Brain metastases in adult patients with melanoma of unknown primary in the Netherlands (2011-2020).

BACKGROUND: Although patients with melanoma of unknown primary (MUP) have a better prognosis than similar-staged melanoma patients with known primary, the occurrence of brain metastases (BM) entails a serious complication. This study provides an overview of the incidence, treatment patterns, and overall survival (OS) of adult patients with BM-MUP in the Netherlands. METHODS: BM-MUP cases were retrieved from the Netherlands Cancer Registry. Patient, disease and treatment-related characteristics were summarised using descriptive statistics. Overall survival (OS) was calculated by the Kaplan-Meier method, and the impact of prognostic factors on OS was assessed using Cox proportional hazard regression analyses. RESULTS: Among 1779 MUP patients, 450 were identified as BM-MUP (25.3%). Of these patients, 381 (84.7%) presented with BM along with other metastases, while 69 (15.3%) had BM only. BM-MUP patients were predominantly male (68.2%), and had a median age of 64 years at diagnosis (interquartile range 54-71 years). Over time, the proportion of BM along other metastatic sites increased, and the occurrence of BM decreased (p = 0.01). 1-Year OS improved for the total population, from 30.0% (95% confidence interval (CI): 19.8-40.9%) in 2011-2012 to 43.6% (95%CI: 34.5-52.3%) in 2019-2020, and median OS more than doubled from 4.2 months (95%CI: 3.3-6.2 months) to 9.8 months (95%CI: 7.0-13.2 months). Patient's age, localisation of BM, presence of synchronous liver metastasis and treatment were identified as independent predictors of OS. CONCLUSION: Notwithstanding the progress made in OS for patients with BM-MUP in the past decade, their overall prognosis remains poor, and further efforts are needed to improve outcomes.

Medulloblastoma in adults: evaluation of the Dutch society for neuro-oncology treatment protocol.

PURPOSE: Medulloblastoma is a rare tumor in adults. The objective of this nationwide, multicenter study was to evaluate the toxicity and efficacy of the Dutch treatment protocol for adult medulloblastoma patients. METHODS: Adult medulloblastoma patients diagnosed between 2010 and 2018 were identified in the Dutch rare tumors registry or nationwide pathology database. Patients with intention to treat according to the national treatment protocol were included. Risk stratification was performed based on residual disease, histological subtype and extent of disease. All patients received postoperative radiotherapy [craniospinal axis 36 Gy/fossa posterior boost 19.8 Gy (14.4 Gy in case of metastases)]. High-risk patients received additional neoadjuvant (carboplatin-etoposide), concomitant (vincristine) and adjuvant chemotherapy (carboplatin-vincristine-cyclophosphamide) as far as feasible by toxicity. Methylation profiling, and additional next-generation sequencing in case of SHH-activated medulloblastomas, were performed. RESULTS: Forty-seven medulloblastoma patients were identified, of whom 32 were treated according to the protocol. Clinical information and tumor material was available for 28 and 20 patients, respectively. The histological variants were mainly classic (43%) and desmoplastic medulloblastoma (36%). Sixteen patients (57%) were considered standard-risk and 60% were SHH-activated medulloblastomas. Considerable treatment reductions and delays in treatment occurred due to especially hematological and neurotoxicity. Only one high-risk patient could complete all chemotherapy courses. 5-years progression-free survival (PFS) and overall survival (OS) for standard-risk patients appeared worse than for high-risk patients (PFS 69% vs. 90%, OS 81% vs. 90% respectively), although this wasn't statistically significant. CONCLUSION: Combined chemo-radiotherapy is a toxic regimen for adult medulloblastoma patients that may result in improved survival.

Blended online learning for oncologists to improve skills in shared decision making about palliative chemotherapy: a pre-posttest evaluation.

PURPOSE: To improve shared decision making (SDM) with advanced cancer patients, communication skills training for oncologists is needed. The purpose was to examine the effects of a blended online learning (i.e. e-learning and online training session) for oncologists about SDM in palliative oncological care and to compare this blended format with a more extensive, fully in-person face-to-face training format. METHODS: A one-group pre-posttest design was adopted. Before (T0) and after (T2) training, participants conducted simulated consultations (SPAs) and surveys; after the e-learning (T1), an additional survey was filled out. The primary outcome was observed SDM (OPTION12 and 4SDM). Secondary outcomes included observed SDM per stage, SPA duration and decision made as well as oncologists' self-reported knowledge, clinical behavioural intentions, satisfaction with the communication and evaluation of the training. Additionally, outcomes of the blended learning were compared with those of the face-to-face training cohort. Analyses were conducted in SPSS by linear mixed models. RESULTS: Oncologists (n = 17) showed significantly higher SDM scores after the blended online learning. The individual stages of SDM and the number of times the decision was postponed as well as oncologists' beliefs about capabilities, knowledge and satisfaction increased after the blended learning. Consultation duration was unchanged. The training was evaluated as satisfactory. When compared with the face-to-face training, the blended learning effects were smaller. CONCLUSION: Blended online SDM training for oncologists was effective. However, the effects were smaller compared to face-to-face training. The availability of different training formats provides opportunities for tailoring training to the wishes and needs of learners.

Accuracy and repeatability of joint sparsity multi-component estimation in MR Fingerprinting.

MR fingerprinting (MRF) is a promising method for quantitative characterization of tissues. Often, voxel-wise measurements are made, assuming a single tissue-type per voxel. Alternatively, the Sparsity Promoting Iterative Joint Non-negative least squares Multi-Component MRF method (SPIJN-MRF) facilitates tissue parameter estimation for identified components as well as partial volume segmentations. The aim of this paper was to evaluate the accuracy and repeatability of the SPIJN-MRF parameter estimations and partial volume segmentations. This was done (1) through numerical simulations based on the BrainWeb phantoms and (2) using in vivo acquired MRF data from 5 subjects that were scanned on the same week-day for 8 consecutive weeks. The partial volume segmentations of the SPIJN-MRF method were compared to those obtained by two conventional methods: SPM12 and FSL. SPIJN-MRF showed higher accuracy in simulations in comparison to FSL- and SPM12-based segmentations: Fuzzy Tanimoto Coefficients (FTC) comparing these segmentations and Brainweb references were higher than 0.95 for SPIJN-MRF in all the tissues and between 0.6 and 0.7 for SPM12 and FSL in white and gray matter and between 0.5 and 0.6 in CSF. For the in vivo MRF data, the estimated relaxation times were in line with literature and minimal variation was observed. Furthermore, the coefficient of variation (CoV) for estimated tissue volumes with SPIJN-MRF were 10.5% for the myelin water, 6.0% for the white matter, 5.6% for the gray matter, 4.6% for the CSF and 1.1% for the total brain volume. CoVs for CSF and total brain volume measured on the scanned data for SPIJN-MRF were in line with those obtained with SPM12 and FSL. The CoVs for white and gray matter volumes were distinctively higher for SPIJN-MRF than those measured with SPM12 and FSL. In conclusion, the use of SPIJN-MRF provides accurate and precise tissue relaxation parameter estimations taking into account intrinsic partial volume effects. It facilitates obtaining tissue fraction maps of prevalent tissues including myelin water which can be relevant for evaluating diseases affecting the white matter.

Prognostic factors among patients with brain metastases from cancer of unknown primary site.

PURPOSE: Cancers of an unknown primary site (CUPs) have a dismal prognosis, and the situation is even worse for CUPs patients with brain metastases (BM-CUPs). This study aims to give better insight into the occurrence and survival of BM-CUPs patients. METHODS: Cases were selected from the Netherlands Cancer Registry (1,430 BM-CUPs/17,140 CUPs). Baseline characteristics between CUPs patients with and without BM were tested using chi-square tests and Mann-Whitney U tests. Patients' overall survival (OS) times were estimated by the Kaplan-Meier method and prognostic factors on OS was assessed using Cox proportional hazards regression analyses. RESULTS: The proportion of BM-CUPs patients among CUPs increased from 8% in 2009-2010 to 10% in 2017-2018 (p < 0.001). Most patients presented with multiple brain lesions (53%). Survival of BM-CUPs improved over time: one-year OS increased from 10% for patients diagnosed in 2009-2010 to 17% (2017- 2018) (p < 0.01), and median survival times increased from 1.8 months to 2.2 months. Independent predictors of poor survival were multiple (HR 1.25; p < 0.01) or unknown (HR 1.48; p < 0.01) locations of BM, unknown/poorly/undifferentiated carcinoma histology (HR 1.53; p < 0.01), or clinical symptoms of BM (HR 1.74; p < 0.01), accompanying liver metastasis (HR 1.43; p < 0.01) and more than one metastatic site outside the brain compared to none (HR 1.52; p < 0.01). CONCLUSION: The incidence of patients with BM-CUPs is steadily increasing over time and overall prognosis remains dismal. Our results, however, show distinct patient subgroups that exhibit comparatively better outcomes, and more predictors may likely still be identified.

Assessment of data consistency through cascades of independently recurrent inference machines for fast and robust accelerated MRI reconstruction.

Objective.Machine Learning methods can learn how to reconstruct magnetic resonance images (MRI) and thereby accelerate acquisition, which is of paramount importance to the clinical workflow. Physics-informed networks incorporate the forward model of accelerated MRI reconstruction in the learning process. With increasing network complexity, robustness is not ensured when reconstructing data unseen during training. We aim to embed data consistency (DC) in deep networks while balancing the degree of network complexity. While doing so, we will assess whether either explicit or implicit enforcement of DC in varying network architectures is preferred to optimize performance.Approach.We propose a scheme called Cascades of Independently Recurrent Inference Machines (CIRIM) to assess DC through unrolled optimization. Herein we assess DC both implicitly by gradient descent and explicitly by a designed term. Extensive comparison of the CIRIM to compressed sensing as well as other Machine Learning methods is performed: the End-to-End Variational Network (E2EVN), CascadeNet, KIKINet, LPDNet, RIM, IRIM, and UNet. Models were trained and evaluated on T1-weighted and FLAIR contrast brain data, and T2-weighted knee data. Both 1D and 2D undersampling patterns were evaluated. Robustness was tested by reconstructing 7.5× prospectively undersampled 3D FLAIR MRI data of multiple sclerosis (MS) patients with white matter lesions.Main results.The CIRIM performed best when implicitly enforcing DC, while the E2EVN required an explicit DC formulation. Through its cascades, the CIRIM was able to score higher on structural similarity and PSNR compared to other methods, in particular under heterogeneous imaging conditions. In reconstructing MS patient data, prospectively acquired with a sampling pattern unseen during model training, the CIRIM maintained lesion contrast while efficiently denoising the images.Significance.The CIRIM showed highly promising generalization capabilities maintaining a very fair trade-off between reconstructed image quality and fast reconstruction times, which is crucial in the clinical workflow.

Brain tumour diagnostics using a DNA methylation-based classifier as a diagnostic support tool.

AIMS: Methylation profiling (MP) is increasingly incorporated in the diagnostic process of central nervous system (CNS) tumours at our centres in The Netherlands and Scandinavia. We aimed to identify the benefits and challenges of MP as a support tool for CNS tumour diagnostics. METHODS: About 502 CNS tumour samples were analysed using (850 k) MP. Profiles were matched with the DKFZ/Heidelberg CNS Tumour Classifier. For each case, the final pathological diagnosis was compared to the diagnosis before MP. RESULTS: In 54.4% (273/502) of all analysed cases, the suggested methylation class (calibrated score ≥0.9) corresponded with the initial pathological diagnosis. The diagnosis of 24.5% of these cases (67/273) was more refined after incorporation of the MP result. In 9.8% of cases (49/502), the MP result led to a new diagnosis, resulting in an altered WHO grade in 71.4% of these cases (35/49). In 1% of cases (5/502), the suggested class based on MP was initially disregarded/interpreted as misleading, but in retrospect, the MP result predicted the right diagnosis for three of these cases. In six cases, the suggested class was interpreted as 'discrepant but noncontributory'. The remaining 33.7% of cases (169/502) had a calibrated score <0.9, including 7.8% (39/502) for which no class indication was given at all (calibrated score <0.3). CONCLUSIONS: MP is a powerful tool to confirm and fine-tune the pathological diagnosis of CNS tumours, and to avoid misdiagnoses. However, it is crucial to interpret the results in the context of clinical, radiological, histopathological and other molecular information.

Orientation Prior and Consistent Model Selection Increase Sensitivity of Tract-Based Spatial Statistics in Crossing-Fiber Regions.

The goal of this paper is to increase the statistical power of crossing-fiber statistics in voxelwise analyses of diffusion-weighted magnetic resonance imaging (DW-MRI) data. In the proposed framework, a fiber orientation atlas and a model complexity atlas were used to fit the ball-and-sticks model to diffusion-weighted images of subjects in a prospective population-based cohort study. Reproducibility and sensitivity of the partial volume fractions in the ball-and-sticks model were analyzed using TBSS (tract-based spatial statistics) and compared to a reference framework. The reproducibility was investigated on two scans of 30 subjects acquired with an interval of approximately three weeks by studying the intraclass correlation coefficient (ICC). The sensitivity to true biological effects was evaluated by studying the regression with age on 500 subjects from 65 to 90 years old. Compared to the reference framework, the ICC improved significantly when using the proposed framework. Higher t-statistics indicated that regression coefficients with age could be determined more precisely with the proposed framework and more voxels correlated significantly with age. The application of a fiber orientation atlas and a model complexity atlas can significantly improve the reproducibility and sensitivity of crossing-fiber statistics in TBSS.

Reconstructing 3D proton dose distribution using ionoacoustics.

In proton therapy high energy protons are used to irradiate a tumor. Ideally, the delivered proton dose distribution is measured during treatment to ensure patient safety and treatment effectiveness. Here we investigate if we can use the ionoacoustic wave field to monitor the actual proton dose distribution for the two most commonly used proton accelerators; the isochronous cyclotron and the synchrocyclotron. To this end we model the acoustic field generated by the protons when irradiating a heterogeneous cancerous breast with a 89 MeV proton beam. To differentiate between the systems, idealized temporal micro-structures of the beams have been implemented. Results show that by employing model-based inversion we are able to reconstruct the 3D dose distributions from the simulated noisy pressure fields. Good results are obtained for both systems; the absolute error in the position of the maximum amplitude of the dose distribution is 5.0 mm for the isochronous cyclotron and 5.2 mm for the synchrocyclotron. In conclusion, this numerical study suggests that the ionoacoustic wave field may be used to monitor the proton dose distribution during breast cancer treatment.

Automated versus subjective assessment of spatial and temporal MRI small bowel motility in Crohn's disease.

AIM: To investigate whether subjective radiologist grading of motility on magnetic resonance enterography (MRE) is as effective as software quantification, and to determine the combination of motility metrics with the strongest association with symptom severity. MATERIALS AND METHODS: One hundred and five Crohn's disease patients (52 male, 53 female, 16-68 years old, mean age 34 years old) recruited from two sites underwent MRE, including a 20 second breath-hold cine motility sequence. Each subject completed a Harvey-Bradshaw Index (HBI) symptom questionnaire. Five features within normally appearing bowel were scored visually by two experienced radiologists, and then quantified using automated analysis software, including (1) mean motility, (2) spatial motility variation, (3) temporal motility variation, (4) area of motile bowel, (5) intestinal distension. Multivariable linear regression derived the combination of features with the highest association with HBI score. RESULTS: The best automated metric combination was temporal variation (p<0.05) plus area of motile bowel (p<0.05), achieving an R2 adjusted value of 0.036. Spatial variation was also associated with symptoms (p<0.05, R2 adjusted = 0.034); however, when visually assessed by radiologists, none of the features had a significant relationship with the HBI score. CONCLUSION: Software quantified temporal and spatial variability in bowel motility are associated with abdominal symptoms in Crohn's disease. Subjective radiologist assessment of bowel motility is insufficient to detect aberrant motility. Automated analysis of motility patterns holds promise as an objective biomarker for aberrant physiology underlying symptoms in enteric disorders.

Cortical motor threshold determination in dogs.

In humans, determining the cortical motor threshold (CMT) is a critical step in successfully applying a transcranial magnetic stimulation (TMS) treatment. Stimulus intensity, safety and efficacy of a TMS treatment are dependent of the correct assessment of the CMT. Given that TMS in dogs could serve as a natural animal model, an accurate and reliable technique for the measurement of the CMT should be available for dogs. Using a visual descending staircase paradigm (Rossini paradigm), the CMT repeatability was assessed and compared to the electromyographic (EMG) variant. The influence of a HF-rTMS treatment on the CMT was examined. Subsequently, the CMT was measured under sedation and general anaesthesia. Finally, the coil-cortex distance was associated with the CMT, weight, age and gender. During one year the CMT was measured three times, during which it remained constant, although a higher CMT was measured (40% higher machine output) when using EMG (P-value < .001) and under general anaesthesia (P-value = .005). On average, a 40% and 12% higher machine output were registered. An aHF-rTMS protocol does not influence the CMT. Males have on average a 5.2 mm larger coil cortex distance and an 11.81% higher CMT. The CMT was positively linearly associated (P-value < .05) with the weight and age of the animals. Only within female subjects, a positive linear association was found between the CMT and the coil-cortex distance (P-value = .02). Using the visual Rossini paradigm, the CMT can be reliably used over time and during a TMS treatment. It has to be kept in mind that when using EMG or assessing the CMT under general anaesthesia, a higher CMT is to be expected. As in humans, every parameter that influences the coil-cortex distance may also influence the CMT.

Comparison between dynamic gadoxetate-enhanced MRI and 99mTc-mebrofenin hepatobiliary scintigraphy with SPECT for quantitative assessment of liver function.

OBJECTIVES: To compare Gd-EOB-DTPA dynamic hepatocyte-specific contrast-enhanced MRI (DHCE-MRI) with 99mTc-mebrofenin hepatobiliary scintigraphy (HBS) as quantitative liver function tests for the preoperative assessment of patients undergoing liver resection. METHODS: Patients undergoing liver surgery and preoperative assessment of future remnant liver (FRL) function using 99mTc-mebrofenin HBS were included. Patients underwent DHCE-MRI. Total liver uptake function was calculated for both modalities: mebrofenin uptake rate (MUR) and Ki respectively. The FRL was delineated with both SPECT-CT and MRI to calculate the functional share. Blood samples were taken to assess biochemical liver parameters. RESULTS: A total of 20 patients were included. The HBS-derived MUR and the DHCE-MRI-derived mean Ki correlated strongly for both total and FRL function (Pearson r = 0.70, p = 0.001 and r = 0.89, p < 0.001 respectively). There was a strong agreement between the functional share determined with both modalities (ICC = 0.944, 95% CI 0.863-0.978, n = 20). There was a significant negative correlation between liver aminotransferases and bilirubin for both MUR and Ki. CONCLUSIONS: Assessment of liver function with DHCE-MRI is comparable with that of 99mTc-mebrofenin HBS and has the potential to be combined with diagnostic MRI imaging. This can therefore provide a one-stop-shop modality for the preoperative assessment of patients undergoing liver surgery. KEY POINTS: • Quantitative assessment of liver function using hepatobiliary scintigraphy is performed in the preoperative assessment of patients undergoing liver surgery in order to prevent posthepatectomy liver failure. • Gd-EOB-DTPA dynamic hepatocyte-specific contrast-enhanced MRI (DHCE-MRI) is an emerging method to quantify liver function and can serve as a potential alternative to hepatobiliary scintigraphy. • Assessment of liver function with dynamic gadoxetate-enhanced MRI is comparable with that of hepatobiliary scintigraphy and has the potential to be combined with diagnostic MRI imaging.

Changes in canine cerebral perfusion after accelerated high frequency repetitive transcranial magnetic stimulation (HF-rTMS): A proof of concept study.

Repetitive transcranial magnetic stimulation (rTMS) has been proposed as a treatment for several neuropsychiatric disorders in human beings, but the neurobiological effects of rTMS in dogs have not been investigated to date. A proof of concept study was designed to evaluate the effect of rTMS on cerebral perfusion, measured with single photon emission computed tomography (SPECT), in dogs. An accelerated high frequency (aHF)-rTMS (20Hz) protocol was applied to the canine left frontal cortex. To accurately target this area, eight dogs underwent a 3 Tesla magnetic resonance imaging (MRI) scan before stimulation. The left frontal cortex was subjected to five consecutive aHF-rTMS sessions with a figure-of-eight coil designed for human beings at an intensity of 110% of the motor threshold. The dogs underwent 99mTc-d,1 hexamethylpropylene amine oxime (HMPAO) SPECT scans 1 week prior to and 1day after the stimulations. Perfusion indices (PIs) were determined semi-quantitatively; aHF-rTMS resulted in significantly increased PIs in the left frontal cortex and the subcortical region, whereas no significant differences were noted for the other regions. Behaviour was not influenced by the stimulation sessions. As has been observed in human beings, aHF-rTMS applied to the left frontal cortex alters regional cerebral perfusion in dogs.

A randomized controlled trial of a skills training for oncologists and a communication aid for patients to stimulate shared decision making about palliative systemic treatment (CHOICE): study protocol.

BACKGROUND: Systemic treatment for advanced cancer offers uncertain and sometimes little benefit while the burden can be high. Hence, treatment decisions require Shared Decision Making (SDM). The CHOICE trial examines the separate and combined effect of oncologist training and a patient communication aid on SDM in consultations about palliative systemic treatment. METHODS: A RCT design with four parallel arms will be adopted. Patients with metastatic or irresectable cancer with a median life expectancy <12 months who meet with a medical oncologist to discuss the start or continuation of palliative systemic treatment are eligible. A total of 24 oncologists (in training) and 192 patients will be recruited. The oncologist training consists of a reader, two group sessions (3.5 h; including modelling videos and role play), a booster feedback session (1 h) and a consultation room tool. The patient communication aid consists of a home-sent question prompt list and a value clarification exercise to prepare patients for SDM in the consultation. The control condition consists of care as usual. The primary outcome is observed SDM in audio-recorded consultations. Secondary outcomes include patient and oncologist evaluation of communication and decision-making, the decision made, quality of life, potential adverse outcomes such as anxiety and hopelessness, and consultation duration. Patients fill out questionnaires at baseline (T0), before (T1) and after the consultation (T2) and at 3 and 6 months (T3 and T4). All oncologists participate in two standardized patient assessments (before-after training) prior to the start of patient inclusion. They will fill out a questionnaire before and after these assessments, as well as after each of the recorded consultations in clinical practice. DISCUSSION: The CHOICE trial will enable evidence-based choices regarding the investment in SDM interventions targeting either oncologists, patients or both in the advanced cancer setting. The trial takes into account the immediate effect of the interventions on observed communication, but also on more distal and potential adverse patient outcomes. Also, the trial provides evidence regarding the assumption that SDM about palliative cancer treatment results in less aggressive treatment and more quality of life in the final period of life. TRIAL REGISTRATION: Netherlands Trial Registry number NTR5489 (prospective; 15 Sep 2015).

Biodistribution and tolerance of intravenous iodine-131-labelled hypericin in healthy dogs.

Hypericin (Hyp) is a necrosis-avid compound that can be efficiently labelled with radioiodine for both diagnostic and therapeutic purposes. Before 131 I-Hyp can be considered as a clinically useful drug in a combination therapy for canine cancer patients, evaluation of its toxicity is necessary. The aim of this study was to investigate the biodistribution and tolerance of a single dose administration of 131 I-Hyp. Three healthy dogs were included. 131 I-Hyp at a dose of 0.2 mg/kg and an activity of 185 MBq was intravenously injected. The effects on physical, haematological and biochemical parameters were characterized and the biodistribution and elimination pattern, the effective half-life and dose rate were assessed. Drug-related adverse events were limited to mild gastrointestinal signs, resolving within 48 hours. No significant differences were found in blood haematology and serum biochemistry before and after treatment. Following administration, highest percentage of injected dose (%ID ± SD) was found in the liver (5.5 ± 0.33), the lungs (4.17 ± 0.14) and the heart (3.11 ± 0.78). After 24 hours, highest %ID was found in colon (4.25 ± 1.45) and liver (3.45 ± 0.60). Clearance from all organs was effective within 7 days. Effective half-life was established at 80 hours, and the dose rate fell below <20 µSv/h at 1 m within 1 day. The current study reveals that single dose treatment with 131 I-Hyp at the described dose is well tolerated by healthy dogs and supports the use of radioiodinated hypericin in a combination therapy for canine cancer patients.

Successful treatment of leptomeningeally metastasised pituitary carcinoma with temozolomide.

A 69-year-old man presented with leptomeningeally metastasised pituitary carcinoma, rapidly progressing despite previous treatment with resection, radiotherapy and cabergoline. The patient received temozolomide chemotherapy, resulting in a complete clinical, radiological and biochemical response after 14 cycles, which has been maintained since then. This case lends further support to the role of temozolomide in refractory pituitary tumours.

[A woman with a neck abscess but no current fever]. / Een vrouw met een halsabces zonder koorts.

A 28-year-old woman, originally from the Philippines, presented with a painful, fluctuating swelling of the neck, preceded by peeking fever. CT-imaging showed a multiloculated abscess. A chest X-ray did not show any abnormalities. Incision and drainage were performed. Both PCR and culture revealed an infection with Mycobacterium tuberculosis and the diagnosis of cervical tuberculous lymphadenitis was made.

A phase I, dose escalation, pharmacodynamic, pharmacokinetic, and food-effect study of α2 integrin inhibitor E7820 in patients with advanced solid tumors.

UNLABELLED: Introduction E7820 is an orally administered sulfonamide that inhibits alfa-2-integrin mRNA expression. Pre-clinically E7820 showed tumor anti-angiogenic effects in various tumor cell lines and xenograft mouse models. Human daily dosing of 100 mg QD had previously been shown to be safe and tolerable. Methods The study consisted of two parts: Part A (food effect) and Part B (determination of maximum tolerated dose (MTD) for bi-daily (BID) dosing). E7820 dosing started at 50 mg BID with planned escalation to 60, 80 and 100 mg BID every 28 days. Results Fifteen patients were enrolled in Part A and 26 in Part B. The most frequent adverse events of all grades were constipation, diarrhea, nausea, and fatigue while anemia, neutropenia, and fatigue were most frequent grade ≥3 toxicities. At dose-level 60 mg BID, two patients experienced dose-limiting toxicities (grade 3 neutropenic sepsis and grade 4 neutropenia). Therefore the recommended dose (RD) was 50 mg BID. Food had no effect on E7820 exposure. E7820 exposure following twice daily administration was dose-proportional. Expression of platelet integrin-α2 measured as a response biomarker in Part B, generally decreased by a median 7.7 % from baseline following treatment with 50 mg BID E7820. Reduction was most pronounced within 1-week post treatment. The median duration of treatment was median 54, range 20-111 days. The best overall response in any treatment group was stable disease (SD): 23.1 % in Part A (100 mg QD); at the RD 66.7 % (12 of 18 patients) and 40 % in the 60 mg BID group in Part B. CONCLUSIONS: Food had no effect on E7820 exposure. A dose of 50 mg BID was considered the MTD. Treatment with E7820 is safe and tolerable with 2/3 of patients (66.7 %) at MTD having SD as their best response.

Rare cause of bilateral sudden deafness.

In this paper, we describe the case of a 62-year-old female with recurring episodes of sudden deafness with vertigo and facial paresis. Within a month's time, this resulted in bilateral deafness and vestibular areflexia. Erroneously, the patient was diagnosed with sudden deafness of unknown origin and subsequently with neuroborreliosis (Lyme disease). The true diagnosis of relapsing polychondritis (RP) was revealed 9 months after initial presentation. The diagnostic delay is in part explained by the fact that, by definition, the disease has to relapse before the diagnosis can be made, but also by its pluriform clinical presentation. Timely identification of RP as the cause of this profound sensorineural hearing loss proved to be important. It was key in instigating adequate follow-up, and allowed for cochlear implantation before total cochlear obliteration, which might have hampered optimal hearing rehabilitation.

Prognostic value and kinetics of circulating endothelial cells in patients with recurrent glioblastoma randomised to bevacizumab plus lomustine, bevacizumab single agent or lomustine single agent. A report from the Dutch Neuro-Oncology Group BELOB trial.

BACKGROUND: Angiogenesis is crucial for glioblastoma growth, and anti-vascular endothelial growth factor agents are widely used in recurrent glioblastoma patients. The number of circulating endothelial cells (CECs) is a surrogate marker for endothelial damage. We assessed their kinetics and explored their prognostic value in patients with recurrent glioblastoma. METHODS: In this side study of the BELOB trial, 141 patients with recurrent glioblastoma were randomised to receive single-agent bevacizumab or lomustine, or bevacizumab plus lomustine. Before treatment, after 4 weeks and after 6 weeks of treatment, CECs were enumerated. RESULTS: The number of CECs increased during treatment with bevacizumab plus lomustine, but not during treatment in the single-agent arms. In patients treated with lomustine single agent, higher absolute CEC numbers after 4 weeks (log10CEC hazard ratio (HR) 0.41, 95% CI 0.18-0.91) and 6 weeks (log10CEC HR 0.16, 95% CI 0.05-0.56) of treatment were associated with improved overall survival (OS). Absolute CEC numbers in patients receiving bevacizumab plus lomustine or bevacizumab single agent were not associated with OS. CONCLUSION: CEC numbers increased during treatment with bevacizumab plus lomustine but not during treatment with either agent alone, suggesting that this combination induced the greatest vascular damage. Although the absolute number of CECs was not associated with OS in patients treated with bevacizumab either alone or in combination, they could serve as a marker in glioblastoma patients receiving lomustine single agent.