Half-dose glucarpidase as efficient rescue for toxic methotrexate levels in patients with acute kidney injury

Purpose!#!High-dose methotrexate (HDMTX)-associated acute kidney injury with delayed MTX clearance has been linked to an excess in MTX-induced toxicities. Glucarpidase is a recombinant enzyme that rapidly hydrolyzes MTX into non-toxic metabolites. The recommended dose of glucarpidase is 50 U/kg, which has never been formally established in a dose finding study in humans. Few case reports, mostly in children, suggest that lower doses of glucarpidase might be equally effective in lowering MTX levels.!##!Methods!#!Seven patients with toxic MTX plasma concentrations following HDMTX therapy were treated with half-dose glucarpidase (mean 25 U/kg, range 17-32 U/kg). MTX levels were measured immunologically as well as by liquid chromatography-mass spectrometry (LC-MS). Toxicities were assessed according to National Cancer Institute-Common Terminology Criteria for Adverse Events (CTCAE) v5.0.!##!Results!#!All patients experienced HDMTX-associated kidney injury (median increase in creatinine levels within 48 h after HDMTX initiation compared to baseline of 251%, range 80-455%) and showed toxic MTX plasma concentrations (range 3.1-182.4 µmol/L) before glucarpidase injection. The drug was administered 42-70 h after HDMTX initiation. Within one day after glucarpidase injection, MTX plasma concentrations decreased by ≥ 97.7% translating into levels of 0.02-2.03 µmol/L. MTX rebound was detected in plasma 42-73 h after glucarpidase initiation, but concentrations remained consistent at < 10 µmol/L.!##!Conclusion!#!Half-dose glucarpidase seems to be effective in lowering MTX levels to concentrations manageable with continued intensified folinic acid rescue

Safety and efficacy of Holmium-166 selective internal radiotherapy of primary and secondary liver cancer confirmed by real-world data

Purpose: Holmium-166 has emerged as a promising option for selective internal radiotherapy (SIRT) for hepatic malignancies, but data on routine clinical use are lacking. The purpose of this study was to describe the safety and effectiveness of Holmium-166 SIRT in real-world practice through retrospective analysis of a multicenter registry. Methods: Retrospective analysis was conducted on Holmium-166 SIRT procedures performed between July 15, 2019, and July 15, 2021, across seven European centers. Treatment planning, treatment realization and post-treatment follow-up were conducted according to routine local practice. Safety and effectiveness data were extracted from the patients’ health records. Primary endpoint analysis was assessed for the entire study population with separate analysis for subgroups with hepatocellular carcinoma, metastatic colorectal cancer and intrahepatic cholangiocarcinoma. Results: A total of 167 SIRT procedures in 146 patients (mean age 66 ± 11 years, 68% male) were retrospectively evaluated. Most common tumor entities were hepatocellular carcinoma (n=55), metastatic colorectal cancer (n=35), intrahepatic cholangiocarcinoma (n=19) and metastatic neuroendocrine tumors (n=10). Nine adverse events grade ≥ 3 according to Common Terminology Criteria for Adverse Events were recorded, including one fatal case of radioembolization-induced liver disease. Response rates and median overall survival for the above mentioned subgroups were comparable to results from previous Holmium-166 trials as well as to results from Yttrium-90 registries. Conclusion: This study confirms that the safety and effectiveness of Holmium-166 SIRT derived from prospective trials also applies in routine clinical practice, reinforcing its potential as a viable treatment option for primary and secondary liver cancer.SCOPUS: ar.jinfo:eu-repo/semantics/publishe

Sustainable Control of Onchocerciasis: Ocular Pathology in Onchocerciasis Patients Treated Annually with Ivermectin for 23 Years: A Cohort Study

<div><p>The evolution and persistence of ocular pathology was assessed in a cohort of <i>Onchocerca volvulus</i> infected patients treated annually with ivermectin for 23 years. Patients were resident in rural Central and Kara Region of Togo and ocular examinations included testing of visual acuity, slit lamp examination of the anterior eye segment and the eye fundus by ophthalmoscopy. Before ivermectin treatment, vivid <i>O.volvulus</i> microfilariae (MF) were observed in the right and left anterior eye chamber in 52% and 42% of patients (n = 82), and dead MF were seen in the right and left cornea in 24% and 15% of cases, respectively. At 23 years post initial treatment (PIT), none of the patients (n = 82) presented with MF in the anterior chamber and cornea. A complete resolution of punctate keratitis (PK) lesions without observable corneal scars was present at 23 years PIT (p<0.0001), and sclerosing keratitits (SK) lessened by half, but mainly in patients with lesions at early stage of evolution. Early-stage iridocyclitis diminished from 42%(rE) and 40%(lE) to 13% (rE+lE)(p<0.0001), but advanced iridocyclitis augmented (p<0.001) at 23 years PIT compared to before ivermectin. Advanced-stage papillitis and chorioretinitis did not regress, while early-stage papillitis present in 28%(rE) and 27%(lE) of patients at before ivermectin regressed to 17%(rE) and 18%(lE), and early-stage chorioretinitis present in 51%(rE+lE) of cases at before ivermectin was observed in 12%(rE) and 13%(lE) at 23 years PIT (p<0.0001). Thus, regular annual ivermectin treatment eliminated and prevented the migration of <i>O. volvulus</i> microfilariae into the anterior eye chamber and cornea; keratitis punctata lesions resolved completely and early-stage sclerosing keratitits and iridocyclitis regressed, whilst advanced lesions of the anterior and posterior eye segment remained progressive. In conclusion, annual ivermectin treatments may prevent the emergence of ocular pathology in those populations still exposed to <i>O.volvulus</i> infection.</p><p><i>Trial Registration</i>: <a href="http://www.pactr.org" target="_blank">www.pactr.org</a><a href="http://www.pactr.org/ATMWeb/appmanager/atm/atmregistry?dar=true&tNo=PACTR201303000464219" target="_blank">PACTR201303000464219</a>)</p></div

Ocular anomalies not caused by <i>Onchocerca volvulus</i> infection in patients (n = 82) examined before ivermectin treatment, and at 4 and 23 years post initial ivermectin treatment (PIT).

<p>Ocular anomalies not caused by <i>Onchocerca volvulus</i> infection in patients (n = 82) examined before ivermectin treatment, and at 4 and 23 years post initial ivermectin treatment (PIT).</p

Causes of bilateral visual impairment and blindness in the onchocerciasis patients' cohort (n = 82) before ivermectin treatment, and at 4 years and 23 years post initial treatment (PIT).

<p>The patients' visual acuity was graded according to WHO criteria; blind were those with a visual acuity on the right (RE) or left eye (LE) or both eyes (RLE) of less than 1/20 (3/60 or unable to count fingers at 3 meters); impaired vision had those with a visual acuity between 1/20 (3/60) and less than 3/10 (6/18); good vision had those with a visual acuity equal or greater than 3/10.</p

Iridocyclitis, cataract, papillitis and chorioretinitis in onchocerciasis patients (n = 82) post ivermectin treatment. Differences were evaluated using Pearson's chi-square test.

$<p>PIT =  post initial treatment.</p><p>PES =  Posterior Eye Segment.</p>$$<p>Other Lesions: Phtyse, Pupille scleroatrophic, Synechie post trauma, Pigments on posterior Capsule.</p>§§<p>Other Lesions: Phtyse, dead O.volvulus microfilariae on posterior capsule.</p>&&<p>Other Lesions: optic cup/disc >0.5.</p>§§§<p>Other Lesions  =  retina detachment from the retinal pigment epithelium, drusen.</p><p>*p<0.001 compared to 4 years PIT;</p><p>**p<0.001 compared to before ivermectin;</p><p>***p<0.0001 compared to before ivermectin and 4 years PIT.</p>&<p>p<0.01 compared to before ivermectin.</p

Microfilaria in the anterior chamber of the eye, the cornea, and puctate and sclerosing keratitis in onchocerciasis patients (n = 82) post ivermectin treatment. Differences were evaluated using Pearson's chi-square test.

$<p>PIT =  post initial treatment.</p><p>*p<0.001 compared to 4 years PIT;</p><p>**p<0.001 compared to before ivermectin;</p><p>***p<0.0001 compared to before ivermectin and 4 years PIT.</p