Publications by authors named "Wendy W J De Leng"

Purpose: The treatment efficacy of nivolumab was evaluated in patients with advanced, treatment-refractory solid mismatch repair deficiency/microsatellite-instable (dMMR/MSI) tumors, and in-depth biomarker analyses were performed to inform precision immunotherapy approaches.

Patients And Methods: Patients with dMMR/MSI tumors who exhausted standard-of-care treatment options were enrolled in the Drug Rediscovery Protocol, a pan-cancer clinical trial that treats patients with cancer based on their tumor molecular profile with off-label anticancer drugs (NCT02925234). Patients received nivolumab (four cycles of 240 mg every 2 weeks, thereafter 480 mg every 4 weeks).

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  • Melanocytic neoplasms with spitzoid histomorphology are tricky to classify without genetic testing, as traditional methods often provide unclear results.
  • The Idylla GeneFusion Assay has been compared to the Archer fusion assay on its ability to detect certain gene fusions (ALK, pan-NTRK, RET, and ROS1), showing promising results with a 75% sensitivity and 100% specificity in analyzing 147 samples.
  • Idylla is effective with isolated RNA and could be a useful initial screening tool for spitzoid melanocytic tumors, even though it may not replace more detailed tests like the Archer assay.
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Purpose: To evaluate the efficacy of pembrolizumab across multiple cancer types harboring different levels of whole-genome sequencing-based tumor mutational load (TML; total of nonsynonymous mutations across the genome) in patients included in the Drug Rediscovery Protocol (NCT02925234).

Patients And Methods: Patients with solid, treatment-refractory, microsatellite-stable tumors were enrolled in cohort A: breast cancer cohort harboring a TML of 140 to 290, cohort B: tumor-agnostic cohort harboring a TML of 140 to 290, and cohort C: tumor-agnostic cohort harboring a TML >290. Patients received pembrolizumab 200 mg every 3 weeks.

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Background: One targeted treatment option for isocitrate dehydrogenase ()-wild-type glioblastoma focuses on tumors with fibroblast growth factor receptor 3::transforming acidic coiled-coil-containing protein 3 () fusions. fusion detection can be challenging, as targeted RNA next-generation sequencing (NGS) is not routinely performed, and immunohistochemistry is an imperfect surrogate marker. Fusion status can be determined using reverse transcription polymerase chain reaction (RT-PCR) on fresh frozen (FF) material, but sometimes only formalin-fixed, paraffin-embedded (FFPE) tissue is available.

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  • * Out of 24 patients, 46% showed clinical benefit, with a significant number achieving an objective response, and the overall treatment was considered safe with no unexpected side effects.
  • * Whole genome sequencing helped identify potential resistance reasons in some patients, reinforcing the clinical significance of targeted therapy for HER2+mCRC.
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Purpose: Next generation sequencing (NGS) is an important tool used in clinical practice to obtain the required molecular information for accurate diagnostics of high-grade adult-type diffuse glioma (HGG). Since individual centers use either in-house produced or standardized panels, interlaboratory variation could play a role in the practice of HGG diagnosis and treatment. This study aimed to investigate the current practice in NGS application for both primary and recurrent HGG.

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Background: The prognosis of malignant primary high-grade brain tumors, predominantly glioblastomas, is poor despite intensive multimodality treatment options. In more than 50% of patients with glioblastomas, potentially targetable mutations are present, including rearrangements, altered splicing, and/or focal amplifications of epidermal growth factor receptor (EGFR) by signaling through the RAF/RAS pathway. We studied whether treatment with the clinically available anti-EGFR monoclonal antibody panitumumab provides clinical benefit for patients with RAF/RAS-wild-type (wt) glioblastomas in the Drug Rediscovery Protocol (DRUP).

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  • The T2-FLAIR mismatch sign on MRI indicates a specific feature of IDH-mutant astrocytomas, showing signal loss that may relate to microcystic changes in the tumor, but not all tumors display this sign.
  • A study of patients with lower-grade IDH-mutant astrocytomas aimed to explore the prognostic significance of this sign after surgical resections and its relationship with tumor characteristics.
  • Results revealed that the presence of the T2-FLAIR mismatch is associated with Grade 2 tumors, a better overall survival rate, and expansive tumor growth, suggesting its potential as a positive prognostic marker for these patients.
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Chromosomal rearrangements are important drivers in cancer, and their robust detection is essential for diagnosis, prognosis, and treatment selection, particularly for bone and soft tissue tumors. Current diagnostic methods are hindered by limitations, including difficulties with multiplexing targets and poor quality of RNA. A novel targeted DNA-based next-generation sequencing method, formalin-fixed, paraffin-embedded-targeted locus capture (FFPE-TLC), has shown advantages over current diagnostic methods when applied on FFPE lymphomas, including the ability to detect novel rearrangements.

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The Dutch Drug Rediscovery Protocol (DRUP) and the Australian Cancer Molecular Screening and Therapeutic (MoST) Program are similar nonrandomized, multidrug, pan-cancer trial platforms that aim to identify signals of clinical activity of molecularly matched targeted therapies or immunotherapies outside their approved indications. Here, we report results for advanced or metastatic cancer patients with tumors harboring cyclin D-CDK4/6 pathway alterations treated with CDK4/6 inhibitors palbociclib or ribociclib. We included adult patients that had therapy-refractory solid malignancies with the following alterations: amplifications of CDK4, CDK6, CCND1, CCND2 or CCND3, or complete loss of CDKN2A or SMARCA4.

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  • A study was conducted to evaluate the effectiveness of menin immunohistochemistry in diagnosing multiple endocrine neoplasia type 1 (MEN1) syndrome, particularly in parathyroid adenomas.
  • The research analyzed parathyroid tumors from patients with MEN1 and various non-MEN1 conditions, finding that menin loss was present in all MEN1 patients but only in a small percentage of non-MEN1 patients.
  • The results indicate that menin immunohistochemistry is a reliable tool for confirming MEN1 syndrome and can aid in cases where genetic testing results are ambiguous.
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Background: Liquid biopsies combine minimally invasive sample collection with sensitive detection of residual disease. Pediatric malignancies harbor tumor-driving copy number alterations or fusion genes, rather than recurrent point mutations. These regions contain tumor-specific DNA breakpoint sequences.

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  • * A panel of 39 Dutch experts used a modified Delphi method to discuss and vote on the appropriateness of testing, reaching consensus on only 44% of their questions.
  • * Key findings suggest that patients with a family history might benefit from certain types of genetic testing, but limitations include a lack of scientific evidence for some recommendations and a limited number of specialists involved in the discussions.
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  • This study evaluated the effectiveness and safety of the PD-L1 inhibitor durvalumab in patients with mismatch repair deficient (dMMR) or microsatellite instability-high (MSI-H) tumors as part of a clinical trial called the Drug Rediscovery Protocol (DRUP).
  • A total of 26 patients with various solid tumors, who had no other treatment options left, were treated with durvalumab, showing a clinical benefit in 50% of them, with a 27% objective response rate.
  • The results suggested that durvalumab was well-tolerated, and specific genetic markers were linked to patients who did not respond well, indicating potential areas for further research in larger studies.
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Cutaneous deep penetrating melanocytic neoplasms frequently simulate melanoma and might occasionally progress to metastatic melanoma. Distinguishing deep penetrating nevi (DPN) and deep penetrating melanocytomas (DPM) from malignant deep penetrating tumors (MDPT) is difficult based on histopathology alone, and diagnostic criteria for MDPT are currently lacking. Using a molecular workup, we aimed to provide readily available diagnostic tools for classification of deep penetrating tumors.

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Purpose: To assess the efficacy of olaparib, a PARP inhibitor (PARPi) in patients with tumors with mutations, regardless of histologic tumor type.

Patients And Methods: Patients with treatment-refractory mutated cancer were included for treatment with off-label olaparib 300 mg twice daily until disease progression or unacceptable toxicity. In Drug Rediscovery Protocol (DRUP), patients with treatment-refractory solid malignancies receive off-label drugs based on tumor molecular profiles while whole-genome sequencing (WGS) is performed on baseline tumor biopsies.

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Whole genome sequencing (WGS) using fresh-frozen tissue and matched blood samples from cancer patients may become the most complete genetic tumor test. With the increasing availability of small biopsies and the need to screen more number of biomarkers, the use of a single all-inclusive test is preferable over multiple consecutive assays. To meet high-quality diagnostics standards, we optimized and clinically validated WGS sample and data processing procedures, resulting in a technical success rate of 95.

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Glioblastoma (GBM) is the most malignant primary brain tumor for which no curative treatment options exist. Non-invasive qualitative (Visually Accessible Rembrandt Images (VASARI)) and quantitative (radiomics) imaging features to predict prognosis and clinically relevant markers for GBM patients are needed to guide clinicians. A retrospective analysis of GBM patients in two neuro-oncology centers was conducted.

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Purpose: The primary origin of neuroendocrine tumor metastases can be difficult to determine by histopathology alone, but is critical for therapeutic decision making. DNA methylation-based profiling is now routinely used in the diagnostic workup of brain tumors. This has been enabled by the availability of cost-efficient array-based platforms.

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Background: Molecular tumor boards (MTBs) provide rational, genomics-driven, patient-tailored treatment recommendations. Worldwide, MTBs differ in terms of scope, composition, methods, and recommendations. This study aimed to assess differences in methods and agreement in treatment recommendations among MTBs from tertiary cancer referral centers in The Netherlands.

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Background: Molecular diagnostics can be decisive in the differential diagnosis between a somatic metastasis of type II testicular germ cell tumor (TGCT) or a second primary carcinoma. This is in line with recent recommendations from the International Society of Urological Pathology, based on an international survey which showed that molecular testing is currently only performed by a minority of urological pathologists.

Case Presentations: This case report illustrates the necessity of molecular testing in two patients with a history of type II TGCT and a metastatic (retro) peritoneal carcinoma years later.

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The 2020 COVID-19 crisis has had and will have many implications for healthcare, including pathology. Rising number of infections create staffing shortages and other hospital departments might require pathology employees to fill more urgent positions. Furthermore, lockdown measures and social distancing cause many people to work from home.

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Desmoplastic small round cell tumors (DSRCTs) are highly aggressive sarcomas that most commonly occur intra-abdominally, and are defined by EWSR1-WT1 gene fusion. Intracranial DSRCTs are exceptionally rare with only seven previously reported fusion-positive cases. Herein, we evaluate the clinical, morphologic, immunohistochemical and molecular features of five additional examples.

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A diagnosis of clear cell chondrosarcoma of the ulna was made in a patient with Von Hippel-Lindau disease (VHL). After surgery, genetic analysis of the tumor tissue showed loss of heterozygosity at the VHL gene locus. Immunohistochemical analysis confirmed loss of expression of the VHL protein in the tumor cells.

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Purpose: BRAF V600E mutation is a distinctive genomic alteration of pediatric low-grade gliomas with prognostic and therapeutic implications. The aim of this retrospective multicenter study was to analyze imaging features of BRAF V600E-mutant and wild-type cerebral pilocytic astrocytomas (PAs) and gangliogliomas (GGs), focusing on the role of diffusion weighted imaging (DWI).

Methods: We retrospectively evaluated 56 pediatric patients with histologically proven, treatment-naïve PAs and GGs who underwent conventional MRI, DWI, and molecular analysis for BRAF V600E mutation.

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