Abstract BACKGROUND Malignant brain tumors, such as Glioblastoma (GBM), are a major challenge in oncology with a dismal prognosis. This can be in part explained by the inability to deliver more effective drugs, as Doxorubicin (DOX), into the brain because of resistance mechanisms. Malignant tumors as GBM also show an elevated glycolytic rate through glucose transporters and GLUT1 is reported to be the main mediator of BBB glucose uptake. For these reasons, we have developed an innovative approach able to increase drug efficiency and selectivity, by conjugating the anticancer agents DOX to glucose. METHODS Two glycoconjugates (EB73 and EB74) were synthesized, using an oxime-based linkers between position 6 of glucose and carbonyl group of DOX, and characterized for absorbance, fluorescence and binding affinity to ctDNA. The cytotoxic effect of EB73 and EB74 was evaluated in two GBM cell lines (A172 and T98G). These cells were also used to study the effect of glucose deprivation on GLUT1 and breast cancer resistance protein (BCRP) expression. Moreover, cellular uptake of the glicoconjugates was evaluate in an in vitro BBB model and by immunofluorescence (IF) in GBM cells. RESULTS Our results indicated that EB73 and EB74 maintained Ka binding constants comparable to DOX, confirming that functionalization with glucose did not alter DOX intercalation capability and fluorescence. The cytotoxicity results demonstrated that EB74 has the major effect in A172 and T98G DOX-resistant cells starting from 24h of treatment. Moreover, glucose deprivation showed a GLUT1 overexpression and BCRP downregulation in both cell lines improving EB74 efficacy. BBB in vitro model and IF experiments revealed that only EB74 is able to accumulate in cells nuclei as conventional DOX CONCLUSION In conclusion, these results indicated that glycoconjugation of DOX and glucose deprivation may be helpful instruments to increase drugs uptake and effectiveness in aggressive and chemoresistant tumor cells.
Abstract BACKGROUND Optic pathway gliomas (OPG) are low-grade tumors (LGG) that affect the precortical visual pathway, representing 3-5% of pediatric brain tumors, more often diagnosed before the age of 5 years. Although histologically benign, due to their location and thus their unresectability, they carry considerable morbidity, bringing to progressive visual loss. In up to 20% of cases they are detected in patients with neurofibromatosis type 1 (NF1). Consolidated chemotherapy regimen with or without biopsy or debulking, if feasible, remains so far the standard management, moving to new personalized frontiers. MATERIAL AND METHODS In Meyer Children’s Hospital IRCCS Neuro-oncology Unit in Florence (Italy), from February 2013 to April 2024, for visual impairment at diagnosis or for disease progression, thirty-seven OPG patients (female/male ratio 1.3, median age at onset 4 years) completed the first line LGG chemotherapy (carboplatin-etoposide scheme adopted in our institution, built upon the INT Milan strategy and the standard SIOP LGG trial). Fourteen patients (37.8%) presented NF1-related OPG diagnosis, mostly made on a clinical/neuroradiological data. Response was assessed according to RAPNO criteria. RESULTS Non-NF1 OPG patients debuted at a lower median age (3 years) and mostly in a chiasmatic-hypothalamic location, predominantly with a pilocytic astrocytoma histology and manifested with nystagmus, secondarily with visual impairment. Despite the most frequent pre-chiasmatic involvement, during follow-up NF1 patients surprisingly presented a mean and median higher thickness (μm) of the retinal nerve fiber layer (RNFL) on optic coherence tomography (OCT) compared to non-NF1 patients, tested in the majority of patients (mean right RNFL 74.4 versus 58.0, median 66.0 versus 50.0, mean left RNFL 77.2 versus 55.3, median 73.0 versus 49.5). Four non-NF1 patients progressed during treatment or immediately afterwards. Considering the whole follow-up from the stop therapy (median time 5 years), non-NF1 patients progressed by far much more (15/23, 65.2% with one death versus 2/14, 14.3%). Overall survival was 97.3%. CONCLUSION NF1-related and not related pediatric OPG represent two distinct subgroups, with different clinical and prognostic characteristics. In agreement to other series our data show that non-NF1 OPG are less chemotherapy responsive than NF1-related OPG, surely due to the molecular landscape at the basis of tumor growth, warranting the needing of precision medicine directed to targets also in first- line treatment. A worse OCT outcome was found in the former cohort.
Abstract BACKGROUND Pediatric high grade gliomas (pHGGs) are leading causes of tumor related death in pediatric age. Beyond surgical and radiotherapy backbone treatment, chemotherapy regimen is a fundamental part of the therapeutic strategy, but its standardization and benefits are still disputed. Recent advances in molecular understanding are promising, nevertheless prognosis remains dismal. After proof-of-concept in vitro and in vivo assays to explore HGG cell lines sensibility to anthracyclines, we aim to introduce doxorubicin (DOX) as add-on therapy to the standard of care. MATERIAL AND METHODS Pediatric patients with newly diagnosed, histologically confirmed HGG were randomly assigned to receive radiotherapy plus concomitant and adjuvant temozolomide and valproic acid (as Weller-Stupp 2011 treatment) with or without doxorubicin (DOX) in a monocentric single-arm open-label phase II interventional study. We opted for a 96-hours continuous infusion DOX schedule (25 mg per square meter of body-surface area per day). We initially administered 3 DOX courses during standard radio-chemiotherapy regimen, then reduced to 1 course after 8 weeks from the end of radiotherapy due to an increasing heamatologic toxicities after the third course. The primary end point was safety and tolerability of experimental treatment, the secondary end point was clinical outcome. RESULTS From February 2016 to January 2020, 21 patients underwent randomization. 7 (33.3%) patients were affected by glioblastoma, 10 (47,6%) by diffuse intrinsic pontine glioma, 4 (19%) by anaplastic astrocytoma. All patients were Caucasian, 42.9% were females and the mean age was 10 years. 12 patients were treated with doxorubicin (DOX group), whom 2 patients received three doxorubicin (DOX) courses and 10 a single DOX course. 19 of 21 (90.5%) presented at least one serious adverse event (SAEs). 6 of 12 (50%) patients exposed to DOX group had clinically relevant toxic effects related to DOX, mainly as cytopenias, mucositis and febrile neutropenia. After the switch to a 1 DOX course outline the treatment showed a more tolerable toxicity profile. No patients had suspected unexpected serious adverse reactions (SUSAR), early DOX-treatment interruption or death related to DOX. All study withdrawals were related to disease progression and not to investigational drug side effects. 18/21 (85.7%) patients showed disease progression. Among DOX-group, 1 patient show complete remission and 2 showed stable disease. DOX-group show a longer progression free survival (EFS) compared to control group, although this trend was not statistically significative. CONCLUSION Adjuvant doxorubicin as add-on therapy to the standard of care treatment of pHGGs is a safe and tolerable option. We need further investigations to optimize the timing and dosing of doxorubicin and to verify the effects on clinical outcome. SAEs must be carefully evaluated.
Glioblastoma multiforme (GBM) is the most malignant primary brain tumor. Conventional therapies are considered palliative and long-term progression-free survival remains low for most GBM patients even after surgical excision, concomitant radiotherapy and/or chemotherapy with nitrosoureas or Temozolomide. We report the case of a 47-year-old man who presented worsening headache over a month, accompanied by episodes of morning vomiting and hyposthenia of the left hemisoma. Cerebral tomographic scan revealed an expansive process on the right frontal site. Following surgical resection, the patient was diagnosed with diffusely infiltrating GBM. After surgery, the patient underwent radiotherapy and chemotherapy with Temozolomide for 6 months. Eleven months later, the patient underwent a second-look surgery with excision of a new right superior frontal nodule. This time the patient refused both radio and chemotherapy and underwent follow-up only. After 12 months he underwent a new craniotomy for the excision of a third GBM relapse. Following resection, the patient agreed to be treated for 6 months with fotemustine (FTM) 100 mg/m2 intravenously every 4 weeks as chemotherapy. After 3 months of treatment the patient underwent a full physical examination and diagnostic monitoring of the tumor using Magnetic Resonance Imaging (MRI) of the brain and whole body Computerised Tomography (CT). During FTM treatment, the most frequent, but reversible toxic effect was hematological grade 2 anemia and thrombocytopenia but no other grade >2 toxicity was recorded, so there was no reduction or delay in treatment. Presently, after 8 years of follow-up, the patient is in excellent health and has no evidence of intracranial disease recurrence. In light of this case, post-surgical FTM treatment seems to represent an interesting well-tolerated treatment possibility in patients with recurrent malignant GBM of the brain, given that there are very few reports of such a remission in the literature.
Low grade gliomas (LGGs) of pineal region are usually difficult to remove and they frequently relapse or progress after front line chemotherapy. Bevacizumab-Irinotecan (BEVIRI) combination has been successfully attempted in children with recurrent LGGs, in most cases not previously irradiated. The efficacy of bevacizumab has also been described in radiation necrosis. Considering the possible overlapping of radiation treatment effect and disease progression and difficulty in differentiating, we report on the use of BEVIRI in a case of a recurrent relapsing low-grade glioma of the pineal region, subjected to multiple neurosurgical interventions, also treated with a carboplatin-etoposide regimen and a radiation course, at present at one-year follow-up showing a stable response, with no adverse events.
Abstract BACKGROUND Despite the multimodal approach, medulloblastoma remains a leading cause of cancer-related death in children. We proposed the preliminary data of an interventional, open-label, phase II study to evaluate the safety and efficacy of standard and high-dose chemotherapy associated with craniospinal proton therapy in patients with metastatic medulloblastoma and other embryonal cancers. MATERIAL AND METHODS A total of 19 patients have been enrolled from the beginning of the study from February 2018 to May 2022 . The median age was 7,5 years (range; 13 males and 6 female). The protocol predicted the first phase of induction with 4 cycles of chemotherapy. After induction patients with favorable histology without evidence of disease were enrolled to proton therapy (with concomitant vinorelbine biweekly). The maintenance phase with Lomustine repeated every 9 weeks and vinorelbine every 3 weeks for overall 12-18 months (PR). Conversely LC/A MB, pineoblastoma or other high risk embryonic tumors were subjected to consolidation phase with high dose of chemotherapy with tiothepa followed by autologous HSC transplant and successive maintenance phase of 6 months. RESULTS At December 2022, the median follow up was 23 months. 18 patients had high risk medulloblastoma and one had a primary leptomeningeal primitive neuroectodermal tumor. After the induction phase 14 patients showed CR, 3 PR, 1PD, 1SD. At subsequent re-evaluations two of the three patients with PR, showed disease control, one CR and the other SD and the patient with PD showed CR. At the end of proton therapy 18 patients had CR. During the reporting period three patient died for progression of the underlying disease. At 15 months from the start of treatment the PFS and OS were 68.8% (95% CI: 34.1% - 87.6%) and 94.7% (95% CI: 68.1% - 99.2%) respectively. The principal expected side effects of chemotherapy were hematology toxicity (fever and neutropenia prevalent after etoposide and carboplatin plus vinorelbine). Among the unexpected side effect was CMV retinopathy with complete blindness and leukoencephalopathy after high dose of thiotepa and proton irradiation. CONCLUSION As the study did not reveal any safety issues, proton therapy combined with intensive chemotherapy, and myeloablative chemotherapy only in selected cases and always before irradiation, proved feasible and successful in treating high-risk medulloblastomas and other embryonal tumors.
'/%3e%3cpath d='M200 752.362h200v300H200z' style='fill:%23fff;fill-opacity:1;stroke:none' transform='translate(0 -752.362)'/%3e%3cpath d='M400 752.362h200v300H400z' style='fill:%23ff883e;fill-opacity:1;stroke:none' transform='translate(0 -752.362)'/%3e%3c/svg%3e)