Injection Of Melphalan Research Articles

Liposomal Phenylephrine Nanoparticles Enhance the Antitumor Activity of Intratumoral Chemotherapy in a Preclinical Model of Melanoma.

Intratumoral injection of anticancer agents has limited efficacy and is not routinely used for most cancers. In this study, we aimed to improve the efficacy of intratumoral chemotherapy using a novel approach comprising peri-tumoral injection of sustained-release liposomal nanoparticles containing phenylephrine, which is a potent vasoconstrictor. Using a preclinical model of melanoma, we have previously shown that systemically administered (intravenous) phenylephrine could transiently shunt blood flow to the tumor at the time of drug delivery, which in turn improved antitumor responses. This approach was called dynamic control of tumor-associated vessels. Herein, we used liposomal phenylephrine nanoparticles as a "local" dynamic control strategy for the B16 melanoma. Local dynamic control was shown to increase the retention and exposure time of tumors to intratumorally injected chemotherapy (melphalan). C57BL/6 mice bearing B16 tumors were treated with intratumoral melphalan and peri-tumoral injection of sustained-release liposomal phenylephrine nanoparticles (i.e., the local dynamic control protocol). These mice had statistically significantly improved antitumor responses compared to melphalan alone (p = 0.0011), whereby 58.3% obtained long-term complete clinical response. Our novel approach of local dynamic control demonstrated significantly enhanced antitumor efficacy and is the subject of future clinical trials being designed by our group.

Clinical and pathomorphological changes in the rabbit retina after an injection of various doses of the cytostatic melphalan

Background: In recent years, there have been individual reports on intracameral chemotherapy (ICC) for aqueous seeding in retinoblastoma. The effect of melphalan on the structures of the ocular anterior segment (including the cornea, iris and anterior lens capsule) is however, still unknown, since no relevant experimental studies have been carried out so far. Purpose: To experimentally assess the changes in the rabbit anterior segment induced by intracameral injection of various concentrations of the alkylating cytostatic melphalan. Material and Methods: Twelve adult Chinchilla rabbits (22 eyes; age, 5–6 months; weight, 2.5–3 kg) were involved in this experimental study and maintained in the vivarium of the Filatov institute in separate cages under standard conditions. Results: After a 5-µg melphalan injection, corneal and iris changes were reversible and the lens was still clear. With an increase in melphalan concentration in injection solution (to 10, 15 and 20 µg) and time point (to 1 month and 3 weeks) after injection, degenerative changes in some epithelial cells of the iris became irreversible, anterior capsular cataract developed, but the cornea and anterior chamber aqueous remained clear. After a single 20-µg intracameral injection of melphalan, there was depigmentation of the iris, posterior synechia and anterior capsular cataract. Conclusion: Clinical and ultrastructural responses of ocular anterior segment tissue to intracameral melphalan injection depended on the injected dose and time point after injection. Most cells of examined tissues showed the capability to restore their ultrastructure following ceasing of the toxic effect of the drug.

Paraganglioma with high-grade intraepithelial neoplasia in the oesophagus treated by endoscopic submucosal dissection.

A 37-year-old woman was hospitalised with a 4-month history of retrosternal pain. Gastroscopy revealed a protrusion lesion of approximately 0.6 cm in diameter in the left wall of the oesophagus, approximately 27 cm from the incisor (Fig. 1). Consequently, one biopsy specimen was taken from the oesophagus. Based on the pathology and immunohistochemistry findings, the patient was initially diagnosed with paraganglioma with high-grade squamous intraepithelial neoplasia. The patient underwent endoscopic submucosal dissection 12 days after the biopsy. The protrusion lesion was again observed under gastroscopy, with visible scarring on the surface (Fig. 2A). A hypoechoic and heterogeneous mass of about 7.1 mm × 2.0 mm in the muscularis mucosae layer was detected on endoscopic ultrasonography (Fig. 2B). The mass was excised after submucosal injection of adrenaline, melphalan, and glycerol fructose injection (Fig. 2C). The postoperative gross specimen was a mucosal tissue measuring 2 cm × 1.8 cm × 0.2 cm, with a bulging mass underneath (Fig. 2D). The results of immunohistochemical analysis were positive for CD56, Syn, CK8/18, LCK, and S-100 and negative for SSTR2 (Fig. 3D, E). Expression of wild-type P53, focal positivity of CgA, and weak positivity of NSE were noted. The Ki-67 labelling index was 1–2%. The diagnosis of paraganglioma with high-grade squamous intraepithelial neoplasia was confirmed based on the histopathology findings (Fig. 3A, B, C). The patient recovered well during the follow-up. Fig. 2(A) The protrusion lesion was found again under gastroscopy, with visible scarring on the surface. (B) Endoscopic ultrasonography detected a hypoechoic and heterogeneous mass of about 7.1 mm × 2.0 mm in the muscularis mucosae layer. (C) Adrenaline, melphalan and glycerol fructose injection was injected in the submucosa after the lesion was marked with a dual knife. (D) Gross specimen after endoscopic submucosal dissection. View Large Image Figure Viewer Download Hi-res image Fig. 3Microscopic examination. (A) Significant cytological atypia in squamous epithelium with continuous basement membrane, and arrangement of the cells in nests (“Zellballen”) in muscularis mucosae. (HE stain × 4) (B) The tumour was composed of chief cells and sustentacular cells. (HE stain × 10) (C) The chief cell is polygonal with a fine granular cytoplasm of acidophilia as well as basophilia. The nucleus is round to elliptical. The sustentacular cells of spindle-shape are distributed around the tumour cell nests or interdigitated amongst the sustentacular cells. (HE stain × 40) (D) positivity of S-100 protein (× 10). (E) positivity of Syn. (× 10). View Large Image Figure Viewer Download Hi-res image

Efficacy of intravitreal injections of melphalan in the treatment of retinoblastoma vitreous seeding.

The introduction of intravitreal injections of melphalan (IVIM) has significantly improved the efficacy of retinoblastoma treatment and the prognosis for eye preservation. To evaluate the results of using IVIM to treat retinoblastoma vitreous seeding. This was a clinical, retrospective, single-center study. Twenty-six children (27 eyes) who met all of the following inclusion criteria qualified for the study: 1) active vitreous seeding at the time of retinoblastoma diagnosis; 2) IVIM performed between 1 January 2017 and 30 September 2020; and 3) a minimum follow-up period of 12 months since the last IVIM. Doses of 20-40 μg melphalan per injection were used. The eye observation period from the last IVIM to the last ophthalmic examination averaged 32.41 months (median 30.00; range 13.00-56.00). Success (no active tumors in the vitreous body) was achieved in 24 eyes (88.9%), and a doubtful result (recurrence in the retina with a difficult-to-determine etiology) in 2 eyes (7.4%). In 1 eye (3.7%), despite treatment, active tumors were still present in the vitreous body. Out of all 27 eyes, 4 eyeballs were removed, but the direct cause of enucleation was not vitreous seeding. There were no complications in the form of intraocular inflammation, extraocular retinoblastoma or distant metastases. There was 1 case of anterior uveitis and 1 case of cataract. The IVIM is a highly effective and safe form of treatment for retinoblastoma vitreous seeding.

Vitreous metastasis from cutaneous melanoma: diagnosis and management

Purpose: To report the clinical findings, treatments, and outcomes in a series of patients with vitreous metastasis from cutaneous melanoma. Methods: This single-center, retrospective, interventional case series included patients with biopsy-confirmed vitreous metastasis from cutaneous melanoma diagnosed between 1997 and 2020. Standard 23- or 25-gauge pars plana vitrectomy was performed for diagnostic sampling. Sclerotomies were treated with double or triple freeze-thaw cryotherapy. Perioperative intravitreal injections of melphalan (32 µg/0.075 mL) were administered, when indicated. Visual acuity, intraocular pressure, and systemic and ocular treatment responses were reported. Results: Five eyes of five patients with unilateral vitreous metastasis from cutaneous melanoma were identified. The median age at diagnosis was 84 (range, 37-88) years. The median follow-up after ophthalmic diagnosis was 28 (8.5-36) months; one patient did not have a follow-up. The initial visual acuity ranged from 20/30 to hand motions. Baseline clinical findings included pigmented or non-pigmented cellular infiltration of the vitreous (5/5), anterior segment (4/5), and retina (3/5). Four patients had secondary glaucoma. Systemic therapy included checkpoint inhibitor immunotherapy (n=3, all with partial/complete response), systemic chemotherapy (n=2), surgical resection (n=3), and radiation (n=2). The median time from primary diagnosis to vitreous metastasis was 2 (2-15) years. One patient had an active systemic disease at the time of vitreous metastasis. The final visual acuity ranged from 20/40 to no light perception. Ophthalmic treatment included vitrectomy in all five patients, intravitreal administration of melphalan in three, and intravitreal administration of methotrexate in one. One patient required enucleation, and histopathology revealed extensive invasion by melanoma cells. Conclusions: Vitreous metastasis from cutaneous melanoma can present as a diffuse infiltration of pigmented or non-pigmented cells into the vitreous and may be misdiagnosed as uveitis. Diagnostic pars plana vitrectomy and periodic intravitreal chemotherapy may be indicated.

Ten-year experience with intracameral chemotherapy for aqueous seeding in retinoblastoma: long-term efficacy, safety and toxicity

AimsTo report long-term results of intracameral chemotherapy (ICC) for aqueous seeding (AS) in retinoblastoma.MethodsRetrospective study including 20 patients with primary (n=4) or secondary non-iatrogenic (n=16) AS treated with ICC according...

RetinoblastomainAdults: Clinical Features, Gene Mutations and Treatment Outcomes: A Study of Six Cases.

PurposeTo report six Asian adult patients with retinoblastoma (RB).DesignRetrospective and observational small case series.ParticipantsSix patients with a white dome-shaped tumor of the retina were evaluated from May 10, 1995, to September 10, 2021.Main Outcome MeasuresInitial tumor and associated fundus features, pathology, gene mutation, treatment, tumor course on follow-up, and salvage globe outcome.ResultsThe six affected Asian patients consisted of three men and three women. The mean age at the time of diagnosis was 36.5 years (median: 31 years, range: 20-55 years). All patients were unilateral. In all cases, the tumors were white, dome-shaped, with full-thickness retinal involvement, and mushroom-like protrusions into the vitreous cavity. The mean tumor thickness measured by ultrasonography was 4.5 mm (median: 3.2 mm, range: 3.2-6.8 mm). Associated characteristic symptoms included dilated retinal feeding artery and draining vein (100%), surrounding subretinal infiltration (83%), exudative retinal detachment (83%), and vitreous seeds (67%). Local tumor resection was performed in three patients, I-125 plaque brachytherapy combined with transpupillary thermotherapy (TTT) and intravitreous injection of melphalan (combination treatment) in one patient, I-125 plaque brachytherapy in two patients, and enucleation in one (20%) patient. RB1 gene testing was carried out on four patients and pathological diagnosis on five patients. Genetic analysis revealed that the RB1 mutation was a mosaic c.709dupG (p.Glu237GlyfsTer4) duplication in one patient, a mosaic c.763C>T(p.Arg255Ter) mutation in another patient, while the remaining two patients were RB1 negative. At the end of the follow-up, none of the patients had developed tumor-related metastasis or died. The findings were consistent in all patients who had an adequate follow-up. This study focused on this rare lesion to distinguish it from other intraocular white lesions in adults, including choroidal osteoma, vitreoretinal lymphoma, and retinal capillary hemangioma, all of which are different clinical entities.ConclusionIn adults, RB is typically a white, full-thickness retinal mass that is unilateral, often combining with retinal feeding vessels, subretinal infiltration, and vitreous seeds. Genetic studies on adult-onset RB are essential and still require elucidation. Despite RB being a malignant tumor, patient survival was minimally affected.

Ocular and systemic toxicity of high-dose intravitreal topotecan in rabbits: Implications for retinoblastoma treatment

Although many more eyes of children with retinoblastoma are salvaged now compared to just 10 years ago, the control of vitreous seeding remains a challenge. The introduction of intravitreal injection of melphalan has enabled more eyes to be salvaged safely but with definite retinal toxicity. Intensive treatment with high-dose intravitreal topotecan may be a strategy to control tumor burden because of its cell cycle-dependent cytotoxicity and the proven safety in humans. Therefore, we evaluated the ocular and systemic safety of repeated high-dose intravitreal injections of topotecan in rabbits.Systemic and ocular toxicity was assessed in non-tumor-bearing rabbits after four weekly injections of three doses of topotecan (10 μg, 25 μg, and 50 μg) or vehicle alone. Animals were evaluated weekly for general and ophthalmic clinical status. One week after the last injection, vitreous and plasma samples were collected for drug quantification and the enucleated eyes were subjected to histological assessment.Weight, hair loss, or changes in hematologic values were absent during the study period across all animal groups. Eyes injected with all topotecan doses or vehicle showed no signs of anterior segment inflammation, clinical or histologic evidence of damage to the retina, and ERG parameters remained unaltered throughout the study. Vitreous and plasma topotecan lactone concentrations were undetectable.Four weekly intravitreal injections of topotecan up to 50 μg in the animal model or a 100 μg human equivalent dose were not toxic for the rabbit eye. High doses of topotecan may show promising translation to the clinic for the management of difficult-to-treat retinoblastoma vitreous seeds.

Combination of Brachytherapy and Intravitreal Chemotherapy in the Treatment of Retinoblastoma with Vitreous Seeding

Purpose: The aim of this study was to report the efficacy of combined intravitreal chemotherapy (IVC) and ruthenium-106 brachytherapy in retinoblastoma, either as first-line or second-line treatment, following systemic chemoreduction or intra-arterial chemotherapy. Methods: Retrospective data of 18 eyes from 18 patients treated with IVC and brachytherapy from August 2014 to December 2019 were collected. Results: The method described was our first-line therapy in 6 patients, whereas it was used as second-line treatment after chemoreduction in the remaining 12 patients. The eyes showed the following classification at initial presentation: 2 group B eyes, 3 group C eyes, and 13 group D eyes. The mean follow-up was 19.5 months (range 2–53 months). The mean patient age at brachytherapy was 34.0 months (range 15–83 months). The median prescribed dose at the tumour base and apex was 574.5 ± 306.7 Gy and 88.5 ± 12.2 Gy, respectively. The ocular retention rate was 66.7%. Six eyes had to be enucleated due to uncontrollable subretinal and recurrent vitreous seeding, tumour relapse, recurrence of a solid tumour elsewhere in the eye, and persistent vitreous bleeding with loss of tumour control. The mean number of intravitreal injections of melphalan was 5.0. Two patients received a simultaneous injection of topotecan for insufficient therapeutic response. With regard to radiogenic complications, we could observe temporary retinal and vitreous bleeding (27.8%), serous retinal detachment (44.4%), and radiogenic maculopathy and retinopathy (11.1%). None of the children showed metastatic disease during follow-up. Conclusion: Ruthenium-106 plaque therapy in combination with IVC is an effective local therapy with good tumour control rates even in advanced eyes. Overall, the analysed therapeutic approach shows an acceptable side-effect profile, especially when considering that external-beam radiation therapy and systemic polychemotherapy or at least the number of cycles needed, with their increased incidence of adverse events, can thus be avoided.

Less is more: new one-step intracameral chemotherapy technique.

Purpose: To describe the feasibility of a new one-step approach to aspirate the aqueous and apply melphalan in a single-go without repeated entries into the anterior chamber.Methods: This retrospective non-comparative study was conducted at a referral center and included 12 patients. The one-step approach is described in a step-wise manner. No complications were observed among the patients.Results: One single injection of intracameral melphalan proved to be a successful treatment in nine cases. Two patients required a second injection, which was administered two weeks after the first one following the same technique.Conclusions: This proved to be a reasonable technique for the smooth application of melphalan in the anterior chamber studded with retinoblastoma seeds. Our outcomes revealed that it is an effective, quick, and cost-effective technique. Longer-term data collection is underway, though initial findings are encouraging.

Management of cataracts secondary to intravitreal chemotherapy injections for retinoblastoma seeding.

To report our experience in the management of cataracts presumably due to intravitreal chemotherapy administration in eyes with vitreous disease associated with retinoblastoma. This retrospective study consisted of a cohort of five eyes of five retinoblastoma patients who developed cataracts secondary to intravitreal chemotherapy administration and who then underwent cataract surgery. All patients underwent lensectomy and anterior vitrectomy with/without intraocular lens implantation via clear corneal approach. All cases were administered intraoperative intravitreal melphalan (35-40 mcg) and topotecan (10-20 mcg) at the end of cataract surgery as a preventive measure against retinoblastoma spread. Injections were repeated as needed in monthly follow-ups. Main outcome measures were enucleation rate and disease-free survival time. The age at surgery ranged between 5 and 10 years. Follow-up time varied from 12 to 16 months. Treatment-free period before surgery ranged between 3 and 20 months. Time from last injection to cataract detection was: 2, 2, 10, 6, and 7 months; and time from last injection to cataract surgery was: 8, 3, 20, 7, and 15 months in cases 1-5, respectively. None of the eyes required enucleation. Tumor control was achieved in all patients at the end of follow-up. Injection of melphalan and topotecan into anterior parts of the vitreous may lead to cataract formation. This can be safely managed with lensectomy and anterior vitrectomy and the use of intravitreal administration of melphalan and topotecan at the conclusion of the surgery as a precautionary measure against the potential risk of extraocular spread.

Outcomes of intravitreal melphalan for vitreous seedings in retinoblastoma resistant to systemic chemotherapy

PurposeTo determine the efficacy of intravitreal injection of melphalan for vitreous seedings resistant to systemic chemotherapy. Methods and materialProspective non comparative study investigates 105 consecutive eyes of 105 retinoblastoma patients in a tertiary care hospital. Patients with persistent or recurrent vitreous seeds were included in the study. Injection melphalan was prepared under aseptic conditions. Injection was given at 2–4 mm away from the limbus using 27gauge needle. Cryotherapy was applied at injection site before and during removal of needle. Eye was copiously irrigated soon after the injection to minimize the chances of surface toxicity. After injection intravitreal melphalan, eye pad was applied for 2 h and patients were instructed to instill topical antibiotic and steroid drops for one week. Patients were examined the next day and then weekly till 3rd week. At each follow up, examination under microscope (EUA) and indirect ophthalmoscopy was done. Retinal images were taken using retcam MII for comparison with the previous ones. ResultsTwenty-five (23.8%) out of 105 eyes showed complete regression of vitreous seeds with one injection of intravitreal melphalan after one month. Thirty-one (29.5%) eyes required further 3 intravitreal injections for complete regression, while thirty-four (32.4%) eyes required further 6 intravitreal injections for complete regression. Fifteen (14.3%) eyes did not show regression of vitreous seeds even after 6 intravitreal injections and were planned for second line chemotherapy. ConclusionIntravitreal injection melphalan shows promising results in the treatment of vitreous seeds in retinoblastoma, resistant to systemic chemotherapy.

Vitreous Seed Classification and Regression Patterns in Eyes With Retinoblastoma.

This work subclassifies retinoblastoma vitreous seeds and evaluates the efficacy, regression patterns, and adverse effects of combination intravitreal melphalan and topotecan chemotherapy for resistant and recurrent vitreous seeds. A retrospective review of medical records was conducted of patients with retinoblastoma and resistant or recurrent vitreous seeds who were treated with intravitreal melphalan and topotecan injections from August 2014 to July 2018. Main outcome measures included regression pattern, time for regression, time for recurrence of seeds, treatment outcomes, and ocular toxicity. Nineteen eyes received 138 intravitreal injections over 74 treatment sessions (mean, 7.26 injections per eye); vitreous seeds regressed in 18 eyes. Of cloud vitreous seeds, curvilinear (n = 2) and sphero-linear (n = 2) subtypes were observed. During regression, some sphere seeds showed an intermediary streak-like pattern and took longer to regress (mean, 11.13 ± 14.05 months and 11.67 ± 8.62 injections) than those without the intermediary streak-like pattern (mean, 3.55 ± 2.57 months and 4.2 ± 1.87 injections). Mean follow-up was 34.87 ± 21.09 months (median, 35 months; range, 11-96 months). Anterior segment toxicity was seen in 10 (53%) eyes and posterior segment toxicity in 5 (26%) eyes. Kaplan-Meier survival estimates for globe salvage at 2 years was 94% and 73% at 5 years. Kaplan-Meier survival for vitreous seed-free status was 94% at 2 years and 65% at 5 years. An expanded vitreous seed classification system that further subcategorizes hitherto unrecognized vitreous seed morphology is needed. An intermediate streaking process results in a prolonged regression time for sphere vitreous seeds.

Successful treatment of ciliary body medulloepithelioma with intraocular melphalan chemotherapy: a case report

BackgroundIntraocular medulloepithelioma is commonly treated with primary enucleation. Conservative treatment options include brachytherapy, local resection and/or cryotherapy in selected cases. We report for the first time the use of targeted chemotherapy to treat a ciliary body medulloepithelioma with aqueous and vitreous seeding.Case presentationA 17-month-old boy with a diagnosis of ciliary body medulloepithelioma with concomitant seeding and neovascular glaucoma in the right eye was seen for a second opinion after parental refusal of enucleation. Examination under anesthesia showed multiple free-floating cysts in the pupillary area associated with iris neovascularization and a subluxated and notched lens. Ultrasound biomicroscopy revealed a partially cystic mass adjacent to the ciliary body between the 5 and 9 o’clock meridians as well as multiple nodules in the posterior chamber invading the anterior vitreous inferiorly. Fluorescein angiography demonstrated peripheral retinal ischemia. Left eye was unremarkable. Diagnosis of intraocular medulloepithelioma with no extraocular invasion was confirmed and conservative treatment initiated with combined intracameral and intravitreal melphalan injections given according to the previously described safety-enhanced technique. Ciliary tumor and seeding totally regressed after a total of 3 combined intracameral (total dose 8.1 μg) and intravitreal (total dose 70 μg) melphalan injections given every 7–10 days. Ischemic retina was treated with cryoablation as necessary. Three years later, ab interno trabeculotomy followed by 360° gonioscopy-assisted transluminal trabeculotomy 6 months later was performed for uncontrolled intraocular pressure despite antihypertensive drugs combined to cyclophotocoagulation and 7 intravitreal anti-VEGF injections for recurrent iris neovascularization. Cataract was removed at the same operative time. The child has remained disease- and metastasis-free at a 5-year follow-up since the last melphalan injection (25-month follow-up after the combined lensectomy-trabeculotomy) with a controlled intraocular pressure under topical quadritherapy and a best corrected Snellen visual acuity of 0.08.ConclusionsWe report for the first time complete regression of a non-infiltrating ciliary body medulloepithelioma with seeding achieved with only a small number of intracameral and intravitreal melphalan injections. Concomitant secondary neovascular glaucoma and cataract needed appropriate management to allow long-term eye and vision preservation.

Intravitreal melphalan therapy for vitreous seeds in retinoblastoma: Implementation and outcomes of a new chemotherapy protocol.

Retinoblastoma is the most common paediatric ocular tumour, which appears in the retina. Without treatment, retinoblastoma grows and destroys the internal ocular globe architecture, even leading to metastasis. When treated, overall survival is close to 97%, the alkylating drug melphalan being the most extensively used chemotherapeutic agent in localised treatment. The aim of this study is to describe the implementation of a new intravitreal chemotherapy retinoblastoma treatment protocol for children implanting vitreous seeds through intravitreal melphalan injections and to evaluate the patients' health outcomes treated with it. Between December 2014 and July 2018, seven patients were treated with this protocol. They received a mean of 3.3 cycles of intravitreal melphalan with standard doses of 30 mcg per cycle. In the seven eyes treated in our hospital, the response was as expected; three eyes with vitreous seedings (43%) were successfully treated. The main adverse effects presented by all patients were scars at cryogenisation points. In two patients, the appearance of 'salt and pepper' retinopathy was reported. Oncology pharmacists, as part of the treatment team, can provide information about recommended doses, expected adverse effects, stability of preparations, most appropriate method of processing, packaging, and methods of drug administration, to ensure efficacy and especially safety in the administration of these drugs.

Effect of Primary and Secondary Beads of Carbon Enterosorbent on Haematological Parameters and Oxidative Stress Development Caused by Melphalan in Rats.

Background and Objectives: Side effects of anti-cancer drugs are usually accompanied by oxidative stress, including myelotoxicity. We evaluated the potential of oral highly activated micro-/macroporous carbon adsorbents (bulk density of 0.16 g/cm3, surface area calculation by Brunauer–Emmett–Teller model (SBET) > 2200 m2/g, derived from proprietary phenolic resin beads) to alleviate oxidative stress and myelotoxicity in rats. Materials and Methods: A single injection of cytostatic melphalan (L-PAM) at a dose of 4 mg/kg was used for modelling. Two forms of activated carbon were used: AC1—primary beads with the particle size range of 125–250 µm, and AC2—micronized AC1 with a mean particle size of ~1 µm. We measured haematological parameters white blood cells, red blood cells, platelet count, and haemoglobin level. Oxidative stress intensity was evaluated using the following markers: total levels of reactive oxygen species (ROS) in blood plasma; catalase activity (CAT) and pro-oxidant/antioxidant ratio in blood haemolysate samples; level of reduced glutathione (GSH) in liver tissues; oxidative modification of proteins, OPM (APHD, aldehyde–dinitrophenylhydrazone derivatives and KPHD, ketone dinitrophenylhydrazone derivatives) and malonic dialdehyde (MDA) in blood plasma and liver samples. Results: AC2 administration promoted significant myeloprotective effect: 1.5-fold increase in leukocytes, 2-fold in neutrophils, 1.5-fold in lymphocytes, and 1.23-fold in platelet count compared to the experimental Melphalan Group. At the same time, AC1 administration resulted in a slight increase in haematological parameters. Both ACs positively corrected important, but diverse, components of oxidative stress. They significantly reduced oxidative modification of blood and liver proteins (especially the AC1 form), normalized the level of reduced glutathione, pro-oxidant/antioxidant ratio and other markers. For some markers, such as ROS production in blood plasma, the use of enterosorbents resulted in non-significant a shift towards normal parameters. Conclusions: Oral activated carbon adsorbents reduce oxidative stress intensity and myelotoxicity; they can be promising means to combat the adverse effects of chemotherapy in clinical practice.

The Role of Intra-Arterial Chemotherapy in the Manegment of Advanced Retinoblastoma; Group D & E

AbstractBackground: The treatment modalities for managing retinoblastoma have evolved in the past decade. While globe-salvage still relies heavily on intravenous chemotherapy, tumors in advanced stages D and E that failed chemotherapy are now referred for intra-arterial chemotherapy (IAC) to avoid enucleation.Aim of the Study: To evaluate the effectiveness and com-plications of intra-arterial chemotherapy (IAC) for treating advanced refractory group D and E retinoblastoma (RB).Material and Methods: 30 intro-ocular advanced refractory retinoblastoma of 26 consecutive patients who received IAC were included in the study during the period between Novem-ber 2013 and January 2017. These patients failed to respond adequately to a standard systemic chemotherapy (i.e., carbo-platin, vincristine, and etoposide) with or without local therapy. Clinical outcomes and complications of these patients were reviewed.Results: All our patients received IAC with injection of melphalan. The mean follow-up period was 14.2 months after final IAC (ranged from 6 to 20 months). The rate of overall globe salvage was 95% in Group D and 30% in Group E of this study. Short-term ocular adverse events included eyelid edema (n=15, 50%), bulbar conjunctiva congestion (n=7, 23.3%), mild ptosis (n=5, 16.7%) and long-term complications included ophthalmic artery spasm with reperfusion (n=2, 6.7%) retinal atrophy (n=1, 3.3%). Fever was observed after IAC in 10 patients and transient vomiting was observed in 16 patients.Conclusion: IAC can be an evolving optional treatment to save Group D RB that failed in systemic chemotherapy and were destined for enucleation. However, it should be cautioned for Group E. Both the ocular and systemic toxicities of IAC were within tolerance.

An audit of retinal lymphoma treatment at the University of California San Francisco.

To evaluate retinal lymphoma treatment at the University of California San Francisco. Prospective observational audit. Patients were treated systemically, usually with: methotrexate, temozolomide, and rituximab induction; etoposide consolidation; and maintenance with lenalidomide or another immunomodulatory agent. Persistent disease was treated initially by ocular radiotherapy or intravitreal melphalan and latterly by vitrectomy. The cohort comprised eight females and two males. The median age was 58 years (range, 38-73). Ocular manifestations were initially unilateral in four patients. Vitreous and subretinal infiltrates were initially present in 16 and 12 eyes, respectively, with three eyes having vision of 20/200 or worse. Four patients had a history of central nervous system (CNS) lymphoma. The median ophthalmic follow-up was 37 months (range, 8-56). Diagnostic and therapeutic vitrectomy were performed in 10 and 2 eyes, respectively. All patients had systemic chemotherapy and eight received maintenance immunotherapy. Four patients underwent ocular radiotherapy, bilaterally in two. One patient received bilateral intravitreal melphalan injections. Two eyes of four patients developed lymphoma during the study and two patients developed CNS disease. At study close, subretinal deposits were subtle in nine eyes and more prominent in two, whereas vitreous infiltrates were minimal in nine eyes, mild in one and moderate in one. The latest visual acuity was significantly worse than at presentation in two eyes and better in two. All patients were alive with no active CNS disease. Subretinal lymphomatous infiltrates respond to systemic chemotherapy with immunomodulatory maintenance, but dense vitreous infiltrates require therapeutic vitrectomy.

EFFICACY OF GRANULOCYTE COLONY-STIMULATING FACTOR AND ENTEROSORPTION IN MELPHALAN-INDUCED BONE MARROW SUPPRESSION IN GUERIN CARCINOMA GRAFTED RATS

Background. Side effects of antineoplastic agents (especially leukopenia and neutropenia) could be the main limiting factors for efficient treatment.
 Objective. The research is aimed at the study of myeloprotective capability of biosimilars of granulocyte colony stimulating factor (G-CSF) and granular carbon oral adsorbent C2 in melphalan-induced bone marrow suppression in Guerin carcinoma-grafted rats.
 Methods. Melphalan at the dose of 5.5 mg/kg was used to promote bone marrow suppression in the Guerin carcinoma grafted rats. To fight myelosuppression, we used filgrastim and its analogue, designed and produced by IEPOR, a recombinant granulocyte colony-stimulating factor (r-GCSF). Carbon granulated enterosorbent C2 was used for enteral sorption therapy (bulk density γ=0.18 g/cm3, diameter of granules 0.15-0.25 mm, BET pore surface – 2162 m2/g). All rats were sacrificed on the 17th day after carcinoma cells inoculation or on the 8th day after Melphalan injection.
 Results. Alkylating cytostatic agent caused severe leukopenia (by 95.7%), neutropenia (by 73.9%), and thrombocytopenia (by 84.9%) in the experimental rats. Mortality rate was 57%. Filgrastim and enterosorption with carbon oral adsorbent C2 increased the studied indices, but the most prominent results were observed when combination of both factors was used. Studied means did not affect the anti-tumor efficacy of Melphalan alone and in combination.
 Conclusions. Our results are perspective for further investigation of the efficacy of the combination of carbon oral adsorbents and hematopoietic cytokines in cases of ameliorate anti-cancer chemotherapy side effects, and its implementation into clinics.

Heterochromia following intravitreal chemotherapy in two cases

Intravitreal chemotherapy is recognized as an effective treatment for retinoblastoma with vitreous (and occasionally subretinal) seeding refractory to intravenous or intra-arterial chemotherapy. However, this treatment carries with it the risk of toxicity to both the posterior and anterior segments of the eye, including retinal pigment epithelial mottling, ischemic/hemorrhagic retinopathy, posterior synechia, cataract, scleral necrosis, and focal iris depigmentation. We report 2 cases of iris heterochromia secondary to profound iris stromal depigmentation following intravitreal melphalan and topotecan injections.