Background: The complete response rate of cervical high-grade squamous intraepithelial lesion (cHSIL) patients to imiquimod immunotherapy is approximately 60%. Consequently, many patients are... Show moreBackground: The complete response rate of cervical high-grade squamous intraepithelial lesion (cHSIL) patients to imiquimod immunotherapy is approximately 60%. Consequently, many patients are exposed to unnecessary adverse effects of imiquimod. On the other hand, conventional surgical large loop excision therapy is associated with increased risk of premature births in subsequent pregnancies. An in-depth analysis of the cHSIL immune microenvironment was performed in order to identify and develop a predictive biomarker for response to imiquimod, to maximize therapy efficacy and to avoid adverse effects in patients unlikely to respond. Methods: Biopsies of 35 cHSIL patients, before and 10 weeks on imiquimod treatment, were analyzed by two multispectral seven-color immunofluorescence panels for T cell and myeloid cell composition in relation to treatment response. Based on these results a simplified immunohistochemical detection protocol was developed. Samples were scanned with the Vectra multispectral imaging system and cells were automatically identified using machine learning. Results: The immune microenvironment of complete responders (CR) is characterized by a strong and coordinated infiltration by T helper cells (activated PD1(+)/type 1 Tbet(+)), M1-like macrophages (CD68(+)CD163(-)) and dendritic cells (CD11c(+)) prior to imiquimod. The lesions of non-responders (NRs) displayed a high infiltration by CD3(+)FOXP3(+) regulatory T cells. At 10 weeks on imiquimod, a strong influx of intraepithelial and stromal CD4(+) T cells was observed in CR but not NR patients. A steep decrease in macrophages occurred both in CR and NR patients, leveling the pre-existing differences in myeloid cell composition between the two groups. Based on the pre-existing immune composition differences, the sum of intraepithelial CD4 T cell, macrophage and dendritic cell counts was used to develop a quantitative simplified one color immunohistochemical biomarker, the CHSIL immune biomarker for imiquimod (CIBI), which can be automatically and unbiasedly quantified and has an excellent predictive capacity (receiver operating characteristic area under the curve 0.95, p<0.0001). Conclusion: The capacity of cHSIL patients to respond to imiquimod is associated with a pre-existing coordinated local immune process, fostering an imiquimod-mediated increase in local T cell infiltration. The CIBI immunohistochemical biomarker has strong potential to select cHSIL patients with a high likelihood to experience a complete response to imiquimod immunotherapy. Show less
Background: Meningiomas, the most common primary intracranial tumors, can be separated into 3 DNA methylation groups with distinct biological drivers, clinical outcomes, and therapeutic... Show moreBackground: Meningiomas, the most common primary intracranial tumors, can be separated into 3 DNA methylation groups with distinct biological drivers, clinical outcomes, and therapeutic vulnerabilities. Alternative meningioma grouping schemes using copy number variants, gene expression profiles, somatic short variants, or integrated molecular models have been proposed. These data suggest meningioma DNA methylation groups may harbor subgroups unifying contrasting theories of meningioma biology. Methods: A total of 565 meningioma DNA methylation profiles from patients with comprehensive clinical follow-up at independent discovery (n = 200) or validation (n = 365) institutions were reanalyzed and classified into Merlin-intact, Immune-enriched, or Hypermitotic DNA methylation groups. RNA sequencing from the discovery (n = 200) or validation (n = 302) cohort were analyzed in the context of DNA methylation groups to identify subgroups. Biological features and clinical outcomes were analyzed across meningioma grouping schemes. Results: RNA sequencing revealed differential enrichment of FOXM1 target genes across two subgroups of Hypermitotic meningiomas. Differential expression and ontology analyses showed the subgroup of Hypermitotic meningiomas without FOXM1 target gene enrichment was distinguished by gene expression programs driving macromolecular metabolism. Analysis of genetic, epigenetic, gene expression, or cellular features revealed Hypermitotic meningioma subgroups were concordant with Proliferative or Hypermetabolic meningiomas, which were previously reported alongside Merlin-intact and Immune-enriched tumors using an integrated molecular model. The addition of DNA methylation subgroups to clinical models refined the prediction of postoperative outcomes compared to the addition of DNA methylation groups. Conclusions: Meningiomas can be separated into three DNA methylation groups and Hypermitotic meningiomas can be subdivided into Proliferative and Hypermetabolic subgroups, each with distinct biological and clinical features. Show less
Ho, K.; Fleseriu, M.; Kaiser, U.; Salvatori, R.; Brue, T.; Lopes, M.B.; ... ; Melmed, S. 2021
The WHO Classification of Endocrine Tumours designates pituitary neoplasms as adenomas. A proposed nomenclature change to pituitary neuroendocrine tumors (PitNETs) has been met with concern by some... Show moreThe WHO Classification of Endocrine Tumours designates pituitary neoplasms as adenomas. A proposed nomenclature change to pituitary neuroendocrine tumors (PitNETs) has been met with concern by some stakeholder groups. The Pituitary Society coordinated the Pituitary Neoplasm Nomenclature (PANOMEN) workshop to address the topic. Experts in pituitary developmental biology, pathology, neurosurgery, endocrinology, and oncology, including representatives nominated by the Endocrine Society, European Society of Endocrinology, European Neuroendocrine Association, Growth Hormone Research Society, and International Society of Pituitary Surgeons. Clinical epidemiology, disease phenotype, management, and prognosis of pituitary adenomas differ from that of most NETs. The vast majority of pituitary adenomas are benign and do not adversely impact life expectancy. A nomenclature change to PitNET does not address the main challenge of prognostic prediction, assigns an uncertain malignancy designation to benign pituitary adenomas, and may adversely affect patients. Due to pandemic restrictions, the workshop was conducted virtually, with audiovisual lectures and written precis on each topic provided to all participants. Feedback was collated and summarized by Content Chairs and discussed during a virtual writing meeting moderated by Session Chairs, which yielded an evidence-based draft document sent to all participants for review and approval. There is not yet a case for adopting the PitNET nomenclature. The PANOMEN Workshop recommends that the term adenoma be retained and that the topic be revisited as new evidence on pituitary neoplasm biology emerges. Show less
Davies, M.; Lalam, R.; Woertler, K.; Bloem, J.L.; Astrom, G. 2020
The diagnosis of tumors and tumorlike lesions of bone is a routine part of both general and specialist radiologic practices. The spectrum of disorders ranges from the small incidental lesion to the... Show moreThe diagnosis of tumors and tumorlike lesions of bone is a routine part of both general and specialist radiologic practices. The spectrum of disorders ranges from the small incidental lesion to the potentially life-limiting malignancies whether primary or secondary. In this review, authored by experts from several European orthopaedic oncology centers, we present a collection of pieces of advice in the form of 10 commandments. Adherence in daily practice to this guidance should help minimize adverse patient experiences and outcomes. Show less
PURPOSE. A subgroup of uveal melanoma (UM) gives rise to metastases at a late stage. Our objective was to identify patient and tumor characteristics that are associated with UM-related death in... Show morePURPOSE. A subgroup of uveal melanoma (UM) gives rise to metastases at a late stage. Our objective was to identify patient and tumor characteristics that are associated with UM-related death in patients who survived 5 years following enucleation.METHODS. A retrospective analysis was performed in 583 primary UM cases, enucleated at the Leiden University Medical Center between 1983 and 2013. Univariable and multivariable Cox regression analyses were performed in the total cohort and separately in those surviving more than 5 years (n = 297).RESULTS. In the total cohort, the median age was 62.6 years, and the median tumor diameter was 12.0 mm. Monosomy 3 was detected in 53% of cases and gain of 8q in 47%. In the cohort surviving 5 years, the median age was 59.5 years, and the median tumor diameter was 11.0 mm. Monosomy 3 and gain of 8q were detected in 33% and 31% of cases, respectively. In the total cohort, male gender (P = 0.03), tumor diameter (P < 0.001), mitotic count (P < 0.001), extravascular matrix loops (P = 0.03), extraocular growth (P < 0.001), and gain of 8q (P < 0.001) were independently associated with UM-related death. In patients surviving 5 years after enucleation, univariable analysis revealed that age (P = 0.03), tumor diameter (P < 0.001), monosomy 3 (P = 0.04), and 8q gain (P = 0.003) were associated with subsequent UM-related death. Using a multivariable analysis, only male gender (P = 0.03) and gain of 8q (P = 0.01) remained significant.CONCLUSIONS. Predictors of UM-related death change over time. Among UM patients who survived the initial 5 years following enucleation, male gender and chromosome 8q status were the remaining factors related to UM-related death later on. Show less
Aydemirli, M.D.; Corver, W.; Beuk, R.; Roepman, P.; Solleveld-Westerink, N.; Wezel, T. van; ... ; Morreau, H. 2019
Objective: To evaluate the efficacy and treatment rationale of Hurthle cell carcinoma (HCC) following a patient with progressive and metastatic HCC. HCC was recently shown to harbor a distinct... Show moreObjective: To evaluate the efficacy and treatment rationale of Hurthle cell carcinoma (HCC) following a patient with progressive and metastatic HCC. HCC was recently shown to harbor a distinct genetic make-up and the mitogen-activated protein kinase (MAPK) and phosphatidylinositol 3-kiase (PI3K)/AKT signaling pathways are potential targets for anti-cancer agents in the management of recurrent HCC. The presence or absence of gene variants can give a rationale for targeted therapies that could be made available in the context of drug repurposing trials. Methods: Treatment included everolimus, sorafenib, nintedanib, lenvatinib, and panitumumab. Whole genome sequencing (WGS) of metastatic tumor material obtained before administration of the last drug, was performed. We subsequently evaluated the rationale and efficacy of panitumumab in thyroid cancer and control cell lines after epidermal growth factor (EGF) stimulation and treatment with panitumumab using immunofluorescent Western blot analysis. EGF receptor (EGFR) quantification was performed using flow cytometry. Results: WGS revealed a near-homozygous genome (NHG) and a somatic homozygous TSC1 variant, that was absent in the primary tumor. In the absence of RAS variants, panitumumab showed no real-life efficacy. This might be explained by high constitutive AKT signaling in the two thyroid cancer cell lines with NHG, with panitumumab only being a potent inhibitor of pEGFR in all cancer cell lines tested. Conclusions: In progressive HCC, several treatment options outside or inside clinical trials are available. WGS of metastatic tumors might direct the timing of therapy. Unlike other cancers, the absence of RAS variants seems to provide insufficient justification of single-agent panitumumab administration in HCC cases harboring a near-homozygous genome. Show less
Manen, L. van; Handgraaf, H.J.M.; Diana, M.; Dijkstra, J.; Ishizawa, T.; Vahrmeijer, A.L.; Mieog, J.S.D. 2018
