Molecular screening program to select molecular-based recommended therapies for metastatic cancer patients: analysis from the ProfiLER trial.

BACKGROUND: Antitumor activity of molecular-targeted agents is guided by the presence of documented genomic alteration in specific histological subtypes. We aim to explore the feasibility, efficacy and therapeutic impact of molecular profiling in routine setting. PATIENTS AND METHODS: This multicentric prospective study enrolled adult or pediatric patients with solid or hematological advanced cancer previously treated in advanced/metastatic setting and noneligible to curative treatment. Each molecular profile was established on tumor, relapse or biopsies, and reviewed by a molecular tumor board (MTB) to identify molecular-based recommended therapies (MBRT). The main outcome was to assess the incidence rate of genomic mutations in routine setting, across specific histological types. Secondary objectives included a description of patients with actionable alterations and for whom MBRT was initiated, and overall response rate. RESULTS: Four centers included 2579 patients from February 2013 to February 2017, and the MTB reviewed the molecular profiles achieved for 1980 (76.8%) patients. The most frequently altered genes were CDKN2A (N = 181, 7%), KRAS (N = 177, 7%), PIK3CA (N = 185, 7%), and CCND1 (N = 104, 4%). An MBRT was recommended for 699/2579 patients (27%), and only 163/2579 patients (6%) received at least one MBRT. Out of the 182 lines of MBRT initiated, 23 (13%) partial responses were observed. However, only 0.9% of the whole cohort experienced an objective response. CONCLUSION: An MBRT was provided for 27% of patients in our study, but only 6% of patients actually received matched therapy with an overall response rate of 0.9%. Molecular screening should not be used at present to guide decision-making in routine clinical practice outside of clinical trials.This trial is registered with ClinicalTrials.gov, number NCT01774409.

[Tolerability and short-term efficacy of the Ozurdex® dexamethasone intravitreal implant for treatment of uveitic cystoid macular edema: A retrospective study of 52 injections performed at the Clermont-Ferrand teaching hospital]. / Efficacité et tolérance de l'implant intraoculaire de dexaméthasone Ozurdex(®) dans le traitement des œdèmes maculaires liés aux uvéites : série rétrospective sur 52 injections réalisées au CHU de Clermont-Ferrand.

Macular edema is the main cause of decreased visual acuity in uveitis and determines the visual prognosis. We retrospectively analyzed the tolerability and efficacy of the dexamethasone intravitreal implant in the management of uveitis. Twenty-five patients with uveitic cystoid macular edema were all treated with the Ozurdex(®) dexamethasone intravitreal implant from January 2012 to August 2014. The main outcome measures were visual acuity recovery, changes in macular thickness and resolution of the vitritis. Thirty-two eyes of 25 patients received 52 injections of Ozurdex(®). Both complete regression of the macular edema and resolution of the vitritis occurred in 100 % patients. Visual acuity improved in 62 % of patients: the mean reduction in macular thickness was 252 (±171µm); the mean time between injections was 6.7 (±3.8) months. Secondary ocular hypertension was seen in 33 % of patients. No patient required secondary surgery although a selective laser trabeculoplasty was required for one patient. The dexamethasone intravitreal implant Ozurdex(®) resulted in continuous and complete regression of uveitic cystoid macular edema. It allows evaluation of the potential visual recovery of treated eyes. The tolerability and duration of action provide a rationale for considering Ozurdex(®) as a first-line therapy for uveitis which remains uncontrolled despite optimal systemic treatment.

[Vitreous hemorrhage as the initial manifestation of familial exudative vitreoretinopathy in an eight-year-old child]. / Une hémorragie intravitréenne comme manifestation initiale de vitréorétinopathie exsudative familiale chez un enfant de huit ans.

PURPOSE: To report vitreous hemorrhage as the initial manifestation of familial exudative vitreoretinopathy (FEVR). METHODS: Case report. RESULTS: An 8-year-old child presented with vitreous hemorrhage leading to the discovery of large neovascularization. Fundus examination and fluorescein angiography showed the typical appearance of FEVR. A genetic study confirmed the diagnosis. Treatment by laser photocoagulation was performed with good recovery of visual acuity. CONCLUSION: Ophthalmologists should be aware of familial exudative vitreoretinopathy (FEVR) so as not to misdiagnose this sight-threatening disease.

[Apropos of 5 cases of optic nerve tumors diagnosed during a 6-year-period]. / À propos de 5 cas de tumeurs du nerf optique sur une période de 6ans.

INTRODUCTION: Optic nerve tumors are uncommon and rarely described. By way of five patients treated at the University Hospital of Clermont-Ferrand, France, over a six-year-period, we discuss their clinical and radiological characteristics, their treatment and their course. OBSERVATIONS: We report two cases of optic nerve glioma in small children, two cases of optic nerve sheath meningioma and a 57-year-old patient treated for lung cancer with an optic nerve metastasis and choroidal and brain metastases. The diagnosis was confirmed by imaging in all patients and histologically for the cases of optic nerve glioma. RESULTS: The children with glioma were exclusively treated with chemotherapy, the two women with meningioma exclusively with radiation therapy, and the man with the optic nerve metastasis by chemotherapy and radiotherapy. The tumors were stabilized in all cases except for a progression in one case of glioma, one year after treatment. DISCUSSION: Gliomas and meningiomas are the most frequent tumors; other tumors are rare. Through a literature review and many illustrations, we discuss epidemiologic, clinical and radiologic characteristics, treatment and course of these uncommon tumors. CONCLUSION: The diagnosis of optic nerve tumors must be considered in cases of anterior or posterior progressive optic neuropathy. Treatment must be a compromise between effective treatment of the tumor and preservation of visual function. Decisions are made through multidisciplinary consultations, in which the role of the ophthalmologist is crucial for the diagnosis and success of the treatment.

[Assessment of postoperative pain after corneal collagen cross-linking by iontophoresis vs the rapid epithelium-off technique in progressive keratoconus patients]. / Évaluation de la douleur en postopératoire de cross-linking du collagène cornéen en comparant la procédure par iontophorèse à la technique épithélium-off rapide chez des patients atteints de kératocône évolutif.

INTRODUCTION: Cross-linking (CXL) increases corneal biomechanical strength in progressive keratoconus. Since riboflavin cannot penetrate intact corneal epithelium, removal of epithelium is necessary for the classic CXL procedure (epi-off), but can cause severe postoperative pain. To avoid this problem, a method preserving the epithelium (epi-on) is used. In this study, we aimed to evaluate and compare postoperative pain after epi-off CXL and epi-on CXL. MATERIALS AND METHODS: We present a retrospective study assessing the level of pain postoperatively in 38 patients between the age of 12 and 53 years who underwent CXL procedures at the University Hospital of Clermont-Ferrand from July 2013 to May 2014. Epi-off consisted of manual corneal de-epithelialization and riboflavin instillation for 20minutes, followed by UVA exposure for 9minutes. The epi-on technique used an applicator on the eye, filled with riboflavin, and a generator delivered a continuous low-level current for 5minutes. The duration of light exposure was similar in both groups. Postoperative medications were the same for both techniques. Assessment of pain and analgesic intake were reported by the patient on paper questionnaires. Pain was evaluated from preoperatively up until the end of the month. Statistical analyses were performed in bilateral formulation to an alpha type I and error risk of 5%. RESULTS: Twenty-three epi-off patients and 15 epi-on patients. Twenty-nine men and 9 women (76.3%/23.7%). Mean age: 28 years. Reference base time was the return from the operating room. In the epi-off group, pain increased significantly until the morning of D2 and did not return to its intraoperative level until noon D2, 1.8±2.0 vs 2.5±2.5 (P=0.12). Pain remained stable until the morning of D4. From noon D4 until D30, it was significantly less than intraoperatively 1.8±2.0 vs 0.7±1.4 (P=0.01). In the epi-on group, pain was significantly higher than intraoperatively until noon of D1 2.5±2.2 vs 3.8±2.5 (P=0.01). From the evening of D1, it returned to its intraoperative level until the evening of D2 2.5±2.2 vs 2±1.7 (P=0.34). From the morning of D3 it was significantly less than intraoperatively 2.5±2.2 vs 0.8±0.9 (P=0.001). Considering all measurement times, there was no significant difference between the two groups (P=0.75), except from evening of D2 until evening of D3 in favor of iontophoresis: 1.9±2.3 vs 1.0±1.3 (P=0.038). DISCUSSION: Epi-on seems less painful in the short term (up to noon of D1 for epi-on vs morning of D2 for epi-off) and with a shorter duration than epi-off. This can be explained by the absence of corneal de-epithelialization. However, the reduction in pain is not significant at all postoperative times, and a risk of epithelial abrasion during placement and removal of the corneal applicator may exist. CONCLUSION: Iontophoresis maintains the corneal epithelium, decreases pain and improves patient comfort. A new study involving more patients and strict monitoring of medication intake would strengthen the validity of these results.

[Intraocular lymphoma associated with primary malignant lymphoma of the central nervous system: Seven-year experience of a tertiary center]. / Lymphome intraoculaire associé au lymphome primitif non hodgkinien du système nerveux central : expérience d'un centre tertiaire sur une durée de sept ans.

INTRODUCTION: Primary intraocular lymphoma (PIOL), associated with primary central nervous system lymphoma (PCNSL), is a rare malignancy disease. By way of a seven-year experience of a tertiary center, we discuss the presentation and we review the diagnostic and therapeutic modalities. OBSERVATIONS: We report six cases of PIOL associated with PCNSL. For all patients, the clinical presentation was a vitreoretinal syndrome. The diagnosis was histologically confirmed by vitreal sample or brain biopsy. Five patients developed a diffuse large B-cell lymphoma. Only one patient developed a T-cell lymphoma. The treatment consisted of conformational radiation therapy, systemic chemotherapy and intravitreal injections of methotrexate. The median survival after the diagnosis was 24 months. DISCUSSION: PIOL, associated with PCNSL, is the most common type of ocular lymphoma. In most cases, ocular manifestations inaugurate the disease. PIOL is often fatal because of ultimate central nervous system presentation. The role of the ophthalmologist consists in early diagnosis. Typical clinical findings include vitroretinal tumor syndrome but can mascarade other eye pathologies. Diagnosis requires histology. The majority of PIOL is diffused large B-cell lymphoma. Decisions are made through multidisciplinary consultation. PIOL exhibits high responsiveness to methotrexate. CONCLUSION: Through a literature review and many illustrations, we discuss epidemiological, clinical, histological, radiological and treatment characteristics of PIOL associated with PCNSL.

[DSAEK after failed penetrating keratoplasty]. / DSAEK après échec de kératoplastie perforante.

PURPOSE: To report the anatomic and functional outcomes of Descemet's stripping automated endothelial keratoplasty (DSAEK) in 32 eyes after failed penetrating keratoplasty (PK). SUBJECTS AND METHODS: This retrospective, single-center observational study was performed on 32 eyes of 26 patients with failed PK grafts who underwent DSAEK between June 2009 and June 2013 at Clermont-Ferrand University Medical Center. Primary outcomes measured were: graft survival rates, functional improvement (visual acuity), and complications. RESULTS: Mean follow-up was 16.45 months [6-36]. Graft survival at 12 months was 76.1 % [68.1-82.3]. PK grafts cleared in 75 % of cases. Eight primary DSAEKs detached and/or decentered early (prior to day 8, average 6.22 days): 3 underwent repeat DSAEK with a new graft, and 3 underwent conversion to PK. Results were available for 26 patients at 6 months. Mean preoperative best-corrected visual acuity (BCVA) in logMAR increased from 1.48 (counting fingers at 2 meters) to 0.996 logMAR (1/10) at 6 months. BCVA improved in 17 patients (68 %). BCVA improved an average of 5.2 lines (P=0.0006). Eight patients had a large number of comorbid conditions that limited final visual acuity. DISCUSSION: Anatomic outcomes are similar to other studies. Final average BCVA was limited by severe comorbid conditions and performance of DSAEK solely for comfort. Many surgical strategies have been described to decrease graft dislocation and primary graft failure. Adapting graft trephine diameter to the host cornea as measured by AS-OCT, using a nomogram based on posterior corneal curvature obtained on AS-OCT, may be an interesting approach. CONCLUSION: DSAEK allows for quick visual recovery by preserving the anterior corneal curvature. It is an essential option for restoring corneal clarity in PK failure due to endothelial decompensation. A longer follow-up would allow a comparison of graft survival for the two techniques in this context.

[Ocular involvement with Candida albicans: report of 2 cases]. / Atteinte oculaire à Candida albicans : à propos de 2 cas.

INTRODUCTION: Ocular involvement by Candida albicans is rare and may present as endogenous endophthalmitis or choroiditis. It occurs in the context of C. albicans septicemia, in the context of intensive care unit hospitalization or intravenous drug use. We report two cases referred to our department with different characteristics, background, diagnostic modalities and different courses. OBSERVATIONS: A 37-year-old woman, with a history of intravenous drug use, presented with C. albicans endophthalmitis. Intravenous combination antifungal therapy was begun, but vitrectomy and intravitreal amphotericin B were performed due to worsening of the endophthalmitis. The second case was a 53-year-old man who was hospitalized in the intensive care unit for C. albicans septicemia with a left macular chorioretinitis. Intravenous antifungal therapy was initiated and allowed regression of the ocular lesion. DISCUSSION: Our cases illustrate both types of ophthalmic involvement by candidiasis requiring different treatments with well-described recommendations: in the case of endophthalmitis, the use of vitrectomy and intravitreal amphotericin B injection in association with intravenous antifungal treatment, whereas parenteral antifungal treatment is often sufficient in the case of chorioretinitis. CONCLUSION: Early detection, initiation of treatment and ophthalmologic monitoring are difficult but necessary in these populations non-compliant with follow-up or in intensive care units. The management of ocular candidiasis requires good collaboration between the ophthalmology, infectious diseases and intensive care unit departments.

Two cases of bilateral amiodarone-associated optic neuropathy.

INTRODUCTION: The widespread use of amiodarone is limited by its toxicity, notably to the optic nerve. We report two cases of bilateral optic nerve neuropathy due to amiodarone, and provide a detailed description of the disease. OBSERVATIONS: The first case was a 59-year-old man complaining from insidious monocular loss of vision within ten months of initiating amiodarone. Funduscopy and optical coherence tomography showed bilateral optic disc edema. The second case was a 72-year-old man presenting with a decrease in visual acuity in his left eye for a month. Funduscopy showed a left optic nerve edema, and fluorescein angiography showed bilateral papillitis. In both cases, the clinical presentation was not suggestive of ischemic neuropathy, because of the preservation of visual acuity and the insidious onset. In addition, both cardiovascular and inflammatory work-up were normal. An amiodarone-associated neuropathy was suspected, and amiodarone was discontinued with the approval of the cardiologist, with complete regression of the papilledema and a stabilization of visual symptoms. DISCUSSION: Differentiating between amiodarone-associated optic neuropathy and anterior ischemic optic neuropathy may be complicated by the cardiovascular background of such patients. The major criterion is the absence of a severe decrease in visual acuity; other criteria are the normality of cardiovascular and inflammatory work-up, and the improvement or the absence of worsening of symptoms after discontinuation of amiodarone. CONCLUSION: Amiodarone-associated neuropathy remains a diagnosis of exclusion, and requires amiodarone discontinuation, which can only be done with the approval of a cardiologist, and sometimes requires replacement therapy.

[Selective laser trabeculoplasty: results after a first and a second session, overall comparison and results for three indications]. / Trabéculoplastie au laser sélective: résultats après première et deuxième séances, comparaison globale puis dans trois indications.

PURPOSE: To compare the results obtained with SLT trabeculoplasty after an initial treatment (SLT-1) and after a second treatment (SLT-2). Subgroup analysis according to trabecular pigmentation and the existence of a high myopia. MATERIALS AND METHODS: Retrospective study of 77 patients, 152 SLT sessions performed in the Ophthalmology Department of Clermont-Ferrand University Medical Center, 118 SLT-1, 34 SLT-2. Three comparable groups of patients were assembled: group 1 (glaucoma patients with normal or subnormal trabecular pigmentation), group 2 (glaucoma patients with high myopia), and group 3 (glaucoma patients with significant trabecular pigmentation). The results were compared between groups, for SLT-1 and SLT-2. RESULTS: Intraocular pressure lowering was consistent with data reported in the literature. Comparison of the results of SLT-1 versus SLT-2 did not find any significant difference in terms of IOP change. However, after SLT-2, the IOP response appears significantly greater (P=0.03) in the group with significant trabecular pigmentation compared to the non-myopic group with normal trabecular pigmentation. DISCUSSION: Our results are consistent with the literature for efficacy, tolerance and reproducibility of SLT. No reduction in SLT efficacy was observed after a second session. Trabecular pigmentation is not a predictor of the response after the first session. In the case of retreatment (SLT-2), the differences observed lead to the hypothesis that it may be appropriate to perform at least two SLT treatments in patients with significant trabecular pigmentation in order to obtain maximal effect. Myopia, a variable not previously studied, does not seem to influence SLT outcomes. CONCLUSION: Trabecular pigmentation and the presence of myopia do not appear to be predictive of a successful first treatment. However, our study leads us to suggest the hypothesis that the maximal response of SLT in patients with significant trabecular pigmentation is not obtained until after at least two sessions. This observation opens an interesting perspective on the therapeutic strategy to adopt in the case of pigmentary glaucoma.

[Carotid-cavernous fistula: comparison of clinical and neuroradiologic features pre- and post-embolization]. / Fistule carotido-caverneuse : confrontation des aspects cliniques et neuroradiologiques pré- et post-embolisation.

We report the case of an 85-year-old patient, referred by her ophthalmologist for neuro-ophthalmologic consultation at the Clermont-Ferrand University Medical Center, for conjunctival hyperemia and ocular hypertension in the left eye for 12 months. The patient's only past medical history was treated, controlled arterial hypertension and there was no mention of falling or head trauma. MRI (magnetic resonance imaging) and angiography identified a type D carotid-cavernous fistula. Intravenous embolization was performed under general anesthesia by retrograde selective catheterization facial vein and ophthalmic vein and placement of coils into the cavernous sinus, resulting in regression of physical and functional signs immediately after the procedure. This case illustrates the symptoms of spontaneous carotid-cavernous fistula and immediate efficacy of embolization. We report the epidemiology, characteristics and various presentations of the condition.

[Combined hamartoma of the retinal pigment epithelium and retina: case report]. / Hamartome combiné de l'épithélium pigmentaire et de la rétine: à propos d'un cas.

We report the case of a 19-year-old woman with a combined hamartoma of the retinal pigment epithelium and retina incidentally discovered during her first eye exam. By way of this case, we describe and illustrate the epidemiological and clinical characteristics of the condition and its potential complications.

[Optic nerve trauma: case report of partial optic nerve avulsion]. / Papillopathie traumatique: à propos d'un cas d'arrachement partiel du nerf optique.

INTRODUCTION: Partial avulsion of the optic nerve head is a rare and severe complication of ocular blunt trauma. OBSERVATION: We report the case of a 28-year-old man presenting to the emergency department for blunt trauma to his right eye with a basketball. Visual acuity was decreased to hand motion, and fundus examination showed a prepapillary hemorrhage. After five days, the preretinal hematoma spontaneously dispersed into the vitreous cavity. Because of the persistence of an intravitreal hemorrhage and the lack of visual recovery, a vitrectomy was performed 2 months later, leading to the diagnosis of a partial optic nerve avulsion with cicatricial gliosis on fundus exam and angiography. Six months after vitrectomy, the visual acuity was 4/10 P4 in the right eye and the visual field showed an absolute infero-nasal scotoma corresponding to the temporal injury. Seven months later, the visual acuity had decreased progressively, secondary to the development of a macular epiretinal membrane. A membrane peel was performed with a visual acuity recovery to 3/10 P4 after a 3-year follow-up. DISCUSSION: Through a complete literature review, we describe the clinical signs, the mechanism, the treatment and the natural history of this poorly known disease. CONCLUSION: Optic nerve avulsion must be considered in cases of trauma with forced rotation of the eye. Individualized management and monitoring of complications are essential to the preservation of residual visual acuity, especially in case of partial avulsion.

[A case report of syphilitic uveitis and deafness]. / Uvéite syphilitique et surdité : à propos d'un cas.

We report the case of a 43-year-old male patient presenting for neuro-ophthalmologic and uveitis consultation at Clermont-Ferrand University Medical Center for a reduction in visual acuity in his right eye. Two months previously, the patient had complained of decreased hearing on the left, which remained undiagnosed. Fundus examination and fluorescein angiogram showed the appearance of vasculitis with papillitis and a choroidal plaque. TPHA-VDRL serology was positive in blood and cerebrospinal fluid. Internal medicine work-up revealed many associated abnormalities: hyperhomocysteinemia, positive anticardiolipin antibody, positive anti-ß2GP1 antibodies, increased partial thromboplastin time not corrected by the addition of control plasma, presence of an anti-prothrombinase antibody, positive activated protein C resistance. ENT examination showed a left harmonic vestibular syndrome; audiography showed a sensorineural hearing loss of -40 dB. The patient received treatment for neurosyphilis, which led to the disappearance of the vasculitis, the choroidal plaque and the papillitis. From an ENT standpoint, the vestibular syndrome and the left vestibular areflexia resolved. The audiogram improved, with persistence of left hearing loss (about -20 dB) with useful speech intelligibility. Immunologic abnormalities had also disappeared. Our case illustrates the protean presentations of syphilis and its possible association with sensorineural deafness and immunological abnormalities.

[Case report of a 45-year-old man with uveal melanoma and suspect controlateral choroidal nævus]. / Mélanome choroïdien et « tumeur mélanocytaire à potentiel évolutif ¼ controlatérale chez un patient de 45ans, à propos d'un cas.

INTRODUCTION: Uveal melanoma is the most common adult primary intraoculary tumor. Bilateral tumor is very rare, but must not be underestimated because early diagnosis and care improve the survival and the visual prognosis. OBSERVATION: We report the case of a patient treated for a left parapapillary choroidal melanoma by disk of ruthenium ((106)Ru), and a follow-up every 3 months for an atypical choroidal large-sized controlateral nævus levelling the macular area. This right nævus changed in 2009 leading to suspicion of a growing melanoma. Because the visual acuity of the left eye was limited to 20/2000, we wanted to confirm this growth before beginning a treatment. But for 3 years the tumor has remained stable and asymptomatic, with a disease staging still negative. To this day, no curative treatment has been started on the right eye. DISCUSSION: In spite of clinical (To Find Small Ocular Melanomas (TFSOM) for example) and paraclinical arguments, it is sometimes difficult to differentiate a large nævus from an early melanoma. Evolution of the tumor often allows to confirm the diagnosis. However, the sole growth of a nævus is not specific of a choroidal melanoma. When confronted with suspicion of a small choroidal melanoma, some authors recommend an immediate treatment for the tumor; others prefer to confirm without a doubt a tumoral growth. It is necessary to weigh out the iatrogenic risks of a conservative treatment on the visual acuity in a monophtalm patient on one side, and the vital risk for the patient on the other side, which seems to be limited in case of small-sized melanoma with a slow evolution. CONCLUSION: A bilateral choroidal melanoma is rare. Systematic and repeated examinations of both eyes are essential. Management of these complicated cases often leads to discussion.

Plasma levels and systemic safety of 0.1% unpreserved timolol maleate gel, 0.5% timolol aqueous solution and 0.5% timolol maleate gel.

PURPOSE: To compare systemic absorption of three formulations of timolol eye drops: 0.1% timolol maleate gel, 0.5% timolol aqueous solution, and 0.5% timolol maleate gel. METHODS: This was a double cross-over phase I study. Cross-over 1: two weeks of 0.1% timolol gel once daily, followed by a 3-week wash-out period and then two weeks of 0.5% timolol aqueous solution twice a day (group 1) or the reverse (group 2). Cross-over 2: two weeks of 0.1% timolol gel once daily, followed by a 3-week wash-out period, and then two weeks of 0.5% timolol gel once daily (group 3) or the reverse (group 4). Subjects underwent tonometry, blood sampling, and heart rate and blood pressure assessments (during bicycle exercise and head-up tilt tests) before and after instillation at the beginning and end of each treatment period. RESULTS: Forty-three healthy volunteers were randomized: 11 subjects in groups 1, 2, and 3, and 10 subjects in group 4. Areas under the concentration-time curve (AUC) values after administration of timolol 0.5% formulations were 15- to 38-fold higher than those seen after administration of timolol 0.1% gel. Maximum timolol concentrations after instillation of 0.1% gel are reduced by almost 90% compared to concentrations obtained after both 0.5% aqueous solution and 0.5% gel instillation. The AUC between 0 and 12 h post-administration were also reduced by up to 93 to 98%. CONCLUSIONS: After treatment with a timolol 0.1% gel formulation, systemic concentrations found were considerably lower than after administration of timolol 0.5% gel or in aqueous solution.