Single-cell spatial immune landscapes of primary and metastatic brain tumours.

Single-cell technologies have enabled the characterization of the tumour microenvironment at unprecedented depth and have revealed vast cellular diversity among tumour cells and their niche. Anti-tumour immunity relies on cell-cell relationships within the tumour microenvironment1,2, yet many single-cell studies lack spatial context and rely on dissociated tissues3. Here we applied imaging mass cytometry to characterize the immunological landscape of 139 high-grade glioma and 46 brain metastasis tumours from patients. Single-cell analysis of more than 1.1 million cells across 389 high-dimensional histopathology images enabled the spatial resolution of immune lineages and activation states, revealing differences in immune landscapes between primary tumours and brain metastases from diverse solid cancers. These analyses revealed cellular neighbourhoods associated with survival in patients with glioblastoma, which we leveraged to identify a unique population of myeloperoxidase (MPO)-positive macrophages associated with long-term survival. Our findings provide insight into the biology of primary and metastatic brain tumours, reinforcing the value of integrating spatial resolution to single-cell datasets to dissect the microenvironmental contexture of cancer.

A review on genetic alterations in CNS metastases related to breast cancer treatment. Is there a role for liquid biopsies in CSF?

Acquired mutations or altered gene expression patterns in brain metastases (BM) and/or leptomeningeal metastases (LM) of breast cancer may play a role in therapy-resistance and offer new molecular targets and treatment options. Despite expanding knowledge of genetic alterations in breast cancer and their metastases, clinical applications for patients with central nervous system (CNS) metastases are currently limited. An emerging tool are DNA-techniques that may detect genetic alterations of the CNS metastases in the cerebrospinal fluid (CSF). In this review we discuss genetic studies in breast cancer and CNS metastases and the role of liquid biopsies in CSF.

Local and systemic therapy in breast cancer patients with central nervous system metastases.

PURPOSE: As survival of patients with central nervous system (CNS) metastases from breast cancer is poor and incidence rates are increasing, there is a growing need for better treatment strategies. In the current study, the efficacy of local and systemic therapies was analyzed in breast cancer patients with CNS metastases. METHODS: Medical records from breast cancer patients with brain and/or leptomeningeal metastases (LM) treated at a tertiary referral center and a teaching hospital between 2010 and 2020 were retrospectively studied. Main outcomes of interest were overall survival (OS) and CNS progression free survival. Analyses were performed among patients with brain metastases (BM) and patients with LM, for the different systemic and local therapies for CNS metastases, and for subgroups based on breast cancer subtypes. RESULTS: We identified 155 patients, 97 with BM and 58 with LM. Median OS was 15.9 months for patients with BM and 1.5 months for patients with LM. Median OS was significantly longer for HER2-positive patients with BM (22.8 months) vs triple negative (8.4 months) and hormone receptor positive/HER2-negative (5.9 months) (P < 0.001). Patients with BM receiving both local and systemic therapy also had a longer median OS (21.8 months), compared to the other three subgroups (local therapy only: 9.9 months, systemic therapy only: 4.3 months, no therapy: 0.5 months, P < 0.001). No significant difference in OS was observed between different systemic treatment regimens. CONCLUSION: Breast cancer patients with BM show longest median OS when the subtype is HER2-positive and when they are treated with both local and systemic therapy.

Intracranial antitumor responses of nivolumab and ipilimumab: a pharmacodynamic and pharmacokinetic perspective, a scoping systematic review.

BACKGROUND: Recently, two phase II trials showed intracranial activity of the immune checkpoint inhibitors nivolumab and ipilimumab in patients with melanoma brain metastases. However, it is generally assumed that large molecules like monoclonal antibodies nivolumab and ipilimumab cannot penetrate and pass an intact blood brain barrier (BBB). In this systematic review we provide a pharmacodynamic and pharmacokinetic consideration of the clinical activity of the immune checkpoint inhibitors nivolumab and ipilimumab in melanoma brain metastases. METHODS: Pubmed was systematically searched for prospective phase II and III studies on nivolumab and ipilimumab in melanoma brain metastases and cerebrospinal fluid (CSF) levels of nivolumab and ipilimumab. Results were discussed and a perspective on the pharmacodynamics and pharmacokinetics for the intracranial activity of these agents was given. RESULTS: Two phase II studies with the combination nivolumab and ipilimumab and one phase II study with ipilimumab monotherapy in melanoma brain metastases were included in this review. One article reported drug levels of nivolumab in CSF. Intracranial responses were achieved in 16 of 35 patients (46%; 95% confidence interval (CI) 29-63) in a phase II study cohort treated with nivolumab and ipilimumab. In a second phase II study in 94 patients, the rate of intracranial clinical benefit was 57% (95% CI 47-68). The CSF/serum ratio of nivolumab was 0.88-1.9% in a cohort of metastatic melanoma patients treated with nivolumab 1-3 mg/kg. Nivolumab concentrations ranged from 35 to 150 ng/ml in CSF of these patients, which is in the range of the half maximal effective concentration (EC50) of 0.64 nM. CONCLUSIONS: Ipilimumab and nivolumab are active in melanoma brain metastases. Nivolumab penetrates into the CSF. Based on the described findings the general consensus that monoclonal antibodies do not penetrate into the central nervous system (CNS) and cannot have a direct intracranial effect needs to be reconsidered.

Patients' and physicians' interpretation of chemotherapy-induced peripheral neurotoxicity.

To test if and how chemotherapy-induced peripheral neurotoxicity (CIPN) is perceived differently by patients and physicians, making assessment and interpretation challenging. We performed a secondary analysis of the CI-PeriNomS study which included 281 patients with stable CIPN. We tested: (a) the association between patients' perception of activity limitation in performing eight common tasks and neurological impairment and (b) how the responses to questions related to these daily activities are interpreted by the treating oncologist. To achieve this, we compared patients' perception of their activity limitation with neurological assessment and the oncologists' blind interpretation. Distribution of the scores attributed by oncologists to each daily life maximum limitation ("impossible") generated three groups: Group 1 included limitations oncologists attributed mainly to motor impairment; Group 2 ones mainly attributed to sensory impairment and Group 3 ones with uncertain motor and sensory impairment. Only a subset of questions showed a significant trend between severity in subjective limitation, reported by patients, and neurological impairment. In Group 1, neurological examination confirmed motor impairment in only 51%-65% of patients; 76%-78% of them also had vibration perception impairment. In Group 2, sensory impairment ranged from 84% to 100%; some degree of motor impairment occurred in 43%-56% of them. In Group 3 strength reduction was observed in 49%-50% and sensory perception was altered in up to 82%. Interpretation provided by the panel of experienced oncologists was inconsistent with the neurological impairment. These observations highlight the need of a core set of outcome measures for future CIPN trials.

EpCAM-based assays for epithelial tumor cell detection in cerebrospinal fluid.

The diagnosis of leptomeningeal metastases (LM) of solid tumors is complicated due to low sensitivities of both magnetic resonance imaging (MRI) and cytology. MRI has a sensitivity of 76% for the diagnosis of LM and cerebrospinal fluid (CSF) cytology has a sensitivity of 44-67% at first lumbar puncture which increases to 84-91% upon second CSF sampling. Epithelial cell adhesion molecule (EpCAM) is expressed by solid tumors of epithelial origin like non-small-cell lung cancer, breast cancer or ovarium cancer. Recently, a CELLSEARCH® assay and flow cytometry laboratory techniques have been developed to detect circulating tumor cells (CTCs) of epithelial origin in CSF. These laboratory techniques are based on capture antibodies labelled with different fluorescent tags against EpCAM. In this review, we provide an overview of the available laboratory techniques and diagnostic accuracy for tumor cell detection in CSF. The reported sensitivities of the EpCAM-based CTC assays for the diagnosis of LM across the different studies are highly promising and vary between 76 and 100%. An overview of the different EpCAM-based techniques for the enumeration of CTCs in the CSF is given and a comparison is made with CSF cytology for the diagnoses of LM from epithelial tumors.

Diagnosis and treatment patterns for patients with leptomeningeal metastasis from solid tumors across Europe.

Leptomeningeal metastases are a late manifestation of systemic cancer which affects up to 10% of patients with solid tumors. Prognosis is poor, and overall survival at 1 year is only approximately 10%. Management depends mainly on general and neurological condition, primary tumor, and patterns of metastasis, notably absence or presence of concurrent systemic or solid brain metastases. Here we set out to characterize current practice patterns of diagnosis and treatment of patients with leptomeningeal metastasis in Europe. We prepared a web-based survey including 25 simple or multiple choices questions on best practice supplemented by eight case vignettes with various diagnosis and management options. The survey was sent to the membership of the European Association of Neuro-Oncology and the European Organisation for Research and Treatment of Cancer Brain Tumor Group. Between April 7, 2016 and August 8, 2016, 224 colleagues from 26 countries initiated the survey, 115 colleagues completed the whole survey. There were major differences both in the general diagnostic and therapeutic approach, e.g., regarding the use of cerebrospinal fluid (CSF) flow studies, intra-CSF chemotherapy, various types of radiotherapy, and even more so when selecting decisions on diagnostic and therapeutic measures for single case vignettes. Diagnosis and treatment decisions for patients with leptomeningeal metastasis from solid tumors vary widely across Europe. Standardization of diagnosis and evaluation tools as well as controlled studies to improve the level of evidence for all therapeutic approaches to LM are required.

EANO guidelines for the diagnosis and treatment of meningiomas.

Although meningiomas are the most common intracranial tumours, the level of evidence to provide recommendations for the diagnosis and treatment of meningiomas is low compared with other tumours such as high-grade gliomas. The meningioma task force of the European Association of Neuro-Oncology (EANO) assessed the scientific literature and composed a framework of the best possible evidence-based recommendations for health professionals. The provisional diagnosis of meningioma is mainly made by MRI. Definitive diagnosis, including histological classification, grading, and molecular profiling, requires a surgical procedure to obtain tumour tissue. Therefore, in many elderly patients, observation is the best therapeutic option. If therapy is deemed necessary, the standard treatment is gross total surgical resection including the involved dura. As an alternative, radiosurgery can be done for small tumours, or fractionated radiotherapy in large or previously treated tumours. Treatment concepts combining surgery and radiosurgery or fractionated radiotherapy, which enable treatment of the complete tumour volume with low morbidity, are being developed. Pharmacotherapy for meningiomas has remained largely experimental. However, antiangiogenic drugs, peptide receptor radionuclide therapy, and targeted agents are promising candidates for future pharmacological approaches to treat refractory meningiomas across all WHO grades.

Single-agent bevacizumab or lomustine versus a combination of bevacizumab plus lomustine in patients with recurrent glioblastoma (BELOB trial): a randomised controlled phase 2 trial.

BACKGROUND: Treatment options for recurrent glioblastoma are scarce, with second-line chemotherapy showing only modest activity against the tumour. Despite the absence of well controlled trials, bevacizumab is widely used in the treatment of recurrent glioblastoma. Nonetheless, whether the high response rates reported after treatment with this drug translate into an overall survival benefit remains unclear. We report the results of the first randomised controlled phase 2 trial of bevacizumab in recurrent glioblastoma. METHODS: The BELOB trial was an open-label, three-group, multicentre phase 2 study undertaken in 14 hospitals in the Netherlands. Adult patients (≥18 years of age) with a first recurrence of a glioblastoma after temozolomide chemoradiotherapy were randomly allocated by a web-based program to treatment with oral lomustine 110 mg/m(2) once every 6 weeks, intravenous bevacizumab 10 mg/kg once every 2 weeks, or combination treatment with lomustine 110 mg/m(2) every 6 weeks and bevacizumab 10 mg/kg every 2 weeks. Randomisation of patients was stratified with a minimisation procedure, in which the stratification factors were centre, Eastern Cooperative Oncology Group performance status, and age. The primary outcome was overall survival at 9 months, analysed by intention to treat. A safety analysis was planned after the first ten patients completed two cycles of 6 weeks in the combination treatment group. This trial is registered with the Nederlands Trial Register (www.trialregister.nl, number NTR1929). FINDINGS: Between Dec 11, 2009, and Nov 10, 2011, 153 patients were enrolled. The preplanned safety analysis was done after eight patients had been treated, because of haematological adverse events (three patients had grade 3 thrombocytopenia and two had grade 4 thrombocytopenia) which reduced bevacizumab dose intensity; the lomustine dose in the combination treatment group was thereafter reduced to 90 mg/m(2). Thus, in addition to the eight patients who were randomly assigned to receive bevacizumab plus lomustine 110 mg/m(2), 51 patients were assigned to receive bevacizumab alone, 47 to receive lomustine alone, and 47 to receive bevacizumab plus lomustine 90 mg/m(2). Of these patients, 50 in the bevacizumab alone group, 46 in the lomustine alone group, and 44 in the bevacizumab and lomustine 90 mg/m(2) group were eligible for analyses. 9-month overall survival was 43% (95% CI 29-57) in the lomustine group, 38% (25-51) in the bevacizumab group, 59% (43-72) in the bevacizumab and lomustine 90 mg/m(2) group, 87% (39-98) in the bevacizumab and lomustine 110 mg/m(2) group, and 63% (49-75) for the combined bevacizumab and lomustine groups. After the reduction in lomustine dose in the combination group, the combined treatment was well tolerated. The most frequent grade 3 or worse toxicities were hypertension (13 [26%] of 50 patients in the bevacizumab group, three [7%] of 46 in the lomustine group, and 11 [25%] of 44 in the bevacizumab and lomustine 90 mg/m(2) group), fatigue (two [4%], four [9%], and eight [18%]), and infections (three [6%], two [4%], and five [11%]). At the time of this analysis, 144/148 (97%) of patients had died and three (2%) were still on treatment. INTERPRETATION: The combination of bevacizumab and lomustine met prespecified criteria for assessment of this treatment in further phase 3 studies. However, the results in the bevacizumab alone group do not justify further studies of this treatment. FUNDING: Roche Nederland and KWF Kankerbestrijding.

Correspondence between neurophysiological and clinical measurements of chemotherapy-induced peripheral neuropathy: secondary analysis of data from the CI-PeriNomS study.

Chemotherapy-induced peripheral neuropathy (CIPN) lacks standardized clinical measurement. The objective of the current secondary analysis was to examine data from the CIPN Outcomes Standardization (CI-PeriNomS) study for associations between clinical examinations and neurophysiological abnormalities. Logistic regression estimated the strength of associations of vibration, pin, and monofilament examinations with lower limb sensory and motor amplitudes. Examinations were classified as normal (0), moderately abnormal (1), or severely abnormal (2). Among 218 participants, those with class 1 upper extremity (UE) and classes 1 or 2 lower extremity (LE) monofilament abnormality were 2.79 (95% confidence interval [CI]: 1.28-6.07), 3.49 (95%CI: 1.61-7.55), and 4.42 (95%CI: 1.35-14.46) times more likely to have abnormal sural nerve amplitudes, respectively, compared to individuals with normal examinations. Likewise, those with class 2 UE and classes 1 or 2 LE vibration abnormality were 8.65 (95%CI: 1.81-41.42), 2.54 (95%CI: 1.19-5.41), and 7.47 (95%CI: 2.49-22.40) times more likely to have abnormal sural nerve amplitudes, respectively, compared to participants with normal examinations. Abnormalities in vibration and monofilament examinations are associated with abnormal sural nerve amplitudes and are useful in identifying CIPN.

ELISA assay for the quantification of ipilimumab in human serum, plasma, milk, and cerebrospinal fluid.

Ipilimumab is an immune checkpoint inhibitor of the cytotoxic T-lymphocyte-associated protein 4 (CTLA-4). Ipilimumab has become part of the standard of care for different types of cancer. The efficacy of these treatments is limited due to immune-related toxicity and high economic costs. Dose rationalization studies based on pharmacokinetic data may help to address these limitations. For this purpose, more sensitive analytical methods are needed. We report the development and validation of the first enzyme-linked immunosorbent assay (ELISA) for sensitive determination of ipilimumab concentrations in human serum, plasma, cerebrospinal fluid (CSF), and milk. Our assay is based on the specific capture of ipilimumab by immobilized CTLA-4. The lower limit of quantifications of ipilimumab in serum, plasma, and milk are 50 ng/mL and 10 ng/mL in CSF. The ELISA method showed long-term storage stability for at least one year at -80°C and was successfully cross-validated with ultraperformance liquid chromatography coupled with tandem mass spectrometry. The ELISA method is reliable, relatively inexpensive, and can be used in serum, plasma, CSF, and milk from patients treated with ipilimumab, as evidenced by the analysis of real clinical samples.

Prognostic Role of Ventricular Size and Its Dynamics in Patients With Leptomeningeal Metastasis From Solid Tumors.

BACKGROUND AND OBJECTIVES: Hydrocephalus is a common radiologic sign in patients with leptomeningeal metastasis (LM) from solid tumors which can be assessed using the Evans index (EI). Here, we explored the prognostic value of ventricular size in LM. METHODS: We identified patients with LM from solid tumors by chart review at 3 academic hospitals to explore the prognostic associations of the EI at diagnosis, first follow-up, and progression. RESULTS: We included 113 patients. The median age was 58.3 years (interquartile range [IQR] 46.1-65.8), 41 patients (36%) were male, and 72 patients (64%) were female. The most frequent cancers were lung cancer (n = 39), breast cancer (n = 36), and melanoma (n = 23). The median EI at baseline was 0.28 (IQR 0.26-0.31); the EI value was 0.27 or more in 67 patients (59%) and 0.30 or more in 37 patients (33%). Among patients with MRI follow-up, the EI increased by 0.01 or more in 16 of 31 patients (52%), including 8 of 30 patients (30%) without and 10 of 17 patients (59%) with LM progression at first follow-up. At LM progression, an increase of EI of 0.01 or more was noted in 18 of 34 patients (53%). The median survival was 2.9 months (IQR 1-7.2). Patients with a baseline EI below 0.27 had a longer survival than those with an EI of 0.27 or more (5.3 months, IQR 2.4-10.8, vs 1.3 months, IQR 0.6-4.1) (HR 1.70, 95% CI 1.135-2.534, p = 0.0099). The median survival was 3.7 months (IQR 1.4-8.3) with an EI below 0.30 vs 1.8 months (IQR 0.8-4.1) with an EI of 0.30 or more (HR 1.40, 95% CI 0.935-1.243, p = 0.1113). Among patients with follow-up scans available, the overall survival was 9.4 months (IQR 5.6-21.0) for patients with stable or decreased EI at first follow-up as opposed to 5.6 months (IQR 2.5-10.5) for those with an increase in the EI (HR 1.08, 95% CI 0.937-1.243; p = 0.300). DISCUSSION: The EI at baseline is prognostic in LM. An increase of EI during follow-up may be associated with inferior LM progression-free survival. Independent validation cohorts with larger sample size and evaluation of confounding factors will help to better define the clinical utility of EI assessments in LM.

Survival, neurocognitive function, and health-related quality of life outcomes after rituximab-methotrexate, BCNU, teniposide, and prednisolone for primary CNS lymphoma: Final results of the HOVON 105/ALLG NHL 24 study.

BACKGROUND: Studies on the efficacy of rituximab in primary CNS lymphoma (PCNSL) reported conflicting results. Our international randomized phase 3 study showed that the addition of rituximab to high-dose methotrexate, BCNU, teniposide, and prednisolone (MBVP) in PCNSL was not efficacious in the short term. Here we present long-term results after a median follow-up of 82.3 months. METHODS: One hundred and ninety-nine eligible newly diagnosed, nonimmunocompromised patients with PCNSL aged 18-70 years with WHO performance status 0-3 was randomized between treatment with MBVP chemotherapy with or without rituximab, followed by high-dose cytarabine consolidation in responding patients, and reduced-dose WBRT in patients aged ≤ 60 years. Event-free survival was the primary endpoint. Overall survival rate, neurocognitive functioning (NCF), and health-related quality of life (HRQoL) were additionally assessed, with the IPCG test battery, EORTC QLQ-C30 and QLQ-BN20 questionnaires, respectively. RESULTS: For event-free survival, the hazard ratio was 0.85, 95% CI 0.61-1.18, P = .33. Overall survival rate at 5 years for MBVP and R-MBVP was 49% (39-59) and 53% (43-63) respectively. In total, 64 patients died in the MBVP arm and 55 in the R-MBVP arm, of which 69% were due to PCNSL. At the group level, all domains of NCF and HRQoL improved to a clinically relevant extent after treatment initiation, and remained stable thereafter up to 60 months of follow-up, except for motor speed which deteriorated between 24 and 60 months. Although fatigue improved initially, high levels persisted in the long term. CONCLUSIONS: Long-term follow-up confirms the lack of added value of rituximab in addition to MBVP and HD-cytarabine for PCNSL.

Leptomeningeal metastases from solid tumors: A SNO and ASCO consensus review on clinical management and future directions.

Leptomeningeal metastases are increasingly becoming recognized as a treatable, yet generally incurable, complication of advanced cancer. As modern cancer therapeutics have prolonged the lives of patients with metastatic cancer, specifically in patients with parenchymal brain metastases, treatment options and clinical research protocols for patients with leptomeningeal metastases from solid tumors have similarly evolved to improve survival within specific populations. Recent expansion in clinical investigation, early diagnosis, and drug development have given rise to new unanswered questions. These include leptomeningeal metastasis biology and preferred animal modeling, epidemiology in the modern cancer population, ensuring validation and accessibility of newer leptomeningeal metastasis diagnostics, best clinical practices with multi-modality treatment options, clinical trial design and standardization of response assessments, and avenues worthy of further research. An international group of multi-disciplinary experts in the research and management of leptomeningeal metastases, supported by the Society for Neuro-Oncology and American Society of Clinical Oncology, were assembled to reach a consensus opinion on these pressing topics and provide a roadmap for future directions. Our hope is that these recommendations will accelerate collaboration and progress in the field of leptomeningeal metastases and serve as a platform for further discussion and patient advocacy.

Cervical osteomyelitis after carbon dioxide laser excision of recurrent carcinoma of the posterior pharyngeal wall.

Two patients with recurrent carcinoma of the posterior pharyngeal wall, previously treated with carbon dioxide (CO2) laser excision and (chemo)radiotherapy, presented with neck pain due to cervical osteomyelitis. In one patient this led to cervical spine instability, for which a haloframe was applied. Our working hypothesis was that cervical osteomyelitis was caused by an infected wound bed induced by CO2 laser excision of the tumor in the already vascular-compromised area of the irradiated posterior pharyngeal wall. We discuss the risks of leaving a wound for secondary granulation after CO2 laser excision of the posterior pharyngeal wall and prophylactic antibiotic treatment.

Neurological immune-related adverse events of ipilimumab.

Ipilimumab enhances the T lymphocyte mediated immune response to both tumour cells and healthy tissue, improving survival in patients with metastatic melanoma but also leads to more immune-related adverse events (irAEs) than previously used treatments, such as dacarbazine. We present three patients with neurological irAEs from ipilimumab treatment: hypophysitis, meningitis and Guillain-Barré syndrome. Once an irAE occurs, ipilimumab should be stopped and corticosteroids started. Usually, ipilimumab-induced irAE symptoms improve within days to weeks, but can be life-threatening if unrecognised.

CD103+ regulatory T cells underlie resistance to radio-immunotherapy and impair CD8+ T cell activation in glioblastoma.

Glioblastomas are aggressive primary brain tumors with an inherent resistance to T cell-centric immunotherapy due to their low mutational burden and immunosuppressive tumor microenvironment. Here we report that fractionated radiotherapy of preclinical glioblastoma models induce a tenfold increase in T cell content. Orthogonally, spatial imaging mass cytometry shows T cell enrichment in human recurrent tumors compared with matched primary glioblastoma. In glioblastoma-bearing mice, α-PD-1 treatment applied at the peak of T cell infiltration post-radiotherapy results in a modest survival benefit compared with concurrent α-PD-1 administration. Following α-PD-1 therapy, CD103+ regulatory T cells (Tregs) with upregulated lipid metabolism accumulate in the tumor microenvironment, and restrain immune checkpoint blockade response by repressing CD8+ T cell activation. Treg targeting elicits tertiary lymphoid structure formation, enhances CD4+ and CD8+ T cell frequency and function and unleashes radio-immunotherapeutic efficacy. These results support the rational design of therapeutic regimens limiting the induction of immunosuppressive feedback pathways in the context of T cell immunotherapy in glioblastoma.

Prospective validation of a new imaging scorecard to assess leptomeningeal metastasis: A joint EORTC BTG and RANO effort.

BACKGROUND: Validation of the 2016 RANO MRI scorecard for leptomeningeal metastasis failed for multiple reasons. Accordingly, this joint EORTC Brain Tumor Group and RANO effort sought to prospectively validate a revised MRI scorecard for response assessment in leptomeningeal metastasis. METHODS: Coded paired cerebrospinal MRI of 20 patients with leptomeningeal metastases from solid cancers at baseline and follow-up after treatment and instructions for assessment were provided via the EORTC imaging platform. The Kappa coefficient was used to evaluate the interobserver pairwise agreement. RESULTS: Thirty-five raters participated, including 9 neuroradiologists, 17 neurologists, 4 radiation oncologists, 3 neurosurgeons, and 2 medical oncologists. Among single leptomeningeal metastases-related imaging findings at baseline, the best median concordance was noted for hydrocephalus (Kappa = 0.63), and the worst median concordance for spinal linear enhancing disease (Kappa = 0.46). The median concordance of raters for the overall response assessment was moderate (Kappa = 0.44). Notably, the interobserver agreement for the presence of parenchymal brain metastases at baseline was fair (Kappa = 0.29) and virtually absent for their response to treatment. 394 of 700 ratings (20 patients x 35 raters, 56%) were fully completed. In 308 of 394 fully completed ratings (78%), the overall response assessment perfectly matched the summary interpretation of the single ratings as proposed in the scorecard instructions. CONCLUSION: This study confirms the principle utility of the new scorecard, but also indicates the need for training of MRI assessment with a dedicated reviewer panel in clinical trials. Electronic case report forms with "blocking options" may be required to enforce completeness and quality of scoring.

Prognostic validation and clinical implications of the EANO ESMO classification of leptomeningeal metastasis from solid tumors.

BACKGROUND: The EANO ESMO guidelines have proposed a classification of leptomeningeal metastases (LM) from solid cancers based on clinical, magnetic resonance imaging (MRI), and cerebrospinal fluid (CSF) cytology presentation. MRI patterns are classified as linear, nodular, both, or neither. Type I LM is defined by positive CSF cytology (confirmed LM) whereas type II LM is defined by typical clinical and MRI signs (probable or possible LM). Here we explored the clinical utility of these LM subtypes. PATIENTS AND METHODS: We retrospectively assembled data from 254 patients with newly diagnosed LM from solid tumors. Survival curves were derived using the Kaplan-Meier method and compared by Log-rank test. RESULTS: Median age at LM diagnosis was 56 years. Typical clinical LM features were noted in 225 patients (89%); 13 patients (5%) were clinically asymptomatic. Tumor cells in the CSF were observed in 186 patients (73%) whereas the CSF was equivocal in 24 patients (9.5%) and negative in 44 patients (17.5%). Patients with confirmed LM had inferior outcome compared with patients with probable or possible LM (P = 0.006). Type I patients had inferior outcome than type II patients (P = 0.002). Nodular disease on MRI was a negative prognostic factor in type II LM (P = 0.014), but not in type I LM. Administration of either intrathecal pharmacotherapy (P = 0.020) or systemic pharmacotherapy (P = 0.0004) was associated with improved outcome in type I LM, but not in type II LM. CONCLUSION: The EANO ESMO LM subtypes are highly prognostic and should be considered for stratification and overall design of clinical trials.

Extent of radiological response does not reflect survival in primary central nervous system lymphoma.

BACKGROUND: In primary central nervous system lymphoma (PCNSL), small enhancing lesions can persist after treatment. It is unknown whether a difference in response category (complete response [CR], complete response unconfirmed [CRu], or partial response [PR]) reflects survival. We aimed to determine the value of a central radiology review on response assessment and whether the extent of response influenced progression-free and/or overall survival. METHODS: All patients in the HOVON 105/ALLG NHL 24 study with at least a baseline MRI and one MRI made for response evaluation available for central review were included. Tumor measurements were done by 2 independent central reviewers, disagreements were adjudicated by a third reviewer. Crude agreement and interobserver agreement (Cohen's kappa) were calculated. Differences in progression-free and overall survival between different categories of response at the end-of-protocol-treatment were assessed by the log-rank test in a landmark survival-analysis. RESULTS: Agreement between the central reviewers was 61.7% and between local and central response assessment was 63.0%. Cohen's kappa's, which corrects for expected agreement, were 0.44 and 0.46 (moderate), respectively. Progression agreement or not was 93.3% (kappa 0.87) between local and central response assessment. There were no significant differences in progression-free and overall survival between patients with CR, CRu, or PR at the end-of-protocol-treatment, according to both local and central response assessment. CONCLUSIONS: Reliability of response assessment (CR/CRu/PR) is moderate even by central radiology review and these response categories do not reliably predict survival. Therefore, primary outcome in PCNSL studies should be survival rather than CR or CR/CRu-rate.