Reaction on "Ocular ultrasound versus MRI in the detection of extrascleral extension in a patient with choroidal melanoma".

BACKGROUND: In the recently published article entitled "Ocular ultrasound versus MRI in the detection of extrascleral extension in a patient with choroidal melanoma" Jacobsen et al. describe a case in which a hyper-intense extra-ocular lesion on MRI was erroneously diagnosed as an extrascleral extension of the tumor. Based upon this the authors conclude "the superiority of ocular ultrasound in the diagnostic management of extra scleral extension in choroidal melanoma". In our view, there are numerous flaws in the investigation that cast doubt on this message. MAIN: First of all, this is quite a bold statement when only one patient has been evaluated. Secondly, the manuscript only presents a post-contrast T1-weighted image, whereas multiple MRI-sequences need to be included to determine if a hyperintense region is an extrascleral invasion. Moreover, no modern MRI-techniques such Dynamic Contrast Enhanced (DCE) or Diffusion Weighted Imaging (DWI) have been included in the evaluation of this patient, making it hard to use this single case to compare the efficacy of MRI and Ultrasound. The presented data do, however, give clear clues that the hyperintense lesion is likely to be inflammatory. CONCLUSION: Although the study falls short in providing a comprehensive comparison between current MRI techniques and ultrasound, it does show that the evaluation of ocular MR-images should be made in a multi-disciplinary setting involving both ophthalmologist and radiologists, since the field of ocular MRI is continuously progressing.

CT and MR imaging of orbital inflammation.

PURPOSE: Orbital inflammation can be idiopathic or in the context of a specific disease and it can involve different anatomical orbital structures. On imaging, inflammatory disease is frequently mistaken for infection and malignant tumors, and its underlying cause is often not determined. Through this article we aim to improve orbital inflammation diagnosis and underlying inflammatory diseases recognition. METHODS: The imaging protocols and characteristics of orbital inflammation were reviewed. RESULTS: A decision tree for the evaluation of these patients is provided. First, a combination of clinical and radiological clues is used to recognize inflammation, in particular to differentiate it both from orbital infection and tumor. Subsequently, different radiological patterns are recognized, often allowing the differentiation of the several orbital inflammatory diseases. CONCLUSION: The use of adequate imaging protocols and subsequent evaluation allow the recognition of an orbital lesion as inflammatory and the diagnosis of the underlying inflammatory disease. All in all, a proper treatment can be established, and at times, a biopsy can be avoided.

[A woman with iris heterochromia]. / Een vrouw met irisheterochromie.

A 20-year-old woman with congenital iris heterochromia presented with loss of vision of her right eye. We made de diagnosis of a large 'uvea melanoma' and enucleated the eye. Pathological examination showed an underlying oculodermal melanocytosis (ODM). The life-time risk of uveal melanoma in the general population is 0.7:100,000, but 1:400 in patients with ODM. Therefore, annual fundoscopy is recommended in these patients.

Biocompatibility of a fish scale-derived artificial cornea: Cytotoxicity, cellular adhesion and phenotype, and in vivo immunogenicity.

PURPOSE: To determine whether a fish scale-derived collagen matrix (FSCM) meets the basic criteria to serve as an artificial cornea, as determined with in vitro and in vivo tests. METHODS: Primary corneal epithelial and stromal cells were obtained from human donor corneas and used to examine the (in)direct cytotoxicity effects of the scaffold. Cytotoxicity was assessed by an MTT assay, while cellular proliferation, corneal cell phenotype and adhesion markers were assessed using an EdU-assay and immunofluorescence. For in vivo-testing, FSCMs were implanted subcutaneously in rats. Ologen(®) Collagen Matrices were used as controls. A second implant was implanted as an immunological challenge. The FSCM was implanted in a corneal pocket of seven New Zealand White rabbits, and compared to sham surgery. RESULTS: The FSCM was used as a scaffold to grow corneal epithelial and stromal cells, and displayed no cytotoxicity to these cells. Corneal epithelial cells displayed their normal phenotypical markers (CK3/12 and E-cadherin), as well as cell-matrix adhesion molecules: integrin-α6 and ß4, laminin 332, and hemi-desmosomes. Corneal stromal cells similarly expressed adhesion molecules (integrin-α6 and ß1). A subcutaneous implant of the FSCM in rats did not induce inflammation or sensitization; the response was comparable to the response against the Ologen(®) Collagen Matrix. Implantation of the FSCM in a corneal stromal pocket in rabbits led to a transparent cornea, healthy epithelium, and, on histology, hardly any infiltrating immune cells. CONCLUSION: The FSCM allows excellent cell growth, is not immunogenic and is well-tolerated in the cornea, and thus meets the basic criteria to serve as a scaffold to reconstitute the cornea.

The genetic basis of uveal melanoma.

Uveal melanoma (UM) is the most common intraocular malignancy in adults with an incidence of about 1/100,000 new cases per year in the Western world. Risk factors are having a light skin, blond hair and blue eyes. As some UM patients have a young age at diagnosis or an affected family history for UM or other malignancies, there may be an underlying genetic basis. This review discusses known or suspected risk factors for UM, the cancer risk in UM patients and their family members, and the genes that have been reported to predispose to UM (germline mutations) and tumor development (somatic mutations).

High-resolution MRI of uveal melanoma using a microcoil phased array at 7 T.

High-field MRI is a promising technique for the characterisation of ocular tumours, both in vivo and after enucleation. For in vivo imaging at 7 T, a dedicated three-element microcoil array was constructed as a high-sensitivity receive-only device. Using a dedicated blink/fixation protocol, high-resolution in vivo images could be acquired within 3 min in volunteers and patients with no requirement for post-acquisition image registration. Quantitative measures of axial length, aqueous depth and lens thickness in a healthy volunteer were found to agree well with standard ocular biometric techniques. In a patient with uveal melanoma, in vivo MRI gave excellent tumour/aqueous body contrast. Ex vivo imaging of the enucleated eye showed significant heterogeneity within the tumour.

[Orbital metastases of breast cancer. Radiologic features]. / Mammakarzinommetastasen der Orbita. Radiologische Eigenschaften.

BACKGROUND: We reviewed the radiologic features of 15 patients with orbital metastases originating from breast cancer. METHODS: This was a retrospective consecutive case series. Fifteen consecutive patients with orbital metastases originating from breast carcinoma were identified between March 1997 and September 2008. A retrospective chart review was carried out, and the radiologic findings were reviewed. RESULTS: The metastases were preseptal in 53%, intraconal in 60%, and both intraconal and extraconal in 33%. Lacrimal gland enlargement was noted in 33%, episcleral space involvement in 33%, bone involvement in 13%, and globe dystopia in 53%. The extraocular muscles were involved in 87%; in 60%, two or more muscles were involved. The medial and lateral rectus muscles were affected in 53% and 47%, respectively, and the inferior and superior rectus muscles in 33%. In 47% one or more radiologic features had not been noted by the radiologist, and in 20% the findings were misinterpreted as an"orbital pseudotumor." CONCLUSION: Orbital metastases originating from breast cancer may present heterogeneously. Orbital imaging most commonly shows unilateral and multifocal involvement of multiple extraocular muscles and intraconal and preseptal areas by an irregular lesion.

Episodic Src activation in uveal melanoma revealed by kinase activity profiling.

BACKGROUND: The RAS/RAF/MEK/ERK pathway is involved in the balance between melanocyte proliferation and differentiation. The same pathway is constitutively activated in cutaneous and uveal melanoma (UM) and related to tumour growth and survival. Whereas mutant BRAF and NRAS are responsible for the activation of the RAS/RAF/MEK/ERK pathway in most cutaneous melanoma, mutations in these genes are usually absent in UM. METHODS: We set out to explore the RAS/RAF/MEK/ERK pathway and used mitogen-activated protein kinase profiling and tyrosine kinase arrays. RESULTS: We identified Src as a kinase that is associated with ERK1/2 activation in UM. However, low Src levels and reduced ERK1/2 activation in metastatic cell lines suggest that proliferation in metastases can become independent of Src and RAS/RAF/MEK/ERK signalling. Inhibition of Src led to the growth reduction of primary UM cultures and cell lines, whereas metastatic cell line growth was only slightly reduced. CONCLUSION: We identified Src as an important kinase and a potential target for treatment in primary UM. Metastasis cell lines seemed largely resistant to Src inhibition and indicate that in metastases treatment, a different approach may be required.

Frequency of Von Hippel-Lindau germline mutations in classic and non-classic Von Hippel-Lindau disease identified by DNA sequencing, Southern blot analysis and multiplex ligation-dependent probe amplification.

The current clinical diagnosis of Von Hippel-Lindau (VHL) disease demands at least one specific [corrected] VHL manifestation in a patient with familial VHL disease, or, in a [corrected] sporadic patient, at least two or more hemangioblastomas or a single hemangioblastoma in combination with a typical visceral lesion. To evaluate this definition, we studied the frequency of germline VHL mutation in three patients groups: (i) multi-organ involvement (classic VHL), (ii) limited VHL manifestations meeting criteria (non-classic VHL) and (iii) patients with VHL-associated tumors not meeting current diagnostic VHL criteria. In addition, we validated multiplex ligation-dependent probe amplification (MLPA) as a rapid and reliable quantitative method for the identification of germline VHL deletions. The frequency of germline VHL mutations was very high in classic VHL cases with multi-organ involvement (95%), lower in non-classic cases that meet current diagnostic criteria but have limited VHL manifestations or single-organ involvement (24%) and low (3.3%), but tangible in cases not meeting current diagnostic VHL criteria. The detection of germline VHL mutations in patients or families with limited VHL manifestations, or single-organ involvement is relevant for follow-up of probands and early identification of at-risk relatives.

A phase I and pharmacologic study of the MDR converter GF120918 in combination with doxorubicin in patients with advanced solid tumors.

BACKGROUND: Resistance to chemotherapy can partly be explained by the activity of membrane bound P-glycoprotein. Competitive inhibition of P-glycoprotein, by multidrug resistance (MDR) converters, may overcome this MDR. Previously studied MDR converters either have serious intrinsic side effects or considerably influence the pharmacokinetics of cytotoxic agents at concentrations theoretically required to convert MDR. GF120918 is a third-generation MDR converter with high affinity for P-glycoprotein and can be given orally. We performed a phase 1 study with escalating doses of GF120918 in combination with doxorubicin. PATIENTS AND METHODS: The study group comprised 46 patients with advanced solid tumors. Doxorubicin was administered on day 1 (cycle 1), GF120918 on days 22-24 (cycle 2), and on days 29-33 with doxorubicin administered on day 31 (cycle 3). Pharmacokinetics of both GF120918 and doxorubicin were studied. The starting daily dose of GF120918 was 50 mg and was to be increased in subsequent cohorts until a steady state plasma level of 100 ng/ml was reached. The starting dose of doxorubicin was 50 mg/m2 and was to be increased after reaching the target dose level of GF120918. RESULTS: In 37 of the 46 patients, full pharmacokinetic data from the three scheduled cycles were obtained. Pharmacokinetics of GF120918 showed a less than linear increase in Cmax with increasing doses, with considerable interpatient variation. The target steady-state plasma level for GF120918 was exceeded in 12 out of 19 patients who received 400 mg GF120918 alone twice daily and in 12 of 17 patients who received 400 mg GF120918 twice daily in combination with doxorubicin. GF120918 pharmacokinetics were not influenced by coadministration of doxorubicin. The doxorubicin AUC was only marginally influenced by GF120918 and only at the highest dose levels. In these patients there was a significant increase in the AUC of doxorubicinol in cycle 3 as compared to cycle 1. Hematologic toxicity mainly consisted of neutropenia and was more severe in cycle 3 than in cycle 1 (13 vs 5 patients with grade 4 neutropenia, P=0.003). Neutropenic fever was the dose-limiting toxicity at a doxorubicin dose of 75 mg/m2 with 400 mg GF120918 twice daily. The toxicity of GF120918 was limited to somnolence in eight patients and occasional gastrointestinal complaints. CONCLUSION: GF120918 is an MDR converter with only minimal side effects at a dose level yielding concentrations able to convert the action of P-glycoprotein in vitro. A doxorubicin dose of 60 mg/m2 on day 3 in combination with 400 mg GF120918 twice daily on days 1-5 is an acceptable regimen for further clinical trials.