Purpose of reviewA concise review of recent findings in brain tumor-related epilepsy (BTRE), with focus on the effect of antitumor treatment on seizure control and the management of antiepileptic... Show morePurpose of reviewA concise review of recent findings in brain tumor-related epilepsy (BTRE), with focus on the effect of antitumor treatment on seizure control and the management of antiepileptic drugs (AEDs).Recent findingsIsocitrate dehydrogenase mutation and its active metabolite d-2-hydroxyglutarate seem important contributing factors to epileptogenesis in BTRE. A beneficial effect of antitumor treatment (i.e. surgery, radiotherapy, and chemotherapy) on seizure control has mainly been demonstrated in low-grade glioma. AED prophylaxis in seizure-naive BTRE patients is not recommended, but AED treatment should be initiated after a first seizure has occurred. Comparative efficacy randomized controlled trials (RCTs) are currently lacking, but second-generation AED levetiracetam seems the preferred choice in BTRE. Levetiracetam lacks significant drug-drug interactions, has shown favorable efficacy compared to valproic acid in BTRE, generally causes no hematological or neurocognitive functioning adverse effects, but caution should be exercised with regard to psychiatric adverse effects. Potential add-on AEDs in case of uncontrolled seizures include lacosamide, perampanel, and valproic acid. Ultimately, in the end-of-life phase when oral intake of medication is hampered, benzodiazepines via nonoral administration routes are potential alternatives.SummaryManagement of seizures in BTRE is complex and with currently available evidence levetiracetam seems the preferred choice. Comparative efficacy RCTs in BTRE are warranted. Show less
Purpose of review Studies on treatment options for patients with locally advanced vulvar cancer (LAVC) are scarce, and high-level evidence for a primary treatment choice is lacking. Furthermore,... Show morePurpose of review Studies on treatment options for patients with locally advanced vulvar cancer (LAVC) are scarce, and high-level evidence for a primary treatment choice is lacking. Furthermore, current treatment options are associated with extensive morbidity and high complication rates. More effective treatment options are urgently needed. This review describes current treatment possibilities, focusing on literature regarding neoadjuvant chemotherapy (NACT) followed by surgery. Recent findings Although data are heterogeneous and limited, NACT followed by surgery might be an effective and well tolerated treatment alternative associated with lower morbidity compared with current treatment options, such as excenterative surgery or definitive chemoradiation. Up until now, several studies describe an overall response rate of 40-86%. Surgery turned out to be possible in 40-90% of the LAVC patients who received NACT. Prospective studies on the efficacy and safety of NACT followed by surgery with a homogeneous chemotherapy regimen are urgently awaited. NACT should, at this point, still be considered investigational. Show less
Purpose of review The advances of molecular techniques have led to the refinement of the classification of mesenchymal tumors, leading to newly introduced entities in the recently published fifth... Show morePurpose of review The advances of molecular techniques have led to the refinement of the classification of mesenchymal tumors, leading to newly introduced entities in the recently published fifth edition of the WHO Classification of Soft Tissue and Bone Tumors, which are discussed in this review. Recent findings For the first time, entities are included of which the name refers to the underlying molecular alteration including round cell sarcoma with EWSR1-non-ETS fusions, CIC-rearranged sarcoma, and sarcoma with BCOR genetic alteration. EWSR1-SMAD3-positive fibroblastic tumor and NTRK-rearranged spindle cell neoplasm are provisionally included as 'emerging' entities based on the underlying molecular alteration, though the entity still needs to be better defined. Other newly recognized entities are not named after their molecular change, but the molecular alteration helped to delineate them from others: atypical spindle cell/pleomorphic lipomatous tumor, anastomosing hemangioma, angiofibroma of soft tissue, myxoid pleomorphic liposarcoma, and poorly differentiated chordoma. Classification of mesenchymal tumors is increasingly based on the underlying molecular changes, although this cannot be interpreted separately from clinical, morphological, and immunohistochemical characteristics. Show less
Heijden, L. van der; Lipplaa, A.; Langevelde, K. van; Bovee, J.V.M.G.; Sande, M.A.J. van de; Gelderblom, H. 2022
Purpose of review Giant cell tumors of bone (GCTB) are intermediate, locally aggressive primary bone tumors. For conventional GCTB, surgery remains treatment of choice. For advanced GCTB, a more... Show morePurpose of review Giant cell tumors of bone (GCTB) are intermediate, locally aggressive primary bone tumors. For conventional GCTB, surgery remains treatment of choice. For advanced GCTB, a more important role came into play for systemic therapy including denosumab and bisphosphonates over the last decade. Recent findings In diagnostics, focus has been on H3F3A (G34) driver mutations present in GCTB. The most frequent mutation (G34W) can be detected using immunohistochemistry and is highly specific in differentiating GCTB from other giant cell containing tumors. PD-L1 expression can be used as biological marker to predict higher recurrence risks in GCTB patients. The use of bisphosphonate-loaded bone cement is under investigation in a randomized controlled trial. A new technique consisting of percutaneous microwave ablation and bisphosphonate-loaded polymethylmethacrylate cementoplasty was proposed for unresectable (pelvic) GCTB. Increased experience with use of denosumab raised concern on elevated recurrence rates. However, conclusions of meta-analyses should be interpreted with risk of indication bias in mind. Several small studies are published with short-course denosumab (varying from 3 to 6 doses). One small trial directly compared denosumab and zoledronic acid, with no statistical differences in radiological and clinical outcome, and nonsignificantly higher recurrence rate after denosumab. As bisphosphonates directly target neoplastic stromal cells in GCTB, larger directly comparative trials are still warranted. Neoadjuvant denosumab is highly effective for advanced GCTB, and a short-course is advised to facilitate surgery, whereas increased recurrence rates remain of concern. Randomized controlled trials are conducted on bisphosphonate-loaded bone cement and on optimal dose and duration of neoadjuvant denosumab. PD-L1 could be a potential new therapy target in GCTB. Show less
Heijden, L. van der; Dijkstra, S.; Sande, M. van de; Gelderblom, H. 2020
Purpose of review Giant cell tumour of bone (GCTB) is an intermediate, locally aggressive primary bone tumour. In addition to local therapy, new drugs became available for this disease. Denosumab,... Show morePurpose of review Giant cell tumour of bone (GCTB) is an intermediate, locally aggressive primary bone tumour. In addition to local therapy, new drugs became available for this disease. Denosumab, a receptor activator of nuclear factor kappa-B-ligand inhibitor, was introduced as systemic targeted therapy for advanced or inoperable and metastatic GCTB. Also, the bisphosphonate zoledronic acid has activity in GCTB by directly targeting the neoplastic stromal cells. Recent findings In a small RCT, bisphosphonates were successful in controlling tumour growth and a higher apoptotic index of tumour cells was seen after zoledronic acid versus controls. Although bisphosphonate-loaded bone cement has not been studied to a large extent, it does not seem harmful and may constitute a logical local adjuvant. From the largest clinical trial to date, the risk-to-benefit ratio for denosumab in patients with advanced GCTB remains favourable, also in facilitating less morbid surgery. Concerns have arisen that recurrence rates would be higher than after conventional treatment, ranging from 20 to 100% in a systematic review, although this may be because of bias. H3F3A (G34W) driver mutations are helpful in the differentiation between GCTB and other giant cell-containing malignancies. H3.3-G34W proved sufficient to drive tumourigenesis. The cumulative incidence of malignancy in GCTB is estimated at 4%, of which primary malignancy 1.6% and secondary malignancy 2.4%, the latter mainly after radiation. To date, a potential causal relationship between denosumab and pulmonary metastases has not been confirmed; if they do not behave indolently, it would be advised to reassess diagnosis and consider malignancy. Denosumab remains a highly effective treatment option for patients with advanced GCTB. A short duration of 2-4 months neoadjuvant denosumab is advised to facilitate less morbid surgery and prevent incomplete curettage by macroscopic tumour alterations. Reduced dose intensity is being studied to reduce long term side-effects. Further research on bisphosphonates and other targets including H3.3-G34W remains warranted. Show less
Purpose of review Although the majority of pheochromocytoma and paraganglioma are benign, 15-17% develop metastatic disease, being present at the initial diagnosis in about 11-31% of cases. The... Show morePurpose of review Although the majority of pheochromocytoma and paraganglioma are benign, 15-17% develop metastatic disease, being present at the initial diagnosis in about 11-31% of cases. The natural course of metastasized disease is highly heterogeneous, with an overall 5-year survival rate varying between 40% and 85%. For individual patients, overall survival, progression-free survival, and clinical outcome are difficult to predict. Management of metastasized pheochromocytoma and paraganglioma is challenging. Currently available therapeutic options are surgical debulking, treatment with radiopharmaceuticals (I-131-MIBG, Y-90 and Lu-177-DOTATATE), chemotherapy and targeted therapy. Recent findings The pathogenesis of pheochromocytoma and paraganglioma (PPGL) is largely driven by genomic alterations in PPGL susceptibility genes related to three different clusters: altered pseudo-hypoxic signaling (cluster-1), altered MAP-kinase signaling (cluster-2) and altered Wnt signaling (cluster-3). Novel targeted therapies (tyrosine kinase inhibitors) and potential future therapeutic options, guided by improved knowledge about the oncogenic cluster 1-3 signaling pathways, will be discussed. Treatment of metastasized pheochromocytoma and paraganglioma remains challenging. Profiling of gene expression and methylation can serve as a powerful tool for characterizing disease clusters and for guiding targeted therapy to improve selectivity and efficacy. Current knowledge of signatures involved in molecular signaling, metabolism, and resistance mechanisms of PPGLs suggests that therapeutic regimens can be optimized to each molecular subtype. Show less
Purpose of review Increased life expectancy in brain tumour patients had led to the need for strategies that preserve and improve cognitive functioning, as many patients suffer from cognitive... Show morePurpose of review Increased life expectancy in brain tumour patients had led to the need for strategies that preserve and improve cognitive functioning, as many patients suffer from cognitive deficits. The tumour itself, as well as antitumor treatment including surgery, radiotherapy and chemotherapy, supportive treatment and individual patient factors are associated with cognitive problems. Here, we review the recent literature on approaches that preserve and improve cognitive functioning, including pharmacological agents and rehabilitation programs. Recent findings Minimizing cognitive dysfunction and improving cognitive functioning in brain tumour patients may be achieved both by preserving cognitive functioning during antitumor treatment, including techniques such as awake brain surgery, less invasive radiation therapies such as stereotactic radiotherapy and proton therapy, as well as with interventions including cognitive rehabilitation programmes. Novel rehabilitation programs including computer-based cognitive rehabilitation therapy (CRT) programmes that can be adjusted to the specific patient needs and can be administered at home are promising. Furthermore, personalized/precision medicine approaches to identify patients who are at risk for cognitive decline may facilitate effective treatment strategies in the future. Cognitive functioning has gained greater awareness in the neuro-oncological community, and methods to preserve and improve cognitive functioning have been explored. Rehabilitation programmes for brain tumour patients should be further developed and referred to in clinical practice. Show less
Purpose of review Giant cell tumor of bone (GCTB) is an uncommon benign primary bone tumor, consisting of receptor activator of nuclear factor kappa-B (RANK) expressing reactive osteoclast-like... Show morePurpose of review Giant cell tumor of bone (GCTB) is an uncommon benign primary bone tumor, consisting of receptor activator of nuclear factor kappa-B (RANK) expressing reactive osteoclast-like giant cells and neoplastic spindle-shaped cells. Denosumab was approved by FDA in 2013 and by EMA in 2014 to treat adults and skeletally mature adolescents with unresectable GCTB or when resection is likely to result in severe morbidity. However, there is much discussion regarding the optimal applied treatment strategy.Recent findingsNeoadjuvant treatment of GCTB with denosumab can effectively downstage tumors to facilitate less morbid surgery or completely avoid the need for resection, but there is concern about local recurrence postsurgery. Definitive treatment of unresectable GTCB improves symptoms and halts tumor progression. The optimal treatment duration is unclear and long-term treatment is associated with adverse events like osteonecrosis of the jaw (ONJ) and atypical femoral fractures. Denosumab maintenance dose interval is currently being investigated.SummaryFor the related but heterogenous group of giant cell rich tumors of bone, like aneurysmal bone cysts (ABC) and central giant cell granuloma (CGCG), denosumab is a new treatment modality under investigation. Given the effectiveness in GCTB, this could be a promising treatment option for selected patients with advanced disease. Show less
Purpose of reviewRetroperitoneal sarcoma (RPS) is a rare disease, and until recently, its natural history and outcome were poorly understood. Recently, collaborations between individual centers... Show morePurpose of reviewRetroperitoneal sarcoma (RPS) is a rare disease, and until recently, its natural history and outcome were poorly understood. Recently, collaborations between individual centers have led to an unprecedented collection of retrospective and prospective data and successful recruitment to the first randomized trial as described here.Recent findingsA debate about the beneficial role of extended surgery in RPS triggered an initial collaboration between Europe and North America, the TransAtlantic RetroPeritoneal Sarcoma Working Group (TARPSWG). This collaboration has been instrumental in harmonizing the surgical approach among expert centers, characterizing the pattern of postresection failure of the different histological subtypes, identifying new ways to stage RPS and testing the role of preoperative radiotherapy in a randomized fashion (STRASS-1 study). The collaboration has now expanded to include centers from Asia, Australia and South America. A prospective registry has been started and a new randomized trial, STRASS-2, is in preparation to analyze the role of neoadjuvant chemotherapy for high-grade liposarcoma and leiomyosarcoma of the retroperitoneum.SummaryCollaboration is critical to study a rare disease like RPS. Both retrospective and prospective data are useful to improve knowledge, generate hypotheses and build evidence to test, whenever possible, in clinical trials. Show less
Purpose of review: Giant cell tumor of bone (GCTB) is an uncommon benign primary bone tumor, consisting of receptor activator of nuclear factor kappa-B (RANK) expressing reactive osteoclast-like... Show morePurpose of review: Giant cell tumor of bone (GCTB) is an uncommon benign primary bone tumor, consisting of receptor activator of nuclear factor kappa-B (RANK) expressing reactive osteoclast-like giant cells and neoplastic spindle-shaped cells. Denosumab was approved by FDA in 2013 and by EMA in 2014 to treat adults and skeletally mature adolescents with unresectable GCTB or when resection is likely to result in severe morbidity. However there is much discussion regarding the optimal applied treatment strategy.Recent findings and conclusion: Neo-adjuvant treatment of GCTB with denosumab can effectively downstage tumors to facilitate less morbid surgery or completely avoid the need for resection, but there is concern about local recurrence post-surgery. Definitive treatment of unresectable GTCB improves symptoms and halts tumor progression. The optimal treatment duration is unclear and long-term treatment is associated with adverse events like osteonecrosis of the jaw (ONJ) and atypical femoral fractures. Denosumab maintenance dose interval is currently being investigated.For the related but heterogenous group of giant cell rich tumors of bone, like aneurysmal bone cysts (ABC) and central giant cell granuloma (CGCG), denosumab is a new treatment modality under investigation. Given the effectiveness in GCTB this could be an promising treatment option for selected patients with advanced disease. Show less
Purpose of reviewRetroperitoneal sarcoma (RPS) is a rare disease, and until recently, its natural history and outcome werepoorly understood. Recently, collaborations between individual centers have... Show morePurpose of reviewRetroperitoneal sarcoma (RPS) is a rare disease, and until recently, its natural history and outcome werepoorly understood. Recently, collaborations between individual centers have led to an unprecedentedcollection of retrospective and prospective data and successful recruitment to the first randomized trial asdescribed here.Recent findingsA debate about the beneficial role of extended surgery in RPS triggered an initial collaboration betweenEurope and North America, the TransAtlantic RetroPeritoneal Sarcoma Working Group (TARPSWG). Thiscollaboration has been instrumental in harmonizing the surgical approach among expert centers,characterizing the pattern of postresection failure of the different histological subtypes, identifying newways to stage RPS and testing the role of preoperative radiotherapy in a randomized fashion (STRASS-1study). The collaboration has now expanded to include centers from Asia, Australia and South America. Aprospective registry has been started and a new randomized trial, STRASS-2, is in preparation to analyzethe role of neoadjuvant chemotherapy for high-grade liposarcoma and leiomyosarcoma of theretroperitoneum.SummaryCollaboration is critical to study a rare disease like RPS. Both retrospective and prospective data are useful toimprove knowledge, generate hypotheses and build evidence to test, whenever possible, in clinical trials. Show less
Speetjens, F.M.; Jong, Y. de; Gelderblom, H.; Bovee, J.V.M.G. 2016
PURPOSE OF REVIEW The clinical significance of lymphadenectomy in ovarian cancer is controversial. In early ovarian cancer (EOC), it is the extent of the procedure that is the main focus of debate.... Show morePURPOSE OF REVIEW The clinical significance of lymphadenectomy in ovarian cancer is controversial. In early ovarian cancer (EOC), it is the extent of the procedure that is the main focus of debate. In advanced disease [advanced ovarian cancer (AOC)], the issue is whether or not lymphadenectomy independently impacts survival. This review summarizes the current standard of care as it relates to the role of lymphadenectomy in ovarian cancer. RECENT FINDINGS Lymphadenectomy in EOC is a diagnostic procedure in as much as it is an integral and mandatory part of a complete surgical staging. The required extent of the procedure, however, remains uncertain. It has been suggested that at least 10 nodes from different, predefined retroperitoneal sites should be the minimum number removed. Lymphadenectomy in AOC is of potential therapeutic value. The only published randomized clinical trial (RCT) showed no overall survival benefit after radical/systematic lymphadenectomy, although there was an impact on 6-month disease-free survival. Conversely, retrospective studies, a meta-analysis and a re-analysis of three RCTs in AOC do suggest an overall survival benefit for radical/systematic lymphadenectomy. SUMMARY This review concludes with the recommendation that lymphadenectomy in EOC is a mandatory part of surgical staging and that a minimum of 10 nodes should be harvested from different retroperitoneal sites. In AOC, lymphadenectomy can be considered when intraperitoneal cytoreduction has been complete or when there are bulky nodes. Show less
