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Biomedical subjects

L Desjardins

Publications and source records attributed to L Desjardins.

At least 19 recordsLinked to original sources

Proton beam therapy for iris melanomas.

AIMS: To describe the results in terms of local control, eye preservation and systemic evolution of iris melanomas treated by proton beam irradiation. METHODS: Retrospective review of the charts of patients with iris melanoma treated by proton beam therapy between April 1998 and September 2002. Ciliary body melanomas with iris involvement or tumours with extrascleral invasion were excluded. Treatment consisted of 60 Gy of proton beam irradiation delivered in four fractions to the tumour volume. RESULTS: A total of 21 patients were treated, median follow-up of 33 months (8-72 months). 15 patients presented a lesion with documented growth. The median clinical diameter was 5 mm (2-8 mm), the median ultrasound diameter 4.8 mm (2-7.7 mm) The patients were 6% T1, 57.1% T2, and 14.3% T3 all N0M0. The iridocorneal angle was invaded by the tumour in 71.4% of patients. At the end of follow-up, all patients were alive with no proven metastatic disease except one patient with suspicious liver lesions. None of the patients showed tumour progression or ocular relapse. The tumour response at 2 years was a flat lesion for 6.3% of cases, partial regression in 75% and stable in 18.8%. None of the patients required secondary enucleation. The main complication was cataract (45% within 24 months of treatment). Raised intraocular pressure was observed in 15% of patients but no neovascular glaucoma. CONCLUSIONS: Proton beam therapy shows potential utility for selected cases of localised iris melanomas allowing excellent local tumour control and eye preservation. Further follow-up on larger series is needed to confirm these results.

Adolescent↗

Combined proton beam radiotherapy and transpupillary thermotherapy for large uveal melanomas: a randomized study of 151 patients.

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.

Adult↗

[Cavitary choroidal melanoma in a child].

Uveal melanoma is very rare in children, and in both adults and children it can in rare cases develop intralesional cavities resembling an intraocular cyst. The presence of a solid mass at the base and a thick wall surrounding the cavity can assist in differentiating cavitary melanoma from a benign cyst. We report the case of a 5-year-old girl who presented with a large intraocular pigmented mass in the left eye, showing multiple hollow cavities on ocular ultrasonography, CT scan, and MRI. The patient was treated by enucleation and the pathology confirmed the diagnosis of choroidal melanoma. FISH revealed no aberration in chromosome 3.

Child, Preschool↗

[Prognostic factors for malignant uveal melanoma. Retrospective study on 2,241 patients and recent contribution of monosomy-3 research].

INTRODUCTION: We conducted a retrospective study on the clinical factors influencing the local and general prognosis of patients treated for uveal melanoma with a preliminary analysis of the prognostic value of monosomy 3. PATIENTS: and method: The patients sent to Curie Institute for uveal melanoma have a complete initial clinical evaluation, conservative management by radiotherapy or enucleation, and local and general long-term follow-up. Over the last 5 years, the status of chromosome 3 has been assessed by FISH in the tumors of enucleated patients. Findings concerning the initial workup, treatment, and follow-up are recorded prospectively. We conducted a retrospective study with multivariate analysis of the clinical factors influencing local recurrence, ocular conservation metastasis, and survival and studied the effect of monosomy 3. RESULTS: A total of 2241 patients were registered with a median follow-up of 72 months. Of these patients, 92.8% had conservative management with iodine 125 brachytherapy or proton beam therapy and 7.2% of the patients had enucleation (n=160). Tumors from 120 patients were studied for the status of chromosome 3 by FISH. The overall survival rate was 76.3% and the metastatic rate was 19.5%. The clinical factors influencing survival were the size and location of the tumor, age of the patient, gender, and initial treatment. The factors influencing the metastatic risk were the same plus retinal detachment and local recurrence. Monosomy 3 was a significant risk factor for metastatic disease. DISCUSSION: This study found the usual risk factors with the difference that location on the equator seems to be of worse prognosis than ciliary body involvement for survival and metastasis. In addition, the initial retinal detachment appears to be a risk factor for local recurrence and metastasis. At present, the evaluation of chromosome 3 is available for enucleated tumors but it could probably be done on needle biopsy performed during conservative management as well. CONCLUSION: This study confirms previous results on the prognostic factors of uveal melanoma and on the value of monosomy 3. The increasingly precise identification of a group of high-risk patients should allow us to propose adjuvant therapy and to adapt follow-up.

Disease-Free Survival↗

[Functional results of retinoblastoma treatment with local treatment used in isolation or associated with chemotherapy].

INTRODUCTION: Because of long-term complications of external beam radiation in retinoblastoma, a new therapeutic modality using chemotherapy and local treatments is used whenever possible. We conducted a retrospective study to evaluate visual results. PATIENTS AND METHOD: We studied visual acuity and ocular side effects in children presenting uni- or bilateral retinoblastoma in whom we were able to achieve conservative management without external beam treatment. The treatments that were used included chemotherapy, chemothermotherapy, diode laser, iodine 125 plaque brachytherapy, and cryotherapy. The initial characteristics (diameter, subretinal or vitreous seeding, and location) of each tumor, the treatments used, their results, and the visual function after age 4 years were recorded. RESULTS: We treated 429 children for retinoblastoma at the Curie Institute between October 1994 and December 2002. Two hundred twenty-seven eyes had conservative treatment without external beam. We were able to study the visual function in 102 eyes at a median age of 67 months. The median follow-up after the end of the treatment was 5 years. The mean visual acuity was 20/37 and 60% of the children had visual acuity of more than 20/40. Macular alteration was observed in 34 eyes. Statistical analysis showed that a larger tumor diameter of the retinal surface (p<0.0003) and location close to the macula (p<0.0001) were the most significant risk factors for vision loss. CONCLUSION: The visual results of the treatment of retinoblastoma by chemotherapy and local treatments is good when the tumors are not located close to the macula. Larger tumors also have a worse prognosis for vision.

Child, Preschool↗

[Normal and malignant choroidal melanocytes: from cell to clinical approach].

The molecular and cellular basis of human choroidal malignant melanoma progression has remained largely unknown. However, choroidal melanoma is the most important primary intraocular tumor in adults. Developmentally, choroidal melanocytes are of neural crest origin similar to cutaneous melanocytes. However, there are some significant differences between cutaneous and uveal melanocytes that have yet to be fully assessed. The purpose of this study is to describe choroidal melanocytes. We will describe the significant differences between cutaneous and uveal melanocytes as well as the congenital and acquired diseases of uveal melanocytes. We will then describe the cellular and molecular mechanisms involved in melanoma progression.

Cell Proliferation↗

[Results of treating uveal melanoma with proton beam radiation: 10-year follow-up].

PURPOSE: We analyzed the long-term results of uveal melanoma treatment with proton beam irradiation in a series of patients with a follow-up of at least 10 years. PATIENTS AND METHODS: The patients were treated with proton beam radiation between September 1991 and December 1992. They had an initial examination including visual acuity, funduscopy, A and B scan ultrasonography of the eye, fundus photographs and fluorescein angiography. General examination included chest radiography and B scan ultrasonography of the liver. All tumors received a total dose of 60 cobalt-Gray equivalents (applied in four daily fractions) at the Orsay proton therapy center. RESULTS: A total of 167 patients were treated with a median follow-up of 116 months. Their median age was 59 years. Thirteen tumors were anterior to the equator, 76 overlapped the equator and 78 were posterior to the equator. An initial retinal detachment was present in 41 cases. The optic disk was invaded in 10 cases. The median tumor diameter was 12 mm and the median tumor thickness was 5.8 mm. The mean initial acuity was 20/50. The survival rate was 62.93% at 10 years; 72.9% of deaths resulted from metastasis. Statistically significant risk factors for death identified in the multivariate analysis were tumor diameter greater than 12 mm (p=0.0004) and age over 60 years (p=0.0001). The metastasis rate at 10 years was 31%. The liver was affected in 97.8% of these patients. Risk factors for metastasis were the anterior site of the tumor, its volume greater than 0.4 cc and the presence of retinal detachment at diagnosis. The secondary enucleation rate at 10 years was 13.23%, mainly attributable to secondary neovascular glaucoma. The local recurrence rate was 6%. The visual acuity rate in 42.1% of patients was better than 20/100 at 10 years. Visual loss was mainly due to postradiation maculopathy and neuropathy. CONCLUSION: Our study confirms the long-term results found in the literature on proton beam radiation. This therapy allows good tumor control, an excellent eye retention rate, and good final visual acuity for approximately half of the patients.

Adolescent↗

[Benign pigmented lesions of the eyelids].

We describe benign pigmented tumors of the lids, including benign lesions of the epithelium such as papillomas, seborrheic keratosis, and inverted follicular keratosis; precancerous lesions of the epithelium such as xeroderma pigmentosum and actinic keratosis; melanocytic lesions such as Ota nevus, lentigo, and lentigo maligna; and nevi and other lesions simulating a melanoma such as pigmented hidrocystoma, angiomas, and epithelial cyst. For each of these lesions, we describe the clinical and histopathological aspect as well as the therapeutic guidelines.

Eyelid Diseases↗

Multiplex PCR/liquid chromatography assay for detection of gene rearrangements: application to RB1 gene.

Screening for large gene rearrangements is established as an important part of molecular medicine but is also challenging. A variety of robust methods can detect whole-gene deletions, but will fail to detect more subtle rearrangements that may involve a single exon. In this paper, we describe a new, versatile and robust method to assess exon copy number, called multiplex PCR/liquid chromatography assay (MP/LC). Multiple exons are amplified using unlabeled primers, then separated by ion-pair reversed-phase high-performance liquid chromatography (IP-RP-HPLC), and quantitated by fluorescent detection using a post-column intercalation dye. The relative peak intensities for each target directly reflect exon copy number. This novel technique was used to screen a panel of 121 unrelated retinoblastoma patients who were tested previously using a reference strategy. MP/LC correctly scored all deletions and demonstrated a previously undetected RB1 duplication, the first to be described. MP/LC appears to be an easy, versatile, and cost-effective method, which is particularly relevant to denaturing HPLC (DHPLC) users since it broadens the spectrum of available applications on a DHPLC system.

Base Sequence↗

Single-arm study of bridging therapy with low-molecular-weight heparin for patients at risk of arterial embolism who require temporary interruption of warfarin.

BACKGROUND: When warfarin is interrupted for surgery, low-molecular-weight heparin is often used as bridging therapy. However, this practice has never been evaluated in a large prospective study. This study was designed to assess the efficacy and safety of bridging therapy with low-molecular-weight heparin initiated out of hospital. METHODS AND RESULTS: This was a prospective, multicenter, single-arm cohort study of patients at high risk of arterial embolism (prosthetic valves and atrial fibrillation with a major risk factor). Warfarin was held for 5 days preoperatively. Low-molecular-weight heparin was given 3 days preoperatively and at least 4 days postoperatively. Patients were followed up for 3 months for thromboembolism and bleeding. Eleven Canadian tertiary care academic centers participated; 224 patients were enrolled. Eight patients (3.6%; 95% CI, 1.8 to 6.9) had an episode of thromboembolism, of which 2 (0.9%; 95% CI, 0.2 to 3.2) were judged to be due to cardioembolism. Of these 8 episodes of thromboembolism, 6 occurred in patients who had warfarin deferred or withdrawn because of bleeding. There were 15 episodes of major bleeding (6.7%; 95% CI, 4.1 to 10.8): 8 occurred intraoperatively or early postoperatively before low-molecular-weight heparin was restarted, 5 occurred in the first postoperative week after low-molecular-weight heparin was restarted, and 2 occurred well after low-molecular-weight heparin was stopped. There were no deaths. CONCLUSIONS: Bridging therapy with subcutaneous low-molecular-weight heparin is feasible; however, the optimal approach for the management of patients who require temporary interruption of warfarin to have invasive procedures is uncertain.

Anticoagulants↗

Comprehensive screening for constitutional RB1 mutations by DHPLC and QMPSF.

Constitutional mutations of the RB1 gene are associated with a predisposition to retinoblastoma. It is essential to identify these mutations to provide appropriate genetic counseling in retinoblastoma patients, but this represents an extremely challenging task, as the vast majority of mutations are unique and spread over the entire coding sequence. Since 2001, we have implemented RB1 testing on a routine basis as part of the clinical management of retinoblastoma. As most screening techniques do not meet the requirements for efficient RB1 testing, we have devised a semi-automated denaturing high-performance liquid chromatography (DHPLC) method for point mutation detection combined with a quantitative multiplex PCR of short fluorescent fragments (QMPSF) approach to screen for gene rearrangements. We report the results of this comprehensive screening of all exons and promoter of RB1 in 192 unrelated patients, mostly of French origin. Among 102 bilateral and/or familial cases and 90 unilateral sporadic probands, mutations were identified in 83 (81.5%) and 5 (5.5%) cases, respectively. A total of 43 mutations have not been previously reported. The mutational spectrum was found to be significantly different from previous published series, displaying a surprising amount of splice mutations and large deletions. This study demonstrates the reliability of DHPLC for RB1 analysis, but also illustrates the need for a deletion scanning approach. Finally, considering the benefits to retinoblastoma patients, RB1 testing should be widely implemented in routine healthcare because our study clearly illustrates its feasibility.

Child, Preschool↗

[Anterior segment tumor imaging: advantages of ultrasound (10, 20 and 50 MHz) and optical coherence tomography].

PURPOSE: Detail the role of different imaging techniques for diagnosis of tumors of the iris. MATERIAL AND METHODS: Sixty-one tumors of the iris were explored using ultrasound at 10 and 20MHz (Cinescan, BVI Quantel Medical) and 50MHz (UBM, Paradigm) and optical coherence tomography (OCT) (Humphrey Zeiss). RESULTS: Ultrasound should be used at frequencies of 20MHz or greater to precisely characterize, localize and measure a lesion. Ultrasound biomicroscopy (UBM) is inadequate to measure large tumors (extending toward the back of the ciliary body), because of the transducer and the considerably lower image quality caused by the lesion. Ultrasound alone cannot characterize a solid lesion, and moreover cannot differentiate benign and malignant lesions. Clinical notions are also important in diagnosis and patient management. OCT recognizes whether a lesion is liquid or solid in certain cases. CONCLUSIONS: With a tumor that seems solid, a 50MHz examination must be done rapidly, and if the entire lesion is difficult to see, a 20MHz ultrasound should be used. With a protruding iris, high-frequency ultrasound and OCT differentiate a cystic lesion from a solid mass, but only BMU provides a precise measurement and regular surveillance capabilities.

Anterior Eye Segment↗

125I plaque brachytherapy for anterior uveal melanomas.

PURPOSE: To describe the results of 125I plaque brachytherapy of uveal melanomas anterior to the equator in terms of local control and the associated complications while trying to identify their risk factors (patients' demographic data, ocular, and tumour characteristics). METHODS: Retrospective analysis of a series of patients treated by 125I between 1990 and 2000 in a single institution. The main outcome measures are evaluation of local tumour control and complications associated with 125I plaque brachytherapy of these melanomas. RESULTS: During the study period, 136 patients were treated for an anterior tumour. The median follow-up was 62 months. The overall 5-year survival rate was 88.3%, the 5-year metastasis rate was 4% and the local recurrence rate was 1.5%. The mean final visual acuity was 20/40. The ocular complications most frequently observed at 5 years were cataract (50.3%), maculopathy (18.3%), intraocular inflammation (19.3%), and glaucoma (10.6%). Optic neuropathy, retinal detachment, keratitis, and intravitreous haemorrhage were also described. Risk factors for worse survival were age greater than 65 years and initial tumour thickness greater than 4 mm. Risk factors for the development of cataract were age more than 65 years old, male gender, and tumour diameter of more than 10 mm. Risk factors for intraocular inflammation were tumour thickness of more than 4 mm and invasion of the ciliary body. CONCLUSIONS: The use of 125I plaque brachytherapy to treat melanomas situated anterior to the equator allows good local and systemic control with a low rate of macular and optic disc complications. The most frequent complication was cataract formation.

Adult↗

Comparison of 1 month with 3 months of anticoagulation for a first episode of venous thromboembolism associated with a transient risk factor.

BACKGROUND: The risk of recurrence is lower after treatment of an episode of venous thromboembolism associated with a transient risk factor, such as recent surgery, than after an episode associated with a permanent, or no, risk factor. Retrospective analyses suggest that 1 month of anticoagulation is adequate for patients whose venous thromboembolic event was provoked by a transient risk factor. METHODS: In this double-blind study, patients who had completed 1 month of anticoagulant therapy for a first episode of venous thromboembolism provoked by a transient risk factor were randomly assigned to continue warfarin or to placebo for an additional 2 months. Our goal was to determine if the duration of treatment could be reduced without increasing the rate of recurrent venous thromboembolism during 11 months of follow-up. RESULTS: Of 84 patients assigned to placebo, five (6.0%) had recurrent venous thromboembolism, compared with three of 81 (3.7%) assigned to warfarin, resulting in an absolute risk difference of 2.3%[95% confidence interval (CI) - 5.2, 10.0]. The incidence of recurrent venous thromboembolism after discontinuation of warfarin was 6.8% per patient-year in those who received warfarin for 1 month and 3.2% per patient-year in those who received warfarin for 3 months (rate difference of 3.6% per patient-year; 95% CI - 3.8, 11.0). There were no major bleeds in either group. CONCLUSION: Duration of anticoagulant therapy for venous thromboembolism provoked by a transient risk factor should not be reduced from 3 months to 1 month as this is likely to increase recurrent venous thromboembolism without achieving a clinically important decrease in bleeding.

Adult↗

Neoadjuvant chemotherapy for extensive unilateral retinoblastoma.

AIM: The role of neoadjuvant chemotherapy was studied when first line enucleation cannot be safely performed in unilateral extensive retinoblastoma (major buphthalmia or radiologically detectable optic nerve involvement). METHODS: Six patients, referred for unilateral retinoblastoma, presented with major buphthalmia (two) or optic nerve invasion (four): they were treated by neoadjuvant chemotherapy using etoposide and carboplatin. RESULTS: Good tumour response was observed in the two patients with buphthalmia and in three of four cases with optic nerve involvement. Meningeal progressive disease was observed in the last patient. The five patients without disease progression were then operated on: anterior enucleation in the patients with buphthalmia and enucleation via a double neurosurgical and ophthalmological approach with prechiasmatic optic nerve section in the other three cases. Postoperative chemotherapy was performed in these five patients. Local radiotherapy to the chiasmatic region and posterior part of the optic canal was necessary in only one patient. The non-operated patient died with disease progression 6 months after the diagnosis. The other five patients are alive with a follow up of 12, 15, 21, 36, and 40 months after stopping treatment. CONCLUSION: Neoadjuvant chemotherapy can be useful in extensive unilateral retinoblastoma with buphthalmia and/or radiological optic nerve invasion at diagnosis.

Antineoplastic Combined Chemotherapy Protocols↗

[Radiotherapy in the treatment of eyelid tumors].

We describe the different radiation therapy techniques for malignant tumors of the eyelid, their results in squamous-cell and basal-cell carcinoma, their side effects, and the advantages and disadvantages compared to surgery. The most frequent indications for radiation in the management of these tumors are also reviewed.

Brachytherapy↗

[Bilateral uveal melanomas. Five case reports].

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.

Aged↗

[Diode laser thermotherapy and chemothermotherapy in the treatment of retinoblastoma].

INTRODUCTION: The use of transpupillary thermotherapy alone or associated with systemic chemotherapy is a therapeutic modality of ocular retinoblastoma that allows ocular preservation without external beam irradiation of the eye. We present our experience with thermotherapy in the treatment of selected cases of retinoblastoma. MATERIAL AND METHODS: This paper reports a retrospective case series of patients treated for retinoblastoma by thermotherapy or chemothermotherapy (carboplatin IV followed by thermotherapy) in a single institution from October 1994 to December 2000. Data collected include general characteristics of the treated children, tumor characteristics, and the results of the treatments on local tumor control. Transpupillar thermotherapy was delivered with a diode laser through an operating microscope. Each tumor was treated separately and laser intensity, spot size, and duration were adapted to the size of the tumor and the clinical response. Chemothermotherapy consisted in thermotherapy delivered shortly after an intravenous injection of carboplatin (560 mg/m(2)) at day 1, followed by thermotherapy alone at day 8 if the lesion was 6mm or more in diameter. This cycle was administered every 28 days. The choice between thermotherapy and chemothermotherapy depended on the initial size of the lesions. Thermotherapy was used when the lesion measured 3mm or less. Lesions measuring more than 15 mm, or associated with substantial vitreous seeding, retinal detachment, or optic nerve head involvement are not suitable for these techniques. RESULTS: During the study period, 239 children were treated in our institution and 109 of them (147 eyes, 372 tumors) could be treated conservatively without external beam radiation. The median tumor diameter at the moment of thermotherapy or chemothermotherapy was 2mm (range, 0.2-15.0mm). One hundred and ninety-four tumors were treated by chemothermotherapy and 18 by thermotherapy alone. In 75% of the cases, the treatment was administered after two courses of chemotherapy (etoposide and carboplatin). After a mean follow-up of 55 months (range, 16-89 months), tumor control was obtained in 87.1% of lesions after chemothermotherapy and 77.8% after thermotherapy. Salvage enucleation was necessary for seven lesions (seven eyes) but none in the cases where thermotherapy was used alone. No severe systemic side effects were noted. DISCUSSION: Diode laser delivers hyperthermia on the tumor bed and its use alone or in association with systemic administration of carboplatin makes it possible to preserve the eye without external beam irradiation, with few side effects and less cumulative doses of chemotherapy. CONCLUSION: Thermotherapy and chemothermotherapy provide excellent local tumor control and eye preservation in selected cases of retinoblastoma.

Antineoplastic Agents↗