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BACKGROUND: Indoleamine 2,3-dioxygenase 1 (IDO1) levels correlate with poor outcomes in urothelial carcinoma (UC). IDO1 and programmed death-ligand 1 (PD-L1) are often co-expressed. Epacadostat is a potent and highly selective inhibitor of IDO1. In a subgroup analysis of patients with advanced UC participating in a phase I/II study, epacadostat-pembrolizumab treatment produced an objective response rate (ORR) of 35%. METHODS: ECHO-303/KEYNOTE-698 was a double-blinded, randomized phase III study of adults with metastatic or unresectable locally advanced UC with recurrence or progression following first-line platinum-based chemotherapy. Participants were randomized to epacadostat 100 mg twice daily (BID) plus pembrolizumab or placebo plus pembrolizumab until completion of 35 pembrolizumab infusions, disease progression, or unacceptable toxicity. The primary endpoint was investigator-assessed ORR per Response Evaluation Criteria in Solid Tumors version 1.1. RESULTS: Target enrollment was 648 patients; enrollment was halted early based on efficacy results from the phase III ECHO-301/KEYNOTE-252 study in metastatic melanoma. Forty-two patients were randomized to each treatment arm. Median duration of follow-up was 62 days in each arm. The investigator-assessed ORR (unconfirmed) was 26.2% (95% CI 16.35-48.11) for epacadostat plus pembrolizumab and 11.9% (95% CI 4.67-29.50) for placebo plus pembrolizumab. Two complete responses were reported, both in the placebo-plus-pembrolizumab arm. Circulating kynurenine levels increased from C1D1 to C2D1 in the placebo-plus-pembrolizumab arm and numerically decreased in the epacadostat-plus-pembrolizumab arm. The safety profile of epacadostat plus pembrolizumab was similar to that of pembrolizumab monotherapy, although a numerically greater proportion of patients in the combination vs. control arm experienced treatment-related grade ≥ 3 adverse events (16.7% vs. 7.3%). One patient in each arm died due to cardiovascular events, which were not deemed drug-related. No new safety concerns were identified for either agent. CONCLUSIONS: Epacadostat plus pembrolizumab demonstrated anti-tumor activity and was generally tolerable as second-line treatment of patients with unresectable locally advanced or recurrent/progressive metastatic UC. Epacadostat 100 mg BID, when administered with pembrolizumab, did not normalize circulating kynurenine in most patients. Further study of combined IDO1/PD-L1 inhibition in this patient population, particularly with epacadostat doses that result in durable normalization of circulating kynurenine, may be warranted. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03374488. Registered 12/15/2017.
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Anticuerpos Monoclonales Humanizados , Protocolos de Quimioterapia Combinada Antineoplásica , Sulfonamidas , Humanos , Anticuerpos Monoclonales Humanizados/administración & dosificación , Anticuerpos Monoclonales Humanizados/uso terapéutico , Masculino , Femenino , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Anciano , Persona de Mediana Edad , Método Doble Ciego , Sulfonamidas/administración & dosificación , Sulfonamidas/uso terapéutico , Oximas/administración & dosificación , Oximas/uso terapéutico , Carcinoma de Células Transicionales/tratamiento farmacológico , Carcinoma de Células Transicionales/patología , Anciano de 80 o más Años , Adulto , Indolamina-Pirrol 2,3,-Dioxigenasa/antagonistas & inhibidores , Indolamina-Pirrol 2,3,-Dioxigenasa/metabolismo , Neoplasias Urológicas/tratamiento farmacológico , Neoplasias Urológicas/patología , Neoplasias de la Vejiga Urinaria/tratamiento farmacológico , Neoplasias de la Vejiga Urinaria/patologíaRESUMEN
BACKGROUND: Indoleamine 2,3- dioxygenase 1 (IDO1) is an immunosuppressive enzyme that has been correlated with shorter disease-specific survival in patients with urothelial carcinoma (UC). IDO1 may counteract the antitumor effects of immune checkpoint inhibitors. Epacadostat is a potent and highly selective inhibitor of IDO1. In the phase I/II ECHO-202/KEYNOTE-037 study, epacadostat plus pembrolizumab resulted in a preliminary objective response rate (ORR) of 35% in a cohort of patients with advanced UC. METHODS: ECHO-307/KEYNOTE-672 was a double-blinded, randomized, phase III study. Eligible adults had confirmed locally advanced/unresectable or metastatic UC of the urinary tract and were ineligible to receive cisplatin-based chemotherapy. Participants were randomly assigned (1:1) to receive epacadostat (100 mg twice daily) plus pembrolizumab (200 mg every 3 weeks) or placebo plus pembrolizumab for up to 35 pembrolizumab infusions. The primary endpoint was investigator-assessed ORR per Response Evaluation Criteria in Solid Tumors (version 1.1). RESULTS: A total of 93 patients were randomized (epacadostat plus pembrolizumab, n = 44; placebo plus pembrolizumab, n = 49). Enrollment was stopped early due to emerging data from the phase III ECHO-301/KEYNOTE-252 study. The median duration of follow-up was 64 days in both arms. Based on all available data at cutoff, ORR (unconfirmed) was 31.8% (95% CI, 22.46-55.24%) for epacadostat plus pembrolizumab and 24.5% (95% CI, 15.33-43.67%) for placebo plus pembrolizumab. Circulating kynurenine levels numerically increased from C1D1 to C2D1 in the placebo-plus-pembrolizumab arm and decreased in the epacadostat-plus-pembrolizumab arm. Epacadostat-plus-pembrolizumab combination treatment was well tolerated with a safety profile similar to the placebo arm. Treatment discontinuations due to treatment-related adverse events were more frequent with epacadostat (11.6% vs. 4.1%). CONCLUSIONS: Treatment with epacadostat plus pembrolizumab resulted in a similar ORR and safety profile as placebo plus pembrolizumab in cisplatin-ineligible patients with previously untreated locally advanced/unresectable or metastatic UC. At a dose of 100 mg twice daily, epacadostat did not appear to completely normalize circulating kynurenine levels when administered with pembrolizumab. Larger studies with longer follow-up and possibly testing higher doses of epacadostat, potentially in different therapy settings, may be warranted. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT03361865, retrospectively registered December 5, 2017.
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Anticuerpos Monoclonales Humanizados , Protocolos de Quimioterapia Combinada Antineoplásica , Cisplatino , Sulfonamidas , Humanos , Anticuerpos Monoclonales Humanizados/uso terapéutico , Anticuerpos Monoclonales Humanizados/administración & dosificación , Anticuerpos Monoclonales Humanizados/efectos adversos , Masculino , Femenino , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Anciano , Sulfonamidas/uso terapéutico , Sulfonamidas/administración & dosificación , Sulfonamidas/efectos adversos , Cisplatino/uso terapéutico , Cisplatino/administración & dosificación , Cisplatino/efectos adversos , Método Doble Ciego , Persona de Mediana Edad , Neoplasias Urológicas/tratamiento farmacológico , Neoplasias Urológicas/patología , Anciano de 80 o más Años , Carcinoma de Células Transicionales/tratamiento farmacológico , Carcinoma de Células Transicionales/patología , Adulto , Indolamina-Pirrol 2,3,-Dioxigenasa/antagonistas & inhibidores , Indolamina-Pirrol 2,3,-Dioxigenasa/metabolismo , OximasRESUMEN
Cutaneous squamous cell carcinoma (CSCC) is an epidermal skin cancer that evolves from normal epidermis along several pre-malignant stages. Previously we found specific miRNAs alterations in each step along these stages. miR-199a-3p expression decreases at the transition to later stages. A crucial step for epithelial carcinoma cells to acquire invasive capacity is the disruption of cell-cell contacts and the gain of mesenchymal motile phenotype, a process known as epithelial-to-mesenchymal transition (EMT). This study aims to study the role of decreased expression of miR-199a-3p in keratinocytes' EMT towards carcinogenesis. First, we measured miR-199a-3p in different stages of epidermal carcinogenesis. Then, we applied Photoactivatable Ribonucleoside-Enhanced Crosslinking and Immunoprecipitation (PAR-CLIP) assay to search for possible biochemical targets of miR-199a-3p and verified that Ras-associated protein B2 (RAP2B) is a bona-fide target of miR-199a-3p. Next, we analyzed RAP2B expression, in CSCC biopsies. Last, we evaluated possible mechanisms leading to decreased miR-199a-3p expression. miR-199a-3p induces a mesenchymal to epithelial transition (MET) in CSSC cells. Many of the under-expressed genes in CSCC overexpressing miR-199a-3p, are possible targets of miR-199a-3p and play roles in EMT. RAP2B is a biochemical target of miR-199a-3p. Overexpression of miR-199a-3p in CSCC results in decreased phosphorylated focal adhesion kinase (FAK). In addition, inhibiting FAK phosphorylation inhibits EMT marker genes' expression. In addition, we proved that DNA methylation is part of the mechanism by which miR-199a-3p expression is inhibited. However, it is not by the methylation of miR-199a putative promoter. These findings suggest that miR-199a-3p inhibits the EMT process by targeting RAP2B. Inhibitors of RAP2B or FAK may be effective therapeutic agents for CSCC.
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Carcinoma de Células Escamosas , MicroARNs , Neoplasias Cutáneas , Humanos , Carcinoma de Células Escamosas/patología , Regulación Neoplásica de la Expresión Génica , Proteínas ras/metabolismo , Línea Celular Tumoral , Neoplasias Cutáneas/patología , MicroARNs/genética , MicroARNs/metabolismo , Transición Epitelial-Mesenquimal/genética , Proliferación Celular , Proteínas de Unión al GTP rap/genética , Proteínas de Unión al GTP rap/metabolismoRESUMEN
INTRODUCTION: Geriatric oncology is the clinical field of cancer treatment in older adults (above 65 years) and in the oldest-old (above 80 years). As age is the most significant risk factor for cancer, and with the aging of the population, there is a vast increase in the number of older cancer patients. BACKGROUND: The cases highlight the unique challenges in geriatric oncology: disease goals may differ; treatment toxicities are higher; the extensive use of prescription medication increases the chances of harmful drug-drug interactions; finally, older adults have unique psychosocial needs. Cancer treatment in older adults poses a risk of under-treatment as well as a risk for over-treatment. DISCUSSION: 'Onco-geriatrics' is a field in geriatrics in which a comprehensive geriatric assessment (CGA) is performed. The CGA focuses on specific therapeutic challenges of the older patient, on frailty and on toxicity-risk assessment. In geriatric oncology, a field in oncology aimed at providing care to older cancer adults, the most important first step is to define treatment intent - cure or palliation. Achievement of cure usually mandates a multi-disciplinary aggressive approach. Compromising any component of the treatment may hamper its success rate, yet administering the full therapeutic plan may be too toxic. Thus, each older patient being considered for definitive treatment must be discussed in a multi-disciplinary tumor board, and preferably assessed by a dedicated geriatrician prior to decision-making. In cases in which treatment intent is palliative - i.e. prolongation of survival and/or improvement in quality of life, we propose the following scheme - accurate definition of the palliative goal; adaptation of the therapeutic regime to the patient's geriatric condition; frequent clinical monitoring and flexibility in administration; continued treatment as long as palliative benefit is achieved, and early cessation in its absence. Such a scheme maintains the principal of 'primum non nocere' while facilitating the palliative benefit for older adults.
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Fragilidad , Geriatría , Neoplasias , Anciano , Anciano de 80 o más Años , Fragilidad/diagnóstico , Fragilidad/terapia , Evaluación Geriátrica , Humanos , Neoplasias/terapia , Sobretratamiento , Calidad de VidaRESUMEN
Renal cell carcinoma (RCC) is comprised of clear-cell (ccRCC) and non-clear-cell (nccRCC) tumors. Despite definitive surgical resection in localized disease, recurrence often occurs. A commercial method based on a multiplex polymerase chain reaction (PCR) assay exclusively targets rearranged T cell receptor (TCR) genes to generate high-throughput sequencing-based data, allowing characterization of the immune repertoire within tumors. In this study we performed a retrospective analysis on archived tumor samples from patients with recurring versus non-recurring T3 ccRCC and on samples from early nccRCC versus ccRCC. Following genomic DNA extraction and multiplex PCR, the fraction of T cells within tumors, the number of unique receptors ('richness') and their relative abundances ('clonality') were calculated. Statistical significance and correlations were calculated using Student's t-test and Spearman's rho, respectively. Average fraction and clonality of T cells in tumors from non-recurring patients was 2.5- and 4.3-fold higher than in recurring patients (P = 0.025 and P = 0.043, respectively). A significant positive correlation was found between T cell fraction and clonality (Spearman's rho = 0.78, P = 0.008). The average fraction of T cells in ccRCC tumors was 2.8-fold higher than in nccRCC tumors (P = 0.015). Clonality and estimated richness were similar between ccRCC and nccRCC tumors. In summary, recurrence of ccRCC is associated with a lower fraction and clonality of T cells within tumors; nccRCC tumors are more 'deserted' than ccRCC, but similar in their ability to generate a clonal T cell repertoire. Our work suggests associations between the characteristics of T cell infiltrate, histology and tumor recurrence.
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Carcinoma de Células Renales/inmunología , Neoplasias Renales/inmunología , Recurrencia Local de Neoplasia/inmunología , Receptores de Antígenos de Linfocitos T/inmunología , Linfocitos T/inmunología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estudios RetrospectivosRESUMEN
Personalised medicine is the future and hope for many patients, including those with cancers. Early detection, as well as rapid, well-selected treatment, are key factors leading to a good prognosis. MicroRNA mediated gene regulation is a promising area of development for new diagnostic and therapeutic methods, crucial for better prospects for patients. Bladder cancer is a frequent neoplasm, with high lethality and lacking modern, advanced therapeutic modalities, such as immunotherapy. MicroRNAs are involved in bladder cancer pathogenesis, proliferation, control and response to treatment, which we summarise in this perspective in response to lack of recent review publications in this field. We further performed a correlation-based analysis of microRNA and gene expression data in bladder cancer (BLCA) TCGA dataset. We identified 27 microRNAs hits with opposite expression profiles to genes involved in immune response in bladder cancer, and 24 microRNAs hits with similar expression profiles. We discuss previous studies linking the functions of these microRNAs to bladder cancer and assess if they are good candidates for personalised medicine therapeutics and diagnostics. The discussed functions include regulation of gene expression, interplay with transcription factors, response to treatment, apoptosis, cell proliferation and angiogenesis, initiation and development of cancer, genome instability and tumour-associated inflammatory reaction.
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Proteínas de Punto de Control Inmunitario/genética , MicroARNs/genética , Neoplasias de la Vejiga Urinaria/genética , Neoplasias de la Vejiga Urinaria/inmunología , Biomarcadores de Tumor/genética , Neoplasias de la Mama/genética , Neoplasias de la Mama/inmunología , Bases de Datos Genéticas , Femenino , Perfilación de la Expresión Génica , Regulación Neoplásica de la Expresión Génica , Redes Reguladoras de Genes , Humanos , Sinapsis Inmunológicas/genética , Modelos Genéticos , ARN Mensajero/genética , ARN Neoplásico/genéticaRESUMEN
BACKGROUND: Prostate cancer is a common malignancy of the elderly, and with the aging of the population, the need is growing for therapies suitable for this age group. Lutetium-177-prostate-specific membrane antigen (Lu-PSMA), a radiolabeled small molecule, binds with high affinity to prostate-specific membrane antigen, enabling beta particle therapy targeted to metastatic castration-resistant prostate cancer (mCRPC). In a recent single-arm phase II trial and a subsequent expansion cohort, a prostate-specific antigen (PSA) decline of ≥50% was observed in approximately 60% of patients receiving Lu-PSMA. Taking into account the specific challenges and potential toxicities of Lu-PSMA administration in elderly men, we sought to retrospectively analyze the safety and activity of Lu-PSMA in men aged older than 75 years with mCRPC. PATIENTS AND METHODS: The electronic medical records of 24 patients aged older than 75 years treated with Lu-PSMA "off-trial" were reviewed, and clinical data were extracted. Clinical endpoints were toxicity and activity, defined as a PSA decline ≥50%. Descriptive statistics were performed using Excel. RESULTS: The median age at treatment start was 81.7 years (range 75.1-91.9). The median number of previous treatment lines was four. The number of treatment cycles ranged from one to four; the mean administered radioactivity was 6 GBq per cycle. Treatment was generally tolerable; side effects included fatigue (n = 8, 33%), anemia (n = 7, 29%), thrombocytopenia (n = 5, 21%), and anorexia/nausea (n = 3, 13%). Clinical benefit was observed in 12 of 22 patients (54%); PSA decline above 50% was observed in 11 patients (48%) and was associated with significantly longer overall survival. CONCLUSION: Our results indicate that Lu-PSMA is safe and active in elderly patients with mCRPC. IMPLICATIONS FOR PRACTICE: Lutetium-177-prostate-specific membrane antigen (Lu-PSMA), a radiolabeled small molecule, binds with high affinity to prostate-specific membrane antigen, enabling beta particle therapy targeted to metastatic castration-resistant prostate cancer (mCRPC). The recently published single-arm phase II trial with Lu-PSMA, describing its safety and activity, did not include patients aged older than 75 years. In this study, Lu-PSMA activity was retrospectively analyzed in patients aged older than 75 years and results indicate that treatment was tolerable and similarly active in this age group, with no new emerging safety signals. Despite the small cohort size, this analysis suggests that Lu-PSMA can serve as an advanced palliative treatment line in mCRPC in elderly patients.
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Neoplasias de la Próstata Resistentes a la Castración , Anciano , Anciano de 80 o más Años , Dipéptidos , Compuestos Heterocíclicos con 1 Anillo , Humanos , Lutecio , Masculino , Neoplasias de la Próstata Resistentes a la Castración/radioterapia , Radioisótopos/uso terapéutico , Radiofármacos , Estudios Retrospectivos , Resultado del TratamientoAsunto(s)
Vacuna BNT162 , COVID-19 , COVID-19/prevención & control , Vacunas contra la COVID-19 , Niño , Humanos , SARS-CoV-2 , VacunaciónRESUMEN
Introduction: Immune checkpoint inhibitors have made a paradigm shift in the treatment of non-small cell lung cancer (NSCLC). However, clinical response varies widely and robust predictive biomarkers for patient stratification are lacking. Here, we characterize early on-treatment proteomic changes in blood plasma to gain a better understanding of treatment response and resistance. Methods: Pre-treatment (T0) and on-treatment (T1) plasma samples were collected from 225 NSCLC patients receiving PD-1/PD-L1 inhibitor-based regimens. Plasma was profiled using aptamer-based technology to quantify approximately 7000 plasma proteins per sample. Proteins displaying significant fold changes (T1:T0) were analyzed further to identify associations with clinical outcomes using clinical benefit and overall survival as endpoints. Bioinformatic analyses of upregulated proteins were performed to determine potential cell origins and enriched biological processes. Results: The levels of 142 proteins were significantly increased in the plasma of NSCLC patients following ICI-based treatments. Soluble PD-1 exhibited the highest increase, with a positive correlation to tumor PD-L1 status, and, in the ICI monotherapy dataset, an association with improved overall survival. Bioinformatic analysis of the ICI monotherapy dataset revealed a set of 30 upregulated proteins that formed a single, highly interconnected network, including CD8A connected to ten other proteins, suggestive of T cell activation during ICI treatment. Notably, the T cell-related network was detected regardless of clinical benefit. Lastly, circulating proteins of alveolar origin were identified as potential biomarkers of limited clinical benefit, possibly due to a link with cellular stress and lung damage. Conclusions: Our study provides insights into the biological processes activated during ICI-based therapy, highlighting the potential of plasma proteomics to identify mechanisms of therapy resistance and biomarkers for outcome.
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Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Humanos , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Receptor de Muerte Celular Programada 1 , Proteómica , Neoplasias Pulmonares/tratamiento farmacológico , Inmunoterapia , Inhibidores de Puntos de Control Inmunológico , PlasmaRESUMEN
PURPOSE: Current guidelines for the management of metastatic non-small cell lung cancer (NSCLC) without driver mutations recommend checkpoint immunotherapy with PD-1/PD-L1 inhibitors, either alone or in combination with chemotherapy. This approach fails to account for individual patient variability and host immune factors and often results in less-than-ideal outcomes. To address the limitations of the current guidelines, we developed and subsequently blindly validated a machine learning algorithm using pretreatment plasma proteomic profiles for personalized treatment decisions. PATIENTS AND METHODS: We conducted a multicenter observational trial (ClinicalTrials.gov identifier: NCT04056247) of patients undergoing PD-1/PD-L1 inhibitor-based therapy (n = 540) and an additional patient cohort receiving chemotherapy (n = 85) who consented to pretreatment plasma and clinical data collection. Plasma proteome profiling was performed using SomaScan Assay v4.1. RESULTS: Our test demonstrates a strong association between model output and clinical benefit (CB) from PD-1/PD-L1 inhibitor-based treatments, evidenced by high concordance between predicted and observed CB (R2 = 0.98, P < .001). The test categorizes patients as either PROphet-positive or PROphet-negative and further stratifies patient outcomes beyond PD-L1 expression levels. The test successfully differentiates between PROphet-negative patients exhibiting high tumor PD-L1 levels (≥50%) who have enhanced overall survival when treated with a combination of immunotherapy and chemotherapy compared with immunotherapy alone (hazard ratio [HR], 0.23 [95% CI, 0.1 to 0.51], P = .0003). By contrast, PROphet-positive patients show comparable outcomes when treated with immunotherapy alone or in combination with chemotherapy (HR, 0.78 [95% CI, 0.42 to 1.44], P = .424). CONCLUSION: Plasma proteome-based testing of individual patients, in combination with standard PD-L1 testing, distinguishes patient subsets with distinct differences in outcomes from PD-1/PD-L1 inhibitor-based therapies. These data suggest that this approach can improve the precision of first-line treatment for metastatic NSCLC.
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Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Humanos , Antígeno B7-H1 , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/genética , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/genética , Receptor de Muerte Celular Programada 1/uso terapéutico , Proteoma , ProteómicaRESUMEN
Lung cancer is the leading cause of cancer-related mortality worldwide. Early detection is essential to achieving a better outcome and prognosis. Volatile organic compounds (VOCs) reflect alterations in the pathophysiology and body metabolism processes, as shown in various types of cancers. The biosensor platform (BSP) urine test uses animals' unique, proficient, and accurate ability to scent lung cancer VOCs. The BSP is a testing platform for the binary (negative/positive) recognition of the signature VOCs of lung cancer by trained and qualified Long-Evans rats as biosensors (BSs). The results of the current double-blind study show high accuracy in lung cancer VOC recognition, with 93% sensitivity and 91% specificity. The BSP test is safe, rapid, objective and can be performed repetitively, enabling periodic cancer monitoring as well as an aid to existing diagnostic methods. The future implementation of such urine tests as routine screening and monitoring tools has the potential to significantly increase detection rate as well as curability rates with lower healthcare expenditure. This paper offers a first instructive clinical platform utilizing VOC's in urine for detection of lung cancer using the innovative BSP to deal with the pressing need for an early lung cancer detection test tool.
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Técnicas Biosensibles , Neoplasias Pulmonares , Compuestos Orgánicos Volátiles , Animales , Ratas , Técnicas Biosensibles/métodos , Detección Precoz del Cáncer/métodos , Neoplasias Pulmonares/diagnóstico , Ratas Long-Evans , Compuestos Orgánicos Volátiles/orina , Método Doble CiegoRESUMEN
Immune checkpoint inhibitors (ICIs) are now the standard of care for metastatic urothelial carcinoma (mUC) patients. Our aim was to describe the activity of ICIs in mUC and find the clinical parameters associated with response. This is a retrospective, single-center chart review of mUC patients receiving ICIs. The overall survival (OS) was plotted using the Kaplan-Meier method and was compared using a log-rank test. Associations between the variables and responses were analyzed by univariate and multivariable analyses, using either logistic regression or a Chi-square/Fisher's exact test. Ninety-four patients received ICIs, 85% of which were in the second line or beyond; the median age was 71.8 years, and 82% were men. Six (6.4%), 11 (11.7%), 7 (7.4%) and 70 (74.5%) patients achieved a complete response (CR), partial response (PR), mixed response/stable disease (M/SD) or progressive disease (PD), respectively. The median overall survival was 3.2 months for the entire cohort and was significantly different according to the response pattern-not reached, 32.3, 6.4 and 2.0 months for CR, PR, M/SD and PD, respectively. The response was not significantly associated with the line of treatment. 'Site of metastasis' was associated with the response, and the absolute neutrophil count was borderline associated with the response. In summary, we found a substantial variance in the potential benefit from ICIs in mUC, emphasizing the need for predictive biomarkers and frequent monitoring of mUC patients receiving ICIs.
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BACKGROUND: Innovations in treatments, imaging, and molecular characterisation in advanced prostate cancer have improved outcomes, but various areas of management still lack high-level evidence to inform clinical practice. The 2021 Advanced Prostate Cancer Consensus Conference (APCCC) addressed some of these questions to supplement guidelines that are based on level 1 evidence. OBJECTIVE: To present the voting results from APCCC 2021. DESIGN, SETTING, AND PARTICIPANTS: The experts identified three major areas of controversy related to management of advanced prostate cancer: newly diagnosed metastatic hormone-sensitive prostate cancer (mHSPC), the use of prostate-specific membrane antigen ligands in diagnostics and therapy, and molecular characterisation of tissue and blood. A panel of 86 international prostate cancer experts developed the programme and the consensus questions. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The panel voted publicly but anonymously on 107 pre-defined questions, which were developed by both voting and non-voting panel members prior to the conference following a modified Delphi process. RESULTS AND LIMITATIONS: The voting reflected the opinions of panellists and did not incorporate a standard literature review or formal meta-analysis. The answer options for the consensus questions received varying degrees of support from panellists, as reflected in this article and the detailed voting results reported in the Supplementary material. CONCLUSIONS: These voting results from a panel of experts in advanced prostate cancer can help clinicians and patients to navigate controversial areas of management for which high-level evidence is scant. However, diagnostic and treatment decisions should always be individualised according to patient characteristics, such as the extent and location of disease, prior treatment(s), comorbidities, patient preferences, and treatment recommendations, and should also incorporate current and emerging clinical evidence and logistic and economic constraints. Enrolment in clinical trials should be strongly encouraged. Importantly, APCCC 2021 once again identified salient questions that merit evaluation in specifically designed trials. PATIENT SUMMARY: The Advanced Prostate Cancer Consensus Conference is a forum for discussing current diagnosis and treatment options for patients with advanced prostate cancer. An expert panel votes on predefined questions focused on the most clinically relevant areas for treatment of advanced prostate cancer for which there are gaps in knowledge. The voting results provide a practical guide to help clinicians in discussing treatment options with patients as part of shared decision-making.
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Neoplasias de la Próstata , Consenso , Humanos , Masculino , Neoplasias de la Próstata/diagnóstico , Neoplasias de la Próstata/patología , Neoplasias de la Próstata/terapiaRESUMEN
Patients with advanced prostate cancer (APC) may be at greater risk for severe illness, hospitalisation, or death from coronavirus disease 2019 (COVID-19) due to male gender, older age, potential immunosuppressive treatments, or comorbidities. Thus, the optimal management of APC patients during the COVID-19 pandemic is complex. In October 2021, during the Advanced Prostate Cancer Consensus Conference (APCCC) 2021, the 73 voting members of the panel members discussed and voted on 13 questions on this topic that could help clinicians make treatment choices during the pandemic. There was a consensus for full COVID-19 vaccination and booster injection in APC patients. Furthermore, the voting results indicate that the expert's treatment recommendations are influenced by the vaccination status: the COVID-19 pandemic altered management of APC patients for 70% of the panellists before the vaccination was available but only for 25% of panellists for fully vaccinated patients. Most experts (71%) were less likely to use docetaxel and abiraterone in unvaccinated patients with metastatic hormone-sensitive prostate cancer. For fully vaccinated patients with high-risk localised prostate cancer, there was a consensus (77%) to follow the usual treatment schedule, whereas in unvaccinated patients, 55% of the panel members voted for deferring radiation therapy. Finally, there was a strong consensus for the use of telemedicine for monitoring APC patients. PATIENT SUMMARY: In the Advanced Prostate Cancer Consensus Conference 2021, the panellists reached a consensus regarding the recommendation of the COVID-19 vaccine in prostate cancer patients and use of telemedicine for monitoring these patients.
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COVID-19 , Neoplasias de la Próstata , Antagonistas de Andrógenos/uso terapéutico , Vacunas contra la COVID-19 , Humanos , Masculino , Pandemias/prevención & control , Neoplasias de la Próstata/patologíaRESUMEN
While penile metastases are rare, PET/CT has facilitated their detection. We aimed to describe penile secondary lesions (PSL) identified by PET/CT. We reviewed 18F-FDG and Ga68-PSMA PET/CT records performed in a single center during May 2012-March 2020, for PSL. Of 16,774 18F-FDG and 1,963 Ga68-PSMA-PET scans, PSL were found in 24(0.13%) men with a mean age of 74. PSMA detected PSL in 12 with prostate cancer; FDG identified PSL in 4 with lymphoma, 3 with colorectal cancer, 2 with lung cancer, and one each with bladder cancer, pelvic sarcoma, and leukemia. Mean SUVmax of PSL was 7.9 ± 4.2 with focal uptake in 13(54%). Mean lesion size was 16.5 ± 6.8 mm; 8 at the penile root, 4 along the shaft, and 1 at the glans. CT detected loss of the penile texture in 15(63%). PSL were observed only during relapse or follow-up of disseminated disease. Among those with prostate cancer, PSA varied widely. Fifteen (62.5%) died, at a mean 13.3 ± 15.9 months following PSL demonstration, nine had non-prostate malignancies. PET/CT identified and characterized PSL in a fraction of cancer patients, most commonly those with prostate cancer. PSL universally surfaced in advanced disease, and signaled high mortality, especially in non-prostate cancers.
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Neoplasias del Pene/diagnóstico por imagen , Neoplasias del Pene/secundario , Tomografía Computarizada por Tomografía de Emisión de Positrones , Anciano , Anciano de 80 o más Años , Biomarcadores de Tumor , Biopsia , Fluorodesoxiglucosa F18 , Humanos , Masculino , Persona de Mediana Edad , Imagen Multimodal/métodos , Neoplasias Pélvicas , Neoplasias del Pene/patología , Tomografía Computarizada por Tomografía de Emisión de Positrones/métodos , Tomografía de Emisión de Positrones , Neoplasias de la Próstata/diagnóstico por imagen , Neoplasias de la Próstata/patología , Neoplasias de la Próstata/terapia , Estudios Retrospectivos , Tomografía Computarizada por Rayos X , Carga TumoralRESUMEN
PURPOSE: The aim was to determine the efficacy, safety, and tolerability of weekly ultra hypofractionated radiation therapy for older unfit patients with invasive bladder cancer. METHODS: We retrospectively analyzed a cohort of patients with muscle invasive bladder cancer deemed unfit for chemoradiation therapy and thus treated with 6 weekly doses of 6 Gy using intensity modulated radiotherapy. Charlson comorbidity was calculated retrospectively. Cystoscopy and computed tomography were used to evaluate local control and toxicity using the common terminology criteria. Survival outcomes were estimated using the Kaplan-Meier method. RESULTS: Twenty-two patients with a median age of 84 (range: 70 to 96) years were included. The median comorbidity index was 6±1.5 SD. Nineteen (90%) patients received the full 36 Gy dose. Median follow-up was 10±7 months (range: 6 to 27 mo). Local control in the bladder was achieved in 16 of 19 evaluable patients (84%). One-year overall survival was 62.5%, 1 patient had a retroperitoneal nodal recurrence and 3 patients developed distant metastasis. Grade 3 genitourinary and gastrointestinal toxicity was observed in 4 (18%) and 1 (4.5%) patients, respectively. CONCLUSION: Weekly ultra hypofractionated intensity modulated radiotherapy with image guidance and bladder training is an effective, safe, and well-tolerated regimen for older patients with invasive bladder cancer unfit for radical treatment.
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Hipofraccionamiento de la Dosis de Radiación , Radioterapia de Intensidad Modulada/métodos , Neoplasias de la Vejiga Urinaria/radioterapia , Anciano , Anciano de 80 o más Años , Femenino , Anciano Frágil , Humanos , Masculino , Recurrencia Local de Neoplasia , Tomografía Computarizada por Tomografía de Emisión de Positrones , Radioterapia de Intensidad Modulada/efectos adversos , Estudios Retrospectivos , Resultado del Tratamiento , Neoplasias de la Vejiga Urinaria/diagnóstico por imagen , Neoplasias de la Vejiga Urinaria/patologíaRESUMEN
OBJECTIVES: We aimed to examine clinical data and baseline blood test results as potential predictive biomarkers for benefit from nivolumab, in advanced non-small cell lung cancer patients (NSCLC). MATERIALS AND METHODS: A chart review was performed of 108 advanced NSCLC patients who commenced treatment with nivolumab between 2015-6 at three Israeli cancer centers, and for whom laboratory tests results were available. Data collected included sex, age, ECOG-PS, histology and number of previous lines of treatment. Baseline blood test results collected: absolute lymphocyte and neutrophil count (ANC), white blood cells (WBC), hemoglobin, platelets, albumin and lactate dehydrogenase (LDH). Neutrophil to Lymphocyte Ratio and 'derived NLR' (dNLR = (ANC/[WBC-ANC])) were calculated. Disease control at six months (DC6) was defined as any tumor shrinkage or stable disease during the first six months of nivolumab treatment. The association between clinical/laboratory variables and survival was tested with a Cox proportional hazard model. Data cut-off occurred in November 2019. RESULTS: 35 patients (32.4%) achieved DC6. Median overall survival (OS) of entire study population was 5.4 months. Four year survival rate was 16%. Achievement of DC6 strongly correlated with longer OS (HR 0.12, 95% C.I. 0.07-0.21, p<0.001). In univariate and multivariate analysis, dNLR, albumin and LDH correlated significantly with OS. No variables correlated significantly with DC6 in multivariate analysis. Based on albumin and LDH, we produced a score called CLAS (combined LDH and albumin score), including four prognostic groups of patients. Patients having low albumin and high LDH had the worst prognosis. CONCLUSION: In real-life setting, long-term efficacy of nivolumab in advanced line treatment of NSCLC is consistent with clinical trials. Response or stability of disease during first six months of treatment is associated with prolonged survival. We propose a novel score (CLAS) that may be useful for predicting outcome in nivolumab-treated NSCLC patients, but further validation is required.
RESUMEN
Lutetium-177-PSMA ([177Lu]-PSMA-617), a radiolabeled small molecule, binds with high affinity to prostate-specific membrane antigen (PSMA), enabling targeted radiation therapy to metastatic prostate lesions. Our objective was to retrospectively analyze the activity of [177Lu]-PSMA-617 given off-trial to men with metastatic castration resistant prostate cancer (mCRPC) and identify clinical factors associated with PSA response. Electronic medical records of all men treated with [177Lu]-PSMA-617 were reviewed and analyzed. Overall survival was calculated using the Kaplan-Meier method. The association between potential variables and PSA response was analyzed by univariate analysis, using either logistic regression or χ2/Fisher's exact test. Multivariable analysis was carried out using logistic regression on all categorical variables with a P-value of <0.1 on univariate analysis. Variables found to be statistically significant were then used to define a categorical score. A total of 52 patients received at least one cycle of [177Lu]-PSMA-617. Clinical benefit was observed in 28 patients (52%). PSA decline ≥20% and ≥50% was observed in 26 (50%) and 18 patients (35%), respectively. Achievement of any PSA decline at first measurement was significantly associated with survival. There was a negative association between the number of previous chemotherapy lines and PSA decline above 20%. Univariate analysis followed by multivariable analysis showed that older age and higher hemoglobin were significantly associated with a PSA decline >20%. A score combining these two parameters was significantly associated with PSA response. In summary, [177Lu]-PSMA-617 is active in the 'real-life' setting of heavily pretreated men with mCRPC.