30 years of ocular proton therapy,the Nice view

PurposeRadiotherapy with protons (PT) is a standard treatment of ocular tumors. It achieves excellent tumor control, limited toxicities, and the preservation of important functional outcomes, such as vision. Although PT may appear as one homogenous technique, it can be performed using dedicated ocular passive scattering PT or, increasingly, Pencil Beam Scanning (PBS), both with various degrees of patient-oriented customization.Materaial and methodsMEDICYC PT facility of Nice are detailed with respect to their technical, dosimetric, microdosimetric and radiobiological, patient and tumor-customization process of PT planning and delivery that are key. 6684 patients have been treated for ocular tumors (1991–2020). Machine characteristics (accelerator, beam line, beam monitoring) allow efficient proton extraction, high dose rate, sharp lateral and distal penumbrae, and limited stray radiation in comparison to beam energy reduction and subsequent straggling with high-energy PBS PT. Patient preparation before PT includes customized setup and image-guidance, CT-based planning, and ocular PT software modelling of the patient eye with integration of beam modifiers. Clinical reports have shown excellent tumor control rates (～95%), vision preservation and limited toxicity rates (papillopathy, retinopathy, neovascular glaucoma, dry eye, madarosis, cataract).ResultsAlthough demanding, dedicated ocular PT has proven its efficiency in achieving excellent tumor control, OAR sparing and patient radioprotection. It is therefore worth adaptations of the equipments and practice.ConclusionsSome of these adaptations can be transferred to other PT centers and should be acknowledeged when using non-PT options.     

uPAR Controls Vasculogenic Mimicry Ability Expressed by Drug-Resistant Melanoma Cells

Malignant melanoma is a highly aggressive skin cancer characterized by an elevated grade of tumor cell plasticity. Such plasticity allows adaptation of melanoma cells to different hostile conditions and guarantees tumor survival and disease progression, including aggressive features such as drug resistance. Indeed, almost 50% of melanoma rapidly develop resistance to the BRAFV600E inhibitor vemurafenib, with fast tumor dissemination, a devastating consequence for patients’ outcomes. Vasculogenic mimicry (VM), the ability of cancer cells to organize themselves in perfused vascular-like channels, might sustain tumor spread by providing vemurafenibresistant cancer cells with supplementary ways to enter into circulation and disseminate. Thus, this research aims to determine if vemurafenib resistance goes with the acquisition of VM ability by aggressive melanoma cells, and identify a driving molecule for both vemurafenib resistance and VM. We used two independent experimental models of drug-resistant melanoma cells, the first one represented by a chronic adaptation of melanoma cells to extracellular acidosis, known to drive a particularly aggressive and vemurafenib-resistant phenotype, the second one generated with chronic vemurafenib exposure. By performing in vitro tube formation assay and evaluating the expression levels of the VM markers EphA2 and VE-cadherin by Western blotting and flow cytometer analyses, we demonstrated that vemurafenib-resistant cells obtained by both models are characterized by an increased ability to perform VM. Moreover, by exploiting the CRISPR-Cas9 technique and using the urokinase plasminogen activator receptor (uPAR) inhibitor M25, we identified uPAR as a driver of VM expressed by vemurafenib-resistant melanoma cells. Thus, uPAR targeting may be successfully leveraged as a new complementary therapy to inhibit VM in drug-resistant melanoma patients, to counteract the rapid progression and dissemination of the disease.     

The role of exosomes in metastasis and progression of melanoma

The mechanisms of melanoma metastasis have been the subject of extensive research for decades. Improved diagnostic and therapeutic strategies are of increasing importance for the treatment of melanoma due to its high burden of mortality in the advanced stages of the disease. Intercellular communication is a critical event for the progression of cancer. Collective evidence suggests that exosomes, small extracellular membrane vesicles released by the cells, are important facilitators of intercellular communication between the cells and the surrounding environment. Although the emerging field of exosomes is rapidly gaining traction in the scientific community, there is limited knowledge regarding the role of exosomes in melanoma. This review discusses the multifaceted role of melanoma-derived exosomes in promoting the process of metastasis by modulating the invasive and angiogenic capacity of malignant cells. The future implications of exosome research and the therapeutic potential of exosomes are also discussed.     

先天性色素痣伴增生性结节10例临床病理分析

【摘要】 目的 探讨先天性色素痣伴增生性结节的临床特点及组织病理特征。方法 收集第四军医大学西京皮肤医院2015—2019年经临床和病理确诊的10例先天性色素痣伴增生性结节患者的临床及病理资料，并进行回顾性分析。结果 10例患者年龄2～45岁（平均15岁），9例增生性结节发生于婴儿，1例发生于成人。皮损位于四肢4例，头面部3例，躯干2例，躯干及四肢同时受累1例。临床表现为黑色斑片或斑块中出现1个或多个结节，6例增生性结节为多发，4例为单发，单个结节直径0.2～1.5 cm，仅1例出现溃疡。组织病理检查显示增生性结节内黑素细胞均存在成熟现象，核分裂象少，细胞无明显异型性，无坏死现象，免疫组化检查显示痣细胞弥漫表达Melan-A，不表达或仅部分表达HMB45，Ki67增殖指数 < 5%。结论 先天性色素痣伴增生性结节可发生于四肢、头面部及躯干；临床表现为原先天性色素痣皮损上的单发或多发结节；病理上增生性结节内黑素细胞可见成熟现象，免疫组化HMB45及Ki67染色有助于诊断，其预后有待长期随访。     

Evaluation of the videoscopic inguinal lymphadenectomy in melanoma patients

IntroductionA completion or therapeutic inguinal lymph node dissection is a procedure accompanied with a high rate of postoperative complications. A novel, minimally invasive alternative has been developed; the videoscopic inguinal lymphadenectomy. The aim of this study is to present our first experience with the videoscopic inguinal lymphadenectomy among melanoma patients with inguinal metastases.MethodsMelanoma patients with a histologically confirmed inguinal metastases who underwent a videoscopic inguinal lymphadenectomy between November 2015 and January 2018 were included. Outcome measures were operation time, nodal yield, and postoperative complications. Furthermore, lymphedema measurements were performed both subjectively and objectively.ResultsA total of 20 patients (3 males and 17 females) underwent a videoscopic inguinal lymphadenectomy. In 75% of patients the procedure was combined with an open iliac lymphadenectomy. Median operation time of the videoscopic procedure was 110 min (range, 79–165). There were no perioperative complications or conversions. In 12 patients (60%) there was ≥1 postoperative complication. The most frequent complications were seroma and wound infection. All complications were treated conservatively without the need for a surgical re-intervention. The median nodal yield of the videoscopic procedure was 9 (range, 1–19). Lymphedema was present in nine patients (45%) after three months of follow-up.ConclusionOur initial results show that the videoscopic inguinal lymphadenectomy is an attractive alternative to the conventional open technique. The number of complications is comparable with the complication rate reported for the conventional open procedure, but they are less severe and there is no need for a surgical re-intervention.