RESUMEN
BACKGROUND: The circulating T-cell receptor (TCR) repertoire is a dynamic representation of overall immune responses in an individual. MATERIALS AND METHODS: We prospectively collected baseline blood from patients treated with first-line pembrolizumab monotherapy or in combination with chemotherapy. TCR repertoire metrics were correlated with clinical benefit rate (CBR), progression-free survival (PFS), overall survival (OS) and immune-related adverse events (irAEs). We built a logistic regression classifier by fitting all four TCR-ß repertoire metrics to the immune checkpoint inhibitor (ICI) CBR data. In the subsequent receiver operating characteristic (ROC) analysis of the resulting logistic regression model probabilities, the best cut-off value was selected to maximise sensitivity to predict CBR to ICI. RESULTS: We observed an association between reduced number of unique clones and CBR among patients treated with pembrolizumab monotherapy (cohort 1) [risk ratio = 2.86, 95% confidence interval (CI) 1.04-8.73, P = 0.039]. For patients treated with pembrolizumab plus chemotherapy (cohort 2), increased number of unique clones [hazard ratio (HR) = 2.96, 95% CI 1.28-6.88, P = 0.012] and Shannon diversity (HR = 2.73, 95% CI 1.08-6.87, P = 0.033), and reduced evenness (HR = 0.43, 95% CI 0.21-0.90, P = 0.025) and convergence (HR = 0.41, 95% CI 0.19-0.90, P = 0.027) were associated with improved PFS, while only an increased number of unique clones (HR = 4.62, 95% CI 1.52-14.02, P = 0.007) were associated with improved OS. Logistic regression models combining the TCR repertoire metrics improved the prediction of CBR (cohorts 1 and 2) and were strongly associated with PFS (cohort 1, HR = 0.38, 95% CI 0.19-0.78, P = 0.009) and OS (cohort 2, HR = 0.20, 95% CI 0.05-0.76, P < 0.0001). Reduced TCR conversion was associated with increased frequency of irAEs needing systemic steroid treatment. CONCLUSION: Combined pre-treatment circulating TCR metrics might serve as a predictive biomarker for clinical outcomes among patients with advanced non-small-cell lung cancer treated with pembrolizumab alone or in combination with chemotherapy.
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Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Humanos , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/patología , Neoplasias Pulmonares/patología , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Biomarcadores , Receptores de Antígenos de Linfocitos TRESUMEN
BACKGROUND: Immune checkpoint inhibitors (ICIs) have revolutionized the management of advanced melanoma (AM). However, data on ICI effectiveness have largely been restricted to clinical trials, thereby excluding patients with co-existing malignancies. Chronic lymphocytic leukemia (CLL) is the most prevalent adult leukemia and is associated with increased risk of melanoma. CLL alters systemic immunity and can induce T-cell exhaustion, which may limit the efficacy of ICIs in patients with CLL. We, therefore, sought to examine the efficacy of ICI in patients with these co-occurring diagnoses. PATIENTS AND METHODS: In this international multicenter study, a retrospective review of clinical databases identified patients with concomitant diagnoses of CLL and AM treated with ICI (US-MD Anderson Cancer Center, N = 24; US-Mayo Clinic, N = 15; AUS, N = 19). Objective response rates (ORRs), assessed by RECIST v1.1, and survival outcomes [overall survival (OS) and progression-free survival (PFS)] among patients with CLL and AM were assessed. Clinical factors associated with improved ORR and survival were explored. Additionally, ORR and survival outcomes were compared between the Australian CLL/AM cohort and a control cohort of 148 Australian patients with AM alone. RESULTS: Between 1997 and 2020, 58 patients with concomitant CLL and AM were treated with ICI. ORRs were comparable between AUS-CLL/AM and AM control cohorts (53% versus 48%, P = 0.81). PFS and OS from ICI initiation were also comparable between cohorts. Among CLL/AM patients, a majority were untreated for their CLL (64%) at the time of ICI. Patients with prior history of chemoimmunotherapy treatment for CLL (19%) had significantly reduced ORRs, PFS, and OS. CONCLUSIONS: Our case series of patients with concomitant CLL and melanoma demonstrate frequent, durable clinical responses to ICI. However, those with prior chemoimmunotherapy treatment for CLL had significantly worse outcomes. We found that CLL disease course is largely unchanged by treatment with ICI.
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Leucemia Linfocítica Crónica de Células B , Melanoma , Adulto , Humanos , Leucemia Linfocítica Crónica de Células B/complicaciones , Leucemia Linfocítica Crónica de Células B/tratamiento farmacológico , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Australia , Melanoma/patología , Supervivencia sin Progresión , Estudios RetrospectivosRESUMEN
BRAF inhibitors revolutionised the management of melanoma patients and although resistance occurs, there is a subgroup of patients who maintain durable disease control. For those cases with durable complete response (CR) it is not clear whether it is safe to cease therapy. Here we identified 13 patients treated with BRAF +/- MEK inhibitors, who cease therapy after prolonged CR (median = 34 months, range 20-74). Recurrence was observed in 3/13 (23%) patients. In the remaining 10 patients with sustained CR off therapy, the median follow up after discontinuation was 19 months (range 8-36). We retrospectively measured ctDNA levels using droplet digital PCR (ddPCR) in longitudinal plasma samples. CtDNA levels were undetectable in 11/13 cases after cessation and remained undetectable in patients in CR (10/13). CtDNA eventually became detectable in 2/3 cases with disease recurrence, but remained undetectable in 1 patient with brain only progression. Our study suggests that consideration could be given to ceasing targeted therapy in the context of prolonged treatment, durable response and no evidence of residual disease as measured by ctDNA.
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Melanoma/tratamiento farmacológico , Recurrencia Local de Neoplasia/tratamiento farmacológico , Proteínas Proto-Oncogénicas B-raf/genética , Adulto , Anciano , Carbamatos/administración & dosificación , ADN Tumoral Circulante/sangre , ADN Tumoral Circulante/efectos de los fármacos , Progresión de la Enfermedad , Femenino , Humanos , Imidazoles/administración & dosificación , Masculino , Melanoma/sangre , Melanoma/genética , Melanoma/patología , Persona de Mediana Edad , Quinasas de Proteína Quinasa Activadas por Mitógenos/antagonistas & inhibidores , Quinasas de Proteína Quinasa Activadas por Mitógenos/genética , Recurrencia Local de Neoplasia/sangre , Recurrencia Local de Neoplasia/genética , Recurrencia Local de Neoplasia/patología , Oximas/administración & dosificación , Inhibidores de Proteínas Quinasas/administración & dosificación , Proteínas Proto-Oncogénicas B-raf/antagonistas & inhibidores , Sulfonamidas/administración & dosificación , Vemurafenib/administración & dosificaciónRESUMEN
BACKGROUND: Anti-programmed cell death protein 1 (PD-1) antibodies (PD1) prolong recurrence-free survival in high-risk resected melanoma; however, approximately 25%-30% of patients recur within 1 year. This study describes the pattern of recurrence, management and outcomes of patients who recur with adjuvant PD1 therapy. PATIENTS AND METHODS: Consecutive patients from 16 centres who recurred having received adjuvant PD1 therapy for resected stage III/IV melanoma were studied. Recurrence characteristics, management and outcomes were examined; patients with mucosal melanoma were analysed separately. RESULTS: Melanoma recurrence occurred in 147 (17%) of â¼850 patients treated with adjuvant PD1. In those with cutaneous melanoma (n = 136), median time to recurrence was 4.6 months (range 0.3-35.7); 104 (76%) recurred during (ON) adjuvant PD1 after a median 3.2 months and 32 (24%) following (OFF) treatment cessation after a median 12.5 months, including in 21 (15%) who ceased early for toxicity. Fifty-nine (43%) recurred with locoregional disease only and 77 (57%) with distant disease. Of those who recurred locally, 22/59 (37%) subsequently recurred distantly. Eighty-nine (65%) patients received systemic therapy after recurrence. Of those who recurred ON adjuvant PD1, none (0/6) responded to PD1 alone; 8/33 assessable patients (24%) responded to ipilimumab (alone or in combination with PD1) and 18/23 (78%) responded to BRAF/MEK inhibitors. Of those who recurred OFF adjuvant PD1, two out of five (40%) responded to PD1 monotherapy, two out of five (40%) responded to ipilimumab-based therapy and 9/10 (90%) responded to BRAF/MEK inhibitors. CONCLUSIONS: Most patients who recur early despite adjuvant PD1 develop distant metastases. In those who recur ON adjuvant PD1, there is minimal activity of further PD1 monotherapy, but ipilimumab (alone or in combination with PD1) and BRAF/MEK inhibitors have clinical utility. Retreatment with PD1 may have activity in select patients who recur OFF PD1.
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Melanoma , Neoplasias Cutáneas , Terapia Combinada , Humanos , Inmunoterapia , Ipilimumab/uso terapéutico , Melanoma/tratamiento farmacológico , Neoplasias Cutáneas/tratamiento farmacológicoRESUMEN
Since the identification of anaplastic lymphoma kinase (ALK) gene rearrangements in non-small cell lung cancer (NSCLC) in 2005, the treatment of ALK-rearranged NSCLC (ALK+ NSCLC) has evolved at a rapid pace. This molecularly distinct subset of NSCLC has uniquely important biology, clinicopathologic features and mechanisms of drug resistance which impact on the choice of treatment for a patient with this disease. There are multiple ALK tyrosine kinase inhibitors now available in clinical practice with efficacy data continuing to emerge and guide the optimal treatment algorithm. A detailed search of medical databases and clinical trial registries was conducted to capture all relevant articles on this topic enabling an updated detailed overview of the landscape of management of ALK-rearranged NSCLC.
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Antineoplásicos/uso terapéutico , Carcinoma de Pulmón de Células no Pequeñas/terapia , Neoplasias Pulmonares/terapia , Inhibidores de Proteínas Quinasas/uso terapéutico , Australia , Carcinoma de Pulmón de Células no Pequeñas/patología , Humanos , Neoplasias Pulmonares/patologíaRESUMEN
BACKGROUND: Previous analysis of COMBI-d (NCT01584648) demonstrated improved progression-free survival (PFS) and overall survival (OS) with combination dabrafenib and trametinib versus dabrafenib monotherapy in BRAF V600E/K-mutant metastatic melanoma. This study was continued to assess 3-year landmark efficacy and safety after ≥36-month follow-up for all living patients. PATIENTS AND METHODS: This double-blind, phase 3 study enrolled previously untreated patients with BRAF V600E/K-mutant unresectable stage IIIC or stage IV melanoma. Patients were randomized to receive dabrafenib (150 mg twice daily) plus trametinib (2 mg once daily) or dabrafenib plus placebo. The primary endpoint was PFS; secondary endpoints were OS, overall response, duration of response, safety, and pharmacokinetics. RESULTS: Between 4 May and 30 November 2012, a total of 423 of 947 screened patients were randomly assigned to receive dabrafenib plus trametinib (n = 211) or dabrafenib monotherapy (n = 212). At data cut-off (15 February 2016), outcomes remained superior with the combination: 3-year PFS was 22% with dabrafenib plus trametinib versus 12% with monotherapy, and 3-year OS was 44% versus 32%, respectively. Twenty-five patients receiving monotherapy crossed over to combination therapy, with continued follow-up under the monotherapy arm (per intent-to-treat principle). Of combination-arm patients alive at 3 years, 58% remained on dabrafenib plus trametinib. Three-year OS with the combination reached 62% in the most favourable subgroup (normal lactate dehydrogenase and <3 organ sites with metastasis) versus only 25% in the unfavourable subgroup (elevated lactate dehydrogenase). The dabrafenib plus trametinib safety profile was consistent with previous clinical trial observations, and no new safety signals were detected with long-term use. CONCLUSIONS: These data demonstrate that durable (≥3 years) survival is achievable with dabrafenib plus trametinib in patients with BRAF V600-mutant metastatic melanoma and support long-term first-line use of the combination in this setting.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Biomarcadores de Tumor/genética , Imidazoles/administración & dosificación , Melanoma/tratamiento farmacológico , Mutación , Oximas/administración & dosificación , Inhibidores de Proteínas Quinasas/administración & dosificación , Proteínas Proto-Oncogénicas B-raf/genética , Piridonas/administración & dosificación , Pirimidinonas/administración & dosificación , Neoplasias Cutáneas/tratamiento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Progresión de la Enfermedad , Supervivencia sin Enfermedad , Método Doble Ciego , Esquema de Medicación , Humanos , Imidazoles/efectos adversos , Imidazoles/farmacocinética , Estimación de Kaplan-Meier , Melanoma/genética , Melanoma/mortalidad , Melanoma/secundario , Oximas/efectos adversos , Oximas/farmacocinética , Inhibidores de Proteínas Quinasas/efectos adversos , Inhibidores de Proteínas Quinasas/farmacocinética , Piridonas/efectos adversos , Piridonas/farmacocinética , Pirimidinonas/efectos adversos , Pirimidinonas/farmacocinética , Factores de Riesgo , Neoplasias Cutáneas/genética , Neoplasias Cutáneas/mortalidad , Neoplasias Cutáneas/patología , Factores de Tiempo , Resultado del TratamientoRESUMEN
BACKGROUND: Focal adhesion kinase (FAK) is important in cancer growth, survival, invasion, and migration. The purpose of this study was to determine the maximum tolerated dose (MTD), safety, pharmacokinetics (PK), and pharmacodynamics (PD) of the FAK inhibitor, GSK2256098, in cancer patients. PATIENTS AND METHODS: The dose of GSK2256098 was escalated, in cohorts of patients with advanced cancer, from 80 to 1500 mg, oral twice daily (BID), until the MTD was determined. Serial blood samples were obtained from all patients, and the PK was determined. Paired tumor biopsies were obtained in select patients, and the level of phospho-FAK (pFAK) was determined. RESULTS: Sixty-two patients (39 males, 23 females; median age 61 y.o., range 21-84) received GSK2256098. Dose-limiting toxicities of grade 2 proteinuria (1000 mg BID), grade 2 fatigue, nausea, vomiting (1250 mg BID), and grade 3 asthenia and grade 2 fatigue (1500 mg BID) were reported with the MTD identified as 1000 mg BID. The most frequent adverse events (AEs) were nausea (76%), diarrhea (65%), vomiting (58%), and decreased appetite (47%) with the majority of AEs being grades 1-2. The PK was generally dose proportional with a geometric mean elimination half-life range of 4-9 h. At the 750, 1000, and 1500 mg BID dose levels evaluated, the pFAK, Y397 autophosphorylation site, was reduced by â¼80% from baseline. Minor responses were observed in a patient with melanoma (-26%) and three patients with mesothelioma (-13%, -15%, and -17%). In the 29 patients with recurrent mesothelioma, the median progression-free survival was 12 weeks with 95% CI 9.1, 23.4 weeks (23.4 weeks merlin negative, n = 14; 11.4 weeks merlin positive, n = 9; 10.9 weeks merlin status unknown, n = 6). CONCLUSIONS: GSK2256098 has an acceptable safety profile, has evidence of target engagement at doses at or below the MTD, and has clinical activity in patients with mesothelioma, particularly those with merlin loss.
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Aminopiridinas/administración & dosificación , Proteína-Tirosina Quinasas de Adhesión Focal/antagonistas & inhibidores , Ácidos Hidroxámicos/administración & dosificación , Neoplasias/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/administración & dosificación , Adulto , Anciano , Anciano de 80 o más Años , Aminopiridinas/efectos adversos , Aminopiridinas/farmacocinética , Biopsia , Supervivencia sin Enfermedad , Relación Dosis-Respuesta a Droga , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/clasificación , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/patología , Femenino , Proteína-Tirosina Quinasas de Adhesión Focal/genética , Humanos , Ácidos Hidroxámicos/efectos adversos , Ácidos Hidroxámicos/farmacocinética , Masculino , Dosis Máxima Tolerada , Persona de Mediana Edad , Neoplasias/sangre , Neoplasias/genética , Neoplasias/patología , Neurofibromina 2/genética , Inhibidores de Proteínas Quinasas/efectos adversos , Inhibidores de Proteínas Quinasas/farmacocinéticaRESUMEN
BACKGROUND: Recent phase III clinical trials have established the superiority of the anti-PD-1 antibodies pembrolizumab and nivolumab over the anti-CTLA-4 antibody ipilimumab in the first-line treatment of patients with advanced melanoma. Ipilimumab will be considered for second-line treatment after the failure of anti-PD-1 therapy. METHODS: We retrospectively identified a cohort of 40 patients with metastatic melanoma who received single-agent anti-PD-1 therapy with pembrolizumab or nivolumab and were treated on progression with ipilimumab at a dose of 3 mg kg(-1) for a maximum of four doses. RESULTS: Ten percent of patients achieved an objective response to ipilimumab, and an additional 8% experienced prolonged (>6 months) stable disease. Thirty-five percent of patients developed grade 3-5 immune-related toxicity associated with ipilimumab therapy. The most common high-grade immune-related toxicity was diarrhoea. Three patients (7%) developed grade 3-5 pneumonitis leading to death in one patient. CONCLUSIONS: Ipilimumab therapy can induce responses in patients who fail the anti-PD-1 therapy with response rates comparable to previous reports. There appears to be an increased frequency of high-grade immune-related adverse events including pneumonitis that warrants close surveillance.
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Anticuerpos Monoclonales/administración & dosificación , Antineoplásicos/administración & dosificación , Melanoma/tratamiento farmacológico , Neoplasias Cutáneas/tratamiento farmacológico , Adulto , Anciano , Anticuerpos Monoclonales/efectos adversos , Antineoplásicos/efectos adversos , Esquema de Medicación , Femenino , Humanos , Ipilimumab , Masculino , Persona de Mediana Edad , Metástasis de la Neoplasia , Estudios Retrospectivos , Resultado del TratamientoRESUMEN
BACKGROUND: We sought to determine whether the substantial benefits of topical nitroglycerin with first-line, platinum-based, doublet chemotherapy in advanced nonsmall-cell lung cancer (NSCLC) seen in a phase II trial could be corroborated in a rigorous, multicenter, phase III trial. PATIENTS AND METHODS: Patients starting one of five, prespecified, platinum-based doublets as first-line chemotherapy for advanced NSCLC were randomly allocated treatment with or without nitroglycerin 25 mg patches for 2 days before, the day of, and 2 days after, each chemotherapy infusion. Progression-free survival (PFS) was the primary end point. RESULTS: Accrual was stopped after the first interim analysis of 270 events. Chemotherapy was predominantly with carboplatin and gemcitabine (79%) or carboplatin and paclitaxel (18%). The final analysis included 345 events in 372 participants with a median follow-up of 33 months. Topical nitroglycerin had no demonstrable effect on PFS [median 5.0 versus 4.8 months, hazard ratio (HR) = 1.07, 95% confidence interval (CI) 0.86-1.32, P = 0.55], overall survival (median 11.0 versus 10.3 months, HR = 0.99, 95% CI 0.79-1.24, P = 0.94), or objective tumor response (31% versus 30%, relative risk = 1.03, 95% CI 0.82-1.29, P = 0.81). Headache, hypotension, syncope, diarrhea, dizziness, and anorexia were more frequent in those allocated nitroglycerin. CONCLUSION: The addition of topical nitroglycerin to carboplatin-based, doublet chemotherapy in NSCLC had no demonstrable benefit and should not be used or pursued further. CLINICAL TRIALS NUMBER: Australian New Zealand Clinical Trials Registry Number ACTRN12608000588392.
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Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Carcinoma de Pulmón de Células no Pequeñas/diagnóstico , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/tratamiento farmacológico , Nitroglicerina/administración & dosificación , Adulto , Anciano , Anciano de 80 o más Años , Australia/epidemiología , Carcinoma de Pulmón de Células no Pequeñas/epidemiología , Femenino , Estudios de Seguimiento , Humanos , Neoplasias Pulmonares/epidemiología , Masculino , Persona de Mediana EdadRESUMEN
BACKGROUND: Data from murine models suggest that CD40 activation may synergize with cytotoxic chemotherapy. We aimed to determine the maximum tolerated dose (MTD) and toxicity profile and to explore immunological biomarkers of the CD40-activating antibody CP-870,893 with cisplatin and pemetrexed in patients with malignant pleural mesothelioma (MPM). PATIENTS AND METHODS: Eligible patients had confirmed MPM, ECOG performance status 0-1, and measurable disease. Patients received cisplatin 75 mg/m(2) and pemetrexed 500 mg/m(2) on day 1 and CP-870,893 on day 8 of a 21-day cycle for maximum 6 cycles with up to 6 subsequent cycles single-agent CP-870,893. Immune cell subset changes were examined weekly by flow cytometry. RESULTS: Fifteen patients were treated at three dose levels. The MTD of CP-870,893 was 0.15 mg/kg, and was exceeded at 0.2 mg/kg with one grade 4 splenic infarction and one grade 3 confusion and hyponatraemia. Cytokine release syndrome (CRS) occurred in most patients (80%) following CP-870,893. Haematological toxicities were consistent with cisplatin and pemetrexed chemotherapy. Six partial responses (40%) and 9 stable disease (53%) as best response were observed. The median overall survival was 16.5 months; the median progression-free survival was 6.3 months. Three patients survived beyond 30 months. CD19+ B cells decreased over 6 cycles of chemoimmunotherapy (P < 0.001) with a concomitant increase in the proportion of CD27+ memory B cells (P < 0.001) and activated CD86+CD27+ memory B cells (P < 0.001), as an immunopharmacodynamic marker of CD40 activation. CONCLUSIONS: CP-870,893 with cisplatin and pemetrexed is safe and tolerable at 0.15 mg/kg, although most patients experience CRS. While objective response rates are similar to chemotherapy alone, three patients achieved long-term survival. AUSTRALIA NEW ZEALAND CLINICAL TRIALS REGISTRY NUMBER: ACTRN12609000294257.
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Anticuerpos Monoclonales/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Antígenos CD40/metabolismo , Cisplatino/administración & dosificación , Neoplasias Pulmonares/tratamiento farmacológico , Mesotelioma/tratamiento farmacológico , Pemetrexed/administración & dosificación , Neoplasias Pleurales/tratamiento farmacológico , Adulto , Anciano , Anticuerpos Monoclonales Humanizados , Antígenos CD40/agonistas , Estudios de Cohortes , Femenino , Estudios de Seguimiento , Humanos , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/metabolismo , Masculino , Mesotelioma/diagnóstico , Mesotelioma/metabolismo , Mesotelioma Maligno , Persona de Mediana Edad , Neoplasias Pleurales/diagnóstico , Neoplasias Pleurales/metabolismo , Estudios ProspectivosRESUMEN
BACKGROUND: Few studies have examined the familial aggregation of melanoma or its co-aggregation with other cancers using whole-population based designs. This study aimed to investigate aggregation patterns in young Western Australian families, using population-based linked health data to identify individuals born in Western Australia between 1974 and 2007, their known relatives, and all incident cancer diagnoses within the resulting 1,506,961 individuals. METHODS: Cox proportional hazards regression models were used to compare the risk of melanoma for first-degree relatives of melanoma cases to that for first-degree relatives of controls, with bootstrapping used to account for correlations within families. The risk of (i) developing melanoma based on the number of first-degree relatives with other cancers, and (ii) developing non-melanoma cancers based on the number of first-degree relatives diagnosed with melanoma was also investigated. RESULTS: First-degree relatives of melanoma cases had a significantly greater incidence of melanoma than first-degree relatives of individuals not affected with melanoma (Hazard Ratio (HR)=3.58, 95% bootstrap confidence interval (CI): 2.43-5.43). Sensitivity analyses produced a higher hazard ratio estimate when restricted to melanoma cases diagnosed before 40 years of age (HR=3.77, bootstrap 95% CI: 2.49-6.39) and a lower estimate when only later-onset cases (>40 years) were considered (HR=2.45, bootstrap 95% CI: 1.23-4.82). No significant evidence was found for co-aggregation between melanoma and any other cancers. CONCLUSIONS: Results indicated a strong familial basis of melanoma, with the higher than expected hazard ratio observed likely to reflect early-age at onset cases in this young cohort, supported by the results of the sensitivity analyses. Exploratory analyses suggested that the determinants of melanoma causing the observed aggregation within families may be independent of other malignancies, although these analyses were limited by the young age of the sample. Determining familial aggregation patterns will provide valuable knowledge regarding improved clinical risk prediction and the underlying biological mechanisms of melanoma and other cancers.
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Predisposición Genética a la Enfermedad , Melanoma/epidemiología , Melanoma/genética , Adulto , Edad de Inicio , Australia/epidemiología , Femenino , Humanos , Incidencia , Masculino , Persona de Mediana Edad , Modelos de Riesgos Proporcionales , Riesgo , Australia Occidental/epidemiologíaRESUMEN
Cancer stem cells (CSCs) of head and neck squamous cell carcinoma (HNSCC) are defined by high self-renewal and drug refractory potential. Involvement of Wnt/ß-catenin signaling has been implicated in rapidly cycling cells such as CSCs, and inhibition of the Wnt/ß-catenin pathway is a novel approach to target CSCs from HNSCC. In this study, we found that an antagonist of FrzB/Wnt, the secreted frizzled-related protein 4 (sFRP4), inhibited the growth of CSCs from two HNSCC cell lines, Hep2 and KB. We enriched the CD44(+) CSC population, and grew them in spheroid cultures. sFRP4 decreased the proliferation and increased the sensitivity of spheroids to a commonly used drug in HNSCC, namely cisplatin. Self-renewal in sphere formation assays decreased upon sFRP4 treatment, and the effect was reverted by the addition of Wnt3a. sFRP4 treatment of spheroids also decreased ß-catenin, confirming its action through the Wnt/ß-catenin signaling pathway. Quantitative PCR demonstrated a clear decrease of the stemness markers CD44 and ALDH, and an increase in CD24 and drug-resistance markers ABCG2 and ABCC4. Furthermore, we found that after sFRP4 treatment, there was a reversal in the expression of epithelial to mesenchymal (EMT) markers with the restoration of the epithelial marker E-cadherin, and depletion of EMT-specific markers twist, snail and N-cadherin. This is the first report demonstrating that the naturally occurring Wnt inhibitor, sFRP4, can be a potential drug to destroy CSC-enriched spheroids from HNSCCs. The repression of EMT and the decrease in stemness profile further strengthen the use of sFRP4 as a potent therapeutic against CSCs.
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Apoptosis/efectos de los fármacos , Neoplasias de Cabeza y Cuello/metabolismo , Neoplasias de Cabeza y Cuello/patología , Células Madre Neoplásicas/efectos de los fármacos , Células Madre Neoplásicas/metabolismo , Proteínas Proto-Oncogénicas/farmacología , Proteínas Wnt/antagonistas & inhibidores , Antígenos de Superficie/metabolismo , Línea Celular Tumoral , Resistencia a Antineoplásicos/genética , Transición Epitelial-Mesenquimal/efectos de los fármacos , Transición Epitelial-Mesenquimal/genética , Humanos , Inmunofenotipificación , Esferoides Celulares , Células Tumorales Cultivadas , Vía de Señalización Wnt/efectos de los fármacosRESUMEN
BACKGROUND: In a randomized phase III study (BREAK-3), dabrafenib showed prolonged progression-free survival (PFS) (median 5.1 versus 2.7 months; hazard ratio = 0.30; 95% confidence interval 0.18-0.53; P < 0.0001) compared with dacarbazine (DTIC) in patients with BRAF V600E metastatic melanoma. Assessing how these results are transformed into a real health benefit for patients is crucial. METHODS: The EORTC QLQ-C30 questionnaire assessed quality of life (QoL) at baseline and follow-up visits. RESULTS: For DTIC, all functional dimensions except role dimension worsened from baseline at follow-up. For dabrafenib, all functionality dimensions remained stable relative to baseline or improved at week 6; mean change in seven symptom dimensions improved from baseline, with appetite loss, insomnia, nausea and vomiting, and pain showing the greatest improvement. In the DTIC arm, symptom dimensions were unchanged or worsened from baseline for all symptoms except pain (week 6), with the greatest exacerbations observed for fatigue and nausea and vomiting. Mixed-model-repeated measures analyses showed significant (P < 0.05) and/or clinically meaningful improvements from baseline in favor of dabrafenib for emotional and social functioning, nausea and vomiting, appetite loss, diarrhea, fatigue, dyspnea, and insomnia at weeks 6 and/or 12. After crossing over to dabrafenib upon progression (n = 35), improvements in all QoL dimensions were evident after receiving dabrafenib for 6 (n = 31) to 12 (n = 25) weeks. CONCLUSIONS: This first reported QoL analysis for a BRAF inhibitor in metastatic melanoma demonstrates that the high tumor response rates and PFS superiority of dabrafenib over DTIC is not only a theoretical advantage, but also transforms in a rapid functional and symptomatic benefit for the patient. ClinicalTrials.gov Identifier: NCT01227889.
Asunto(s)
Antineoplásicos/uso terapéutico , Dacarbazina/uso terapéutico , Imidazoles/uso terapéutico , Melanoma/tratamiento farmacológico , Metástasis de la Neoplasia , Oximas/uso terapéutico , Calidad de Vida , Humanos , Melanoma/patologíaRESUMEN
BACKGROUND: Breslow thickness is the most important predictor of survival in localized malignant melanoma. A number of melanoma risk factors have been shown to be associated with Breslow thickness; however, the role of genetic loci has been little investigated to date. OBJECTIVES: To investigate the association of known melanoma susceptibility genetic loci with Breslow thickness. METHODS: Participants were 800 individuals from the Western Australian Melanoma Health Study who completed a questionnaire and provided a DNA sample. Genetic association analyses between single-nucleotide polymorphisms (SNPs) from 15 candidate melanoma susceptibility genes and Breslow thickness were performed, controlling for relevant covariates. RESULTS: Older age at diagnosis and absence of naevi were associated with increased Breslow thickness. Following adjustment for multiple testing, no SNPs were significantly associated with Breslow thickness. CONCLUSIONS: Associations observed between Breslow thickness and age and naevi reinforce current knowledge. Some evidence of shared genetic determinants between melanoma risk and Breslow thickness was found. Further studies are required to confirm this finding.
Asunto(s)
Melanoma/genética , Polimorfismo de Nucleótido Simple/genética , Neoplasias Cutáneas/genética , Femenino , Frecuencia de los Genes , Predisposición Genética a la Enfermedad/epidemiología , Predisposición Genética a la Enfermedad/genética , Genotipo , Humanos , Masculino , Melanoma/epidemiología , Melanoma/patología , Persona de Mediana Edad , Sistema de Registros , Factores de Riesgo , Neoplasias Cutáneas/epidemiología , Neoplasias Cutáneas/patología , Australia Occidental/epidemiologíaRESUMEN
We present three patients with lung nodules with an antecedent history of primary cutaneous melanoma or metastasis of melanoma to extrathoracic lymph nodes. Based on radiological findings, it was suspected that these patients had metastatic disease. Subsequent investigations confirmed the cause of the nodules was non-tuberculous mycobacterial infection. We discuss the similarities in symptoms and radiological features between atypical mycobacterial infections and metastatic disease and why a biopsy is important prior to planning a patient's treatment.
Asunto(s)
Neoplasias Pulmonares/secundario , Melanoma/diagnóstico , Melanoma/secundario , Mycobacterium/aislamiento & purificación , Neumonía Bacteriana/diagnóstico , Neoplasias Cutáneas/diagnóstico , Adulto , Anciano de 80 o más Años , Infecciones Bacterianas/complicaciones , Infecciones Bacterianas/diagnóstico , Infecciones Bacterianas/terapia , Diagnóstico Diferencial , Femenino , Humanos , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/microbiología , Masculino , Melanoma/microbiología , Persona de Mediana Edad , Mycobacterium/patogenicidad , Neumonía Bacteriana/complicaciones , Neumonía Bacteriana/terapia , Neoplasias Cutáneas/complicaciones , Neoplasias Cutáneas/microbiologíaRESUMEN
BACKGROUND: Tremelimumab, a fully human cytotoxic T-lymphocyte antigen 4 monoclonal antibody, and PF-3512676, a Toll-like receptor-9 agonist, are targeted immune modulators that elicit durable single-agent antitumour activity in advanced cancer. METHODS: To determine the maximum tolerated dose (MTD) of these agents combined during this phase I study, patients received intravenous tremelimumab (6.0, 10.0, or 15.0 mg kg(-1)) every 12 weeks plus subcutaneous PF-3512676 (0.05, 0.10, or 0.15 mg kg(-1)) weekly. Primary end points were safety and tolerability; secondary end points included pharmacokinetics and antitumour activity. RESULTS: Twenty-one patients with stage IV melanoma (n=17) or advanced solid tumours (n=4) were enrolled. Injection-site reactions (n=21; 100%), influenza-like illness (n=18; 86%), and diarrhoea (n=13; 62%) were the most common treatment-related adverse events (TAEs). Grade ≥3 TAEs were reported (n=7; 33%). Dose-limiting toxicities (prespecified 6-week observation) occurred in one of the six patients in the 10 mg kg(-1) tremelimumab plus 0.05 mg kg(-1) PF-3512676 cohort (grade 3 hypothalamopituitary disorder) and two of the six patients in the 15 mg kg(-1) tremelimumab plus 0.05 mg kg(-1) PF-3512676 cohort (grade 3 diarrhoea). Consequently, 15 mg kg(-1) tremelimumab plus 0.05 mg kg(-1) PF-3512676 exceeded the MTD. Two melanoma patients achieved durable (≥170 days) partial response. No human antihuman antibody responses to tremelimumab were observed. CONCLUSION: Weekly PF-3512676 (≤0.15 mg kg(-1)) plus tremelimumab (≤10 mg kg(-1) every 12 weeks) was tolerable.
Asunto(s)
Anticuerpos Monoclonales/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Melanoma/tratamiento farmacológico , Neoplasias/tratamiento farmacológico , Oligodesoxirribonucleótidos/administración & dosificación , Neoplasias Cutáneas/tratamiento farmacológico , Adulto , Anciano , Anciano de 80 o más Años , Anticuerpos Monoclonales/efectos adversos , Anticuerpos Monoclonales/farmacocinética , Anticuerpos Monoclonales Humanizados , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Progresión de la Enfermedad , Femenino , Humanos , Masculino , Melanoma/metabolismo , Melanoma/patología , Persona de Mediana Edad , Neoplasias/metabolismo , Neoplasias/patología , Oligodesoxirribonucleótidos/efectos adversos , Oligodesoxirribonucleótidos/farmacocinética , Neoplasias Cutáneas/metabolismo , Neoplasias Cutáneas/patología , Resultado del Tratamiento , Adulto JovenRESUMEN
BACKGROUND: Multimarker quantitative real-time polymerase chain reaction (qRT-PCR) represents an effective method for detecting circulating tumour cells in the peripheral blood of patients with melanoma. OBJECTIVES: To investigate whether the phenotype of circulating melanoma cells represents a useful indicator of disease stage, recurrence and treatment efficacy. METHODS: Peripheral blood was collected from 230 patients with melanoma and 152 healthy controls over a period of 3years and 9months. Clinical data and blood samples were collected from patients with primary melanoma (early stages, 0-II, n=154) and metastatic melanoma (late stages, III-IV, n=76). Each specimen was examined by qRT-PCR analysis for the expression of five markers: MLANA, ABCB5, TGFß2, PAX3d and MCAM. RESULTS: In total, 212 of the patients with melanoma (92%) expressed markers in their peripheral blood. Two markers, MLANA and ABCB5, had the greatest prognostic value, and were identified as statistically significant among patients who experienced disease recurrence within our study period, being expressed in 45% (MLANA) and 49% (ABCB5) of patients with recurrence (P=0·001 and P=0·031, respectively). For patients administered nonsurgical treatments, MCAM expression correlated with poor treatment outcome. CONCLUSIONS: Circulating tumour cells were detectable at all stages of disease and long after surgical treatment, even when patients were considered disease free. Specifically, expression of ABCB5 and MLANA had significant prognostic value in inferring disease recurrence, while MCAM expression was associated with poor patient outcome after treatment, confirming multimarker qRT-PCR as a potential technique for monitoring disease status.
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Biomarcadores de Tumor/sangre , Melanoma/patología , Recurrencia Local de Neoplasia/patología , Células Neoplásicas Circulantes/patología , Neoplasias Cutáneas/patología , Adulto , Anciano , Anciano de 80 o más Años , Estudios de Casos y Controles , Femenino , Humanos , Masculino , Melanoma/sangre , Melanoma/terapia , Persona de Mediana Edad , Fenotipo , Reacción en Cadena en Tiempo Real de la Polimerasa , Neoplasias Cutáneas/sangre , Neoplasias Cutáneas/terapia , Resultado del Tratamiento , Carga Tumoral , Adulto JovenRESUMEN
The greatest potential for improvement of outcome for patients with Cutaneous Malignant Melanoma lies in the prevention of systemic metastasis. Despite extensive investigation, current prognostic indicators either alone or in combination, although related to melanoma progression, are not sufficient to accurately predict the pattern of progression and outcome for any individual patient. Metastasis related death has been recorded in patients initially diagnosed with early stage tumour as well as in patients many years after initial tumour removal. The trouble finding a predictable pattern in the puzzle of melanoma progression may be linked to the fact that most of the material studied for prognosis is either, cutaneous primaries or metastatic deposits, rather than the melanoma cells in the circulatory system which are responsible for disease progression. In this review article we discuss the potential use of circulating tumour cell (CTC) detection and quantification for identifying patients at risk of metastatic deposits. We also discuss current therapies for the treatment of metastatic melanoma and analyse how CTCs may be used to evaluate the effectiveness of current therapies and to pinpoint patients who require further treatment.
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Melanoma/diagnóstico , Melanoma/terapia , Metástasis de la Neoplasia/diagnóstico , Metástasis de la Neoplasia/terapia , Células Neoplásicas Circulantes/patología , Neoplasias Cutáneas/genética , Neoplasias Cutáneas/patología , Progresión de la Enfermedad , Humanos , Melanoma/genética , Melanoma/patología , Metástasis de la Neoplasia/genética , Metástasis de la Neoplasia/patología , Pronóstico , Neoplasias Cutáneas/diagnóstico , Neoplasias Cutáneas/terapiaRESUMEN
PURPOSE: Fenretinide is a synthetic retinoid with activity in prostate cancer and other cell lines. The aim of this study was to assess the efficacy and tolerability of fenretinide in chemotherapy-naïve men with hormone refractory prostate cancer. METHODS: Eligibility criteria included hormone refractory prostate cancer with a rising PSA at least 6 weeks after peripheral anti-androgen withdrawal, ECOG performance status (PS) 0-1, and no prior chemotherapy. Fenretinide was administered orally at 900 mg m(-2) twice daily for 7 of every 21 days. PSA was measured before each cycle. The primary endpoint was a > or =50% reduction in PSA maintained for at least 3 weeks; secondary endpoints included duration of PSA response, time to treatment failure (TTF: treatment stopped for progression or toxicity) and adverse events (AE). RESULTS: Twenty seven pts were recruited from 7 centres over 27 months. Median age was 74 (range 49-86), median baseline PSA was 129 (range 19-1,000), and 70% had a PS of 0. The median number of cycles received was 2 (range 0-11) and 20 pts completed at least 1 cycle. One pt (4%) achieved a 50% reduction in PSA lasting 39 days and 15 pts (56%) had not progressed within 6 weeks of starting fenretinide. The median TTF was 54 days (IQR 19-73): 22 (81%) failed with tumour progression, 3 (11%) failed with toxicity and 2 (7%) never commenced the drug. Grade 3 rash occurred in 1 patient, all other AE were grade 1 or 2. The most common AE were nausea (40%), hot flushes (36%), constipation (32%) and nyctalopia (32%). CONCLUSION: High-dose fenretinide had limited anti-tumour activity in patients with advanced hormone refractory prostate cancer: further evaluation in this setting is not warranted.