Local tumor control after 106Ru brachytherapy of choroidal melanoma

PURPOSE: To report on local tumor control after (106)Ru brachytherapy for choroidal melanoma. METHODS AND MATERIALS: A total of 458 patients with choroidal melanoma were treated at a single institution between January 1993 and December 2001. The tumors had a median longest basal dimension of 10.6 mm and a median height of 3.2 mm. The brachytherapy was administered using a 15- or 20-mm plaque. For posterior tumors, the plaque was positioned eccentrically with its posterior edge aligned with the posterior tumor margin to reduce the radiation dose to the optic disk and fovea. A minimal scleral dose sufficient to cause visible choroidal atrophy provided a permanent ophthalmoscopic record of the distribution of choroidal irradiation. If radiotherapy to the posterior tumor was uncertain, adjunctive transpupillary thermotherapy was administered 6 months postoperatively. RESULTS: The actuarial rates of tumor recurrence were 1%, 2%, and 3% at 2, 5, and 7 years, respectively. Local tumor recurrence correlated with the longest basal tumor dimension (Cox univariate analysis, p = 0.02, risk ratio 1.41, 95% confidence interval 1.06-1.88). Seven of the nine eyes with recurrent tumor were salvaged with additional conservative therapy. CONCLUSION: The low rate of local tumor recurrence suggests that ruthenium plaque radiotherapy is effective with good case selection and if special measures are taken to ensure that the plaque is positioned correctly.     

色素性脉络膜黑素瘤动物模型建立的实验研究

目的　建立兔色素性脉络膜黑素瘤动物模型 ,以供人类研究眼黑素瘤新的治疗方法。方法　 4种黑素瘤细胞株 (B16F10 ,RPMI 184 6 ,OCM1andIIB)种植于 2 0 6只大白兔眼中以建立脉络膜黑素瘤 ,其中 172只动物注射环孢菌素A (Cyclosporine)进行免疫抑制 ,34只作为对照。肿瘤碎片 (或细胞悬液 )经巩膜种植于兔眼脉络膜下腔 ,用间接眼底镜、超声和眼底照像进行观察。结果　 4种黑素瘤细胞生长各异 ,其中B16F10 和RPMI 184 6生长较快 ,典型肿瘤生长 3～ 4mm需 2～ 3周 ,OCM1和IIB生长缓慢。肿瘤生长的位置和形状与种植的肿瘤碎片或细胞悬液有密切关系。结论　兔色素性脉络膜黑素瘤的建立 ,将为人们研究眼黑素瘤新的治疗办法提供更适合的动物模型。     

Treatment of choroidal melanoma by stereotactic radiosurgery

The case of a 49‐year‐old woman with an intermediate‐sized choroidal melanoma who was treated with stereotactic radiosurgery with good tumour resolution is presented. Sight and globe preservation were achieved. The treatment technique is discussed.     

Phase II evaluation of temozolomide in metastatic choroidal melanoma

Temozolomide (Temodar) has demonstrated clinical activity against melanoma equivalent to that of intravenous dacarbazine (DTIC). Phase I clinical studies have shown that low dose chronic administration of temozolomide permits the delivery of higher dose intensities than a 5 day dose schedule. Temozolomide is hydrolysed to its active metabolite monomethyltriazenoimidazole carboxamide (MTIC) upon absorption from the gastrointestinal tract, while DTIC is inactive until it is metabolized in the liver to MTIC. In view of this, a higher concentration of MTIC will pass through the liver during the first pass when its source is temozolomide rather than DTIC. To determine if these characteristics of temozolomide will translate into a higher response rate than that achieved with DTIC, we conducted a phase II clinical trial of temozolomide in patients with uveal melanoma metastatic to the liver. Temozolomide was administered orally at a starting dose of 75 mg/m2 per day for 21 days every 4 weeks. Fourteen patients were enrolled in the trial. No complete or partial responses were observed. Stabilization of disease was achieved in two patients. The treatments were well tolerated. We conclude that, like DTIC, temozolomide at the dose and schedule studied in this trial is not effective for the control of metastatic melanoma of uveal origin.     

Multiple bilateral choroidal metastasis from anal melanoma

A 58-year-old Caucasian woman with bleeding per rectum had a melanoma of the anal canal. She subsequently presented with visual disturbance and was noted to have bilateral multiple choroidal metastasis, along with other multiple systemic metastases. Orbital radiotherapy led to near complete resolution of the ocular metastasis.     

Novel low-kVp beamlet system for choroidal melanoma

Background

Treatment of choroidal melanoma with radiation often involves placement of customized brachytherapy eye-plaques. However, the dosimetric properties inherent in source-based radiotherapy preclude facile dose optimization to critical ocular structures. Consequently, we have constructed a novel system for utilizing small beam low-energy radiation delivery, the Beamlet Low-kVp X-ray, or "BLOKX" system. This technique relies on an isocentric rotational approach to deliver dose to target volumes within the eye, while potentially sparing normal structures.

Methods

Monte Carlo N-Particle (MCNP) transport code version 5.0(14) was used to simulate photon interaction with normal and tumor tissues within modeled right eye phantoms. Five modeled dome-shaped tumors with a diameter and apical height of 8 mm and 6 mm, respectively, were simulated distinct positions with respect to the macula iteratively. A single fixed 9 × 9 mm² beamlet, and a comparison COMS protocol plaque containing eight I-125 seeds (apparent activity of 8 mCi) placed on the scleral surface of the eye adjacent to the tumor, were utilized to determine dosimetric parameters at tumor and adjacent tissues. After MCNP simulation, comparison of dose distribution at each of the 5 tumor positions for each modality (BLOKX vs. eye-plaque) was performed.

Results

Tumor-base doses ranged from 87.1–102.8 Gy for the BLOKX procedure, and from 335.3–338.6 Gy for the eye-plaque procedure. A reduction of dose of at least 69% to tumor base was noted when using the BLOKX. The BLOKX technique showed a significant reduction of dose, 89.8%, to the macula compared to the episcleral plaque. A minimum 71.0 % decrease in dose to the optic nerve occurred when the BLOKX was used.

Conclusion

The BLOKX technique allows more favorable dose distribution in comparison to standard COMS brachytherapy, as simulated using a Monte Carlo iterative mathematical modeling. Future series to determine clinical utility of such an approach are warranted.     

脉络膜恶性黑色素瘤立体定向放射治疗初探

为提高脉络膜恶性黑色瘤的肿瘤控制率并保留患眼及其部分视力探索一条新的治疗途径 ,评价立体定向放射治疗作为脉络膜恶性黑色素瘤治疗方法的价值。方法　 11例脉络膜恶性黑色素瘤患者中单次立体定向放射治疗 2例 ,分次立体定向放射治疗 9例 ;中心 1～ 2个 ,准直器 15～ 40mm ,参考剂量曲线 70 %～ 90 %。单次治疗DT2 5 0 0cGy 次和DT3 5 0 0cGy 次 ,分次治疗DT75 0 y～ 15 0 0cGy 次 ,2～ 4次 ,10～ 15d。结果　中位随访期 30个月 (随访 10～ 43个月内全部患者生存 )。 6例患者保留眼球和部分视力 ,肿瘤缩小或消失 ;5例患者因肿瘤未控 (1例 )、继发性青光眼 (2例 ) ,角膜溃疡 (2例 )而摘除眼球。全部患者未发现远地转移。结论　立体定向放射治疗对眼球后极或后部脉络膜恶性黑色素瘤是一种有效的治疗方法 ,部分患者达到既控制肿瘤又保留眼球和部分视力的目的。     

Episcleral plaque thermoradiotherapy in patients with choroidal melanoma.

From 1988 to 1991, 21 patients with uveal melanoma were treated in a Phase I study with episcleral plaque radiotherapy (EPRT). This irradiation was combined with localized current field episcleral hyperthermia (LCFHT). Tumor stage was: T3 = 15 (71%) and T2 = 6 (29%). Follow-up ranged from 2 to 42 months (mean 9.2 months). EPRT was given using custom built I-125 gold plaques. Radiation doses to the tumor apex ranged from 13 to 123 Gy (mean dose 70.0 Gy) given at a mean dose rate of 55 cGy/hr. LCFHT was given with 500 KHz frequency for 45 min immediately before EPRT. The temperature was controlled on the scleral surface using four thermocouples. T mean ranged from 42.5 degrees C to 45 degrees C +/- 0.5 degrees C (mean 43.4 degrees C). The study patients showed rapid tumor necrosis. A 25% mean decrease of apical tumor dimension was noted, p = 0.0007. At least ambulatory vision (greater than 5/200) was maintained by 17/21 (81%) patients. Visual acuity was seen to improve greater than 6 months post-plaque therapy in 10 (48%) study patients. This was following an intermediate decrease in visual acuity. Severe complications, including large hemorrhagic retinal detachment and large vitreous hemorrhage, were seen in two (9.5%) of the early study patients. A mean scleral temperature reduction to less than or equal to 44 degrees C +/- 0.5 degrees C resulted in good treatment tolerance and a lack of serious complications in subsequently treated patients. A Phase II prospective randomized trial comparing LCFHT with 60 versus 80 Gy EPRT dose to the tumor apex is currently being activated for patients with choroidal melanoma.     

Detection of BRAF gene mutation in primary choroidal melanoma tissue

Numerous BRAF mutations have been detected in melanoma biopsy specimens and cell lines. In contrast, several studies report lack of BRAF mutations in uveal melanoma including primary and metastatic choroidal and ciliary body melanomas. To our knowledge, for the first time, here we report a case of choroidal melanoma harboring the BRAF mutation (V600E). The activation of RAF/MEK/ERK pathway, although independent of BRAF mutation, was reported in uveal melanoma. The presence of V600E mutation indicates that the RAF/MEK/ERK pathway, in addition to cutaneous melanoma progression, may play a role in the choroidal melanoma development.     

Additional cell damage after transpupillary thermotherapy in choroidal malignant melanoma

The aim of this study was to evaluate the effectiveness of transpupillary thermotherapy (TTT) in generating tumour necrosis by light and electron microscopy, as well as to evaluate additional cell damage in the area directly adherent to the necrotic zone. Four eyes of four patients diagnosed with intraocular malignant melanoma of the uvea were treated experimentally with diode laser TTT. In all cases a standard technique was used. All eyes were enucleated: one eye the day after TTT, two eyes 2 days after TTT, and one eye 6 weeks after TTT. Immediately after enucleation the eyes were immersed in standard Karnovsky's fixative with cocodylate buffer and prepared for light and electron microscopy. In the treated area of all four melanomas we found a dense band of necrotic tissue (zone A) consisting of an amorphous mass of dead cells sharply demarcated from the rest of the neoplastic tissue. Next to this zone was a more eosinophilic and also sharply demarcated band (zone B) that consisted of similar but less intensive changes. In the next band (zone C), marked injury to the cellular membrane and subcellular structures were seen on electron microscopy. The next band (zone D) consisted of changes mainly observed only within the cytoplasm of neoplastic cells and significantly less intensive than those in zone C. Outside zone D tumour cells that were normal in appearance were seen. No scleral alterations induced by heat were found. We concluded that after TTT the cytotoxic effect gradually decreases in proportion to the distance from the central point of the diode laser spot, with additional cell damage in the area adjacent to the necrotic zone. The interval between TTT and enucleation had no influence on the histological results.     

Increased expression and mutation of p53 in choroidal melanoma.

Using CM-1 antibody directed against the human p53 protein, high levels of mutant p53 protein expression were found in 12 out of 18 malignant choroidal melanomas. In contrast, we failed to observe elevated p53 expression, indicating the absence of p53 mutation in seven choroidal naevi, a potentially premalignant condition that can progress to form malignant melanoma. For two choroidal melanomas, we demonstrated that high levels of p53 protein were accompanied by exon 7 mutations. The mutations were found at codon 238, TGT-->TTT and codon 253, ACC-->AGC. These observations suggest that acquisition of abnormalities of the p53 gene may be an important step in the development of malignant melanoma.     

Patterns of detection in patients with cutaneous melanoma

BACKGROUND: Despite the importance of early detection in preventing mortality from melanoma, little is known regarding how patients with the disease come to diagnosis. METHODS: The authors prospectively evaluated 471 newly diagnosed melanoma patients between 1995 and 1998. Patients completed a questionnaire that included 1) identification of the person who detected the lesion, 2) the anatomic location of the lesion, and 3) family history of melanoma. Logistic regression analysis was performed to examine the relation between detection patterns and lesion thickness, adjusting for age, gender, anatomic site of the primary lesion, and family history of melanoma. RESULTS: The majority of patients detected their own melanoma (n = 270; 57%). Females were more likely to self-detect than males (69% vs. 47%; P < 0.0001). Physicians detected the melanoma in 16% of patients (n = 74), followed by "spouse" in 11% of patients (n = 51). Within this group, detection by wives was 7.5 times more common than detection by husbands (P < 0.0001). Logistic regression analysis revealed that physicians were 3.6 times more likely to detect thin lesions (相似文献   

Patterns of metastases in familial and non-familial melanoma

Family history is a strong risk factor for the development of primary melanoma and is associated in a subset with inherited mutations in melanoma susceptibility genes. This study sought to determine whether differences in metastatic pattern exist between patients with a positive family history (FH+) and those with a negative family history (FH-). Such differences could have importance for clinical management and in the determination of the function of both known and putative melanoma susceptibility genes. A retrospective, nested case-controlled study was performed. Of the FH+ cohort (n = 38), 26 were from kindreds with two histologically verified affected first-degree relatives and 12 were from kindreds with three or more affected members, at least two of whom were first-degree relatives. Three FH- controls from the Sydney Melanoma Unit database were matched to each case for age, sex, stage at diagnosis, number of primary melanomas and year of diagnosis (n = 114). There were no statistically significant differences between the two groups with regard to overall survival from initial diagnosis (FH+, 57.4 months; FH-, 50.0 months; P = 0.99), median survival from time of first metastasis (FH+, 15.4 months; FH-, 15.9 months; P = 0.94), or median disease-free interval (FH+, 26.4 months; FH-, 29.7 months; P = 0.73). On multivariate conditional logistic regression analysis, there was no statistically significant difference between the two groups in the probability of developing initial metastases or of ever developing metastases at specific sites. Survival, disease-free interval and distribution of metastatic sites are similar in both familial and non-familial melanoma. Genetic susceptibility for melanoma may lower the threshold for entering an otherwise common molecular pathway for tumour development and evolution.     

Brachytherapy of choroidal melanoma using radioactive gold grains--a case report

A brachytherapy of a choroidal melanoma using 198Au grains has been performed. Procedurally, the sclera was first incised, after which a pouch was constructed and the grains then arranged around the tumor in a circle so as to enclose it, said operative procedure according to the Manchester Technique. Total Gy dosage amounted to 120 Gy. Postoperatively, in due course, the disappearance of the tumor was clearly shown on MRI examination. The small size and the short half-life of the gold grains made it possible to insert the grains into the tissue permanently, and to give an adequate Gy dosage to eradicate the tumor while still preserving the eyeball.     

Proton beam radiotherapy of choroidal melanoma: the Liverpool-Clatterbridge experience

PURPOSE: To report on outcomes after proton beam radiotherapy of choroidal melanoma using a 62-MeV cyclotron in patients considered unsuitable for other forms of conservative therapy. METHODS AND MATERIALS: A total of 349 patients with choroidal melanoma referred to the Liverpool Ocular Oncology Centre underwent proton beam radiotherapy at Clatterbridge Centre for Oncology (CCO) between January 1993 and December 2003. Four daily fractions of proton beam radiotherapy were delivered, with a total dose of 53.1 proton Gy, and with lateral and distal safety margins of 2.5 mm. Outcomes measured were local tumor recurrence; ocular conservation; vision; and metastatic death according to age, gender, eye, visual acuity, location of anterior and posterior tumor margins, quadrant, longest basal tumor dimension, tumor height, extraocular extension, and retinal invasion. RESULTS: The 5-year actuarial rates were 3.5% for local tumor recurrence, 9.4% for enucleation, 79.1% for conservation of vision of counting fingers or better, 61.1% for conservation of vision of 20/200 or better, 44.8% for conservation of vision of 20/40 or better, and 10.0% for death from metastasis. CONCLUSION: Proton beam radiotherapy with a 62 MeV cyclotron achieves high rates of local tumor control and ocular conservation, with visual outcome depending on tumor size and location.     

Efficacy of five human melanocytic cell lines in experimental rabbit choroidal melanoma

This study was undertaken to compare the ability of five uveal melanocytic cell lines to produce primary and metastatic uveal melanomas in immunosuppressed rabbits and to determine whether animal survival was improved by antibiotic administration. One hundred albino rabbit eyes, five groups of 20, were implanted in the suprachoroidal space with four melanoma cell lines (MKT-BR, OCM-1, 92-1 and SP 6.5) and one melanocytic line (UW-1). Rabbits were immunosuppressed with cyclosporin A (CsA) at a dosage of 15 mg/kg/day, decreased to 10 mg/kg/day after the fourth week. Prophylactic penicillin G, 10 to 2 x 10 IU, was administered intramuscularly at 5-day intervals. Animals were followed for 12 weeks and the ophthalmoscopic findings, weight and general well-being were recorded weekly. Autopsies were performed to study the eyes, liver and lungs under light microscopy. The mean global survival time in the groups was 43+/-4 days. Ophthalmoscopic intraocular tumours developed in 37% of the MKT-BR group, 50% of the OCM-1 group, 100% of the 92-1 group, 23% of the UW-1 group and 75% of the SP 6.5 group; histologically, tumours appeared in 36.8%, 45%, 100%, 58.8% and 100%, respectively. The 92-1 and SP 6.5 cell lines were associated with the most aggressive local behaviour. Lung metastases developed in the OCM-1 group (5%), 92-1 group (61.1%), UW-1 group (7.1%) and SP 6.5 group (42.1%), but were not present in the MKT-BR group. The 92-1 and SP 6.5 cell lines were the most efficient in local and metastatic tumour production. Prophylactic antibiotic administration did not improve animal survival.     

Stereotactic radiotherapy in the treatment of juxtapapillary choroidal melanoma: preliminary results

PURPOSE: To evaluate the preliminary results of stereotactic radiotherapy in the management of patients with juxtapapillary choroidal melanoma. METHODS & MATERIALS: A retrospective, consecutive case series of 28 patients with choroidal melanoma located within 2 mm of the optic nerve who were treated with stereotactic radiotherapy at Princess Margaret Hospital, Toronto, between October 1998 and May 2001. RESULTS: Median age was 62 years. Median tumor height was 4.6 mm and median maximum tumor diameter was 9.4 mm. The prescribed radiation dose was 70 Gy in five fractions over 10 days and median follow-up was 18.5 months. Posttreatment, 2 patients developed local tumor regrowth and 3 patients developed liver metastases. Actuarial rates of local tumor control, metastases, and survival at 18 months were 96%, 10%, and 94%, respectively. Actuarial rates of radiation-induced neovascular glaucoma, cataract, retinopathy, and optic neuropathy at 18 months were 20%, 29%, 30%, and 37%, respectively. A higher radiation dose to the lens was associated with an increased risk of cataract (p = 0.02). CONCLUSIONS: Stereotactic radiotherapy offers a noninvasive alternative to enucleation and brachytherapy in the management of juxtapapillary choroidal melanoma. However, further efforts are needed to optimize local tumor control and minimize radiation-induced complications.     

Loss of the eukaryotic initiation factor 3f in melanoma

Aberrant regulation of the translation initiation is known to contribute to tumorigenesis. eIF3 plays an important role in translation initiation. eIF3f is the p47 subunit of the eIF3 complex whose function in cancer is not clear. Initial studies from our group indicated that eIF3f expression is decreased in melanoma. Overexpression of eIF3f inhibits translation and induces apoptosis in melanoma cells. The eIF3f gene is located at chromosome region 11p15.4. Loss of 11p15.4 is a common event in many tumors including melanoma. In order to investigate the molecular mechanism of the decreased expression of eIF3f in melanoma, we performed loss of heterozygosity (LOH) analysis in 24 melanoma specimens using three microsatellite markers encompassing the eIF3f gene. We showed that the prevalence of LOH ranged from 75% to 92% in melanoma. We also performed eIF3f gene copy number analysis using quantitative real-time PCR to further confirm the specific allelic loss of the eIF3f gene in melanoma. We demonstrated a statistically significant decrease of the eIF3f gene copy number in melanoma compared with normal tissues with a tumor/normal ratio of 0.52. To further elucidate the somatic genetic alterations, we carried out mutation analysis covering the entire coding region and 5'UTR of the eIF3f gene in melanoma tissues and cell lines. Despite some polymorphisms, we did not find any mutations. Furthermore, immunohistochemistry analysis demonstrated that eIF3f protein expression is decreased in melanoma compared to benign nevi. These data provide new insight into the understanding of the molecular pathogenesis of eIF3f during melanoma tumorigenesis.     

14例脉络膜黑色素瘤的临床观察

目的分析Ⅲ期脉络膜黑色素瘤(CM)的临床特点、手术治疗及辅助治疗对预后的影响。方法对2010年至2017年间收治的Ⅲ期脉络膜黑色素瘤患者临床资料进行回顾性分析。结果14例Ⅲ期脉络膜黑色素瘤,1年无复发生存率为83.3%,3年无复发生存率为58.3%,5年无复发生存率为41.7%。12例患者发生复发转移,其中9例肝转移。除1例患者未行基因检测外,余13例患者黑色素瘤相关基因均未检测到突变。结论脉络膜黑色素瘤恶性度高,预后差,术后复发和肝转移发生率较高,基因突变发生率低。