Gabriel G Malouf

University of Strasbourg | UNISTRA

601 Background: Immunotherapy (IO) has revolutionized the management of metastatic renal cell carcinoma (mRCC) by improving survival, overall response and complete response (CR) rates. CR is achieved in 11 to 17% with the different PD-1-based IO combinations in first-line setting of mRCC. However, local treatment of residual disease after systemic...

Background There remains a paucity of data regarding the efficacy of immune checkpoint therapy (ICT) combinations ± vascular endothelial growth factor (VEGF) targeted therapy (TT) in translocation renal cell carcinoma (tRCC). Methods This is a retrospective study of patients with advanced tRCC treated with ICT combinations at 11 centers in the US,...

Purpose: Immune checkpoint inhibitors have revolutionized the treatment of patients with clear-cell renal carcinomas (ccRCC). Although, analyses of transcriptome, genetic alterations, and the tumor microenvironment have shed light into mechanisms of response and resistance to these agents, the role of epigenetic alterations in this process remains...

Background For patients with metastatic rare cancers, treatments are limited. How systematic tumor sequencing can improve therapeutic possibilities in this population? Patients and methods Patients with rare cancer were identified in the MOSCATO-01 trial. Patients’ outcome was measured by progression-free survival (PFS) and overall survival (OS)....

Tumor heterogeneity is a key feature of melanomas that hinders development of effective treatments. Aiming to overcome this, we identified LINC00518 (LENOX; lincRNA-enhancer of oxidative phosphorylation) as a melanoma-specific lncRNA expressed in all known melanoma cell states and essential for melanoma survival in vitro and in vivo. Mechanisticall...

Background MiT family translocation renal cell carcinoma (TRCC) is a rare and aggressive subgroup of renal cell carcinoma harboring high expression of c-MET. While TRCC response rates to VEGF receptor tyrosine kinase inhibitors (TKIs) and immune checkpoint inhibitors are limited, efficacy of cabozantinib (a VEGFR, MET, and AXL inhibitor) in this su...

Background Tyrosine kinase inhibitors (TKIs) remain a cornerstone of metastatic kidney cancer (mRCC). Adverse events (AEs) may lead to dose downregulation, and optimal management of AEs is needed to maintain an efficient dose intensity (DI). The aim of our study was to evaluate the impact of an app-based and nurse-led supportive-care program on DI...

Background: Kaposi sarcoma (KS) is a rare skin tumor caused by herpesvirus 8 infection and characterized by either indolence or an aggressive course necessitating systemic therapies. The genetic basis of this difference remains unknown. Objectives: To explore the tumor mutational burden in indolent and aggressive KS. Methods: We performed whol...

Nouvelles AMMs : pembrolizumab en adjuvant pour les carcinomes rénaux à cellules claires à haut risque de récidive après néphrectomie New drug approval: Adjuvant Pembrolizumab in clear-cell renal-cell carcinomaat high risk for recurrence after nephrectomy Le cancer du rein est la deuxième cause de cancer urologique en France avec 15 300 nouveaux ca...

Background: Thoracic SMARCA4-deficient undifferentiated tumors (SMARCA4-UT) are aggressive neoplasms. Data linking BAF alterations with tumor microenvironment (TME) and efficacy of immune checkpoint inhibitors (ICI) are contradictory. The TME of SMARCA4-UT and their response to ICI are unknown. Materials and methods: Patients diagnosed with SMAR...

11571 Background: Perivascular Epithelioid Cell Neoplasms (PEComas) encompass a heterogeneous family of mesenchymal tumors. The current understanding of their natural history is limited. Previously described clinicopathological factors aimed to define benign or malignant variants, but there is a lack of prognostic factors associated with recurrence...

To compare the respective value of 68Ga-DOTATOC and 18F-DOPA PET/CT for initial staging or pre-surgical work-up of patients with small intestine neuroendocrine tumors (SiNET). Methods: This is a retrospective, multicenter, non-interventional investigation involving 53 non-operated SiNET patients who underwent both 68Ga-DOTATOC and 18F-DOPA PET/CT w...

Immune checkpoint inhibitors have revolutionized the treatment of patients with clear-cell renal carcinomas. Although, analyses of transcriptome, genetic alterations, and the tumor microenvironment have shed light into mechanisms of response and resistance to these agents, the role of epigenetic alterations in this process remains fully unknown. He...

Background: Renal cell carcinomas represent 2 to 5% of kidney malignancies in children and adolescents. Appropriate diagnostic and classification are crucial for the correct management of the patients and in order to avoid inappropriate preoperative chemotherapy, which is usually recommended if a Wilms tumor is suspected. Methods: a French-Itali...

343 Background: IO combinations are standard of care for first-line therapy of clear-cell RCC; however, non-clear cell histologies including tRCC were not included in the registrational trials. We previously reported a modest efficacy (objective response rate [ORR] <20%) with IO monotherapy (PD-1 blockade) in tRCC (Boilève et al, JITC. 2018). The e...

Renal medullary carcinoma (RMC) is an aggressive tumour driven by bi-allelic loss of SMARCB1 and tightly associated with sickle cell trait. However, the cell-of-origin and oncogenic mechanism remain poorly understood. Using single-cell sequencing of human RMC, we defined transformation of thick ascending limb (TAL) cells into three RMC cell states...

Background: Crosstalk between genetic, epigenetic, and immune alterations in upper tract urothelial carcinomas and their role in shaping muscle invasiveness and patient outcome are poorly understood. Results: We perform an integrative genome-and methylome-wide profiling of diverse non-muscle-invasive and muscle-invasive upper tract urothelial carci...

The development of antiangiogenic treatments, followed by immune checkpoint inhibitors (ICI), has significantly changed the management of metastatic clear cell renal cell cancer. Several phase III trials show the superiority of combination therapy, dual immunotherapy (ICI-ICI) or ICI plus tyrosine kinase inhibitors (TKI) of the vascular endothelium...

PEComas is a family of rare mesenchymal tumors. This systematic review aims to better understand the natural history of advanced PEComas. After a search on the PubMed database and main oncology meeting libraries according to the PRISMA guidelines, 88 articles reported in the English literature were included. Data on clinical and histological featur...

Renal medullary carcinoma (RMC) is an aggressive desmoplastic tumour driven by bi-allelic loss of SMARCB1, however the cell-of-origin, the oncogenic mechanism and the features of its microenvironment remain poorly understood. Using single-cell and multi-region sequencing of human RMC, we defined transformation of thick ascending limb (TAL) cells in...

Upper tract urothelial carcinoma (UTUC) represents a rare and aggressive malignancy arising from the renal pelvis or ureter. It can develop sporadically or have a hereditary origin, such as Lynch syndrome, caused by DNA mismatch repair deficiency, leading to microsatellite instability phenotype. According to molecular characterization studies, UTUC...

Well-differentiated pancreatic neuroendocrine tumors (pNET) have an unpredictable natural history. The identification of both blood and tumor immune features associated with patients’ outcomes remains limited. Herein, we evaluated the best prognostic value of the neutrophils-to-lymphocyte ratio (NLR) in a cohort of 144 pNETs. The NLR ≥ 4 was associ...

11552 Background: SMARCA4-deficient thoracic sarcomas (SDS) are rare and aggressive sarcomas characterized by inactivating SMARCA4 mutations, with no approved treatment to date. Previous data linking SWI/SNF deficiency with tumor immune microenvironment (TME) are contradictory. While an immunogenic microenvironment and efficacy of immune checkpoint...

274 Background: MiT family translocation renal cell carcinomas (TRCC) represent a rare and aggressive subgroup of RCC harboring high expression of c-MET. While response rates of VEGF receptor-tyrosine kinase inhibitor and immune checkpoint inhibitors are limited, efficacy of cabozantinib (a TKI that inhibits VEGFR, MET, and AXL) in this subgroup is...

Immune checkpoint inhibitors (ICIs) have revolutionized the treatment of various cancers by reversing the immunosuppressive mechanisms employed by tumors to restore anticancer immunity. Although ICIs have demonstrated substantial clinical efficacy, patient response can vary in depth and duration, and many do not respond at all or eventually develop...

Background Crosstalk between genetic, epigenetic, and immune alterations in upper tract urothelial carcinomas and their role in shaping muscle invasiveness and patient outcome are poorly understood. Results We perform an integrative genome- and methylome-wide profiling of diverse non-muscle-invasive and muscle-invasive upper tract urothelial carci...

Dedifferentiation and acquisition of chromosomal instability in renal cell carcinoma portends dismal prognosis and aggressive clinical behavior. However, the absence of reliable experimental models dramatically impacts the understanding of mechanisms underlying malignant progression. Here we established an in vivo genetic platform to rapidly genera...

Several interventional treatments have recently been integrated into the therapeutic armamentarium available for the treatment of bone tumors. In some scenarios (e.g., osteoid osteoma), interventional treatments represent the sole and definitive applied treatment. Due to the absence of widely shared protocols and the complex multivariate scenarios...

p>Renal medullary carcinoma (RMC) is a rare but highly lethal renal cell carcinoma (RCC) that predominantly afflicts young African Americans with sickle cell hemoglobinopathies. There are currently no approved targeted therapies for RMC and the median survival from diagnosis is 13 months despite best available treatments. New biomarkers and therape...

Epigenetic processes are essential for normal development and the maintenance of tissue-specific gene expression in mammals. Changes in gene expression and malignant cellular transformation can result from disruption of epigenetic mechanisms, and global disruption in the epigenetic landscape is a key feature of cancer. The study of epigenetics in c...

Renal medullary carcinoma (RMC) is a highly lethal malignancy that mainly afflicts young individuals of African descent and is resistant to all targeted agents used to treat other renal cell carcinomas. Comprehensive genomic and transcriptomic profiling of untreated primary RMC tissues was performed to elucidate the molecular landscape of these tum...

MiT family translocation renal cell carcinomas (tRCC) represent a rare subtype of renal cell carcinomas. These tumors have been introduced for the first time in the World Health Classification (WHO) classification of kidney cancers in 2004. tRCC are characterized by reccurent translocations involving members of the MiT family transcription factors,...

The main objective of the French GETUG/AFU V05 VESPER randomized phase III study was to assess the efficacy of dd-MVAC and GC in term of progression-free survival in patients for whom chemotherapy has been decided, before or after surgery. A total of 500 patients have been randomized in 28 reference centers. Inclusion criteria were urothelial carci...

Sarcomatoid clear-cell renal cell carcinomas (sRCC) are associated with dismal prognosis. Genomic alterations associated with sarcomatoid dedifferentiation are poorly characterized. We sought to define the genomic landscape of sRCC and uncover potentially actionable therapeutic targets. We assessed the genomic landscape of sRCC using targeted panel...

Sarcomatoid features in renal cell carcinoma (RCC) have long been associated with dismal prognosis and poor response to therapy, while biological mechanisms underpinning sarcomatoid dedifferentiation remained obscure. Several efforts have been conducted to break down the molecular profile of sarcomatoid RCC and investigate different targeted therap...

Background: Abiraterone and enzalutamide are recently-approved androgen deprivation therapies (ADTs) for metastatic prostate cancer, with unknown cardiac safety profiles. Abiraterone has a propensity to hypermineralocorticism on top of androgen deprivation, so might carry an additional risk for atrial tachyarrhythmia (AT) and heart failure (HF) co...

Background Abiraterone and enzalutamide are recently approved androgen deprivation therapies (ADT) for metastatic prostate cancer. The cardiac safety profile for the two drugs is unknown. Methods Using French and World Health Organization (WHO) pharmacovigilance databases, we performed a disproportionality-analysis of suspected adverse-drug-reacti...

Introduction: Neoadjuvant chemotherapy (neo-CT) for osteosarcomas is the standard of care. Management of maxillo-facial osteosarcomas (MFOS) is challenging. In this rare disease, we collected a large cohort of patients with the aim to report the histological and radiological local response rates to neo-CT. Patients and methods: All consecutive a...

Olfactory neuroblastomas (ONBs) are rare malignant tumours that arise in the nasal vault. To date, the Hyams grade remains the only widely used histological grading system. However, it is based only on morphologic criteria, and has not been updated since 1988. Aims: The objective of this study was to explore the prognostic potential of the Ki67 p...

e15701 Background: Pseudomyxoma peritonei (PMP) is a rare malignant tumor characterized by the infiltration of the peritoneum by mucus-secreting tumor cells. The genetic landscape of these tumors and correlation with clinico-pathological tumor features is unclear to date. Methods: We performed whole-exome sequencing (WES) on 8 PMPs and matched nor...

4560 Background: Upper-tract urothelial carcinomas (UTUC) may harbor similar genetic profile as compared to bladder cancer, although frequencies of mutated genes have been shown to differ between them. However, to the best of our knowledge, the epigenetic landscapes of UTUC and their association with genetic alterations and clinico-pathological tum...

Long non-coding RNAs (lncRNAs) are regulators of cellular machinery that are commonly dysregulated in genitourinary malignancies. Accordingly, the investigation of lncRNAs is improving our understanding of genitourinary cancers, from development to progression and dissemination. lncRNAs are involved in major oncogenic events in genitourinary malign...

Alterations in chromatin remodeling genes have been increasingly implicated in human oncogenesis. Specifically, the biallelic inactivation of the SWI/SNF subunit SMARCB1 results in the emergence of extremely aggressive pediatric malignancies. Here, we developed embryonic mosaic mouse models of malignant rhabdoid tumors (MRTs) that faithfully recapi...

In melanoma, initiating oncogenic mutations in BRAF or NRAS are detected in premalignant lesions that accumulate additional mutations and genomic instability as the tumor evolves to the metastatic state. Here we investigate evolution of clonal composition and neoantigen landscape in an atypical melanoma displaying recurrent cutaneous lesions over a...

Background: The objective of the study was to evaluate the outcomes in terms of efficacy and safety of a large consecutive series of 362 patients with renal cell carcinoma (RCC) brain metastases treated using stereotactic radiosurgery (SRS) in the tyrosine kinase inhibitor (TKI) era. Patients and methods: From 2005 to 2015, 362 consecutive patie...

Background Alveolar soft part sarcoma (ASPS) is a rare sarcoma characterized by a slow evolution, brain metastasis (BM), and resistance to doxorubicin. Antiangiogenic therapies (AAT) have shown clinical activity, but little is known about the optimal therapeutic strategy, specifically considering BM. Subjects, Materials, and Methods We performed a...

This book provides clinicians with clear guidance on treatment decision-making in patients with rare kidney cancers. After a brief review on epidemiology, pathology, and biology, each chapter focuses on the multidisciplinary management of a particular tumor subtype using the full range of available cancer therapy modalities, including surgery, radi...

Background Microphthalmia Transcription Factor (MITF)family translocation renal cell carcinoma (tRCC) is a rare RCC subtype harboring TFE3/TFEB translocations. The prognosis in the metastatic (m) setting is poor. Programmed death ligand-1 expression was reported in 90% of cases, prompting us to analyze the benefit of immune checkpoint inhibitors (I...

Esthesioneuroblastoma (ENB) is a rare cancer of the olfactory mucosa, with no established molecular stratification to date. We report similarities of ENB with tumors arising in the neural crest and perform integrative analysis of these tumors. We propose a molecular-based subtype classification of ENB as basal or neural, both of which have distinct...

We report the results of serial F-FDG PET/CT investigations in a 49-year-old woman presenting with an advanced cecal high-grade neuroendocrine carcinoma harboring a somatic BRAF mutation. Patient was refractory to standard chemotherapy regimen showing life-threatening hyperlactatemia. Early after the beginning of BRAF-MEK therapy (dabrafenib and tr...

498 Background: Squamous differentiation has been reported to occur in 10-22 % of transitional cell carcinoma. The prognostic impact of squamous differentiation is controversial. In addition, it remains unclear whether the percentage of squamous differentiation impact outcome of patients with nonbilharzial squamous cell carcinoma and transitional c...

614 Background: RMC is a highly aggressive tumor with close to universal fatality despite therapy. It is almost exclusively found in young African-Americans with sickle cell trait, and is characterized by complete loss of expression of SMARCB1, a major chromatin remodeler involved in regulation of gene expression. We investigated the effects of SMA...

Prediction of recurrence is a challenge for the development of adjuvant treatments in clear-cell renal cell carcinoma (ccRCC). In these tumors, expression of long non-coding RNAs (lncRNAs) are deregulated and closely associated with prognosis. Thus, we aimed to predict ccRCC recurrence risk using lncRNA expression. We identified prognostic lncRNAs...

Objectif de l’étude L’objectif de cette étude rétrospective monocentrique était d’évaluer les différentes modalités de radiothérapie en conditions stéréotaxiques des métastases cérébrales de cancer du rein. Matériel et méthode Cent vingt patients atteints d’un cancer du rein ont été pris en charge pour une irradiation cérébrale en conditions stéré...

Extensive dysregulation of chromatin-modifying genes in clear-cell renal cell carcinoma (ccRCC) has been uncovered through next-generation sequencing. However, a scientific understanding of the crosstalk between epigenetic and genomic aberrations remains limited. Here we identify three ccRCC epigenetic clusters, including a clear-cell CpG island me...