New prognostic factors and developing therapy of cutaneous melanoma

The multiple molecular alterations underlying the neoplastic process and clinical characteristics of cutaneous melanoma are currently under intensive investigation. Recent studies have demonstrated that the levels of melanoma-associated proteins in tumor tissue or in patient serum can serve as new markers to predict disease outcome. Similarly, the expression of thousands of genes in melanoma tumors can be surveyed simultaneously using DNA arrays, allowing molecular profiling of individual tumors, which gives the possibility of classifying melanomas based on their biological diversity. Large clinical studies have also identified multiple prognostic factors, such as tumor ulceration, and led to development of a new, more precise melanoma staging system, which emphasizes the biological characteristics of the primary disease. These new findings may have an important role in earlier measurement of the clinical response and provide a basis for tailored melanoma therapy, the development of which will also be discussed in this review.     

The clinical recognition and prognostic factors of primary cutaneous malignant melanoma

The incidence of melanoma continues to increase. In the absence of a defined and preventable etiology, early recognition and proper management offer the best hope for prolonged survival and cure. Clinically suspect lesions must be biopsied for diagnostic confirmation and histologic information. Reliable prognostic information can be gained from histologic and clinical parameters, which are described.     

Update of diagnostic and prognostic markers in cutaneous malignant melanoma

The biomolecules described in this article generally have been studied as possible diagnostic or clinically prognostic markers in the context of melanoma disease progression as measured by the gold standards of tumor thickness and development of metastasis. Most of the markers showed variations in expression phenotype only during the deeply invasive or metastatic stage of tumor progression and were thus predictive of clinical outcome only for these subgroups of patients. Some of the markers may have utility in identifying patients with deeply invasive primary tumors who are likely to develop metastasis and thus should receive earlier, more aggressive treatments. In addition, some of the markers may identify patients likely to respond better to a new type of therapy (e.g., anti-angiogenic therapy in a patient whose tumor is overexpressing VEGF or immunotherapy for a patient whose tumor is expressing high levels of MART-1). In the future, it will probably be possible to employ new techniques, such as laser-guided microdissection of tissues, to isolate individual melanocytes in order to identify the earliest stage-specific defects that contribute to an aggressive biological behavior. Identifying the subset of patients with superficially invasive melanomas who will develop metastatic disease will continue to provide a challenge.     

Immune-related biomarkers for diagnosis/prognosis and therapy monitoring of cutaneous melanoma

Skin melanoma, a life-threatening disease, has a recently reported worldwide increase in incidence, despite primary prevention. Skin melanoma statistics emphasize the need for finding markers related to the immune response of the host. The mechanisms that are able to over-power the local immune surveillance comprise molecules that can be valuable markers for diagnosis and prognosis. This article summarizes the immune markers that can monitor the disease stage and evaluate the efficacy of therapeutic interventions. Recent data regarding immunotherapy are presented in the context of tumor escape from immune surveillance and the immune molecules that are both targets and a means of monitoring. Perspectives for developing immune interventions for skin melanoma management and the position of tissue or soluble immune markers as a diagnostic/prognostic panel are evaluated. State-of-the-art technology is emphasized for developing immune molecular signatures for a complex characterization of the patient's immunological status.     

The genetics of cutaneous melanoma

Although germline mutations in CDKN2A are present in approximately 25% of large multicase melanoma families, germline mutations are much rarer in the smaller melanoma families that make up most individuals reporting a family history of this disease. In addition, only three families worldwide have been reported with germline mutations in a gene other than CDKN2A (i.e., CDK4). Accordingly, current genomewide scans underway at the National Human Genome Research Institute hope to reveal linkage to one or more chromosomal regions, and ultimately lead to the identification of novel genes involved in melanoma predisposition. Both CDKN2A and PTEN have been identified as genes involved in sporadic melanoma development; however, mutations are more common in cell lines than uncultured tumors. A combination of cytogenetic, molecular, and functional studies suggests that additional genes involved in melanoma development are located to chromosomal regions 1p, 6q, 7p, 11q, and possibly also 9p and 10q. With the near completion of the human genome sequencing effort, combined with the advent of high throughput mutation analyses and new techniques including cDNA and tissue microarrays, the identification and characterization of additional genes involved in melanoma pathogenesis seem likely in the near future.     

Therapy of primary cutaneous melanoma

The essential tenets of early recognition, biopsy, and appropriate surgical treatment of melanoma are reviewed. The controversies of elective regional lymph node dissection and isolated limb perfusion are discussed, as well as the newer modalities of immunotherapy.     

Orbital metastasis from cutaneous melanoma

Although orbital extension from ocular melanoma occurs frequently in advanced cases, orbital metastasis from cutaneous melanoma has been reported but eight times previously. We have reported two such cases. One of the patients had three previous primary melanomas; the other had metastasis to the cauda equina. Both patients died when orbital involvement developed years after the initial lesions. Ours are the first cases to include CT and MRI findings in metastatic orbital melanoma.     

Quality-of-life evaluation in an interferon therapy after radical surgery in cutaneous melanoma patients

Melanoma is the fastest growing solid tumor in men and women, and despite accounting for only 4% of skin cancer cases, it accounts for more than 79% of skin cancer-related deaths. The present study was designed to evaluate the impact of interferon (IFN) treatment on patients' quality of life (QOL) after radical surgery of cutaneous melanoma. The tests were carried out in a group of patients treated in the Department of Soft Tissue and Bone Cancer, Institute of Oncology, in Warsaw. The present study included 2 groups of the patients, 110 persons each. One group consisted of patients who had been subjected to radical surgery of cutaneous melanoma, and the other one consisted of 110 patients treated with a supplementary interferon alfa-2b (IFN-alpha-2b) therapy. Data were collected by means of an anonymous QLQ-C30 (version 2.0.) questionnaire elaborated and provided by the European Organisation for Research and Treatment of Cancer. The QLQ-C30 questionnaire consisted of 43 questions. The IFN-alpha-2b treatment significantly affected patients' physical condition, mental health, and social life. The emotional state of the patients was more affected during IFN-alpha-2b treatment. Somatic symptoms were also increased in those patients. The IFN-alpha-2b therapy also significantly affected family and social life. In spite of several adverse effects, the patients assessed their QOL as good. The IFN-alpha-2b treatment is troublesome for the melanoma patients. It is important that the treating physician and nurse should be aware of the 4 major categories of IFN-alpha-2b toxicity: constitutional, neuropsychiatric, hepatic, and hematologic. A number of steps can be taken to minimize the morbidity associated with IFN-alpha-2b therapy, resulting in an improvement in both QOL and patient compliance.     

Current clinical overview of cutaneous melanoma

This article reviews current evidence on epidemiology, diagnosis and management of cutaneous melanoma. Incidence of cutaneous melanoma is rising in all Caucasian populations across the world; thus, melanoma represents a significant public health burden. Although, incidence of melanoma is in continuous increase, a decrease of mortality and improved survival has been observed in most western European populations. Clinical characteristics of four major types of melanoma (superficial spreading, nodular, lentigo maligna melanoma and acral lentiginous melanoma) have been described. Surgical removal of melanoma remains the standard care in all primary melanomas. Current evidence suggests use of 1 to 2 cm excision margins. Wider margins may be necessary in patients with thicker melanomas with higher risk for local recurrence. In the treatment of regional lymph nodes elective lymphadenectomy has been surpassed by the sentinel lymph node biopsy (SLNB). However, although prognostic value of SLNB has been confirmed, its therapeutical benefit still needs to be evaluated. Currently there is no standard adjuvant therapy for melanoma although interferon-alpha has been the most widely used treatment in the adjuvant setting. The role of metastasectomy (removal of distant metastases) is still controversial. Chemotherapeutic agents have a limited activity in patients with metastatic melanoma with response rates up to 25%. Although different vaccines have been tested in melanoma patients their role still remain to be established in phase III trials. Progresses in molecular biology and genetics of melanoma may lead to the development of novel melanoma therapies.     

Early and late relapses of cutaneous melanoma patients

Objectives: Recurrence may most likely develop during the course of the disease in patients presented with early stage melanoma at initial diagnosis. The specific risk factors for early and late recurrences following definitive surgical excision have yet to be determined. The aim of this study was to analyze the early and late relapses in stage I-III cutaneous melanoma patients.

Methods: Of 365 patients with relapses, 189 developed within the first 18 months following surgical intervention (early relapse [ER]) and the remaining 176 occurred later (late relapse [LR]) were analyzed.

Results: ER patients were found to have thicker and ulcerated lesions with higher mitotic rates and lymphovascular invasion, and they were found to be more significantly associated with node involvements. Nearly half of the first recurrences were locoregional (49.9%) that were followed by distant metastases alone (26.6%). The distribution of the initial relapse patterns was similar between the ER and the LR groups. The lung was the most frequently metastasized site (43.1%), and it was followed by bone (21.0%), liver (20.7%) and brain (15.1%). On multivariate analysis risk factors in association with both ER and LR were found as follows: ulcerated lesions, high mitotic rate, and node-positive disease; however nodular histopathological subtype and lymphovascular invasion were found to have impact merely on ER, and male gender merely on LR.

Conclusion: The current study has detected potential risk factors for relapse of patients who developed ER and LR. These indicators may be useful for rational follow-up programs of the patients.     

Sentinel lymph nodes in cutaneous melanoma

Examination of sentinel lymph nodes (SLN) has probably become the most popular method of early staging of patients who have cutaneous melanoma because SLN are considered to be the lymph nodes most likely to contain metastatic deposits; they can be examined in a more intense manner than in standard lymphadenectomy. There are several protocols to examine SLN but most of them use formalin-fixed, paraffin-embedded sections stained with hematoxylin and eosin with the addition of immunohistochemistry. By using these protocols, approximately 20% of patients who have cutaneous melanoma have melanoma cells in the SLN. Current studies are evaluating the possible therapeutic value of removal of positive SLN, but it is accepted by most authors that detection of positive SLN conveys an impaired prognosis for patients who have cutaneous melanoma.     

YWHAZ在皮肤黑色素瘤中的临床及生物学意义

目的探讨YWHAZ在皮肤黑色素瘤中的表达及其临床意义,初步检测YWHAZ在皮肤黑色素瘤中的生物学功能。 方法使用GEO数据库分析YWHAZ在皮肤黑色素瘤与良性痣间的表达差异,使用TCGA皮肤黑色素瘤数据集分析YWHAZ表达与皮肤黑色素瘤患者总生存之间的相关性。通过体外实验,敲减YWHAZ在皮肤黑色素瘤细胞中的表达,CCK8法检测细胞增殖,流式检测细胞凋亡,Transwell实验检测细胞迁移及侵袭能力改变。 结果黑色素瘤组织中YWHAZ的平均相对表达量5.785±0.128,明显高于良性痣中YWHAZ的平均相对表达量（4.704±0.281）,差异有统计学意义（t=4.023,P=0.0002）;YWHAZ高表达组中位生存期（47.28个月）较低表达组（89.13个月）明显缩短（P=0.0085）。体外实验结果显示YWHAZ敲减后黑色素瘤细胞增殖减慢、凋亡细胞比例增加、迁移及侵袭能力减弱。 结论YWHAZ在皮肤黑色素瘤中发挥癌基因的作用,降低YWHAZ表达水平可抑制黑色素瘤的恶性表型。     

亚低温治疗在脑复苏中的应用及影响预后因素分析

目的 探讨影响心肺复苏(CPR)术后亚低温治疗患者预后的因素及动态脑电波监测对预后的价值.方法 对42例循环稳定的CPR术后患者在全身治疗的基础上进行亚低温治疗,体温(颈静脉球温度)控制在31～34℃,维持3～6 d后复温.治疗期间行各项常规检查,同时监测脑电波并进行Hockday分级,对于存活3个月者通过格拉斯哥预后评分(GOS)评估神经系统功能.结果 良好转归组(包括恢复良好、中度残疾,19例)与不良转归组(包括严重残疾、植物状态、死亡,23例)间停跳后至开始CPR时间及复苏后格拉斯哥昏迷评分(GCS)、血中剩余碱、乳酸浓度均存在不同程度差异[停跳后至开始CPR时间(min):4.11±1.80比13.08±11.37,GCS(分):5.48±1.32比4.13±1.61,剩余碱(mmol/L):-10.27±6.23比-13.18±7.29,乳酸(mmol/L):6.82±3.12比8.47±4.14,P＜0.05或P＜0.01];37例患者行动态脑电波监测,Hockday分级Ⅱ级与Ⅲ级间的良好预后率比较差异有统计学意义[85.7%(12/14)比37.5%(3/8),P＜0.05].结论 停跳后至开始CPR时间及复苏后GCS、血中剩余碱、乳酸浓度有助于判定亚低温治疗后患者的预后;脑电波监测对判定亚低温治疗后患者神经功能转归有较大帮助.     

Patients with melanoma metastases at cutaneous and subcutaneous sites are highly susceptible to interleukin-2-based therapy

The authors evaluated the records of 371 patients with metastatic melanoma who received treatment with high-dose bolus interleukin-2. Patients with metastases only at cutaneous or subcutaneous sites had a higher objective response rate (50%) than did patients with metastases at these sites plus visceral sites (14%) or patients with metastases at visceral sites only (13%) (p<0.0001). Five patients with disease at cutaneous or subcutaneous sites plus visceral sites experienced regression only at the cutaneous or subcutaneous sites with progression at the visceral sites. Therefore, in the presence of visceral disease, the response rate at cutaneous or subcutaneous sites was only 17% compared with 50% when disease was at the latter sites only (p<0.001). These data suggest that melanoma lesions at cutaneous or subcutaneous sites are highly susceptible targets to interleukin-2-based therapies, but the presence of visceral disease is associated with a significant inhibition of response at cutaneous or subcutaneous sites.     

Time-resolved fluorescence lifetime for cutaneous melanoma detection

Melanoma is the most aggressive skin cancer type. It is characterized by pigmented lesions with high tissue invasion and metastatic potential. The early detection of melanoma is extremely important to improve patient prognosis and survival rate, since it can progress to the deadly metastatic stage. Presently, the melanoma diagnosis is based on the clinical analysis of the macroscopic lesion characteristics such as shape, color, borders following the ABCD rules. The aim of this study is to evaluate the time-resolved fluorescence lifetime of NADH and FAD molecules to detect cutaneous melanoma in an experimental in vivo model. Forty-two lesions were analyzed and the data was classified using linear discriminant analysis, a sensitivity of 99.4%, specificity of 97.4% and accuracy of 98.4% were achieved. These results show the potential of this fluorescence spectroscopy for melanoma detection.OCIS codes: (300.6500) Spectroscopy, time-resolved; (170.3650) Lifetime-based sensing; (170.3890) Medical optics instrumentation; (170.6510) Spectroscopy, tissue diagnostics; (170.6935) Tissue characterization