15 days after receiving intrathecal methotrexate, cytarabine, and hydrocortisone. Cerebrospinal fluid protein was 107 mg/dl. Compound muscle action potential amplitudes were reduced, F waves were absent, and sensory conduction studies were normal. Needle electromyography (EMG) revealed reduced motor unit potential recruitment. Magnetic resonance imaging (MRI) showed lumbosacral ventral root enhancement. She was treated with intravenous immunoglobulin and slowly recovered. Nerve conduction and EMG abnormalities correlated with MRI root enhancement, facilitated early diagnosis, and distinguished this from a myelopathy or distal polyneuropathy. These findings could represent selective ventral nerve root vulnerability to intrathecal chemotherapy. A selective autoimmune process cannot be excluded.
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Antiinflamatorios/administración & dosificación , Antimetabolitos Antineoplásicos/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Citarabina/administración & dosificación , Hidrocortisona/administración & dosificación , Metotrexato/administración & dosificación , Polirradiculopatía/inducido químicamente , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamiento farmacológico , Antiinflamatorios/efectos adversos , Antimetabolitos Antineoplásicos/efectos adversos , Preescolar , Citarabina/efectos adversos , Electromiografía , Femenino , Humanos , Hidrocortisona/efectos adversos , Inyecciones Espinales , Imagen por Resonancia Magnética , Metotrexato/efectos adversos , Polirradiculopatía/diagnóstico , Polirradiculopatía/fisiopatologíaRESUMEN
CD4+ T cells modulate the magnitude and durability of CTL responses in vivo, and may serve as effector cells in the tumour microenvironment. In order to identify the tumour epitopes recognized by tumour-reactive human CD4+ T cells, we combined the use of an HLA-DR4/peptide binding algorithm with an IFN-gamma ELISPOT assay. Two known and three novel CD4+ T cell epitopes derived from the gp 100/pmel17 and tyrosinase melanocyte-associated antigens were confirmed or identified. Of major interest, we determined that freshly-isolated PBMC frequencies of Th1-type CD4+ T recognizing these peptides are frequently elevated in HLA-DR4+ melanoma patients (but not normal donors) that are currently disease-free as a result of therapeutic intervention. Epitope-specific CD4+ T cells from normal DR4+ donors could be induced, however, after in vitro stimulation with autologous dendritic cell pulsed with antigens (peptides or antigen-positive melanoma lysates) or infected with recombinant vaccinia virus encoding the relevant antigen. Peptide-reactive CD4+ T cells also recognized HLA-DR4+ melanoma cell lines that constitutively express the relevant antigen. Based on these data, these epitopes may serve as potent vaccine components to promote clinically-relevant Th1-type CD4+ T cell effector function in situ.