Papers by Laurence Desjardins
Developments in ophthalmology, Oct 21, 2011
Proton beam irradiation of uveal melanoma has great advantages compared to brachytherapy because ... more Proton beam irradiation of uveal melanoma has great advantages compared to brachytherapy because of the homogenous dose delivered to the tumor and the possibility of sparing normal tissue close to the tumor. We describe the technique of proton beam therapy including the surgical technique of clip positioning, the radiotherapy delivery technique and the dose administered (60 Gy cobalt relative biological effectiveness in 4 fractions). Indications of proton beam are given and the follow-up procedure is described. An inactive residual tumor scar is observed after 2-3 years. Results are given comparing the most recent series of patients treated at the Institut Curie-Orsay proton therapy center with the data published in the literature. The metastasis rate at 10 years varies between 25 and 30%. Local control is excellent. The local recurrence rate at 10 years is usually around 5%. Secondary enucleation is performed in 10-15% of patients either due to complications or local recurrence. Complications such as retinal detachment, maculopathy, papillopathy, cataract, glaucoma, vitreous hemorrhage and dryness are described. The severest complication that usually leads to secondary enucleation is neovascular glaucoma and it is encountered after irradiation of large to extra-large tumors. The toxic tumor syndrome has recently been described. It is hypothesized that the residual tumor scar may produce proinflammatory cytokines and VEGF leading to intraocular inflammation and neovascular glaucoma. Additional treatments after proton beam such as transpupillary thermotherapy, endoresection of the tumor scar or intravitreal injections of anti-VEGF may reduce the rate of these complications.
Purpose: Uveal melanoma is the most common primary intraocular malignant tumor in adults and is d... more Purpose: Uveal melanoma is the most common primary intraocular malignant tumor in adults and is defined by a poor natural outcome, as 50% of patients die from metastases. The aim of this study was to develop and characterize a panel of human uveal melanoma xenografts transplanted into immunodeficient mice.Experimental Design: Ninety tumor specimens were grafted into severe combined immunodeficient mice, and 25 transplantable xenografts were then established (28%). Relationship between tumor graft and clinical, biological, and therapeutic features of the patients included were investigated. Characterization of 16 xenografts included histology, molecular analyses by immunohistochemistry, genetic alteration analysis (single-nucleotide polymorphism), and specific tumor antigen expression by quantitative reverse transcription-PCR. Pharmacologic characterization (chemosensitivity) was also done in four models using two drugs, temozolomide and fotemustine, currently used in the clinical management of uveal melanoma.Results: Take rate of human uveal melanoma was 28% (25 of 90). Tumor take was independent of size, histologic parameters, or chromosome 3 monosomy but was significantly higher in metastatic tumors. Interestingly, in vivo tumor growth was prognostic for a lower metastasis-free survival in patients with primary tumors. A high concordance between the patients' tumors and their corresponding xenografts was found for all parameters tested (histology, genetic profile, and tumor antigen expression). Finally, the four xenografts studied displayed different response profiles to chemotherapeutic agents.Conclusions: Based on these results, this panel of 16 uveal melanoma xenografts represents a useful preclinical tool for both pharmacologic and biological assessments. Clin Cancer Res; 16(8); 2352–62. ©2010 AACR.
Acta Ophthalmologica, Aug 6, 2012
Purpose To study the clinical characteristics, outcome and prognosis of very young patients treat... more Purpose To study the clinical characteristics, outcome and prognosis of very young patients treated for choroidal melanoma at l’ Institut Curie.Methods Retrospective case‐control series. Patients aged ≤16 years were extracted from the database. Patients were treated by enucleation or irradiation depending on tumor size and site. Histology and genomics of the enucleated globes were reviewed. Metastasis and survival were evaluated using the Kaplan‐Meier method.Results From August 1990 to January 2011, 4,857 patients treated for uveal melanoma were prospectively recorded in the database. Fourteen patients (0.3%), 10 girls, 4 boys, mean age 12 years, (median: 14; [range: 2‐16 years]) at onset were extracted. Mean basal tumor diameter was 14 mm (median: 14.5; [range: 6 to 22 mm]). Mean tumor thickness was 7.3 mm (median: 6.4 [range: 2.4 to 16 mm]). One half of patients were enucleated, while the other half was treated conservatively by proton beam or iodine plaque radiotherapy. Histopathology of enucleated globes showed epithelioid cellularity in all patients. Genomic analysis by CGH‐array was available for 4 patients and showed monosomy 3 for 2 patients and 8q gain for 3 patients. Median follow‐up was 91 months [range: 1 to 243 months]. At the end of follow‐up, 13 patients (93%) were alive, one presented metastatic disease and one had died. The eye was retained in all patients treated conservatively.Conclusion Most children had an excellent outcome in terms of survival. An excellent eye retention rate was observed in conservatively treated patients.
Acta Ophthalmologica, Sep 1, 2010
Purpose To document that staging ciliochoroidal melanoma by the Tumor, Node, Metastasis (TNM 7th ... more Purpose To document that staging ciliochoroidal melanoma by the Tumor, Node, Metastasis (TNM 7th edition) system is reproducible between centres. Methods Data of 8252 patients (Berlin 689, Helsinki 270, Liverpool 3305, Lyon 473, Paris 3515) regarding tumour thickness, largest basal diameter, ciliary body and extrascleral extension were staged centre by centre. Stage‐specific survival was compared between centres using Kaplan‐Meier analysis and log rank test. Results Of these tumours, 21% (13‐25%) classified to stage I, 31% (28‐34%) to stage IIA , 23% (19‐32%) to stage IIB, 17% (16‐19%) to stage IIIA, 7% (5‐11%) to stage IIIB and 1% (0‐4%) to stage IIIC, respectively. The survival of patients treated in the five European ocular oncology centers differed significantly overall, probably because of differences in case mix and follow‐up. The survival did not differ significantly between centers in stage groups other than IA (P<0.014 and compared to P<0.013 in stage IIA, P<0.001 in IIB, P<0.001 in IIIA; P<0.001 in IIIB and P<0.003 in IIIC). The corresponding 5‐year survival rates for stages I, IIA‐B and IIIA‐C were 96% (87‐99% in 4 different centers), 89% (74‐93%), 82% (73‐85%), 67% (60‐81%), 46% (33‐61%) and 26% (12‐31%) by 5 years; and 88% (74‐89%), 80% (68‐82%), 68% (60‐65%), 45% (37‐53%), 28% (17‐33%) and 10% (7‐12%) by 10 years, respectively. In the fifth centre, the 5‐ and 10‐year survival rates were 82% and 74% even for Stage IIIB. Conclusion The first evidence‐based TNM classification of malignant ciliochoroidal melanoma equally predicts survival of patients in four of five different European ocular oncology centers regardless of their different case mix and preferred follow‐up and treatment practices.
Journal of Clinical Oncology, May 20, 2012
8546 Background: Overall survival (OS) of MUM pts remains poor. In our retrospective series of 47... more 8546 Background: Overall survival (OS) of MUM pts remains poor. In our retrospective series of 470 MUM pts, median OS was 13 months, ranging from 3 to 12 and 21 months for best supportive care, systemic treatment and surgery groups respectively, stressing the lack of effective therapies in this rare cancer. Targeting angiogenesis seems to be promising in uveal melanoma. Intravitreal application of antiangiogenic agents is used to treat neovascular ocular diseases such as age-related macular degeneration or proliferative diabetic retinopathy. Bevacizumab suppressed in vitro growth and in vivo hepatic establishment of micrometastases in experimental uveal melanoma. Preclinical data suggest a potential clinical benefit of the combination of dacarbazine and bevacizumab. Methods: Phase II study, modified 2-step Fleming plan; with expected 6-month progression-free survival (PFS) rates of 15% with chemotherapy and 40% with BEVATEM, 35 pts are to be recruited for a power of 94% (α and β risk 3 and 6%). After the first 17 pts, the study will be continued and another 18 pts will be enrolled in the second step if ≥3 evaluable pts show stable disease or response. Primary endpoint: 6-month PFS according to RECIST. Secondary objectives: response and survival rates, safety; liver perfusion CT for functional imaging of response; impact of VEGF-A gene polymorphisms on bevacizumab pharmacodynamics. Treatment schedule: Temozolomide 150mg/m2 d1-d7 and d15-d21 oral route, Bevacizumab 10 mg/kg d8 d22 IV infusion, 6 cycles (d1=d28) then Bevacizumab maintenance until toxicity or progression. Results: From May 2010 to January 2011, 17 pts were enrolled according to the first step of the study: 3/17 achieved disease control at 6 months, second step is on going with 26/35 pts already recruited. One patient with minor response in liver and lung metastases is under Bevacizumab maintenance for 12 months. Safety of BEVATEM is as good as expected. Liver perfusion CT study showed decrease in blood flow and blood volume before lesion size decrease in one stable patient. Conclusions: BEVATEM study in first line MUM pts is on going, showing promising results in the first step of 17 pts.
PubMed, Jun 1, 2001
Introduction: We have carried out a retrospective study of 135 patients followed at Curie Institu... more Introduction: We have carried out a retrospective study of 135 patients followed at Curie Institute for choroidal naevus between March 1983 and June 1997. Patients and methods: 54 patients presented naevi considered as benign and 81 patients presented suspicious choroidal naevi (with at least one of the following findings: visual symptoms; serious detachment of the retina; orange pigment; thickness greater than 2mm or a diameter greater than 7mm). These suspicious naevi were followed more carefully. The median follow-up was 49 months. The median diameter of the lesions was 6mm and the median thickness was 1.5mm. We studied the age of the patients, clinical symptoms, the presence or absence of orange pigment, drusen and serious detachment, and the angiographic and echographic findings. Results: 3 patients died of unrelated cause; 7 patients were lost to follow-up; 30 patients presented documented growth; 4 of them belonged to the group considered as benign and 26 to the group considered as suspicious, with a significant difference between the groups. The lesions that grew were treated by proton beam or I125 patches. The risk factors for growth that were statistically significant were the presence of visual symptoms, pin points, orange pigment, serous detachment and thickness greater than 2mm. With drusen, the risk for growth was significantly less. Discussion: These results are very similar to those published in the literature concerning risk factors for growth of choroidal nevi. The absence of metastatic spread in patients whose nevi have grown show that it is possible to monitor choroidal naevi if there is a doubt as to the malignant or benign nature of the lesion. Conclusion: It is important to determine if a choroidal naevus is suspicious or benign and to propose closer follow-up for suspicious lesions.
PubMed, Feb 1, 2003
Purpose: Uveal malignant melanoma is the most common primary intraocular tumor in adults. The occ... more Purpose: Uveal malignant melanoma is the most common primary intraocular tumor in adults. The occurrence of bilateral uveal melanoma is an extremely rare event, but the observed frequency is nevertheless higher than what can be attributed to chance. Possible responsible factors may include a genetic predisposition. Patients and methods: This retrospective study investigated the charts of patients examined from July 1988 to July 2001. For each patient, the clinical characteristics of the tumor (diameter, thickness, location), treatments, and results were noted, as were the eye involved, the presence of ocular melanocytosis, cutaneous melanoma, and second primary cancers. The information was then subjected to statistical analysis. Results: Of 2 461 patients with unilateral primary uveal melanoma, five were identified as having bilateral uveal melanoma (0.2%). The expected number of cases would be less than one, hypothesizing an incidence of second melanoma identical to the incidence of a primary melanoma in the general population. The interval between the diagnosis of first and second primary uveal melanomas ranged from 0 to 6 years (median, 2 years). There was no clinical evidence of ocular melanocytosis in any of the five patients. The uveal melanoma was choroidal in three patients and affected the ciliary body or iris and choroid in two patients. Discussion: The discrepancy between the estimated incidence (thought by Shammas to be one case every 18 years) and the observed incidence of bilateral primary uveal melanoma could be the result of many possible factors. An increased incidence of unilateral uveal melanoma could be a cause but in fact the incidence of uveal melanoma seems stable. Uveal melanoma may have been misdiagnosed in earlier years. The presence of a genetic predisposition to uveal melanoma is a possible explanation (suspected because of bilateral cases, familial cases and association with other primary malignancies). Ocular melanocytosis, which is described as more common in patients with bilateral uveal melanoma, was not seen in our series. Conclusion: Bilateral primary uveal melanoma occurs more frequently than expected. Unidentified germline mutations may be involved in pathogenesis. These cases serve as a reminder of the of the importance of careful examination of the second eye.
PubMed, Mar 1, 2003
Introduction: This retrospective study compared the rate of local recurrence after irradiation of... more Introduction: This retrospective study compared the rate of local recurrence after irradiation of uveal melanoma treated with iodine 125 plaques or proton beam therapy. Patients and methods: Iodine 125 plaques were used to treat all uveal melanomas between the end of 1989 and 1991. Since 1991, we have used iodine plaques for small anterior tumors and proton beam for other tumors. We use a plaque with a larger diameter than the tumor diameter (2-4mm) with a dose of 90Gy at the apex. Proton beam therapy is used for all tumors at the equator or posterior to the equator not thicker than 12mm. The dose given is 60Gy cobalt equivalent in four fractions. For each patient, the initial size and location of the tumor were noted as well as the follow-up each year: the outcome for the eye (local recurrence, ocular conservation, and functional results), the occurrence of metastasis, and survival. A statistical analysis was performed. Results: Between December 1989 and September 1998, 1272 patients were treated: 926 (72.8%) were treated with proton beam irradiation and 346 (27.8%) with iodine 125 plaques. The median follow-up was 5 years (60 months). For the patients treated with proton beam therapy, the mean age was 58 years, the tumor location was anterior to the equator for 3.8%, at the equator for 43.6%, and posterior to the equator for 52.6%. The mean tumor diameter was 13.4mm and the mean tumor thickness was 5.69mm. For the patients treated with iodine 125 plaques, the mean age was 61.5 years. The location of the tumor was anterior to the equator for 34.4%, at the equator for 46.5%, and posterior to the equator for 19.1%. The mean tumor diameter was 11.5mm and the mean tumor thickness was 5.12mm. The recurrence rate was 4% for the proton beam treatment and 3.75% for iodine plaques. There was no statistical difference. Discussion: In the literature, the rate of local recurrence is usually higher with iodine 125 plaques than proton beam therapy. We discuss the risk factors for local recurrence after iodine 125 plaques: tumor diameter, lower dose to the tumor apex and lower dose rate, and posterior location of the tumor. We found a higher mortality rate in patients who presented local recurrence. Conclusion: When we use iodine 125 plaques for anterior tumors with the proper dose and dose rate to the apex of the tumor, we do not find more recurrence than with proton beam therapy.
PubMed, Apr 1, 1999
We have reviewed a serie of 56 patients treated in our Institute for malignant melanoma of the co... more We have reviewed a serie of 56 patients treated in our Institute for malignant melanoma of the conjunctiva between 1980 and 1992. We selected cases where histology had been reviewed. Patients and method: The median follow up is 96 months. The age varies from 13 to 88 years with a mean age of 56 years. There were 22 men and 34 females. In 29 cases (51%) the melanoma appeared de novo, ten cases (17%) it derived from a naevus and in 14 cases (25%) on a precancerous melanosis. The tumour was localized at the limbus and bulbar conjunctiva in 57% of cases. The mean diameter was 6.1 mm and the mean thickness was 2.3 mm. The treatment consisted in surgical excision of the tumour followed by external beam radiothérapy in 49 cases. Histological examination showed invasion of the chorion in 44 cases (78%) and of the sclera in 6 cases (1%). Results: 38 patients are alive and 29 without disease. 2 with disease, 7 lost follow-up. 18 patients died (32%) and among them 14 (25%) died of metastatic disease. 22 patients (39%) have presented local recurrence and among them 10 have had multiple recurrences. The mean delay for recurrence was 56 months. The overall survival was 77% at 5 years and 64% at 10 years. Tumours appeared de novo have a worse prognosis. If we consider the localization tumour located at the limbus or on bulbar conjunctiva have less metastasis. Conclusion: Malignant melanoma of conjunctiva is a tumour that can frequently recur. Metastasis are not infrequent and follow up must be prolonged.
Ophthalmic Research, 2006
Introduction: Exudation from the tumour scar and glaucoma can be major problems after proton beam... more Introduction: Exudation from the tumour scar and glaucoma can be major problems after proton beam irradiation of uveal melanoma and can sometimes lead to secondary enucleation. We conducted a randomized study to determine whether systematic transpupillary thermotherapy (TTT) after proton beam radiotherapy could have a beneficial effect. Patients and Method:Between February 1999 and April 2003, all the patients treated by proton beam radiotherapy for uveal melanomas ≧7 mm thick or ≧15 mm in diameter were included in this study after giving their informed consent. One half of the patients received proton beam radiotherapy alone (60 Gy in 4 fractions) and the other half received the same dose of proton beam radiotherapy followed by TTT at 1, 6 and 12 months. All the information concerning the initial tumour parameters, treatments and follow-up was recorded and a statistical analysis was performed. Results: We randomized 151 patients. The median follow-up was 38 months. The 2 groups of patients were similar in terms of age, gender and tumour characteristics. The patients treated with TTT showed a greater reduction of tumour thickness (p = 0.06), less retinal detachment at the latest follow-up (p = 0.14) and a lower secondary enucleation rate (p = 0.02). Discussion: The present study is the first randomized analysis to demonstrate a significant decrease in the secondary enucleation rate in patients treated with TTT after proton beam radiotherapy. Further studies should be performed to determine whether TTT could be beneficial to smaller tumours and to define its optimal dose.
Acta Ophthalmologica, Sep 4, 2008
ABSTRACT
Acta Ophthalmologica, Aug 6, 2012
Abstract not provided
Nature Communications, 2021
Retinoblastoma is the most frequent intraocular malignancy in children, originating from a maturi... more Retinoblastoma is the most frequent intraocular malignancy in children, originating from a maturing cone precursor in the developing retina. Little is known on the molecular basis underlying the biological and clinical behavior of this cancer. Here, using multi-omics data, we demonstrate the existence of two retinoblastoma subtypes. Subtype 1, of earlier onset, includes most of the heritable forms. It harbors few genetic alterations other than the initiating RB1 inactivation and corresponds to differentiated tumors expressing mature cone markers. By contrast, subtype 2 tumors harbor frequent recurrent genetic alterations including MYCN-amplification. They express markers of less differentiated cone together with neuronal/ganglion cell markers with marked inter- and intra-tumor heterogeneity. The cone dedifferentiation in subtype 2 is associated with stemness features including low immune and interferon response, E2F and MYC/MYCN activation and a higher propensity for metastasis. The...
American Journal of Ophthalmology, 2020
HE AUTHORS HAVE MADE THEIR DATASET available through Zenodo, an open-access repository developed ... more HE AUTHORS HAVE MADE THEIR DATASET available through Zenodo, an open-access repository developed under the European OpenAIRE program: ''Dataset for 'Validation of a Prognostic Staging for Metastatic Uveal Melanoma': A Collaborative Study of the European Ophthalmic Oncology Group'' (
American Journal of Ophthalmology, 2019
Translational Vision Science & Technology, 2019
The 2018 Ocular Oncogenesis and Oncology Conference was held through a partnership of the Associa... more The 2018 Ocular Oncogenesis and Oncology Conference was held through a partnership of the Association for Research in Vision and Ophthalmology (ARVO) and the Champalimaud Foundation. Twenty-one experts from international ocular oncology centers, from the Champalimaud Clinical Centre and the Champalimaud Foundation Cancer Research Program, and from patient advocacy organizations, delivered lectures on subjects that ranged from global ocular oncology, to basic research in mechanisms of ocular malignancy, to clinical research in ocular cancers, and to anticipated future developments in the area. The scientific program of the conference covered a broad range of ocular tumors-including uveal melanoma, retinoblastoma, ocular surface tumors, and adnexal and intraocular lymphomas-and pathogenesis and management were deliberated in the context of the broader systemic cancer discipline. In considering the latest basic and clinical research developments in ocular oncogenesis and oncology, and providing the opportunity for cross-talk between ocular cancer biologists, systemic cancer biologists, ocular oncologists, systemic oncologists, patients, and patient advocates, the forum generated new knowledge and novel insights for the field. This report summarizes the content of the invited talks at the 2018 ARVO-Champalimaud Foundation Ocular Oncogenesis and Oncology Conference.
Cancer cell, Jan 9, 2018
Aneuploidy, whole chromosome or chromosome arm imbalance, is a near-universal characteristic of h... more Aneuploidy, whole chromosome or chromosome arm imbalance, is a near-universal characteristic of human cancers. In 10,522 cancer genomes from The Cancer Genome Atlas, aneuploidy was correlated with TP53 mutation, somatic mutation rate, and expression of proliferation genes. Aneuploidy was anti-correlated with expression of immune signaling genes, due to decreased leukocyte infiltrates in high-aneuploidy samples. Chromosome arm-level alterations show cancer-specific patterns, including loss of chromosome arm 3p in squamous cancers. We applied genome engineering to delete 3p in lung cells, causing decreased proliferation rescued in part by chromosome 3 duplication. This study defines genomic and phenotypic correlates of cancer aneuploidy and provides an experimental approach to study chromosome arm aneuploidy.
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Papers by Laurence Desjardins