P.L. Blanco

Current and emerging treatment options for uveal melanoma

Uveal melanoma (UM) is the most common primary malignant intraocular tumor in adults, with a 10-year cumulative metastatic rate of 34%. The most common site of metastasis is the liver (95%). Unfortunately, the current treatment of metastatic UM is limited by the lack of effective systemic therapy. Options for the management of the primary intraocular tumor include radical surgery as well as conservative treatments in order to preserve visual acuity. For metastatic disease, several approaches have been described with no standard method. Nevertheless, median survival after liver metastasis is poor, being around 4–6 months, with a 1-year survival of 10%–15%. In this review, the authors summarize current and promising new treatments for UM.

Transcriptional profiling of human uveal melanoma from cell lines to intraocular tumors to metastasis

Uveal melanoma is the most common primary intraocular tumor in adults and exclusively disseminates haematogenously in order to form metastases. The aim of this study was to measure the transcriptional profiles of human uveal melanoma cells isolated from a primary intraocular tumor, circulating malignant cells (CMCs), and metastases in order to elucidate the changes in gene expression associated with this progression. Human EST microarrays and universal reference RNA were used to measure the differences between tissue samples isolated from an immunosuppressed xenograft rabbit model of uveal melanoma. Cells were isolated from a single rabbit at the time of sacrifice from an intraocular tumor, peripheral blood, and metastasis. RNA was extracted from each sample and subjected to transcriptional profiling analysis. Results were compared to the transcriptional profiles previously obtained from the original cell line used for intraocular injections. Changes were verified using real-time PCR analysis. A total of 314 significant changes in gene expression were seen from the intraocular tumor to metastasis, as determined by transcript abundance. Principle Components Analysis was used to cluster these changes into four distinct groups. An additional 61 statistically significant changes were observed between the recultured and CMCs, with the latter believed to represent an intermediate step in the progression from intraocular tumor to metastasis. In conclusion, we have produced a detailed analysis of the transcriptional changes that take place as human uveal melanoma cells evolve from a primary tumor to metastasis in a xenograft animal model, including the decrease in expression of specific melanoma markers.

Uveal melanoma dormancy: an acceptable clinical endpoint?

Uveal melanoma is a rare but life-threatening malignancy. Over the past decades, the morbidity of uveal melanoma has been markedly reduced as a result of advances in the diagnostic ability to detect smaller tumors at an earlier stage. This has allowed for the use of more conservative treatments, avoiding enucleation. Mortality, however, has remained unchanged. This indicates that life expectancy is independent of local tumor control. Metastatic disease, the leading cause of death, is usually diagnosed many years later, despite successful treatment of the primary tumor, and at a late stage, when no effective therapy is available. These observations suggest that the disease was already disseminated at the time of tumor diagnosis. The detection of circulating malignant cells in the bloodstream of patients at different time points in the course of the disease supports this observation. Tumor dormancy has been considered as the leading theory for this intriguing delayed appearance of metastasis. Recent knowledge gained about the biological behavior of uveal melanoma as well as novel potential therapeutic targets are presented in this review.

Experimental models of uveal melanoma.

Over the past several decades, considerable effort has been directed toward developing suitable experimental models for the study of uveal melanoma. Animal models of uveal melanoma have undergone many improvements, leading to the development of experimental systems that better represent the disease in human beings. A major advance has come from the use of human uveal melanoma cell lines capable of inducing tumour growth and metastatic disease in immunodeficient hosts. Knowledge gained from the use of experimental models will ultimately be translated into better diagnostic and therapeutic strategies for patients with uveal melanoma. In this review the authors describe the current state-of-the-art designs of experimental models of uveal melanoma, highlighting the advantages and disadvantages of the available models. Novel findings from a rabbit model of uveal melanoma are also presented.

SIRT2 Expression Is Higher in Uveal Melanoma than In Ocular Melanocytes

Purpose: Sirtuins (SIRTs) are the family of proteins associated with the cell cycle and that correlate with cancer development and progression. SIRTs have never been studied in uveal melanocytes. The aim of this study is to characterize the expression of SIRT2 in uveal melanoma (UM) cases and compare it with the expression of SIRT2 in melanocytes of the uveal tract of normal human eyes (NHE). Methods: Twenty-one formalin-fixed, paraffin-embedded human UM cases were immunostained for SIRT2, along with 15 NHE obtained from the Eye Bank of Canada. Results: SIRT2 expression was higher in melanomas than in normal melanocytes of both tumor and donor eyes (p < 0.0001). No significant difference in SIRT2 expression was found when comparing normal melanocytes in UM and NHE cases. Conclusions: SIRT2 expression is significantly stronger in UM cells than in normal ocular melanocytes. This finding may indicate an important role of SIRT2 as a prognostic marker in UM progression. SIRT2 should also be investigated as a possible therapeutic target.

Invasive ductal breast carcinoma detector that is robust to image magnification in whole digital slides

Abstract. Invasive ductal breast carcinomas (IDBCs) are the most frequent and aggressive subtypes of breast cancer, affecting a large number of Canadian women every year. Part of the diagnostic process includes grading the cancerous tissue at the microscopic level according to the Nottingham modification of the Scarff-Bloom-Richardson system. Although reliable, there exists a growing interest in automating the grading process, which will provide consistent care for all patients. This paper presents a solution for automatically detecting regions expressing IDBC in images of microscopic tissue, or whole digital slides. This represents the first stage in a larger solution designed to automatically grade IDBC. The detector first tessellated whole digital slides, and image features were extracted, such as color information, local binary patterns, and histograms of oriented gradients. These were presented to a random forest classifier, which was trained and tested using a database of 66 cases diagnosed with IDBC. When properly tuned, the detector balanced accuracy, F1 score, and Dice’s similarity coefficient were 88.7%, 79.5%, and 0.69, respectively. Overall, the results seemed strong enough to integrate our detector into a larger solution equipped with components that analyze the cancerous tissue at higher magnification, automatically producing the histopathological grade.

Abstract CT118: A randomized phase II study of the CSF-470 therapeutic vaccine plus BCG plus rhGM-CSF versus IFN-α2b in cutaneous melanoma patients stages IIB, IIC and III

Adjuvant treatment of high-risk cutaneous melanoma (CM) patients (pts) is still an unsolved issue, since the cost-benefit ratio of high-dose IFN-α2b is under discussion. The CSF-470 therapeutic vaccine, a mini-allograft of four lethally-irradiated allogeneic CM cell lines, with BCG and rhGM-CSF as adjuvants, is currently being tested in post-surgical adjuvancy vs medium-dose IFN-2b in stage IIB-III CM pts (phase II/III trial CASVAC-0401, NCT01729663).We present here the results of the phase II part of the study. A total of 31 pts (stage IIC = 2; stage III: 29) were enrolled: 20 pts were randomized to receive CSF-470 vaccine and 11 pts to IFN-α2b. Pts assigned to the vaccine arm received i.d. 1.6×10 7 CSF-470 irradiated cells plus 10 6 cfu BCG and 100μg rhGM-CSF (first day); 100 μg rhGM-CSF/day/3days were injected consecutively i.d. at the vaccination site. During the two-year treatment, pts in the vaccine arm received a total of 13 vaccinations. Pts assigned to the IFN-α2b arm received 10 MU/day/5 days a week for 4 weeks; then 5 MU 3/week for 23 months. Imaging studies were performed to follow the clinical evolution of the disease. Analysis of blood chemistry and differential white blood cell counts were performed to monitor systemic toxicity. Immune monitoring was performed at baseline and at 6, 12 and 24 months from protocol start. Also, pts were evaluated by Quality of Life Questionnaires (QOL) along the study. After including 20 pts who received a total of 176 vaccinations, we conclude that: CSF-470 vaccine was well tolerated; the main toxicity was a grade 2 reaction at the injection site; 3/20 pts presented grade 3 allergic reactions that were easily handled with anti-histamines and corticosteroids. Pts in the IFN-α2b arm presented grade 2-3 hematologic toxicity; 9 pts developed adverse events that forced treatment discontinuation provisionally or permanently. With a mean follow-up of 28 months and a maximum follow-up of 67 months, a significant benefit in the distant metastasis-free survival (DMFS) for CSF-470 was observed: 14/20 pts (70%) immunized with CSF-470 vaccine and only 4/11 pts (36.4%) in the IFN-α2b arm remain without distant metastases (p = 0.032). No significant differences in OS were yet observed. QOL was significantly superior for CSF-470 vaccine as compared to IFN-α2b treatment (p th and 12 th vaccine as compared to progressing pts. These results demonstrate a clear superiority of CSF-470 vaccine plus BCG plus GM-CSF vs IFN-α2b in the adjuvant setting in pts with high-risk CM. Citation Format: Jose Mordoh, Maria Betina Pampena, Mariana Aris, Paula Blanco, Alicia I. Bravo, Juan Manuel O9Connor, Julio Kaplan, Franco Ramello, Estrella M. Levy, Maria M. Barrio. A randomized phase II study of the CSF-470 therapeutic vaccine plus BCG plus rhGM-CSF versus IFN-α2b in cutaneous melanoma patients stages IIB, IIC and III. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr CT118. doi:10.1158/1538-7445.AM2015-CT118

Case report: an atypical peripapillary uveal melanoma

BackgroundThe treatment of uveal melanoma has seen a shift towards eye conserving treatments. Efforts have been made towards the identification of patients at high risk of metastatic disease with the use of prognostic fine needle biopsy, Monosomy 3 a risk factor for metastatic death thought to occur early in the development of uveal melanoma.Case presentationWe report a case in which an atypical optic nerve lesion was found to be a peripapillary primary uveal melanoma with distinct non-pigmented and pigmented halves on gross dissection and corresponding disomy 3 and monosomy 3 halves. The tumour demonstrated rapid growth with apparent transformation from disomy 3 to monosomy 3.ConclusionsThese are clinical features that challenge the current concepts of the cytogenetic pathogenesis of uveal melanoma and demonstrate the potential problems and limitations of prognostic fine needle biopsy and molecular classifications.

Sebaceous Cell Carcinoma: A Persistent Challenge in Clinical andHistopathological Diagnosis

Sebaceous cell carcinoma continues to defy clinicians and pathologists in terms of early diagnosis. The tumor may be mistaken as benign lesions such as chalazion and blepharitis, and also as malignant neoplasms, mainly basal cell carcinoma and squamous cell carcinoma. Despite advances in immunohistochemical analysis and treatment options during the last decades, morbidity and metastasis rates remain high. Prognosis is strongly related to the length of time between diagnosis and initiation of treatment, which reinforces the importance of early recognition of this condition. This article reviews key features of sebaceous cell carcinoma, from epidemiology to treatment, and new strategies to improve outcome.