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INTRODUCTION: CDK4/6 inhibitors (ribociclib, palbociclib and abemaciclib) are 1st line therapy in metastatic breast cancer (MBC). No comparative data exists between agents regarding toxicity or efficacy. METHODS: A retrospective study was performed at our tertiary referral centre evaluating patients on a CDK4/6 inhibitor for MBC between July 2017 and December 2021. Toxicity was evaluated along with variability in full blood counts and liver function over the first 12 weeks of therapy. RESULTS: Two hundred and seventeen patients were treated (palbociclib 59%, abemaciclib 25% and ribociclib 16%). 86% received the agent as 1st line therapy. Most patients were white women with a median age of 61 years (32-95) and ECOG 0/1. Twelve patients were switched to an alternative CDK4/6 inhibitor due to toxicity and two did not tolerate this. Toxicity profiles of agents were consistent with published trials. However, there was greater overlap in hepatitis, diarrhoea and bone marrow suppression. Blood results indicated a minimum of four weeks treatment before development of neutropenia. Forty percent of patients went onto have subsequent lines of therapy. The progression-free survival per agent was palbociclib 27.9 months (95% CI 23-32.5), ribociclib 29 months (95% CI 21.5-37.0) and abemaciclib 20.6 months (95% CI 15.0-26.0). The overall survival was palbociclib 38.0 months (95% CI 33.5-42.5), ribociclib 33.9 months (95% CI 26.7-41.1) and abemaciclib 27.3 months (95% CI 22.5-32.1). CONCLUSIONS: Toxicity across CDK4/6 inhibitors overlaps. The optimal sequence of therapies post CDK4/6 inhibitors remains unknown but rechallenge with an alternative agent is possible.
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Neoplasias da Mama , Humanos , Feminino , Adulto , Pessoa de Meia-Idade , Idoso , Idoso de 80 Anos ou mais , Neoplasias da Mama/tratamento farmacológico , Estudos Retrospectivos , Inibidores de Proteínas Quinases/efeitos adversos , Quinase 4 Dependente de CiclinaRESUMO
INTRODUCTION: Immune-related hepatitis is an adverse effect following treatment with immune-checkpoint inhibitors, such as ipilimumab, nivolumab and pembrolizumab. International guidelines advise on the use of corticosteroids as first-line treatment, although guidance on how to treat cases resistant to corticosteroids is limited. We aimed to evaluate the presentation and management of patients with grade 3-4 immune-related hepatitis, following treatment with immune-checkpoint inhibitors for stage 4 or unresectable or stage 3 melanoma, with a particular focus on steroid-refractory cases. METHODS: A retrospective observational review of patients developing immune-related hepatitis whilst undergoing treatment with immune checkpoint inhibitors for advanced melanoma from July 2014 to February 2020 at a tertiary oncology centre. RESULTS: Forty-one patients developed immune-related hepatitis, of which 83% had been treated with the combination of ipilimumab and nivolumab. The median time to onset of IR-hepatitis was 47 days (range: 4-476), and the median time to peak alanine aminotransferase was 71 days (range: 4-478). Four patients had resolution of grade 3 immune-related hepatitis without the introduction of corticosteroids. A total of 37 patients were treated with corticosteroids. A total of 12 required oral treatment only and 13 were successfully managed as outpatients. Six patients had steroid-refractory immune-related hepatitis; and all received tacrolimus, with one also receiving mycophenolate mofetil and infliximab. CONCLUSIONS: This study describes the largest UK series of immune-related hepatitis patients in the literature. We present two important deviations from current guidelines. Firstly, there is some evidence that withholding steroids is possible in grade 3-4 immune-related hepatitis. Secondly, tacrolimus can be used successfully to manage patients resistant to corticosteroids, with the early introduction most beneficial to reduce time on steroids.
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Hepatite , Melanoma , Humanos , Ipilimumab/efeitos adversos , Nivolumabe/efeitos adversos , Inibidores de Checkpoint Imunológico/efeitos adversos , Tacrolimo/uso terapêutico , Estudos Retrospectivos , Melanoma/tratamento farmacológico , Melanoma/patologiaRESUMO
Adoptive cell therapy using autologous tumor-infiltrating lymphocytes (TIL) has shown significant clinical benefit, but is limited by toxicities due to a requirement for post-infusion interleukin-2 (IL-2), for which high dose is standard. To assess a modified TIL protocol using lower dose IL-2, we performed a single institution phase II protocol in unresectable, metastatic melanoma. The primary endpoint was response rate. Secondary endpoints were safety and assessment of immune correlates following TIL infusion. Twelve metastatic melanoma patients were treated with non-myeloablative lymphodepleting chemotherapy, TIL, and low-dose subcutaneous IL-2 (125,000 IU/kg/day, maximum 9-10 doses over 2 weeks). All but one patient had previously progressed after treatment with immune checkpoint inhibitors. No unexpected adverse events were observed, and patients received an average of 6.8 doses of IL-2. By RECIST v1.1, two patients experienced a partial response, one patient had an unconfirmed partial response, and six had stable disease. Biomarker assessment confirmed an increase in IL-15 levels following lymphodepleting chemotherapy as expected and a lack of peripheral regulatory T-cell expansion following protocol treatment. Interrogation of the TIL infusion product and monitoring of the peripheral blood following infusion suggested engraftment of TIL. In one responding patient, a population of T cells expressing a T-cell receptor Vß chain that was dominant in the infusion product was present at a high percentage in peripheral blood more than 2 years after TIL infusion. This study shows that this protocol of low-dose IL-2 following adoptive cell transfer of TIL is feasible and clinically active. (ClinicalTrials.gov identifier NCT01883323.).
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Imunoterapia Adotiva/métodos , Interleucina-2/uso terapêutico , Linfócitos do Interstício Tumoral/imunologia , Melanoma/terapia , Neoplasias Cutâneas/terapia , Adulto , Proliferação de Células , Células Cultivadas , Feminino , Humanos , Interleucina-15/metabolismo , Linfócitos do Interstício Tumoral/transplante , Masculino , Melanoma/imunologia , Pessoa de Meia-Idade , Metástase Neoplásica , Neoplasias Cutâneas/imunologia , Resultado do TratamentoRESUMO
BACKGROUND: The new American Joint Committee on Cancer eighth edition (AJCC8) staging is the first to describe separate clinical and pathology staging systems, but still has low performance to predict prognosis in patients with oesophageal/gastroesophageal junction (O/GOJ) adenocarcinoma, who are candidates for surgery. Recent studies have demonstrated that O/GOJ cancer patients with 18F-fluorodeoxyglucose (FDG) avid regional lymph nodes (RLNs) may have poor prognosis. The aim of our study was to examine whether the baseline assessment of the FDG uptake of RLN improves the prognostic accuracy of the new AJCC8 staging. PATIENTS AND METHODS: This single-centre retrospective study included patients with operable FDG avid O/GOJ adenocarcinoma treated with perioperative chemotherapy. All patients were reclassified according to the new AJCC8 clinical staging. Prognostic factors for time-to-progression (TTP) and overall survival (OS) were explored. RESULTS: Of 430 patients included in the study, 180 (41.9%) had FDG avid RLN at baseline PET/CT scan before starting perioperative chemotherapy. The presence of FDG avid RLN was significantly and independently associated with shorter TTP and OS, especially in clinical stage III patients (p < .001 in both cases). Stage III patients with FDG avid RLN had similar TTP and OS to those with stage IVA. Classifying stage III patients with FDG avid RLN into stage IVA led to a significant improvement of the prognostic accuracy of the new AJCC8 clinical staging system (Harrell's concordance index improved from 0.555 to 0.588, p < .001). Of 430 patients starting perioperative chemotherapy, 332 underwent radical tumour resection. The presence of FDG avid RLN before starting perioperative chemotherapy could additionally predict a significantly shorter postoperative time-to-relapse and OS (p < .001 in both cases). CONCLUSIONS: We propose that the incorporation of RLN status (by FDG PET/CT scan) into the AJCC8 staging system of O/GOJ adenocarcinoma improves its prognostic accuracy and may also improve treatment stratification.
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Adenocarcinoma/secundário , Neoplasias Esofágicas/patologia , Junção Esofagogástrica/patologia , Fluordesoxiglucose F18/metabolismo , Linfonodos/patologia , Recidiva Local de Neoplasia/patologia , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada/métodos , Adenocarcinoma/diagnóstico por imagem , Adenocarcinoma/metabolismo , Adenocarcinoma/cirurgia , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias Esofágicas/diagnóstico por imagem , Neoplasias Esofágicas/metabolismo , Neoplasias Esofágicas/cirurgia , Junção Esofagogástrica/diagnóstico por imagem , Junção Esofagogástrica/metabolismo , Junção Esofagogástrica/cirurgia , Feminino , Humanos , Linfonodos/diagnóstico por imagem , Linfonodos/cirurgia , Metástase Linfática , Masculino , Pessoa de Meia-Idade , Imagem Multimodal , Recidiva Local de Neoplasia/diagnóstico por imagem , Recidiva Local de Neoplasia/metabolismo , Recidiva Local de Neoplasia/cirurgia , Prognóstico , Compostos Radiofarmacêuticos/metabolismo , Estudos RetrospectivosRESUMO
AIM: Malignant bowel obstruction (MBO) in ovarian cancer is poorly understood. METHODS: This retrospective cohort study analyzed 129 patients with ovarian cancer and MBO. RESULTS: At presentation, 69 (53%) had platinum-resistant, 37 (29%) platinum-sensitive and 23 (18%) chemotherapy-naive disease. In patients receiving chemotherapy following the MBO episode, median overall survival (OS) was 107 days for chemotherapy-naive patients compared with 83 and 86 for platinum-sensitive or platinum-resistant patients (p = 0.98). OS was inferior for best supportive care (45 days) compared with chemotherapy (152 days) or surgery (124 days; p < 0.001). The Manchester Bowel Obstruction Score using Eastern Cooperative Oncology Group and obstruction level discriminated patients by median OS of 181 days (neither) versus 98 days (one) versus 42 days (both; p < 0.01). CONCLUSION: The Manchester Bowel Obstruction Score may aide treatment stratification.
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Obstrução Intestinal/diagnóstico , Obstrução Intestinal/etiologia , Neoplasias Ovarianas/complicações , Neoplasias Ovarianas/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Gerenciamento Clínico , Feminino , Humanos , Obstrução Intestinal/cirurgia , Obstrução Intestinal/terapia , Estimativa de Kaplan-Meier , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/mortalidade , Modelos de Riscos Proporcionais , Estudos Retrospectivos , Resultado do TratamentoRESUMO
BACKGROUND: Radiological assessment of response to checkpoint inhibitors remains imperfect. We evaluated individual lesion and inter-patient response by response evaluation (RECIST) 1.1, immune-related response criteria (irRC), CHOI and modified CHOI (mCHOI) and correlated response with overall survival (OS). METHODS: Thirty-seven patients with 567 measurable lesions treated with pembrolizumab in the Keynote 001 trial were studied. Association of response with OS was determined. RESULTS: Response varied according to site; lung lesions had the highest rate of complete response (69 out of 163 (42%) vs other sites 71 out of 404 (18%), P<0.0001). Delayed response post first scan was seen in 2 out of 37 (5%) deemed progressive (PD) by RECIST and 2 out of 14 (14%) deemed PD by irRC. Modified CHOI criteria showed response of 38% (14 out of 37). Change in tumour size and density on first follow-up assessment was associated with OS with each 1000 mm2 increase in tumour size from baseline increasing the hazard of dying by 25.9% (HR=1.259, (95% CI=1.116-1.420), P=0.0002). Similarly, each 20HU increase in density increased the HR by 15% (HR=1.15, (95% CI 1.045-1.260), P=0.004). Response defined by any criteria had superior OS (CHOI P=0.0084; mCHOI P=0.0183; irRC P<0.0001 and RECIST P=0.0003). CONCLUSIONS: Response by any criterion was prognostic. Novel patterns of response and changes on treatment in tumour density suggest complex anti-tumour responses to immunotherapy.
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Antineoplásicos/uso terapêutico , Melanoma/tratamento farmacológico , Melanoma/mortalidade , Receptor de Morte Celular Programada 1/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais Humanizados/uso terapêutico , Feminino , Humanos , Masculino , Melanoma/metabolismo , Melanoma/patologia , Pessoa de Meia-Idade , Critérios de Avaliação de Resposta em Tumores Sólidos , Estudos Retrospectivos , Resultado do TratamentoRESUMO
BACKGROUND: Cabozantinib is an orally available inhibitor of tyrosine kinases including VEGFR2 and c-MET. We performed a post hoc analysis to find associations between select plasma biomarkers and treatment response in patients (pts) with metastatic castration resistant prostate cancer (mCRPC) who received cabozantinib 100 mg daily as part of a phase 2 non-randomized expansion cohort (NCT00940225). METHODS: Plasma samples were collected at baseline, 6 weeks and at time of maximal response from 81 mCRPC pts with bone metastases, of which 33 also had measurable soft-tissue disease. Levels of 27 biomarkers were measured in duplicate using enzyme-linked immunosorbent assay. Spearman correlation coefficients were calculated for the association between biomarker levels or their change on treatment and either bone scan response (BSR) or soft tissue response according to RECIST. RESULTS: A BSR and RECIST response were seen in 66/81 pts (81 %) and 6/33 pts (18 %) respectively. No significant associations were found between any biomarker at any time point and either type of response. Plasma concentrations of VEGFA, FLT3L, c-MET, AXL, Gas6A, bone-specific alkaline phosphatase, interleukin-8 and the hypoxia markers CA9 and clusterin significantly increased during treatment with cabozantinib irrespective of response. The plasma concentrations of VEGFR2, Trap5b, Angiopoietin-2, TIMP-2 and TIE-2 significantly decreased during treatment with caboznatinib. CONCLUSIONS: Our data did not reveal plasma biomarkers associated with response to cabozantinib. The observed alterations in several biomarkers during treatment with cabozantinib may provide insights on the effects of cabozantinib on tumor cells and on tumor micro-environment and may help point to potential co-targeting approaches.
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Anilidas/uso terapêutico , Biomarcadores Tumorais/sangue , Neoplasias de Próstata Resistentes à Castração/sangue , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Piridinas/uso terapêutico , Humanos , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Neoplasias de Próstata Resistentes à Castração/patologia , Reprodutibilidade dos Testes , Estatísticas não ParamétricasRESUMO
BACKGROUND: The vascular endothelial growth factor pathway is strongly implicated in cancer-related angiogenesis. Antiangiogenic agents such as bevacizumab commonly cause hypertension (HTN) and proteinuria (PTN), which may be biomarkers of response and clinical outcome. STUDY: We conducted a retrospective analysis of patients with histologically proven metastatic colorectal cancer (mCRC) treated with either bevacizumab or a tyrosine kinase inhibitor in combination with chemotherapy at The Christie Hospital from January 2006 to September 2009. RESULTS: Of 90 patients evaluated, 50 were eligible. Seventeen (34%), 4 (8%), and 3 (6%) patients developed Common Toxicity Criteria (v 3.0) grades 1, 2, and 3 HTN, respectively. Response rates were 42% for patients with grades 0 to 1 HTN compared with 86% for patients with ≥grade 2 HTN (P=0.043). Median overall survival was 21.6 months for patients with grades 0 to 1 HTN and 25.2 months for patients with ≥grade 2 HTN (P=0.270). Twelve patients (24%) developed grade 1 PTN and 4 patients (8%) developed ≥grade 2 PTN. Median overall survival was 23.9 months for patients with grades 0 to 1 PTN and 4.2 months for those with ≥grade 2 PTN (P=0.028). CONCLUSIONS: To our knowledge, this is the first study to demonstrate the utility of PTN as a surrogate marker of outcome in antiangiogenic therapy for metastatic colorectal cancer. Although HTN is predictive of a significantly higher response rate, the development of PTN during treatment with bevacizumab or tyrosine kinase inhibitor portends poorer survival and should be evaluated prospectively.
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Inibidores da Angiogênese/uso terapêutico , Antineoplásicos/uso terapêutico , Neoplasias Colorretais/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Inibidores da Angiogênese/efeitos adversos , Anticorpos Monoclonais Humanizados/efeitos adversos , Anticorpos Monoclonais Humanizados/uso terapêutico , Antineoplásicos/efeitos adversos , Bevacizumab , Neoplasias Colorretais/irrigação sanguínea , Neoplasias Colorretais/patologia , Feminino , Humanos , Hipertensão/induzido quimicamente , Hipertensão/epidemiologia , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Neovascularização Patológica/tratamento farmacológico , Inibidores de Proteínas Quinases/efeitos adversos , Inibidores de Proteínas Quinases/uso terapêutico , Proteinúria/induzido quimicamente , Proteinúria/epidemiologia , Estudos Retrospectivos , Análise de Sobrevida , Taxa de Sobrevida , Resultado do Tratamento , Fator A de Crescimento do Endotélio Vascular/antagonistas & inibidores , Fator A de Crescimento do Endotélio Vascular/metabolismoRESUMO
BACKGROUND: Circulating tumour cells (CTC) are receiving increasing attention as prognostic, predictive and pharmacodynamic biomarkers in cancer patients. However, their clinical significance can be dependent on an accurate determination of CTC around cut-off values at low cell counts (<10 cells/7.5 ml). Consequently, we have conducted method validation of the CellSearch™ system focusing on clinical samples containing CTC in the cut-off region. METHODS: Analytical accuracy was first assessed employing quality controls (QC) and spiked healthy volunteer blood specimens. Results were analysed by ß-expectation tolerance intervals (BETI). Inter-operator error (6 different readers) was then characterised in 38 different patient samples, 68% of which had ≤5 CTC and data were analysed by ß-content γ-confidence tolerance intervals (BCTI). RESULTS: Results from QCs and spiked blood confirmed a 3-4-fold higher degree of imprecision at the low (48 cells, BETI = + 0.288/-0.345, ß = 95%) compared to the high QC (987 cells, BETI = +0.065/-0.140, ß = 95%). However, when data for individual analysts were interrogated characteristic systematic errors were detected. In the analysis of patient samples again individual analysts introduced a highly specific error into the interpretation of CTC images, which correlated to the level of training and experience. When readers were selected based on BETI and BCTI results, the high level of between-operator error (up to 170%) observed at CTC of ≤ 5 was reduced to < 30%. CONCLUSIONS: Inter-operator variability in enumeration of CTC at low cell counts can be considerable, but is also potentially avoidable by following simple guidance steps.
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Contagem de Células/métodos , Neoplasias/patologia , Células Neoplásicas Circulantes , Biomarcadores Tumorais , Contagem de Células/instrumentação , Contagem de Células/normas , Humanos , Separação Imunomagnética/instrumentação , Separação Imunomagnética/métodos , Microscopia de Fluorescência/instrumentação , Microscopia de Fluorescência/métodos , Neoplasias/diagnóstico , Controle de Qualidade , Reprodutibilidade dos TestesRESUMO
PURPOSE: Extracellular vesicles (EV) secreted from cancer cells are present in various biological fluids, carrying distinctly different cellular components compared to normal cells, and have great potential to be used as markers for disease initiation, progression, and response to treatment. This under-utilised tool provides insights into a better understanding of prostate cancer. METHODS: EV from serum and urine of healthy men and castration-resistant prostate cancer (CRPC) patients were isolated and characterised by transmission electron microscopy, particle size analysis, and western blot. Proteomic and cholesterol liquid chromatography-mass spectrometry (LC-MS) analyses were conducted. RESULTS: There was a successful enrichment of small EV/exosomes isolated from serum and urine. EV derived from biological fluids of CRPC patients had significant differences in composition when compared with those from healthy controls. Analysis of matched serum and urine samples from six prostate cancer patients revealed specific EV proteins common in both types of biological fluid for each patient. CONCLUSION: Some of the EV proteins identified from our analyses have potential to be used as CRPC markers. These markers may depict a pattern in cancer progression through non-invasive sample collection.
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Líquidos Corporais , Exossomos , Vesículas Extracelulares , Neoplasias de Próstata Resistentes à Castração , Masculino , Humanos , Proteômica , Vesículas Extracelulares/metabolismoRESUMO
INTRODUCTION: Circulating tumour DNA (ctDNA) is an emerging biomarker in melanoma. We performed a systematic review and meta-analysis to explore its clinical utility as a prognostic, pharmacodynamic (PD) and predictive biomarker. METHODS: A systematic search was conducted from Jan 2015 to April 2021, of the electronic databases PubMed, Cochrane Library and Ovid MEDLINE to identify studies. Studies were restricted to those published in English within the last 5 years, evaluating ctDNA in humans in ≥10 patients. Survival data were extracted for meta-analysis using pooled treatment effect (TE), i.e. log hazard ratios (HRs) and corresponding standard error of TE for progression-free survival or overall survival differences in patients who were ctDNA positive or negative. PRISMA statement guidelines were followed. RESULTS: A meta-analysis of 19 studies grouped according to methodology of ctDNA detection, revealed a combined estimate for HR of progression-free survival (13 studies using droplet digital Polymerase Chain Reaction (ddPCR) methodology (N = 1002) of 2.10 (95% CI: 1.71-2.59) revealing a poorer prognosis when ctDNA was detected. This result was confirmed in the smaller analysis of (non-ddPCR, N = 347) five studies: HR = 2.45 (95% CI: 1.29-4.63). Similar findings were found in the overall survival analysis of nine studies (ddPCR methodology, N = 841) where the combined HR was 2.78 (95% CI: 2.21-3.49) and of the five studies (non-ddPCR methodology, N = 326) where the combined HR was 2.58 (95% CI: 1.74-3.84). Serial ctDNA levels on treatment showed a pharmacodynamic role reflecting response or resistance earlier than radiological assessment. CONCLUSIONS: Circulating tumour DNA is a predictive, prognostic and PD biomarker in melanoma. Technical standardisation of assays is required before clinical adoption.
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Over the past two decades, there has been a fundamental shift away from traditional cytotoxic chemotherapy towards the identification, and subsequent suppression of specific oncogenes. Immunotherapy and targeted therapy prime the immune system, potentially leading to deleterious side effects. The following case of Guillain-Barré Syndrome (GBS) emphasizes the importance of considering every agent when iatrogenic toxicity is suspected. We underline the possibility of immune priming by checkpoint inhibitors. An optimal understanding of the pathogenesis and toxicity of targeted therapy is key in an era where the prognosis of melanoma is revolutionized by the use of novel agents. Our case emphasizes the importance of considering every agent in the context of toxicity induced by combined novel therapies.
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Metastatic melanoma carries a poor prognosis despite modern systemic therapies. Understanding the evolution of the disease could help inform patient management. Through whole-genome sequencing of 13 melanoma metastases sampled at autopsy from a treatment naïve patient and by leveraging the analytical power of multi-sample analyses, we reveal evidence of diversification among metastatic lineages. UV-induced mutations dominate the trunk, whereas APOBEC-associated mutations are found in the branches of the evolutionary tree. Multi-sample analyses from a further seven patients confirmed that lineage diversification was pervasive, representing an important mode of melanoma dissemination. Our analyses demonstrate that joint analysis of cancer cell fraction estimates across multiple metastases can uncover previously unrecognised levels of tumour heterogeneity and highlight the limitations of inferring heterogeneity from a single biopsy.
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Evolução Clonal , Heterogeneidade Genética , Melanoma/genética , Neoplasias Cutâneas/genética , Idoso , Biópsia , Análise Mutacional de DNA , Humanos , Masculino , Melanoma/secundário , Estudos Prospectivos , Pele/patologia , Neoplasias Cutâneas/patologia , Sequenciamento Completo do GenomaRESUMO
Metastatic uveal melanoma (MUM) has a poor prognosis, with no established standard of care. Delineation of prognostic factors in MUM patients may enable stratified treatment algorithms of stage-specific survival. Overall, 132 MUM patients who presented to a single tertiary institution in Toronto, Canada, over 12 years were identified and data (demographics, clinical status, radiographic images, and laboratory values) were extracted. Associations with systemic first-line treatment outcome 12 weeks after first-line treatment, time to progression (TTP), and overall survival (OS) were explored by univariate and multivariable analysis. Age, presence of liver metastases, and time from primary presentation to metastatic presentation were significant variables affecting first-line treatment outcomes. Age, Eastern Cooperative Oncology Group (ECOG) score, presence of liver metastases, liver metastasis size, neutrophil lymphocyte ratio, absolute neutrophil count, lactate dehydrogenase (LDH), alkaline phosphatase, time from primary presentation to metastatic presentation, and patients receiving surgery as the first-line treatment were significant variables affecting TTP. Age, ECOG score, presence of liver metastases, liver metastasis size, neutrophil lymphocyte ratio, absolute neutrophil count, LDH, and alkaline phosphatase were significant variables affecting OS. Patients who underwent surgery, chemotherapy, immunotherapy, liver-directed therapy, or targeted therapy had better OS compared with patients not receiving treatment with surgery, associated with a significantly better OS compared with all other therapies. Multivariable analysis showed increased age, absence of liver metastases, and absence of bone metastases to be associated with positive treatment outcomes. ECOG score of at least 1, increased LDH, and decreased time from primary to metastatic presentation would predict decreased TTP. Increased LDH, older age, and ECOG score of at least 1 were associated with decreased OS. These results identified prognostic markers and models thereof of treatment benefit and survival. Further validation in larger cohorts is required.
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Melanoma/tratamento farmacológico , Neoplasias Cutâneas/tratamento farmacológico , Neoplasias Uveais/tratamento farmacológico , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Canadá , Criança , Feminino , Humanos , Masculino , Melanoma/mortalidade , Melanoma/patologia , Pessoa de Meia-Idade , Prognóstico , Neoplasias Cutâneas/mortalidade , Neoplasias Cutâneas/patologia , Análise de Sobrevida , Neoplasias Uveais/mortalidade , Neoplasias Uveais/patologia , Adulto JovemRESUMO
INTRODUCTION: Programmed death-1 (PD-1) axis inhibitors have become standard therapy in advanced non-small-cell lung cancer (NSCLC). Response might be delayed and pseudo-progression occasionally occurs in patients who eventually benefit from treatment. Additional markers beyond programmed death ligand 1 (PD-L1) expression are needed to assist in patient selection, response evaluation, and treatment decisions. MATERIALS AND METHODS: The relationship between prospectively collected clinical outcomes (response, disease control rate [DCR], treatment duration, overall survival) and hematologic parameters (neutrophil to lymphocyte ratio [NLR], absolute neutrophil count [ANC], and platelet to lymphocyte ratio [PLR]) was explored retrospectively in advanced NSCLC patients treated with PD-1 axis inhibitors at a major cancer center from May 2013 to August 2016. Hematologic parameters at baseline and during treatment (week 2 or 3 and week 8) were included. RESULTS: Of 88 patients treated with PD-1 axis inhibitors, 22 (25%) experienced partial response. Baseline NLR ≤4 was associated with superior DCR (74% vs. 50%; P = .025), treatment duration (P = .037), time to progression (P = .053), and overall survival (P = .019), with no differential association according to PD-L1 tumor expression. Lower NLR and ANC during treatment were also associated with response to treatment (P = .025 and P = .017, respectively), and treatment duration (P = .036 and P = .008). No association was found between baseline PLR and DCR, response, treatment duration, nor overall survival. CONCLUSION: Baseline NLR ≤4 and lower NLR and ANC during treatment might correlate with disease control and treatment response and should be explored further as potential predictors of treatment benefit in larger studies.
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Antineoplásicos Imunológicos/uso terapêutico , Antígeno B7-H1/antagonistas & inibidores , Biomarcadores Tumorais/análise , Carcinoma Pulmonar de Células não Pequenas/patologia , Neoplasias Pulmonares/patologia , Linfócitos/patologia , Neutrófilos/patologia , Adenocarcinoma/tratamento farmacológico , Adenocarcinoma/metabolismo , Adenocarcinoma/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma de Células Grandes/tratamento farmacológico , Carcinoma de Células Grandes/metabolismo , Carcinoma de Células Grandes/patologia , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Carcinoma de Células Escamosas/tratamento farmacológico , Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/patologia , Feminino , Seguimentos , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/metabolismo , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Prospectivos , Taxa de SobrevidaRESUMO
Prostate cancer is a leading cause of cancer-related death in men worldwide. Aberrant signaling in the androgen pathway is critical in the development and progression of prostate cancer. Despite ongoing reliance on androgen receptor (AR) signaling in castrate resistant disease, in addition to the development of potent androgen targeting drugs, patients invariably develop treatment resistance. Interactions between the AR and PI3K pathways may be a mechanism of treatment resistance and inhibitors of this pathway have been developed with variable success. Herein we outline the role of the PI3K pathway in prostate cancer and, in particular, its association with androgen receptor signaling in the pathogenesis and evolution of prostate cancer, as well as a review of the clinical utility of PI3K targeting.
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BACKGROUND: Prognostic models in metastatic castrate resistant prostate cancer (mCRPC) may have clinical utility. Using data from PDS, we aimed to 1) validate a contemporary prognostic model (Templeton et al., 2014) 2) evaluate prognostic impact of concomitant medications and PSA decrease 3) evaluate factors associated with docetaxel toxicity. METHODS: We accessed data on 2,449 mCRPC patients in PDS. The existing model was validated with a continuous risk score, time-dependent receiver operating characteristic (ROC) curves, and corresponding time-dependent Area under the Curve (tAUC). The prognostic effects of concomitant medications and PSA response were assessed by Cox proportional hazards models. One year tAUC was calculated for multivariable prognostic model optimized to our data. Conditional logistic regression models were used to assess associations with grade 3/4 adverse events (G3/4 AE) at baseline and after cycle 1 of treatment. RESULTS: Despite limitations of the PDS data set, the existing model was validated; one year AUC, was 0.68 (95% CI 95% CI, .66 to .71) to 0.78 (95%CI, .74 to .81) depending on the subset of datasets used. A new model was constructed with an AUC of .74 (.72 to .77). Concomitant medications low molecular weight heparin and warfarin were associated with poorer survival, Metformin and Cox2 inhibitors were associated with better outcome. PSA response was associated with survival, the effect of which was greatest early in follow-up. Age was associated with baseline risk of G3/4 AE. The odds of experiencing G3/4 AE later on in treatment were significantly greater for subjects who experienced a G3/4 AE in their first cycle (OR 3.53, 95% CI 2.53-4.91, p < .0001). CONCLUSION: Despite heterogeneous data collection protocols, PDS provides access to large datasets for novel outcomes analysis. In this paper, we demonstrate its utility for validating existing models and novel model generation including the utility of concomitant medications in outcome analyses, as well as the effect of PSA response on survival and toxicity prediction.
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Antineoplásicos/efeitos adversos , Antineoplásicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Antígeno Prostático Específico/sangue , Neoplasias de Próstata Resistentes à Castração , Taxoides/efeitos adversos , Taxoides/uso terapêutico , Área Sob a Curva , Inibidores de Ciclo-Oxigenase 2/efeitos adversos , Inibidores de Ciclo-Oxigenase 2/uso terapêutico , Progressão da Doença , Docetaxel , Heparina de Baixo Peso Molecular/efeitos adversos , Heparina de Baixo Peso Molecular/uso terapêutico , Humanos , Masculino , Metformina/efeitos adversos , Metformina/uso terapêutico , Modelos Teóricos , Modelos de Riscos Proporcionais , Neoplasias de Próstata Resistentes à Castração/sangue , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Neoplasias de Próstata Resistentes à Castração/mortalidade , Curva ROC , Resultado do Tratamento , Varfarina/efeitos adversos , Varfarina/uso terapêuticoRESUMO
Immuno-oncology has changed the landscape of cancer treatment in recent years. Immune checkpoint inhibitors (ICI) have shown survival advantage with long term remissions in a variety of cancers. However, there is another approach to harnessing the power of the immune system in combating cancer: the adoptive cell therapy (ACT) strategy. Although ACT is restricted to small specialized centres and has yet to deliver as much success as ICI, some important results were presented at this year's ASCO meeting. Important lessons have been learned from these studies, including the prospects and challenges ahead. In this editorial, we summarize the important studies on ACT presented at the ASCO 2016 meeting and discuss the way forward.
RESUMO
Approved by the Food and Drug Administration in 2011, the anti-cytotoxic T-lymphocyte-associated protein 4 checkpoint inhibitor ipilimumab has delivered a survival benefit of ≥3 years in a subset of metastatic melanoma patients. After participating in the registration trial, patients were treated with this agent in routine practice. Toxicity and efficacy of agents in "real world" settings may differ from trials. The present study aimed to evaluate, with respect to toxicity and outcome, all patients treated with ipilimumab to date at the Princess Margaret Hospital (Toronto, Canada). Patients treated with ipilimumab between 2008 and 2013 were identified, and patient characteristics (age, gender, tumour burden, oncogenic mutation status, number of treatments received and toxicities from treatment) were collected. Progression-free survival (PFS) and overall survival (OS) were calculated from the commencement of ipilimumab treatment. Associations between clinical characteristics and outcome or toxicity were assessed. Between 2008 and 2013, 129 patients with metastatic cutaneous melanoma were treated. Since, during this period, ipilimumab was approved in the second line setting, ipilimumab was delivered in the second or subsequent line in all patients, and 70% did not receive any further anticancer therapy. Immune-related toxicities were observed, the onset of which varied from 1 to 162 days. The majority resolved within 6 weeks of the final treatment, with the exception of endocrinopathies and bowel related toxicity. The median PFS and OS were 2.83 and 8.44 months, respectively. No pre-treatment factor independently predicted toxicity. The number of infusions (4 vs. ≤3) and presence of toxicity were significantly associated with superior survival. The onset of toxicity secondary to ipilimumab could occur later than previously reported. Toxicities were manageable, but required long-term vigilance.