D. J. A. de Groot

Long‐term cerebral imaging after pre‐eclampsia

Please cite this paper as: Aukes A, De Groot J, Wiegman M, Aarnoudse J, Sanwikarja G, Zeeman G. Long‐term cerebral imaging after pre‐eclampsia. BJOG 2012;119:1117–1122.

Rectal and colon cancer : Not just a different anatomic site

Due to differences in anatomy, primary rectal and colon cancer require different staging procedures, different neo-adjuvant treatment and different surgical approaches. For example, neoadjuvant radiotherapy or chemoradiotherapy is administered solely for rectal cancer. Neoadjuvant therapy and total mesorectal excision for rectal cancer might be responsible in part for the differing effect of adjuvant systemic treatment on overall survival, which is more evident in colon cancer than in rectal cancer. Apart from anatomic divergences, rectal and colon cancer also differ in their embryological origin and metastatic patterns. Moreover, they harbor a different composition of drug targets, such as v-raf murine sarcoma viral oncogene homolog B (BRAF), which is preferentially mutated in proximal colon cancers, and the epidermal growth factor receptor (EGFR), which is prevalently amplified or overexpressed in distal colorectal cancers. Despite their differences in metastatic pattern, composition of drug targets and earlier local treatment, metastatic rectal and colon cancer are, however, commonly regarded as one entity and are treated alike. In this review, we focused on rectal cancer and its biological and clinical differences and similarities relative to colon cancer. These aspects are crucial because they influence the current staging and treatment of these cancers, and might influence the design of future trials with targeted drugs.

Indomethacin induces apoptosis via a MRP1-dependent mechanism in doxorubicin-resistant small-cell lung cancer cells overexpressing MRP1

Small-cell lung cancers (SCLCs) initially respond to chemotherapy, but are often resistant at recurrence. The non-steroidal anti-inflammatory drug indomethacin is an inhibitor of multidrug resistance protein 1 (MRP1) function. The doxorubicin-resistant MRP1-overexpressing human SCLC cell line GLC4-Adr was highly sensitive for indomethacin compared with the parental doxorubicin-sensitive line GLC4. The purpose of this study was to analyse the relationship between hypersensitivity to indomethacin and MRP1 overexpression. The experimental design involved analysis of the effect of MRP1 downregulation on indomethacin-induced cell survival and apoptosis in GLC4-Adr and GLC4, using siRNA. In addition the effect of indomethacin on glutathione levels and mitochondrial membrane potential was investigated. Small interfering RNAs directed against MRP1 reduced MRP1 mRNA levels twofold and reduced efflux pump function of MRP1, which was reflected by a 1.8-fold higher accumulation of MRP1 substrate carboxyfluorescein, in si-MRP1 versus si-Luciferase-transfected GLC4-Adr cells. Multidrug resistance protein 1 downregulation decreased initial high apoptosis levels 2-fold in GLC4-Adr after indomethacin treatment for 24 h, and increased cell survival (IC50) from 22.8±2.6 to 30.4±5.1 μM following continuous indomethacin exposure. Multidrug resistance protein 1 downregulation had no effect on apoptosis in GLC4 or on glutathione levels in both lines. Although indomethacin (20 μM) for 2 h decreased glutathione levels by 31.5% in GLC4-Adr, complete depletion of cellular glutathione by L-buthionine (S,R)-sulphoximine only resulted in a small increase in indomethacin-induced apoptosis in GLC4-Adr, demonstrating that a reduced cellular glutathione level is not the primary cause of indomethacin-induced apoptosis. Indomethacin exposure decreased mitochondrial membrane potential in GLC4-Adr cells, suggesting activation of the mitochondrial apoptosis pathway. Indomethacin induces apoptosis in a doxorubicin-resistant SCLC cell line through an MRP1-dependent mechanism. This may have implications for the treatment of patients with MRP1-overexpressing tumours.

T2 lesions and rate of progression of disability in multiple sclerosis.

Background and purpose:  To assess the predictive value of T2 lesions on the rate of progression of disability in multiple sclerosis (MS).

Relationship between the extent of T2 lesions and the onset of secondary progression in multiple sclerosis

Patients with relapsing–remitting multiple sclerosis (MS) are at risk of converting to a secondary progressive disease course. To assess the relationship between brain magnetic resonance imaging (MRI) findings and onset of secondary progression, we reanalysed the initial brain MRI scans of 90 relapsing–remitting MS patients, who were clinically followed up for at least 10 years (median 14 years) after their scan, for the number and volume of T2 lesions, and for two measures of brain atrophy (bicaudate ratio and third ventricle width). The relationship to development of secondary progression was studied with Cox regression models and Kaplan–Meier survival analyses. At the end of follow‐up, 36 patients had become progressive. The presence of more than 10 T2 lesions more than doubled the risk of becoming secondary progressive (hazards ratio 2.36; 95% CI 1.19–4.66). When at least one of the 10 lesions was confluent the risk increased to 3.51 (1.64–7.50). The hazards ratio for an estimated T2 lesion load of more than 800 mm3 was 2.11 (1.07–4.16). Linear brain atrophy measures were not predictive. Our data show a relationship between the extent of brain T2 lesions and the onset of secondary progression in MS.

MR spectroscopy and diffusion tensor imaging of the brain in Sjögren-Larsson syndrome.

Diffusion tensor imaging (DTI) is reported for the first time in a patient with Sjögren-Larsson syndrome, an autosomal recessive neurocutaneous disorder. Magnetic resonance spectroscopy (MRS) revealed normal levels of choline, creatine and N-acetyl aspartate (NAA) and the characteristic lipid signals in the white matter brain tissue. Conventional MRI showed increased signal intensity around the lateral ventricles indicating abnormal myelination. DTI revealed normal apparent diffusion coefficient (ADC) values, but reduced fractional anisotropy (FA) in the white matter. After co-registration of the parameters obtained with DTI with the results of MRS (36 voxels), significant correlations were obtained of lipid content with FA (r=0.81), ADC (r=-0.62), choline (r=0.51), and NAA (r=0.44) (P<0.01, all). These results suggest that in Sjögren-Larsson syndrome, the white matter lipid signals originate from the neurons, with NAA and choline reflecting neuron density and myelination. The comparatively high FA/low ADC values in these lipid-rich locations, indicate a loss of diffusion in directions perpendicular to the fibers. The overall loss of FA in the white matter may reflect a loss of brain tissue water content in SLS patients compared with controls and precede the formation of atrophy.

The antibody–drug conjugate target landscape across a broad range of tumour types

Background Antibody-drug conjugates (ADCs), consisting of an antibody designed against a specific target at the cell membrane linked with a cytotoxic agent, are an emerging class of therapeutics. Because ADC tumour cell targets do not have to be drivers of tumour growth, ADCs are potentially relevant for a wide range of tumours currently lacking clear oncogenic drivers. Therefore, we aimed to define the landscape of ADC targets in a broad range of tumours. Materials and methods PubMed and ClinicalTrials.gov were searched for ADCs that are or were evaluated in clinical trials. Gene expression profiles of 18 055 patient-derived tumour samples representing 60 tumour (sub)types and 3520 healthy tissue samples were collected from the public domain. Next, we applied Functional Genomic mRNA-profiling to predict per tumour type the overexpression rate at the protein level of ADC targets with healthy tissue samples as a reference. Results We identified 87 ADCs directed against 59 unique targets. A predicted overexpression rate of ≥ 10% of samples for multiple ADC targets was observed for high-incidence tumour types like breast cancer (n = 31 with n = 23 in triple negative breast cancer), colorectal cancer (n = 18), lung adenocarcinoma (n = 18), squamous cell lung cancer (n = 16) and prostate cancer (n = 5). In rare tumour types we observed, amongst others, a predicted overexpression rate of 55% of samples for CD22 and 55% for ENPP3 in adrenocortical carcinomas, 81% for CD74 and 81% for FGFR3 in osteosarcomas, and 95% for c-MET in uveal melanomas. Conclusion This study provides a data-driven prioritization of clinically available ADCs directed against 59 unique targets across 60 tumour (sub)types. This comprehensive ADC target landscape can guide clinicians and drug developers which ADC is of potential interest for further evaluation in which tumour (sub)type.

Use of Video-consultation is Feasible During Follow-up Care of Patients with a Neuroendocrine Tumour

Purpose Patients with a neuroendocrine tumour (NET) are increasingly treated in expert centers leading to longer travel times for medical consultations. Video-consultation (VC) potentially allows remote guidance of patients. Studies evaluating VC in NET patients are lacking. Therefore the primary aim of this study was to assess feasibility of VC during follow-up care of NET patients. Methods Clinical stable NET patients (N = 20) received two VCs during follow-up care. Feasibility of VC was assessed by calculation of participation/drop-out rate and safety. Satisfaction questionnaires were filled out by patients and physicians. VC time, patient-reported travel time for an outpatient clinic visit and preference for type of consultation were noted. Results Participation rate was 84%. Six of the 26 (23%) included patients terminated the study prematurely. No safety concerns were reported. Median score for satisfaction of patients and physicians were 4.6 (range 3.3-4.9, five-point Likert scale) and 4.0 (range 3.5-4.9) respectively, indicating high satisfaction with VC. Technical problems leading to prolonged connection time and impaired audio/video quality were reported by 55% and 40% of the patients and physicians respectively. Median VC time was 13 minutes (range 9-25). Patient-reported duration of a follow-up consultation at the outpatient clinic was 240 minutes (range 100-390). Sixty percent of the patients preferred VC. Conclusions Use of VC during follow-up care of patients with clinical stable NET is feasible. Patients’ and physicians’ acceptability and satisfaction with VC is high, but can be improved by solving technical problems.