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The identification of causal BRCA1/2 pathogenic variants (PVs) in epithelial ovarian carcinoma (EOC) aids the selection of patients for genetic counselling and treatment decision-making. Current recommendations therefore stress sequencing of all EOCs, regardless of histotype. Although it is recognised that BRCA1/2 PVs cluster in high-grade serous ovarian carcinomas (HGSOC), this view is largely unsubstantiated by detailed analysis. Here, we aimed to analyse the results of BRCA1/2 tumour sequencing in a centrally revised, consecutive, prospective series including all EOC histotypes. Sequencing of n = 946 EOCs revealed BRCA1/2 PVs in 125 samples (13%), only eight of which were found in non-HGSOC histotypes. Specifically, BRCA1/2 PVs were identified in high-grade endometrioid (3/20; 15%), low-grade endometrioid (1/40; 2.5%), low-grade serous (3/67; 4.5%), and clear cell (1/64; 1.6%) EOCs. No PVs were identified in any mucinous ovarian carcinomas tested. By re-evaluation and using loss of heterozygosity and homologous recombination deficiency analyses, we then assessed: (1) whether the eight 'anomalous' cases were potentially histologically misclassified and (2) whether the identified variants were likely causal in carcinogenesis. The first 'anomalous' non-HGSOC with a BRCA1/2 PV proved to be a misdiagnosed HGSOC. Next, germline BRCA2 variants, found in two p53-abnormal high-grade endometrioid tumours, showed substantial evidence supporting causality. One additional, likely causal variant, found in a p53-wildtype low-grade serous ovarian carcinoma, was of somatic origin. The remaining cases showed retention of the BRCA1/2 wildtype allele, suggestive of non-causal secondary passenger variants. We conclude that likely causal BRCA1/2 variants are present in high-grade endometrioid tumours but are absent from the other EOC histotypes tested. Although the findings require validation, these results seem to justify a transition from universal to histotype-directed sequencing. Furthermore, in-depth functional analysis of tumours harbouring BRCA1/2 variants combined with detailed revision of cancer histotypes can serve as a model in other BRCA1/2-related cancers. © 2023 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.
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Proteína BRCA1 , Neoplasias Ováricas , Femenino , Humanos , Proteína BRCA1/genética , Proteína BRCA2/genética , Proteína BRCA2/metabolismo , Neoplasias Ováricas/genética , Neoplasias Ováricas/patología , Proteína p53 Supresora de Tumor , Carcinoma Epitelial de Ovario/genéticaRESUMEN
BACKGROUND: Patients with irresectable stage III or metastatic melanoma presenting with poor prognostic factors are usually treated with a combination of immune checkpoint inhibitors (ICIs), consisting of ipilimumab and nivolumab. This combination therapy is associated with severe immune related adverse events (irAEs) in about 60% of patients. In current clinical practice, patients are usually treated with ICIs for up to two years or until disease progression or the occurrence of unacceptable AEs. The incidence of irAEs gradually increases with duration of treatment. While durable tumour responses have been observed after early discontinuation of treatment, no consensus has been reached on optimal treatment duration. The objective of the Safe Stop IPI-NIVO trial is to evaluate whether early discontinuation of ICIs is safe in patients with irresectable stage III or metastatic melanoma who are treated with combination therapy. METHODS: The Safe Stop IPI-NIVO trial is a nationwide, multicentre, prospective, single-arm, interventional study in the Netherlands. A total of 80 patients with irresectable stage III or metastatic melanoma who are treated with combination therapy of ipilimumab-nivolumab and have a complete or partial response (CR/PR) according to RECIST v1.1 will be included to early discontinue maintenance therapy with anti-PD-1. The primary endpoint is the rate of ongoing response at 12 months after start of ICI. Secondary endpoints include ongoing response at 24 months, disease control at different time points, melanoma specific and overall survival, the incidence of irAEs and health-related quality of life. DISCUSSION: From a medical, healthcare and economic perspective, overtreatment should be prevented and shorter treatment duration of ICIs is preferred. If early discontinuation of ICIs is safe for patients who are treated with the combination of ipilimumab-nivolumab, the treatment duration of nivolumab could be shortened in patients with a favourable tumour response. TRIAL REGISTRATION: ClinicalTrials.gov ID NCT05652673, registration date: 08-12-2022.
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Protocolos de Quimioterapia Combinada Antineoplásica , Ipilimumab , Melanoma , Nivolumab , Femenino , Humanos , Masculino , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Inhibidores de Puntos de Control Inmunológico/efectos adversos , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Inhibidores de Puntos de Control Inmunológico/administración & dosificación , Ipilimumab/administración & dosificación , Ipilimumab/efectos adversos , Ipilimumab/uso terapéutico , Melanoma/tratamiento farmacológico , Melanoma/patología , Estadificación de Neoplasias , Países Bajos , Nivolumab/administración & dosificación , Nivolumab/efectos adversos , Nivolumab/uso terapéutico , Estudios Prospectivos , Neoplasias Cutáneas/tratamiento farmacológico , Neoplasias Cutáneas/patología , Privación de Tratamiento , Estudios Multicéntricos como AsuntoRESUMEN
BACKGROUND: Programmed cell death protein 1 (PD-1) antibody treatment is standard of care for melanoma and non-small-cell lung cancer (NSCLC). Accurately predicting which patients will benefit is currently not possible. Tumor uptake and biodistribution of the PD-1 antibody might play a role. Therefore, we carried out a positron emission tomography (PET) imaging study with zirconium-89 (89Zr)-labeled pembrolizumab before PD-1 antibody treatment. PATIENTS AND METHODS: Patients with advanced or metastatic melanoma or NSCLC received 37 MBq (1 mCi) 89Zr-pembrolizumab (â¼2.5 mg antibody) intravenously plus 2.5 or 7.5 mg unlabeled pembrolizumab. After that, up to three PET scans were carried out on days 2, 4, and 7. Next, PD-1 antibody treatment was initiated. 89Zr-pembrolizumab tumor uptake was calculated as maximum standardized uptake value (SUVmax) and expressed as geometric mean. Normal organ uptake was calculated as SUVmean and expressed as a mean. Tumor response was assessed according to (i)RECIST v1.1. RESULTS: Eighteen patients, 11 with melanoma and 7 with NSCLC, were included. The optimal dose was 5 mg pembrolizumab, and the optimal time point for PET scanning was day 7. The tumor SUVmax did not differ between melanoma and NSCLC (4.9 and 6.5, P = 0.49). Tumor 89Zr-pembrolizumab uptake correlated with tumor response (P trend = 0.014) and progression-free (P = 0.0025) and overall survival (P = 0.026). 89Zr-pembrolizumab uptake at 5 mg was highest in the spleen with a mean SUVmean of 5.8 (standard deviation ±1.8). There was also 89Zr-pembrolizumab uptake in Waldeyer's ring, in normal lymph nodes, and at sites of inflammation. CONCLUSION: 89Zr-pembrolizumab uptake in tumor lesions correlated with treatment response and patient survival. 89Zr-pembrolizumab also showed uptake in lymphoid tissues and at sites of inflammation.
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Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Anticuerpos Monoclonales Humanizados , Carcinoma de Pulmón de Células no Pequeñas/diagnóstico por imagen , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Humanos , Neoplasias Pulmonares/diagnóstico por imagen , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/metabolismo , Tomografía de Emisión de Positrones/métodos , Receptor de Muerte Celular Programada 1 , Distribución TisularRESUMEN
For more than two decades, the International Summer School Oncology for Medical Students (ISOMS) has organized a biennial 2-week international summer school program in Groningen, the Netherlands. The summer school aims to increase knowledge about general cancer care, reduce fear of talking to cancer patients, and expose students to cancer-related problems. After 22 years, there was a need to improve the summer school format, the application procedure, and the intensity of the course. Here, we describe and evaluate these and additional changes that were made to the program. Several changes were made to the summer school format. The course was shortened from 10 days to a more intensive 7 days. The scientific program was integrated with the clinical program and students were taught scientific writing and presentation skills. The application process involved a personal video pitch. Importantly, the new summer school format was organized by a committee in which medical students had the lead. To evaluate the changes to the summer school, we conducted knowledge tests and regularly obtained feedback. There was a high overall student satisfaction, with a median score of a 9 out of 10. Students appreciated the interactive sessions and practicals and the scientific program, and were satisfied with the course level. All students had improved test scores. Improvement points highlighted the need for a less packed schedule and more lectures on basic oncology principles, or were related to specific lectures. The student-led innovation and adaptation of the ISOMS has been successful.
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Neoplasias , Estudiantes de Medicina , Curriculum , Humanos , Oncología Médica/educación , Neoplasias/terapia , Países Bajos , Instituciones AcadémicasRESUMEN
Immune checkpoint inhibitors (ICIs) are increasingly recognised to effectuate long-lasting therapeutic responses in solid tumours. However, ICI therapy can also result in various immune-related adverse events, such as ICI-associated myocarditis, a rare but serious complication. The clinical spectrum is wide and includes asymptomatic patients and patients with fulminant heart failure, making it challenging to diagnose this condition. Furthermore, the optimal diagnostic algorithm and treatment of ICI-associated myocarditis is unknown. In this review, we describe two cases on both ends of the spectrum and discuss the challenges in recognising, diagnosing and treating ICI-associated myocarditis.
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Neoplasias Endometriales , Inhibidores de Puntos de Control Inmunológico , Humanos , Neoplasias Endometriales/tratamiento farmacológico , Neoplasias Endometriales/inmunología , Neoplasias Endometriales/patología , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Inhibidores de Puntos de Control Inmunológico/efectos adversos , FemeninoRESUMEN
OBJECTIVE: Exercise interventions benefit cancer patients. However, only low numbers of patients adhere to these interventions. This review aimed to identify predictors of exercise intervention adherence in patients with cancer, during and after multimodality cancer treatment. METHODS: A literature search was performed using electronic databases (PubMed, Embase, and Cochrane) to identify relevant papers published before February 1, 2017. Papers reporting randomized controlled trials, conducted in adult cancer patients who participated in an exercise intervention during and/or after multimodality cancer treatment, and providing outcome of factors predicting exercise adherence were included. Papers were assessed for methodological quality by using the Physiotherapy Evidence Database scale. RESULTS: The search identified 720 potentially relevant papers, of which 15 fulfilled the eligibility criteria. In these 15 studies, 2279 patients were included and 1383 of these patients were randomized to an exercise intervention. During cancer treatment, the factors predicting exercise adherence were as follows: location of the rehabilitation center, extensive exercise history, high motivation for exercise, and fewer exercise limitations. After cancer treatment, factors that predicted adherence were as follows: less extensive surgery, low alcohol consumption, high previous exercise adherence, family support, feedback by trainers, and knowledge and skills of exercise. Methodological quality of the included papers was rated "high". CONCLUSIONS: The most prominent predictors of adherence to exercise interventions were location of the rehabilitation center, extensive exercise history, high motivation for exercise, and fewer exercise limitations. To increase the number of cancer patients who will benefit, these results should be considered into the development and implementation of future exercise interventions.
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Supervivientes de Cáncer/psicología , Terapia por Ejercicio/psicología , Conductas Relacionadas con la Salud , Neoplasias/rehabilitación , Cooperación del Paciente/psicología , Adulto , Supervivientes de Cáncer/estadística & datos numéricos , Terapia Combinada , Ejercicio Físico , Terapia por Ejercicio/estadística & datos numéricos , Femenino , Humanos , Masculino , Persona de Mediana Edad , Cooperación del Paciente/estadística & datos numéricos , Ensayos Clínicos Controlados Aleatorios como AsuntoRESUMEN
Ovarian cancer has a high mortality and novel-targeted treatment strategies have not resulted in breakthroughs for this disease. Insight into the molecular characteristics of ovarian tumors may improve diagnosis and selection of patients for treatment with targeted therapies. A potential way to achieve this is by means of molecular imaging. Generic tumor processes, such as glucose metabolism ((18)F-fluorodeoxyglucose) and DNA synthesis ((18)F-fluorodeoxythymidine), can be visualized non-invasively. More specific targets, such as hormone receptors, growth factor receptors, growth factors and targets of immunotherapy, can also be visualized. Molecular imaging can capture data on intra-patient tumor heterogeneity and is of potential value for individualized, target-guided treatment selection. Early changes in molecular characteristics during therapy may serve as early predictors of response. In this review, we describe the current knowledge on molecular imaging in the diagnosis and as an upfront or early predictive biomarker in patients with ovarian cancer.
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Neoplasias Ováricas/diagnóstico por imagen , Animales , Biomarcadores de Tumor/metabolismo , Femenino , Fluorodesoxiglucosa F18/farmacocinética , Humanos , Neoplasias Ováricas/metabolismo , Tomografía de Emisión de Positrones , Distribución TisularRESUMEN
Tumour-necrosis-factor-related apoptosis-inducing ligand (TRAIL) is being investigated as a targeted cancer therapeutic and the expression of its pro-apoptotic receptors, DR4 and DR5, increases during colorectal carcinogenesis. This study investigated the role of ß-catenin in the regulation of these receptors. In human colorectal adenoma and carcinoma cell lines, downregulation of ß-catenin resulted in lower total DR4 and DR5 protein levels. Similarly, cell membrane expression of DR4 and DR5 was reduced after downregulation of ß-catenin in colon carcinoma cells, whereas induction of ß-catenin in HeLa cells led to increased cell membrane expression of DR4 and DR5. Downregulation of ß-catenin decreased the recombinant human TRAIL sensitivity of human colon carcinoma cells. Activation of the transcription factor T-cell factor-4 (TCF-4) is an important function of ß-catenin. Dominant-negative TCF-4 overexpression, however, did not significantly affect TRAIL receptor expression or recombinant human TRAIL sensitivity. Human colorectal adenomas (N = 158) with aberrant (cytoplasmic and nuclear) ß-catenin expression had a higher percentage of immunohistochemical DR4 and DR5 staining per tumour (mean: 73 and 88%, respectively) than those with membranous ß-catenin staining only (mean: 50 and 70%, respectively, P < 0.01 for both). Furthermore, aberrant ß-catenin staining co-localized with DR4 and DR5 expression in 92% of adenomas. In 53 human colorectal carcinomas, aberrant ß-catenin expression was present in most cases and DR4/5 expression was largely homogenous. Similarly, in adenomas from APC(min) mice, cytoplasmic ß-catenin staining co-localized with staining for the murine TRAIL death receptor. In conclusion, the gradual increase in TRAIL receptor expression during colorectal carcinogenesis is at least partially mediated through increased ß-catenin expression, independently of TCF-4-signalling.
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Neoplasias Colorrectales/genética , Regulación Neoplásica de la Expresión Génica , Receptores del Ligando Inductor de Apoptosis Relacionado con TNF/genética , beta Catenina/genética , Adenoma/genética , Adenoma/metabolismo , Adenoma/patología , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Carcinoma/genética , Carcinoma/metabolismo , Carcinoma/patología , Línea Celular Tumoral , Niño , Neoplasias Colorrectales/metabolismo , Neoplasias Colorrectales/patología , Regulación hacia Abajo/genética , Femenino , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Masculino , Persona de Mediana Edad , Clasificación del Tumor , Estadificación de Neoplasias , Unión Proteica , Transporte de Proteínas , Receptores del Ligando Inductor de Apoptosis Relacionado con TNF/metabolismo , Ligando Inductor de Apoptosis Relacionado con TNF/metabolismo , Ligando Inductor de Apoptosis Relacionado con TNF/farmacología , Carga Tumoral , Adulto Joven , beta Catenina/metabolismoRESUMEN
Novel systemic therapies for advanced melanoma improve survival, but carry potential serious side effects and high costs. This study aimed to assess the timing and use of systemic therapies in the months before death. Patients diagnosed with advanced melanoma (July 2017-June 2020) who died before July 2020 were selected from the Netherlands Cancer Registry. We evaluated the timing of systemic therapies within 30 days and 3 months before death, and studied patient and tumor characteristics associated with systemic therapy use between diagnosis and death. Out of 1097 patients 68% received systemic therapy. Almost 25% and 10% started a new therapy within 90 days and within 30 days before death, respectively. Female sex, elevated LDH, BRAF mutation, poor ECOG performance status (≥3), and high comorbidity index reduced the odds of receiving immune therapy. Poor performance status and high comorbidity decreased the odds for both therapies. A considerable number of patients started systemic therapy shortly before death, emphasizing the importance of considering potential benefits and drawbacks through shared decision-making.
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Melanoma , Humanos , Femenino , Melanoma/tratamiento farmacológico , Melanoma/genética , Estudios Retrospectivos , Inmunoterapia , Muerte , Proteínas Proto-Oncogénicas B-raf/genéticaRESUMEN
Immune checkpoint inhibition has transformed the treatment landscape of advanced melanoma and long-term survival of patients is now possible. However, at least half of the patients do not benefit sufficiently. Metabolic reprogramming is a hallmark of cancer cells and may contribute to both tumour growth and immune evasion by the tumour. Preclinical studies have indeed demonstrated that modulating tumour metabolism can reduce tumour growth while improving the functionality of immune cells. Since metabolic pathways are commonly shared between immune and tumour cells, it is essential to understand how modulating tumour metabolism in patients influences the intricate balance of pro-and anti-tumour immune effects in the tumour microenvironment. The key question is whether modulating tumour metabolism can inhibit tumour cell growth as well as facilitate an anti-tumour immune response. Here, we review current knowledge on the effect of tumour metabolism on the immune response in melanoma. We summarise metabolic pathways in melanoma and non-cancerous cells in the tumour microenvironment and discuss models and techniques available to study the metabolic-immune interaction. Finally, we discuss clinical use of these techniques to improve our understanding of how metabolic interventions can tip the balance towards a favourable, immune permissive microenvironment in melanoma patients.
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Inhibidores de Puntos de Control Inmunológico , Melanoma , Microambiente Tumoral , Humanos , Melanoma/tratamiento farmacológico , Melanoma/inmunología , Melanoma/metabolismo , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Inhibidores de Puntos de Control Inmunológico/farmacología , Microambiente Tumoral/inmunología , Animales , Neoplasias Cutáneas/tratamiento farmacológico , Neoplasias Cutáneas/inmunología , Neoplasias Cutáneas/metabolismo , Neoplasias Cutáneas/patologíaRESUMEN
BACKGROUND: Hypoxia-induced glycogen turnover is implicated in cancer proliferation and therapy resistance. Triple-negative breast cancers (TNBCs), characterized by a hypoxic tumor microenvironment, respond poorly to therapy. We studied the expression of glycogen synthase 1 (GYS1), the key regulator of glycogenesis, and other glycogen-related enzymes in primary tumors of patients with breast cancer and evaluated the impact of GYS1 downregulation in preclinical models. METHODS: mRNA expression of GYS1 and other glycogen-related enzymes in primary breast tumors and the correlation with patient survival were studied in the METABRIC dataset (n = 1904). Immunohistochemical staining of GYS1 and glycogen was performed on a tissue microarray of primary breast cancers (n = 337). In four breast cancer cell lines and a mouse xenograft model of triple-negative breast cancer, GYS1 was downregulated using small-interfering or stably expressed short-hairpin RNAs to study the effect of downregulation on breast cancer cell proliferation, glycogen content and sensitivity to various metabolically targeted drugs. RESULTS: High GYS1 mRNA expression was associated with poor patient overall survival (HR 1.20, P = 0.009), especially in the TNBC subgroup (HR 1.52, P = 0.014). Immunohistochemical GYS1 expression in primary breast tumors was highest in TNBCs (median H-score 80, IQR 53-121) and other Ki67-high tumors (median H-score 85, IQR 57-124) (P < 0.0001). Knockdown of GYS1 impaired proliferation of breast cancer cells, depleted glycogen stores and delayed growth of MDA-MB-231 xenografts. Knockdown of GYS1 made breast cancer cells more vulnerable to inhibition of mitochondrial proteostasis. CONCLUSIONS: Our findings highlight GYS1 as potential therapeutic target in breast cancer, especially in TNBC and other highly proliferative subsets.
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Neoplasias de la Mama Triple Negativas , Humanos , Animales , Ratones , Neoplasias de la Mama Triple Negativas/metabolismo , Glucógeno Sintasa/genética , Glucógeno Sintasa/metabolismo , ARN Interferente Pequeño , Glucógeno/metabolismo , ARN Mensajero , Línea Celular Tumoral , Microambiente TumoralRESUMEN
BACKGROUND: Licensed systemic treatment options for platinum-sensitive recurrent ovarian cancer are platinum-based chemotherapy and maintenance treatment with bevacizumab and poly (ADP-ribose) polymerase inhibitors. For platinum-resistant disease, several non-platinum options are available. We aimed to assess the clinical benefit of these treatments according to the European Society of Medical Oncology (ESMO)-Magnitude of Clinical Benefit Scale (MCBS). MATERIALS AND METHODS: A PubMed search was carried out including all studies evaluating systemic treatment of recurrent epithelial ovarian cancer, from 1990 onwards. Randomised trials with an adequate comparator and design showing a statistically significant benefit of the study arm were independently scored by two blinded observers using the ESMO-MCBS. RESULTS: A total of 1127 papers were identified, out of which 61 reported results of randomised trials of sufficient quality. Nineteen trials showed statistically significant results and the studied treatments were graded according to ESMO-MCBS. Only three treatments showed substantial benefit (score of 4 on a scale of 1-5) according to the ESMO-MCBS: platinum-based chemotherapy with paclitaxel in the platinum-sensitive setting and the addition of bevacizumab to chemotherapy in the platinum-resistant setting. The WEE1 inhibitor adavosertib (not licensed) also scores a 4, based on a recent small phase II study. Assessment of quality-of-life data and toxicity using the ESMO-MCBS showed to be complex, which should be taken into account in using this score for clinical decision making. CONCLUSION: Only a few licensed systemic therapies for recurrent ovarian cancer show substantial clinical benefit based on ESMO-MCBS scores. Trials demonstrating overall survival benefit are sparse.
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Recurrencia Local de Neoplasia , Neoplasias Ováricas , Carcinoma Epitelial de Ovario/tratamiento farmacológico , Femenino , Humanos , Oncología Médica , Recurrencia Local de Neoplasia/tratamiento farmacológico , Neoplasias Ováricas/tratamiento farmacológico , Calidad de VidaRESUMEN
BACKGROUND: Patient-derived bulk expression profiles of cancers can provide insight into the transcriptional changes that underlie reprogrammed metabolism in cancer. These profiles represent the average expression pattern of all heterogeneous tumor and non-tumor cells present in biopsies of tumor lesions. Hence, subtle transcriptional footprints of metabolic processes can be concealed by other biological processes and experimental artifacts. However, consensus independent component analyses (c-ICA) can capture statistically independent transcriptional footprints of both subtle and more pronounced metabolic processes. METHODS: We performed c-ICA with 34,494 bulk expression profiles of patient-derived tumor biopsies, non-cancer tissues, and cell lines. Gene set enrichment analysis with 608 gene sets that describe metabolic processes was performed to identify the transcriptional components enriched for metabolic processes (mTCs). The activity of these mTCs was determined in all samples to create a metabolic transcriptional landscape. RESULTS: A set of 555 mTCs was identified of which many were robust across different datasets, platforms, and patient-derived tissues and cell lines. We demonstrate how the metabolic transcriptional landscape defined by the activity of these mTCs in samples can be used to explore the associations between the metabolic transcriptome and drug sensitivities, patient outcomes, and the composition of the immune tumor microenvironment. CONCLUSIONS: To facilitate the use of our transcriptional metabolic landscape, we have provided access to all data via a web portal ( www.themetaboliclandscapeofcancer.com ). We believe this resource will contribute to the formulation of new hypotheses on how to metabolically engage the tumor or its (immune) microenvironment.
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CD103-positive tissue resident memory-like CD8+ T cells (CD8CD103 TRM) are associated with improved prognosis across malignancies, including high-grade serous ovarian cancer (HGSOC). However, whether quantification of CD8, CD103 or both is required to improve existing survival prediction and whether all HGSOC patients or only specific subgroups of patients benefit from infiltration, remains unclear. To address this question, we applied image-based quantification of CD8 and CD103 multiplex immunohistochemistry in the intratumoral and stromal compartments of 268 advanced-stage HGSOC patients from two independent clinical institutions. Infiltration of CD8CD103 immune cell subsets was independent of clinicopathological factors. Our results suggest CD8CD103 TRM quantification as a superior method for prognostication compared to single CD8 or CD103 quantification. A survival benefit of CD8CD103 TRM was observed only in patients treated with primary cytoreductive surgery. Moreover, survival benefit in this group was limited to patients with no macroscopic tumor lesions after surgery. This approach provides novel insights into prognostic stratification of HGSOC patients and may contribute to personalized treatment strategies in the future.
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Cistadenocarcinoma Seroso , Neoplasias Ováricas , Linfocitos T CD8-positivos , Femenino , Humanos , Linfocitos Infiltrantes de Tumor , Pronóstico , Subgrupos de Linfocitos TRESUMEN
AIM: In this study, we determined whether outcome of preterm neonates has improved over a period of 16 years. STUDY DESIGN: Inborn neonates with a gestational age of 25.0-29.9 weeks were included. Patients with severe congenital malformations were excluded. Mortality and morbidity (chronic lung disease; CLD, intraventricular haemorrhage: IVH grade III or IV, cystic periventricular leukomalacia: cPVL, perforated necrotizing enterocolitis: NEC, severe retinopathy of prematurity needing surgery: ROP and cerebral palsy: CP) were compared in three periods (period 1: 1991-1996 n = 434; period 2: 1997-2001 n = 356; period 3: 2002-2006 n = 422). RESULTS: Infant mortality decreased from 15.2% to 10.9%. CLD did not differ significantly between periods (14.1-14.8%). Perforated NEC decreased from 2.8% to 1.6%. IVH grade III and IV both remained at 5.7% in period 3, whereas cPVL decreased significantly from 4.5% to 1.6%. Cerebral palsy decreased from 5.8% to 3.5% in period 3. Two neonates in each period were in need of surgery for ROP. CONCLUSION: Inborn preterm patients showed an improved survival and a significant reduction in cPVL and CP. Perforated NEC showed a trend to decrease. CLD and IVH grade III and IV remain a matter of concern.
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Mortalidad Infantil/tendencias , Enfermedades del Prematuro/epidemiología , Evaluación de Resultado en la Atención de Salud , Edad Gestacional , Humanos , Recién Nacido , Recien Nacido Prematuro , Enfermedades del Prematuro/mortalidad , Enfermedades del Prematuro/terapia , Unidades de Cuidado Intensivo Neonatal , Cuidado Intensivo Neonatal , Países Bajos/epidemiologíaRESUMEN
18F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) is increasingly used in patients with advanced melanoma. Immune checkpoint inhibitors and BRAF/MEK-targeted therapy have transformed the therapeutic landscape of metastatic melanoma. Consequently, a need for markers predicting (early) response to treatment and for monitoring treatment (toxicity) has arisen. This systematic review appraises the current literature evidence for rational use of 18F-FDG PET/CT scans in staging, clinical decision-making, treatment monitoring and follow-up in advanced melanoma. 18F-FDG PET/CT has high overall accuracy for detection of distant metastases and is, combined with cerebral MRI, the preferred imaging strategy for staging metastatic melanoma. In contrast, strong evidence supporting the standard use of 18F-FDG PET/CT for predicting and monitoring therapy response and toxicity is currently lacking. Essential for determining the position of 18F-FDG PET/CT during treatment course in advanced melanoma are well-designed studies with standardized scanning protocols, incorporation of clinical parameters and comparison with contrast-enhanced CT alone.
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Melanoma , Neoplasias Cutáneas/tratamiento farmacológico , Fluorodesoxiglucosa F18 , Humanos , Estadificación de Neoplasias , Tomografía Computarizada por Tomografía de Emisión de Positrones , Tomografía de Emisión de Positrones , RadiofármacosRESUMEN
Metastatic Merkel cell carcinoma (MCC) and cutaneous squamous cell carcinoma (cSCC) are rare and both show impressive responses to immune checkpoint inhibitor treatment. However, at least 40% of patients do not respond to these expensive and potentially toxic drugs. Development of predictive biomarkers of response and rational, effective combination treatment strategies in these rare, often frail patient populations is challenging. This review discusses the pathophysiology and treatment of MCC and cSCC, with a particular focus on potential biomarkers of response to immunotherapy, and discusses how transfer learning using big data collected from patients with common tumours can be used in combination with deep phenotyping of rare tumours to develop predictive biomarkers and elucidate novel treatment targets.
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COVID-19 , Pandemias , COVID-19/epidemiología , COVID-19/prevención & control , Humanos , SARS-CoV-2 , Sociedades MédicasRESUMEN
BACKGROUND: The magnitude of clinical benefit scale (MCBS) was introduced by the European Society of Medical Oncology (ESMO) to quantify the clinical benefit of therapeutic regimens and to prioritise therapies. It distinguishes curative from palliative treatments and ranks their benefit based on overall survival (OS), progression free survival (PFS), quality of life (QoL) and toxicity. Objective of this study on the first line treatment of ovarian cancer was to evaluate the evidence for the current standard of care using the ESMO-MCBSv1.1 with an emphasis on controversial therapeutic options: intraperitoneal chemotherapy, dose-dense paclitaxel and bevacizumab. METHODS: Phase III trials, published since 1992, investigating first line systemic treatment of Fédération Internationale de Gynécologie et d'Obstétrique (FIGO) stage IIB-IV epithelial ovarian cancer were included. Since most studies included patients with FIGO stage IV disease or incomplete debulking, all treatments were judged to be palliative. Treatments were graded 5 to 1 on the ESMO-MCBSv1.1, where grades 5 and 4 represent a high level of clinical benefit. RESULTS: 55 studies met the inclusion criteria. ESMO-MCBS scores were calculated for eleven studies that showed a statistically significant benefit of the experimental treatment. Intraperitoneal (ip) cisplatin scored a 4 and 3, but two other studies were negative and therefore not scored on the ESMO-MCBS. Dose-dense paclitaxel showed substantial clinical benefit in one study (score 4), but three studies were negative. Addition of bevacizumab also scored a 4 in one study subgroup including high-risk patients but a 2 in another trial with a larger study population. CONCLUSION: Based on ESMO-MCBS scores, dose-dense paclitaxel and intraperitoneal chemotherapy cannot be recommended as standard treatment. Bevacizumab should be considered only in the high-risk population. The ESMO-MCBSv1.1. helps to summarise reported studies on controversial treatment regimens, and identifies their weaknesses.