Small Melanoma Research Articles

Ruthenium brachytherapy for uveal melanomas: Factors affecting the development of radiation complications

PurposeTo investigate how treatment complications are related to dosimetric parameters after ruthenium-106 brachytherapy for uveal melanoma, in a large, clinically homogeneous population. Methods and MaterialsA retrospective review was performed to evaluate patients affected by small and medium size uveal melanoma, treated with ruthenium-106 brachytherapy from December 2006 to December 2014. We excluded tumors with posterior margin within 1 mm from the edge of the optic disc and foveola. Main outcome measures were occurrence and time to radiation-related maculopathy, cataract, and optic neuropathy. Secondary end points included local recurrence and distant metastases. Kaplan–Meier analysis with log-rank test and univariate Cox proportional hazards model at 3 years were performed to identify the covariates affecting the outcome of radiation complications. ResultsTwo hundred thirty-nine patients, with sufficient data to evaluate the end points, were enrolled. Three years after plaque treatment, radiation maculopathy was found in 61 (25.5%) patients, cataract developed in 10 patients (4.2%) receiving a dose of 27 Gy or higher to the lens, and optic neuropathy was observed in 13 patients (5.4%) with an optic nerve dose exceeding 50 Gy and tumor proximity to optic disc of less than 4 mm. Tumor recurrences and tumor-related metastasis were found respectively in 20 (8.36%) and 14 (5.85%) patients. ConclusionsRadiation maculopathy occurs within a median time of 31 months in 25% of cases after plaque treatment for uveal melanoma. The most significant risk factors are total dose and distance of tumor margin from the fovea. If the distance is greater than 11.22 mm, no signs of retinal damage are detected.

Differential diagnosis of anemia in 88 years old: Unexpected findings and geriatric dilemmas

We report a case of functionally independent and cognitively intact 88-year-old male, suffering from anemia with suspicion for UGI bleeding. Diagnostic evaluation revealed a small bowel tumor as the source of bleeding. Our presentation will include a discussion about small bowel tumors as a relatively rare entity. The patient was operated on and the tumor was diagnosed as a distant metastasis of melanoma. Further evaluation revealed a relatively small primary melanoma tumor on the posterior part of right heel. The patient was not aware of the tumor until the diagnostic investigation. Radical Surgery was proposed as the choice of treatment with high probability of wheelchair-bound state as the functional outcome. Further discussion is related to the dilemma of choosing between aggressive treatments versus preserving quality of life in elderly persons. Modern options of melanoma treatment and their suitability to the elderly patient are presented together with a review of the literature.

Uveal melanoma: millimeters, personalized prognosis, and new therapies

SummaryThe management of uveal melanoma is going through tremendous transition into the realm of early detection, personalized prognostication and potentially new systemic and local therapies. In this Keynote Lecture, we will discuss four topics relevant to current melanoma management including (1) the importance of detection of small melanoma where thickness is approximately 3 mm or less, (2) optical coherence tomography angiography (OCTA) of melanoma before and after plaque radiotherapy, (3) DNA analysis of >1000 cases of uveal melanoma and the ability to personally prognosticate each patient based on cytogenetic profile, and (4) new systemic and local therapies.

Merkel Cell Carcinoma of Cheek: 2 Case Reports

Merkel cell carcinoma (MCC) is a rare aggressive skin cancer with the mortality rate of 33%. MCC was first described by Toker in 1972 as a trabecular cell carcinoma and is classified as a neuroendocrine tumor similar to small cell lung carcinoma and melanoma. The pathogenesis of MCC remains largely unknown. However, ultraviolet radiation and immunosuppression are likely to play a significant pathogenic role. The primary skin lesion is usually asymptomatic and it typically presents as a red or purple dome-shaped nodule. The management of MCC is controversial, however, local wide excision followed by radiotherapy is accepted as the primary treatment modality. The regional draining nodal basin is the most common site for recurrence. Therefore, sentinel lymph node biopsy is recommended in all cases, except for the clinically node-negative cases. We herein report two cases of MCC on the left cheek with different clinical manifestations. Key words: Cheek ㆍ Merkel cell carcinoma ㆍ Neoplasms

Non-coding small RNA and melanoma

Non-coding small RNA mainly includes microRNA, small interfering RNA and RNA interacting with PIWI protein. Studies have shown that non-coding small RNA plays an increasingly important role in the epigenetic regulation. Non-coding small RNA is involved in the regulation of gene expression by gene transcription, post-transcription and mRNA translation. Non-coding small RNA is closely related to many human diseases, especially the diagnosis, treatment and prognosis of melanoma. Key words: Melanoma; Non-coding small RNA

Abstract 1245: Screening methodologies for the discovery of small molecule melanoma therapeutics targeted at the ErbB4 receptor tyrosine kinase

Abstract Introduction: Gain-of-function mutations in the ErbB4 receptor tyrosine kinase have been found in a significant fraction of melanoma cell lines that are dependent on ErbB4 for proliferation. However, there is a scarcity of therapeutics for treating these ErbB4-dependent tumors. Consequently, we have developed high-throughput screening assays to identify small molecule ErbB4 antagonists that may hold promise as targeted melanoma therapeutics. Our approach is based on the observation that the Q43L mutant of the ErbB4 agonist Neuregulin 2beta (NRG2b) functions as a partial agonist at ErbB4. NRG2b/Q43L stimulates ErbB4 tyrosine phosphorylation, fails to stimulate ErbB4-dependent cell proliferation, and competitively antagonizes agonist stimulation of ErbB4-dependent cell proliferation. Experimental procedures: Therefore, we have developed three high-throughput screening assays to identify ErbB4 partial agonists that function as antagonists. The primary screen identifies molecules that stimulate ErbB4 tyrosine phosphorylation. The secondary screen identifies molecules that stimulate or fail to stimulate ErbB4-dependent cell proliferation. The tertiary screen identifies molecules that antagonize agonist stimulation of ErbB4-dependent cell proliferation. Results: A phospho-ErbB4 sandwich ELISA assay identifies molecules that stimulate ErbB4 tyrosine phosphorylation with high sensitivity and fidelity (Z’ >0.5). IL3-independence assays in conjunction with MTT assays using a cell line that displays ErbB4-dependent cell proliferation distinguish between molecules that stimulate and fail to stimulate ErbB4-dependent proliferation (Z’>0.5) and identify molecules that antagonize agonist stimulation of ErbB4 dependent proliferation. These assays have been used to identify small molecules that stimulate ErbB4 tyrosine phosphorylation. Efforts to determine whether these hits function as ErbB4 full agonists or partial agonists (antagonists) are underway and will be reported. Structures of these small molecule ErbB4 full and partial agonists may be reported, pending submission of a provisional patent application. Conclusions: We have validated an HTS strategy for identifying ErbB4 partial agonists that function as ErbB4 antagonists and deployment of that strategy has led to the identification of several hits (~20 from the primary screen). Such molecules may hold promise as targeted therapeutics for melanoma and other ErbB4-dependent tumors. Citation Format: Richard L. Cullum, John T. Piazza, Jared I. Senfeld, Logan T. Neel, Ram B. Gupta, Allan E. David, David J. Riese. Screening methodologies for the discovery of small molecule melanoma therapeutics targeted at the ErbB4 receptor tyrosine kinase [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1245. doi:10.1158/1538-7445.AM2017-1245

Abstract 3388: Copy number alteration in primary melanoma

Abstract The systematic analysis of the genomic characteristics of melanoma primaries has been infeasible given the limited size of these formalin-fixed paraffin embedded (FFPE) lesions. Further studying a clearly ascertained, deeply phenotyped patient population allows meaningful extrapolation of the prevalence of distinct genomic features and investigation of the association of these features with lifestyle exposures and germline profiles. For these reasons, we focused on a recently recruited patient cohort, the Leeds Melanoma Cohort (LMC) consisting of 2184 recruits from a distinct geographical region of Northern England; the only selection applied to recruitment was to only include those whose melanoma was less than 0.75 mm Breslow thickness in the early years of recruitment. Tumor samples from 703 cases have been analyzed for genome-wide gene expression (Pozniak et al, this meeting). For this study, we wanted to explore the prevalence of copy number alterations (CNA) and the mutation profile of tumors (reflecting the association of C>T mutations with UV exposure, the primary environmental risk factor) and so we have adopted a next-generation sequencing (NGS) approach. Tumor blocks were recovered from local pathology laboratories for those cases already deceased at the time that this CNA analysis was initiated plus those surviving more than 5 years post diagnosis at this same time. Blocks at risk of being compromised for clinical purposes by sampling for this research study were excluded from sampling; this amounted to almost 50% of identified samples. A total of 333 NGS libraries were sequenced on an Illumina GAII or HiSeq sequencer to produce >100bp paired-end reads (either 5 or 1 per lane). DNA reads were aligned and mapped achieving approximately 1.8x coverage (9.4x for those at 1 per lane); the number of reads falling within each 10kb window was adjusted for GC content and mappability and compared to a composite normal FFPE sample to determine local copy number. We adopted various approaches to assess the informativeness of the methodology. (i) Replicate samples showed high reproducibility (all p < 0.0001). (ii) Focused analysis of the CDKN2A region with segmentation analyses to determine CNA breakpoints yielded high quality, biologically plausible data revealing multiple copy number events. 67% of samples showed no CNA across the 4 Mb region covering CDKN2A while, as expected, only a small proportion of CNAs did not involve CDKN2A. Four common distinct patterns were observed. Copy number loss ranged from 20kb to > 4 Mb. (iii) A germline CNA could reliably be identified from the tumor data. (iv) CDKN2A expression levels correlated with estimated copy number. We have shown that small FFPE melanomas can be characterized for genomic alterations using NGS opening up the potential for studies associating epidemiological and germline profile with the resulting tumor. 1. Newton-Bishop, J.A., et al. (2009) J Clin Oncol, 27, 5439-5444. Funded by Worldwide Cancer Research and Cancer Research UK. Citation Format: D. Timothy Bishop, Anastasia Filia, Alastair Droop, Joey Diaz, Mark Harland, Jon Laye, Juliette Randerson-Moor, Julia A. Newton-Bishop. Copy number alteration in primary melanoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3388. doi:10.1158/1538-7445.AM2017-3388

Abstract 5577: A novel CD73-blocking antibody reduces production of immunosuppressive adenosine and restores T cell function

Abstract Adenosine is present at high concentrations in the tumor microenvironment and is immunosuppressive acting on multiple cell types, including suppression of effector T cells. CD73, an ectonucleotidase that converts AMP to adenosine, is expressed on a subset of B and T cells and is a major source of extracellular adenosine. Elevated CD73 expression has been observed in multiple tumor types and is prognostic in triple negative breast cancer supporting a role for CD73 in tumor progression1. Inhibiting catalytic activity of CD73 is an attractive therapeutic strategy to reduce adenosine-mediated suppression of tumor immunity. We developed two types of humanized monoclonal anti-CD73 antibodies. CPX-006 inhibits CD73 catalytic activity by competing directly with AMP for the active site with an affinity of 0.64 nM. CPX-016 is similar to anti-CD73 antibodies described by others2, and inhibits CD73 activity allosterically by binding to a distal site. This was demonstrated using CD73 expressing cells incubated with APCP, a non-hydrolyzable analog of AMP. APCP competes with CPX-006 for binding to CD73 in contrast to CPX-016. The CPX-016 mechanism requires higher order complexes and results in loss of inhibition at high CPX-016/CD73 ratios. In contrast, CPX-006 reduces catalytic activity completely in cell based assays to levels seen when CD73 gene is deleted using CRISPR technology and inhibition was unaffected at high CPX-006/CD73 ratios. In a functional assay, CPX-006 inhibited immune suppression of T cell function induced by exposure of human PBMCs to AMP through direct inhibition of catalytic activity with a mean EC50 of 137 nM (interferon gamma production) and 189 nM (T cell proliferation) (n=12 donors). We analyzed the prevalence of CD73 expression across tumor histologies by immunohistochemistry including renal cell carcinoma (RCC, n=62), non small cell lung cancer (NSCLC, n=68), melanoma (n= 68) and breast cancer (n=94). CD73 was found to be heterogeneously expressed on tumor cells, immune cells and other stromal elements within each of the histologies examined. Expression on tumor cell only was found in 15% of melanoma and 14% of squamous NSCLC cases. In contrast, tumor cell staining was found in a significant fraction of the adenocarcinoma sub-type of NSCLC (55%). Stromal cell staining to varying degrees was seen in all tumor tissues. In summary, we have a generated a therapeutic antibody, CPX-006, that utilizes a novel mechanism of binding to the CD73 active site to completely inhibit CD73 enzymatic activity and restore T cell function. The finding of CD73 expression on tumor cells and stromal cells in a variety of tumors suggest this as a potential new target for immunotherapy of these malignancies. 1. Loi et al., Proc Natl Acad Sci USA 2013; 110: 11091-11096. 2. Geoghegan et al., mAbs 2016; 8: 454-467. Citation Format: Emily C. Piccione, Glen Mikesell, Barbara Daine-Matsuoka, Kimberly Walter, Richard Miller, Ian McCaffery. A novel CD73-blocking antibody reduces production of immunosuppressive adenosine and restores T cell function [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5577. doi:10.1158/1538-7445.AM2017-5577

Abstract 3840: The National Cancer Institute’s patient-derived models repository (PDMR)

Abstract The National Cancer Institute (NCI) is developing a Patient-Derived Models Repository (PDMR) comprised of quality-controlled early-passage clinically-annotated patient-derived xenografts (PDXs) and in vitro patient-derived cell cultures (PDCs), including tumor cell and cancer-associated fibroblast cell cultures, to serve as a resource for public-private partnerships and for academic drug discovery efforts. These PDMs will be clinically-annotated with molecular information (whole exome sequence, RNASeq) available in a publicly accessible database and will be available to the extramural community for research use. The PDMR was established by NCI at the Frederick National Laboratory for Cancer Research (FNLCR) in direct response to discussions with academia and industry; the oncology community’s highest priority need is better preclinical models that more faithfully reflect the patient’s tumor and are associated with the patient’s treatment history. NCI has focused on collecting specimens from patients with cancer that are under-represented in many other PDX collections such as head and neck, pancreatic, bladder, ovarian and small cell lung cancers, melanomas and sarcomas. In addition, NCI is increasing its focus on creating PDXs from minority/underserved populations and will soon be expanding to include pediatric cancers. The PDMR generates the majority of its PDXs by subcutaneous implantation; however certain histologies have better take-rates in either orthotopic or alternate implant sites. All SOPs and quality-control standards developed by the PDMR as well as those shared by collaborators will be posted to the public web site that houses the PDMR database. The overall goal of NCI is to create a long-term home for at least 1000 models such that sufficient biological and clinical diversity is represented to allow researchers to ask questions such as: what is the impact of tumor heterogeneity on target qualification or clinical response; do PDXs more faithfully represent the human tumor for pharmacodynamic assay and predictive marker development; or can an adequately powered preclinical PDX clinical trial lead to better evaluation of therapies for future clinical use? Grant Support: This project has been funded in part with federal funds from the National Cancer Institute, National Institutes of Health, under Contract No. HHSN261200800001E. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government. Citation Format: Yvonne A. Evrard, Michelle Ahalt-Gottholm, Sergio Alcoser, Carrie Bonomi, Suzanne Borgel, John Carter, Biswajit Das, Vivekananda Datta, Cheryl Davis, Kelly Dougherty, Michelle Eugeni, Marion Gibson, Catherine Karangwa, Jason Lih, Dianne Newton, Han Si, Shivaani Kummar, Larry Rubinstein, Alice Chen, P. Mickey Williams, Melinda G. Hollingshead, James H. Doroshow. The National Cancer Institute’s patient-derived models repository (PDMR) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3840. doi:10.1158/1538-7445.AM2017-3840

Current Diagnosis of Choroidal Nevi

Despite the diversity of techniques for documentation and diagnostics of choroidal nevi, the differential diagnosis, especially regarding small uveal melanomas, remains difficult. In many cases, frequent controls to exclude growth or for the detection of an unchanged appearance are recommended. This article reviews-under consideration of the actual literature-different diagnostic techniques for documentation and differentiation of choroidal nevi.

A Case of Primary Small Bowel Melanoma Diagnosed by Single-Balloon Enteroscopy.

Although metastasis from cutaneous malignant melanoma to the small intestine is not uncommon, primary small bowel melanoma (SBM) is extremely rare. This case report describes a rare case of primary SBM, diagnosed by single-balloon enteroscopy. A 74-year-old man presented with recurrent melena. Upper endoscopy and colonoscopy were unremarkable. Abdominal computed tomography (CT) revealed an ileal mass with ileo-ileal intussusception. Subsequent single-balloon enteroscopy identified an ileal tumor, which was histologically diagnosed as melanoma. Extensive clinical examination did not reveal any primary cutaneous lesions. To the best of our knowledge, this is the first case of primary SBM in South Korea.

Prevalence of homologous recombination deficiency among all tumor types.

1502 Background: Triple negative breast and ovarian cancer are known to have a high frequency of homologous recombination deficiencies (HRDef). The prevalence of HRDef among all tumors is unknown. Methods: Molecular profiles of 48,733 tumors obtained from pts with bladder, breast, ovarian, pancreas, prostate, thyroid, cervical, hepatobiliary, colorectal (CRC), endometrial, gastric/esophageal (GE), head/neck, renal, non-small cell lung (NSCLC), small cell lung (SCLC), GIST, glioma, melanoma, sarcoma and unknown 1° cancers were reviewed to identify somatic pathogenic mutations (mut) in HR genes ATM, ATRX, BARD1, BLM, BRCA1/2, BRIP1, FANCA/C/D2/E/F/G/L, MRE11A, NBN, PALB2, PTEN, RAD50, RAD51, RAD51B, or WRN. Molecular profiles were generated from tumors submitted to Caris Life Sciences using multiple technologies including next generation sequencing (average read depth 500X). Results: Overall frequency of HR mut among all tumors is 11.61% (5658/48733). Cancer lineages with highest frequency of HR mut are endometrial (38.08%, 1956/5137), glioma (15.90%, 265/1667), ovarian (12.99%, 1151/8862), prostate (11.21%, 77/687), cervix (10.06%, 79/785) & breast (9.66%, 562/5818). Least commonly mutated lineages include GIST (1.50%, 3/200), sarcoma (3.12%, 55/1763), head/neck (3.70%, 24/648), hepatobiliary (4.72%, 39/827) & pancreas (5.05%, 102/2022). Frequencies of HR gene mutations are depicted in Table 1. Conclusions: HR mutations were seen in 11.61% of tumors. While the percentage of HRDef in pancreatic cancer pts is lower than what has been seen in other datasets, the percentage in breast and ovarian cancer, as well as the percentage of other tumors with HRDef, provide a path to employ HRDef-directed therapies such as platinums, but especially PARP inhibitors and newer agents such as ATRX inhibitors. [Table: see text]

Choroidal nevus

To review the prevalence, clinical features, imaging findings, cytogenetics, and risks and outcomes of choroidal nevus. Choroidal nevus is a benign melanocytic tumor, often discovered incidentally on ophthalmic examination. This lesion is generally well circumscribed and pigmented. The prevalence of choroidal nevus in postequatorial region in United States adults (≥40 years old) is approximately 5%. Choroidal nevus is associated with higher lifetime unopposed estrogen and greater BMI. In population-based evaluation, the mean nevus basal dimension is approximately 1.25 mm. Giant nevus (basal dimension ≥10 mm) carries greater risk for malignant transformation. Imaging modalities for evaluation of choroidal nevus include ultrasonography, fundus autofluorescence, and optical coherence tomography (OCT). Fluorescein angiography is occasionally employed to detect multifocal pinpoint leaks or choroidal neovascular membrane. Recently, OCT angiography demonstrated nevus with minimal overlying macular microvascular changes compared with melanoma. Cytogenetically, GNA11 or GNAQ mutations have been documented in uveal melanoma in 83% and in some cutaneous nevus subtypes. Further mutations lead to the development of melanoma at a rate of one of 8845 cases. Risk factors for transformation of nevus into melanoma are recalled by the mnemonic 'To find small ocular melanoma using helpful hints daily' representing thickness (T) more than 2 mm, subretinal fluid (F), symptoms (S) of flashes/floaters/blurred vision, orange (O) lipofuscin pigment, margin (M) less than 3 mm from optic disk, ultrasonographic hollowness (UH), halo (H) absence, and drusen (D) absence. The presence of three or more risk factors implies more than 50% chance for transformation to melanoma within 5 years. A new, online ocular oncology reading center can help judge nevus risk. Choroidal nevus is a common intraocular lesion, found predominantly in Whites. This mass carries a small risk (<1%) for malignant transformation. Patients with at least three risk factors should be evaluated for possible melanoma at an experienced ocular oncology center.

Сравнительная оценка уровня экспресси молекулярных маркеров активации лимфоцитов периферической крови у больных меланомой хориоидеи малых размеров и у здорових лиц

Сравнительная оценка уровня экспресси молекулярных маркеров активации лимфоцитов периферической крови у больных меланомой хориоидеи малых размеров и у здорових лиц

Cytogenetic Abnormalities in Uveal Melanoma Based on Tumor Features and Size in 1059 Patients: The 2016 W. Richard Green Lecture

To determine the risks for altered cytogenetic profile based on melanoma features and size. Retrospective case series. A total of 1059 patients with uveal melanoma. Fine-needle aspiration biopsy (FNAB) of tumor for DNA amplification and whole genome array-based assay. Risk for cytogenetic abnormalities based on features and size: small (≤3 mm thickness), medium (>3-<8 mm), and large (≥8 mm). Of 1059 patients with uveal melanoma sampled for status of chromosomes 3, 6, and 8, comparison (normal [disomy] chromosomes 3, 6, and 8 vs. any 3, 6, or 8 abnormality) revealed differences in mean age (55 vs. 58 years, P= 0.018), ocular melanocytosis (1% vs. 5%, P= 0.027), mean visual acuity (VA) (20/30 vs. 20/50, P=0.011), poor VA (≤20/200) (9% vs. 15%, P= 0.041), ciliary body location (5% vs. 11%, P < 0.001), extramacular location (73% vs. 87%, P < 0.001), increased mean distance to optic disc (3.3 vs. 5.0 mm, P < 0.001) and foveola (3.1 vs. 4.7 mm, P < 0.001), and increased mean basal diameter (9.8 vs. 12.6 mm, P < 0.001) and thickness (3.8 vs. 5.9 mm, P < 0.001). Tumors classified as small, medium, and large showed abnormalities with loss of disomy of chromosomes 3 (35%/52%/65%), 6 (15%/34%/51%), and 8 (19%/41%/69%), respectively. By comparison (medium/large vs. small melanoma), the odds ratio (OR) included complete monosomy 3 (3.09, P < 0.001), partial monosomy 3 (1.44, P= 0.053), 6p gain (3.78, P < 0.001), 6q gain (1.37, P= 0.537), 6p loss (2.52, P= 0.410), 6q loss (12.61, P < 0.001), 8p gain (6.16, P < 0.001), 8p loss (6.04, P < 0.001), and 8q gain (4.87, P < 0.001). For chromosome 3 monosomy, the OR was highest for ciliary body location (8.17, P < 0.001), tumor thickness ≥8 mm (2.70, P < 0.001), tumor base ≥10 mm (2.59, P < 0.001), and age ≥60 years (1.83, P < 0.001). For chromosome 8p loss, the OR was highest for ciliary body location (53.91, P= 0.008), ocular melanocytosis (3.95, P= 0.038), and thickness ≥8 mm (5.14, P < 0.001), whereas for 8q gain, the OR was highest for ciliary body location (102.87, P= 0.001), thickness >8 mm (4.44, P < 0.001), and ocular melanocytosis (2.75, P= 0.049). Increasing melanoma size demonstrates greater cytogenetic alterations. Alterations in chromosome 8 show unique correlation with melanocytosis. This suggests that prompt management of small melanoma might reduce chromosomal instability and could improve overall patient survival.

Systemic therapy of brain metastases: non-small cell lung cancer, breast cancer, and melanoma.

Brain metastases (BM) occur frequently in many cancers, particularly non-small cell lung cancer (NSCLC), breast cancer, and melanoma. The development of BM is associated with poor prognosis and has an adverse impact on survival and quality of life. Commonly used therapies for BM such as surgery or radiotherapy are associated with only modest benefits. However, recent advances in systemic therapy of many cancers have generated considerable interest in exploration of those therapies for treatment of intracranial metastases.This review discusses the epidemiology of BM from the aforementioned primary tumors and the challenges of using systemic therapies for metastatic disease located within the central nervous system. Cumulative data from several retrospective and small prospective studies suggest that molecularly targeted systemic therapies may be an effective option for the treatment of BM from NSCLC, breast cancer, and melanoma, either as monotherapy or in conjunction with other therapies. Larger prospective studies are warranted to further characterize the efficacy and safety profiles of these targeted agents for the treatment of BM.

Uveal melanoma: relatively rare but deadly cancer.

Although it is a relatively rare disease, primarily found in the Caucasian population, uveal melanoma is the most common primary intraocular tumor in adults with a mean age-adjusted incidence of 5.1 cases per million per year. Tumors are located either in iris (4%), ciliary body (6%), or choroid (90%). The host susceptibility factors for uveal melanoma include fair skin, light eye color, inability to tan, ocular or oculodermal melanocytosis, cutaneous or iris or choroidal nevus, and BRCA1-associated protein 1 mutation. Currently, the most widely used first-line treatment options for this malignancy are resection, radiation therapy, and enucleation. There are two main types of radiation therapy: plaque brachytherapy (iodine-125, ruthenium-106, or palladium-103, or cobalt-60) and teletherapy (proton beam, helium ion, or stereotactic radiosurgery using cyber knife, gamma knife, or linear accelerator). The alternative to radiation is enucleation. Although these therapies achieve satisfactory local disease control, long-term survival rate for patients with uveal melanoma remains guarded, with risk for liver metastasis. There have been advances in early diagnosis over the past few years, and with the hope survival rates could improve as smaller tumors are treated. As in many other cancer indications, both early detection and early treatment could be critical for a positive long-term survival outcome in uveal melanoma. These observations call attention to an unmet medical need for the early treatment of small melanocytic lesions or small melanomas in the eye to achieve local disease control and vision preservation with the possibility to prevent metastases and improve overall patient survival.

Primary melanoma of the small bowel revealed by gastrointestinal bleeding: a case report

BackgroundPrimary melanoma of the small bowel is extremely rare. Only a limited number of cases have been described in the literature. Mostly, the small intestine is affected by metastatic tumors of other primary lesions, especially cutaneous.Case presentationWe report the case of a 75-year-old North African woman with a small bowel melanoma. The diagnosis was made by histological examination and immunohistochemical profile matching after a segmental small bowel resection. Postoperative investigations looking for cutaneous, gastrointestinal or ocular primary lesions found no abnormalities.ConclusionsThe diagnosis of primary small bowel melanoma can be retained although it remains difficult to exclude the possibility of metastatic melanoma.

APOBEC3A intratumoral DNA electroporation in mice.

Human APOBEC3A (A3A) cytidine deaminase shows pro-apoptotic properties resulting from hypermutation of genomic DNA, induction of double-stranded DNA breaks (DSBs) and G1 cell cycle arrest. Given this, we evaluated the antitumor efficacy of A3A by intratumoral electroporation of an A3A expression plasmid. DNA was repeatedly electroporated into B16OVA, B16Luc tumors of C57BL/6J mice as well as the aggressive fibrosarcoma Sarc2 tumor of HLA-A*0201/DRB1*0101 transgenic mice using noninvasive plate electrodes. Intratumoral electroporation of A3A plasmid DNA resulted in regression of ~50% of small B16OVA melanoma tumors that did not rebound in the following 2 months without treatment. Larger or more aggressive tumors escaped regression when so treated. As APOBEC3A was much less efficient in provoking hypermutation and DSBs in B16OVA cells compared with human or quail cells, it is likely that APOBEC3A would be more efficient in a human setting than in a mouse model.

Evaluation of ETV4 and WT1 expression in CIC-rearranged sarcomas and histologic mimics

AbstractA distinct subset of round cell sarcomas harbors capicua transcriptional repressor (CIC) rearrangement. Diagnosing these sarcomas can be difficult owing to their resemblance to Ewing sarcoma and other 'small round blue cell tumors'; molecular techniques are generally required. Recent gene expression studies of CIC-rearranged sarcomas identified the upregulation of ETV4. We assessed the sensitivity and specificity of ETV4 and WT1 immunohistochemistry for CIC-rearranged sarcoma. We evaluated whole-tissue sections from 40 CIC-rearranged sarcomas, 40 Ewing sarcomas, 4 BCOR-CCNB3 sarcomas, 6 unclassified round cell sarcomas, and 150 histologic mimics. Moderate-to-strong nuclear immunoreactivity for ETV4 in at least 50% of cells was observed in 36 (90%) CIC-rearranged sarcomas and 10 (5%) other tumors, including 5 unclassified round cell sarcomas, 2 Wilms tumors, and 1 each desmoplastic small round cell tumor, melanoma, and small cell carcinoma. Thirty-eight (95%) CIC-rearranged sarcomas showed nuclear staining for WT1, and 34 (85%) were positive for both ETV4 and WT1. Of 182 other tumors evaluated, 34 (19%) showed nuclear WT1 positivity, including all Wilms tumors and desmoplastic small round cell tumors, 5 unclassified round cell sarcomas, and a subset of lymphoblastic lymphomas, rhabdomyosarcomas, mesenchymal chondrosarcomas, carcinomas, and melanomas. In summary, diffuse moderate-to-strong ETV4 expression is present in most CIC-rearranged sarcomas and unclassified round cell sarcomas. More limited expression is seen in small subsets of various other round cell neoplasms. Nuclear WT1 expression is also present in most CIC-rearranged sarcomas and unclassified round cell sarcomas, along with Wilms tumors and desmoplastic small round cell tumors, and subsets of various histologic mimics. The sensitivity and specificity of diffuse ETV4 expression for CIC-rearranged sarcomas are 90% and 95%, respectively, whereas the sensitivity and specificity of WT1 are 95% and 81%, respectively. Diffuse ETV4 along with at least focal WT1 expression is helpful to distinguish CIC-rearranged sarcoma from Ewing sarcoma and other histologic mimics.