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Malignant peripheral nerve sheath tumors (MPNSTs) are aggressive sarcomas that can show overlapping features with benign neurofibromas as well as high-grade sarcomas. Additional diagnostic markers are needed to aid in this often challenging differential diagnosis. Recently mutations in two critical components of the polycomb repressor 2 (PRC2) complex, SUZ12 and EED , were reported to occur specifically in MPNSTs while such mutations are absent in neurofibromas, both in the setting of neurofibromatosis (NF) and sporadic cases. Furthermore, both SUZ12 and EED mutations in MPNSTs were associated with loss of H3K27 tri-methylation, a downstream target of PRC2. Therefore, we tested whether H3K27me3 immunohistochemistry is useful as a diagnostic and prognostic marker for MPNSTs. We performed H3K27me3 immunohistochemistry in 162 primary MPNSTs, 97 neurofibromas and 341 other tumors using tissue microarray. We observed loss of H3K27me3 in 34% (55/162) of all MPNSTs while expression was retained in all neurofibromas including atypical ( n =8) and plexiform subtypes ( n =24). Within other tumors we detected loss of H3K27me3 in only 7% (24/341). Surprisingly, 60% (9/15) of synovial sarcomas and 38% (3/8) of fibrosarcomatous dermatofibrosarcoma protuberans (DFSP) showed loss of H3K27 trimethylation. Only 1 out of 44 schwannomas showed loss of H3K27me3 and all 4 perineuriomas showed intact H3K27me3. Furthermore, MPNSTs with loss of H3K27 tri-methylation showed inferior survival compared with MPNSTs with intact H3K27 tri-methylation, which was validated in two independent cohorts. Our results indicate that H3K27me3 immunohistochemistry is useful as a diagnostic marker, in which loss of H3K27me3 favors MPNST above neurofibroma. However, H3K27me3 immunohistochemistry is not suitable to distinguish MPNST from its morphological mimicker synovial sarcoma or fibrosarcomatous DFSP. Since loss of H3K27 tri-methylation was related to poorer survival in MPNST, chromatin modification mediated by this specific histone seems to orchestrate more aggressive tumour biology.

Background/objectivesTo evaluate the management of conjunctival melanoma with local excision and adjuvant brachytherapy.Subjects/methodsData of all patients who received local excision and adjuvant brachytherapy for conjunctival melanoma between 1999 and 2016 in a Dutch national referral centre were reviewed. A protocol with Sr-90 was used until 2012, a protocol with Ru-106 was used hereafter. Local recurrence, metastasis, survival, visual acuity and treatment complications were assessed.ResultsA total of 58 patients was identified: 32 patients were treated with Sr-90 and 26 with Ru-106. Mean follow-up time was 97.3 months (143.1 months after Sr-90, and 40.2 months after Ru-106). All lesions were epibulbar, the median tumour thickness was 0.9 mm. Local recurrence occurred in 13/58 cases (22%), with a 5-year recurrence rate of 21%. Local recurrence occurred equally often in both protocols, with 5-year recurrence rates of 19% (Sr-90) versus 23% (Ru-106) (p = 0.68). Metastasis developed in 3/58 cases (5%), with 2 cases after Sr-90, and 1 after Ru-106 (p = 1.00). The most reported complications were pain (29%), dry eyes (21%), symblepharon (9%), ptosis (12%) and cataract (9%). No severe corneal or scleral complications were observed. Median visual acuity was 1.00 pre-surgery, at the end of follow-up this was 1.00 (Sr-90) and 0.95 (Ru-106).ConclusionLocal excision with adjuvant brachytherapy provides good tumour control with excellent visual outcome and mild side effects in patients with limited conjunctival melanoma. Results after Sr-90 or Ru-106 were comparable; a choice for either treatment may be based on experience of the clinician and availability of materials.

CADASIL is a NOTCH3 -associated cerebral small vessel disease. A pathological ultrastructural disease hallmark is the presence of NOTCH3-protein containing deposits called granular osmiophilic material (GOM), in small arteries. How these GOM deposits develop over time and what their role is in disease progression is largely unknown. Here, we studied the progression of GOM deposits in humanized transgenic NOTCH3 Arg182Cys mice, compared them to GOM deposits in patient material, and determined whether GOM deposits in mice are associated with a functional CADASIL phenotype. We found that GOM deposits are not static, but rather progress in ageing mice, both in terms of size and aspect. We devised a GOM classification system, reflecting size, morphology and electron density. Six-month-old mice showed mostly early stage GOM, whereas older mice and patient vessels showed predominantly advanced stage GOM, but also early stage GOM. Mutant mice did not develop the most severe GOM stage seen in patient material. This absence of end-stage GOM in mice was associated with an overall lack of histological vascular pathology, which may explain why the mice did not reveal functional deficits in cerebral blood flow, cognition and motor function. Taken together, our data indicate that GOM progress over time, and that new GOM deposits are continuously being formed. The GOM staging system we introduce here allows for uniform GOM deposit classification in future mouse and human studies, which may lead to more insight into a potential association between GOM stage and CADASIL disease severity, and the role of GOM in disease progression.

Background Evidence indicates that inflammatory processes are involved in radicular pain as well as in resorption of herniated disc tissue. Furthermore there are indications that the presence of vertebral end plate pathology (Modic changes; MC) is associated with a negative effect on inflammation. It is hypothesized that in patients with MC, the (possibly bacterial induced) inflammation will be accompanied by pro inflammatory cytokines that worsen the outcome, and that in patients without MC, the inflammation is accompanied by cytokines that induce a resorption process to accelerate recovery. Methods This prospective cohort study will include 160 lumbar and 160 cervical patients (total of 320), which are scheduled for surgery for either a lumbar or cervical herniated disc with ages between 18 and 75. The main and interaction effects of local bacterial infection (culture), inflammatory cells in disc material (immunohistology), MC (MRI), and blood biomarkers indicating inflammation or infection (blood sample evaluation) will be evaluated. Clinical parameters to be evaluated are leg pain on the 11 point NRS pain scale, Oswestry (lumbar spine) or Neck (cervical spine) Disability Index, Global Perceived Recovery, Womac Questionnaire, and medication status, at baseline, and after 6, 16, 26 and 52 weeks. Discussion Gaining insight in the aetiology of pain and discomfort in radiculopathy caused by a herniated disc could lead to more effective management of patients. If the type of inflammatory cells shows to be of major influence on the rate of recovery, new immunomodulating treatment strategies can be developed to decrease the duration and intensity of symptoms. Moreover, identifying a beneficial inflammatory response in the disc through a biomarker in blood could lead to early identification of patients whose herniations will resorb spontaneously versus those that require surgery. Trial registration prospectively enrolled at trialregister.nl, ID: NL8464 .

Sequestration of malaria-parasite-infected erythrocytes in the microvasculature of organs is thought to be a significant cause of pathology. Cerebral malaria (CM) is a major complication of Plasmodium falciparum infections, and PfEMP1-mediated sequestration of infected red blood cells has been considered to be the major feature leading to CM-related pathology. We report a system for the real-time in vivo imaging of sequestration using transgenic luciferase-expressing parasites of the rodent malaria parasite Plasmodium berghei. These studies revealed that: (i) as expected, lung tissue is a major site, but, unexpectedly, adipose tissue contributes significantly to sequestration, and (ii) the class II scavenger-receptor CD36 to which PfEMP1 can bind is also the major receptor for P. berghei sequestration, indicating a role for alternative parasite ligands, because orthologues of PfEMP1 are absent from rodent malaria parasites, and, importantly, (iii) cerebral complications still develop in the absence of CD36-mediated sequestration, dissociating parasite sequestration from CM-associated pathology. Real-time in vivo imaging of parasitic processes may be used to evaluate the molecular basis of pathology and develop strategies to prevent pathology.

In Tables 3 and 4: In the first column and row, the text reads “Mixed model test (patients with Modic changes)”. This should have been just “Mixed model”. The complete correct Tables 3 and 4 are given below.

Expression of DNA repair genes was studied in uveal melanoma (UM) in order to identify genes that may play a role in metastases formation. We searched for genes that are differentially expressed between tumors with a favorable and unfavorable prognosis. Gene-expression profiling was performed on 64 primary UM from the Leiden University Medical Center (LUMC), Leiden, The Netherlands. The expression of 121 genes encoding proteins involved in DNA repair pathways was analyzed: a total of 44 genes differed between disomy 3 and monosomy 3 tumors. Results were validated in a cohort from Genoa and Paris and the The Cancer Genome Atlas (TCGA) cohort. Expression of the PRKDC, WDR48, XPC, and BAP1 genes was significantly associated with clinical outcome after validation. PRKDC was highly expressed in metastasizing UM (p < 0.001), whereas WDR48, XPC, and BAP1 were lowly expressed (p < 0.001, p = 0.006, p = 0.003, respectively). Low expression of WDR48 and XPC was related to a large tumor diameter (p = 0.01 and p = 0.004, respectively), and a mixed/epithelioid cell type (p = 0.007 and p = 0.03, respectively). We conclude that the expression of WDR48, XPC, and BAP1 is significantly lower in UM with an unfavorable prognosis, while these tumors have a significantly higher expression of PRKDC. Pharmacological inhibition of DNA-PKcs resulted in decreased survival of UM cells. PRKDC may be involved in proliferation, invasion and metastasis of UM cells. Unraveling the role of DNA repair genes may enhance our understanding of UM biology and result in the identification of new therapeutic targets.

Hereditary cerebral hemorrhage with amyloidosis-Dutch type (HCHWA-D) is an early onset hereditary form of cerebral amyloid angiopathy (CAA) caused by a point mutation resulting in an amino acid change (NP_000475.1:p.Glu693Gln) in the amyloid precursor protein (APP). Post-mortem frontal and occipital cortical brain tissue from nine patients and nine age-related controls was used for RNA sequencing to identify biological pathways affected in HCHWA-D. Although previous studies indicated that pathology is more severe in the occipital lobe in HCHWA-D compared to the frontal lobe, the current study showed similar changes in gene expression in frontal and occipital cortex and the two brain regions were pooled for further analysis. Significantly altered pathways were analyzed using gene set enrichment analysis (GSEA) on 2036 significantly differentially expressed genes. Main pathways over-represented by down-regulated genes were related to cellular aerobic respiration (including ATP synthesis and carbon metabolism) indicating a mitochondrial dysfunction. Principal up-regulated pathways were extracellular matrix (ECM)-receptor interaction and ECM proteoglycans in relation with an increase in the transforming growth factor beta (TGFβ) signaling pathway. Comparison with the publicly available dataset from pre-symptomatic APP-E693Q transgenic mice identified overlap for the ECM-receptor interaction pathway, indicating that ECM modification is an early disease specific pathomechanism.

Point mutations in the amyloid-β (Aβ) coding region produce a combination of mutant and WT Aβ isoforms that yield unique clinicopathologies in familial Alzheimer’s disease (fAD) and cerebral amyloid angiopathy (fCAA) patients. Here, we report a method to investigate the structural variability of amyloid deposits found in fAD, fCAA, and sporadic AD (sAD). Using this approach, we demonstrate that mutant Aβ determines WT Aβ conformation through prion template-directed misfolding. Using principal component analysis of multiple structure-sensitive fluorescent amyloid-binding dyes, we assessed the conformational variability of Aβ deposits in fAD, fCAA, and sAD patients. Comparing many deposits from a given patient with the overall population, we found that intrapatient variability is much lower than interpatient variability for both disease types. In a given brain, we observed one or two structurally distinct forms. When two forms coexist, they segregate between the parenchyma and cerebrovasculature, particularly in fAD patients. Compared with sAD samples, deposits from fAD patients show less intersubject variability, and little overlap exists between fAD and sAD deposits. Finally, we examined whether E22G (Arctic) or E22Q (Dutch) mutants direct the misfolding of WT Aβ, leading to fAD-like plaques in vivo. Intracerebrally injecting mutant Aβ40 fibrils into transgenic mice expressing only WT Aβ induced the deposition of plaques with many biochemical hallmarks of fAD. Thus, mutant Aβ40 prions induce a conformation of WT Aβ similar to that found in fAD deposits. These findings indicate that diverse AD phenotypes likely arise from one or more initial Aβ prion conformations, which kinetically dominate the spread of prions in the brain.

AimsTo evaluate the treatment of conjunctival melanoma at a large Dutch referral centre and to make recommendations for clinical management.MethodsA retrospective review was performed of clinical and histological data of 70 patients treated for a primary conjunctival melanoma between 2001 and 2014 at the Leiden University Medical Center, Leiden, the Netherlands. Detailed follow-up data were available for all patients.ResultsThe mean follow-up time was 70.2 months. The overall 5-year recurrence rate was 29%, the 5-year metastasis rate 12% and the 5-year melanoma-related survival 90%. Treatment with excision alone had a significantly higher 5-year recurrence rate than (the combination of) other treatments (HR 3.73,95% CI 1.19 to 11.6, P=0.02). Initial treatment in an ocular oncology centre was associated with fewer recurrences compared with initial treatment by a local ophthalmologist of a referring centre (HR 0.32,95% CI 0.11 to 0.94, P=0.04), despite similar tumour baseline characteristics.ConclusionConjunctival melanoma is a rare disease with a high recurrence rate. A treatment strategy with local excision and adjuvant therapy gave a good clinical outcome, excision alone as a treatment should be considered obsolete. Initial treatment in a large referral centre improves clinical outcome, and patients should be referred to a specialised centre as soon as possible.