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Δευτέρα 5 Σεπτεμβρίου 2022

P18.11.A Active beam scanning proton therapy for large skull base benign meningiomas: long-term results

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Abstract
Purpose
To report long-term results of active beam scanning proton therapy (PT) for large skull base benign meningiomas
Material and Methods
Eighty-two patients (pts) with large skull base meningiomas were treated with PT between April 2015 and December 2021. Median age was 62 years (range, 48-82) while KPS ranged between 60 and 100 (median 90); 60 were female (73%), and 22 were male (27%). Thirty-two pts (39%) had histologically proven World Health Organization (WHO) Grade I tumors. In remaining pts diagnosis was based on the typical imaging appearance of benign meningioma. All patients received PT for residual, progressive or non-operable lesions. Newly diagnosed tumors received total dose of 50 GyRBE (RBE: relative biologic effectiveness) while progressing meningiomas 54 GyRBE. All the treatments were delivered at 2 GyRBE per fraction. All pts were treated with active beam scanning PT using 3 fields with single field optimiz ation technique. Treatment planning was based on morphological magnetic resonance imaging (MRI) with contrast enhancement medium administration. All pts received also 68-Ga-DOTATOC-PET. Gross tumor volume ranged from 21 to 64 cc. Toxicity was assessed according to Common Terminology Criteria for Adverse Events version 4.0. Median follow-up time was 40 months (range, 3-83).
Results
All pts completed the treatment without breaks. Registered acute side effects include grade 1 (19%) and grade 2 (8%) skin erythema, grade 1 (5%) and grade 2 (5%) alopecia, grade 1 (40%) fatigue, grade 1 (5%) and grade 2 (10%) conjunctivitis, grade 1 (10%) pain, grade 1 (5%) blurred vision, grade 1 (10%) headache, and grade 2 (5%) skin hyperpigmentation. One pts (1%) experienced grade 3 pain. There were no further grade 3 or higher acute toxicities. Registered late side effects include grade 1 (2%) and grade 2 (5%) alopecia, grade 1 (21%) fatigue, grade 1 (5%) and grade 2 (5%) headache, grade 1 (6% ) dizziness, grade 1 (3%) blurred vision, grade 1 (3%) and grade 2 (6%) pain, grade 1 (2%) dry eye, and grade 1 (5%) skin hyperpigmentation. Two pts (2%) experienced grade 3 pain. Two further pts (2%) experienced grade 3 optic neuropathy. There were no further grade 3 or higher late toxicities. During follow-up one pts (1%) with cavernous sinus meningioma experienced complete obstruction of intracavernous carotid artery with mild transient symptoms that resolved in few days and brain tissue ischemia detected at MRI (grade 2). Before irradiation this pts already had a meningioma-related near-complete obstruction of the intracavernous carotid artery and received a vascular surgery evaluation. Currently, absolute tumor control is 99%. Moreover, relief of symptoms recorded before irradiation occurred in 40% of pts.
Conclusion
PT is safe and effective treatment for pts with large skull base benign meningiomas.
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P11.52.A Peripheral neuropathies after BRAF and/or MEK inhibitors treatment: a pharmacovigilance study

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Abstract
Background
BRAF (BRAFi) and MEK inhibitors (MEKi) demonstrated significant efficacy in the treatment of BRAF-activated tumours, firstly melanoma. Nevertheless, they are not devoid of adverse events. Sparse reports in the literature suggest the potential occurrence of peripheral neuropathies (PN) under BRAFi/MEKi treatment, but their characteristics remain poorly defined. We aimed to characterize the clinical phenotypes of PN occurring under BRAFi/MEKi treatment using a national pharmacovigilance database.
Material and Methods
We queried the French pharmacovigilance database for all cases of PN toxicity attributed to at least one BRAFi or MEKi compound. Only cases with a least symptoms description and nerve conduction studies (NCS) conclusion were included.
Results
Sixteen cases of PN occurred in 15 patients were identified. All patients had underlying melanoma. Two main phenotypes were seen. Six patients (dabrafenib-tr ametinib, n=3; vemurafenib, n=2; vemurafenib-cobimetinib, n=1) presented a length-dependent axonal polyneuropathy: symptoms were mostly sensory at lower limbs; NCS disclosed an axonal neuropathy; management and outcome were variable. Nine patients (dabrafenib-trametinib, n=5, encorafenib-binimetinib, n=3, and vemurafenib-cobimetinib, n=1) developed a demyelinating polyradiculoneuropathy: symptoms affected the four limbs and included hypoesthesia, weakness, and ataxia; cranial nerves were involved in four; NCS showed predominantly demyelinating features; most patients received intravenous immunoglobulins (n=6) or glucocorticoids (n=5), but the outcome was variable; one patient was rechallenged with a different BRAFi/MEKi with a rapid relapse.
Conclusion
Patients under treatment with BRAFi/MEKi may develop treatment-induced PN. Two main phenotypes are seen: a symmetric, axonal, length-dependent polyneuropathy, and a demyelinating polyradiculoneuropathy.
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P02.01.B The telomere maintenance mechanism spectrum and its dynamics in gliomas

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Abstract
The activation of the telomere maintenance mechanism (TMM) is one of the critical drivers of cancer cell immortality. In gliomas, TERT expression and TERT promoter mutation are considered to reliably indicate telomerase activation, while ATRX mutation indicates alternative lengthening of telomeres (ALT). However, these relationships have not been extensively validated in tumor tissues. Here, we show through the direct measurement of telomerase activity and ALT in a large set of glioma samples that the TMM in glioma cannot be defined in the dichotomy of telomerase activity and ALT, regardless of TERT expression, TERT promoter mutation and ATRX mutation. Moreover, we observed that a considerable proportion of gli omas lack both telomerase activity and ALT (Neither group). And this Neither group exhibited evidence of slow growth potential. From a set of longitudinal samples from a separate cohort of glioma patients, we discovered that the TMM is not fixed but changes with glioma progression. Collectively, these results suggest that the TMM is a dynamic entity and that reflects the plasticity of the oncogenic biological status of tumor cells and that the TMM should be defined by the direct measurement of telomerase enzyme activity and evidence of ALT.
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P11.74.A Plexiform Neurofibromas prevalence and treatment modalities in a referral comprehensive cancer center

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Abstract
Background
Neurofibromatosis type 1 (NF1) is the most common tumor predisposition syndrome, with an incidence of 1/3500. Plexiform neurofibromas (PN) are benign tumors that can occur along the nerve sheath throughout the body, with unpredictable growth and with risk of malignant transformation. Symptoms will depend on their size and location, and include pain, deformity and functional impairment. There is a great variability in the PN severity and impact on quality-of-life (QOL). An unknown percentage of NF1 patients may need treatment, either medical and/or surgical.
Objectives
To assess the frequency of PN in a NF1 population followed in a comprehensive cancer center.
Material and Methods
Retrospective study. All patients with NF1 and PN followed in our center, between 31/12/2000 and 31/12/2021.
Results
Of 438 NF1 patients, 185 had PN (42%). 52 NF1 patients with PN were children (≤ 18). The most common sym ptoms were pain in 71 people (38,4%), deformity in 70 (37,8%) and functional impairment in 69 (37,3%). Several patients had a combination of these symptoms. Different treatment modalities were used for PN: medical, surgical or both. In this study, 54 patients (29,1%) were treated with MEK inhibitors (selumetinib), 74 patients (40%) were treated surgically and 12,4% (23) needed a combined approach (medical and surgical treatment).
Conclusion
PN are frequent in NF1 patients. A significant percentage is symptomatic and will require treatment, surgical, medical or both. There is no standard of care for PN NF1. The timing and sequence of medical and surgical treatment is yet to be defined.
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P11.71.B Chronic Inflammatory Demyelinating Polyradiculoneuropathy (CIDP) in a patient with blastic plasmacytoid dendritic cell neoplasm: a rare neurologic manifestation in a rare disease

alexandrossfakianakis shared this article with you from Inoreader
Abstract
Background
Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare aggressive myeloid hematological malignancy. Skin lesions, bone marrow, lymph nodes or visceral organs can be involved. 30% of patients will have infiltration to the nervous system,occult asymptomatic infiltration is frequent. Immunophenotype express CD4, CD56, and CD123, and flow cytometry is essential.
Material and Methods
70-yo Hispanic male with a 1-month history of multiple violaceous cutaneous nodules and adenopathies.Neurological complaints included diplopia, hypoesthesia in the left face, dysphagia, gait difficulties, and generalized weakness with distal hypoesthesia. Examination revealed multiple cranial neuropathy (bilateral VI and VII nerve palsies, left V3 and VIII palsies and IX, X involvement), global areflexia, length-dependent weakness, ataxic gait and cerebellar syndrome. An inguinal ganglionar biopsy retrieved cells positive for CD4, TCL 1, CD68 and CD123, whereas CD3, CD20, CD7, CD8, CD30 and myeloperoxidase were negative. PET/CT showed multiple supra and infradiaphragmatic adenopathies, bilateral pleural, pericardial and abdominal implants. Bone marrow biopsy was negative. Brain MRI showed contrast enhancement in the cerebellar folia and in the roots of the cranial nerves clinically involved. Multiple CSFs demonstrated high protein count (281- 310mg/dl), normal glucose and cell count; CSF flow cytometry and cytology reported no blastic infiltration (negative CD4, CD56 and CD123), CSF onconeuronal antibodies were negative. Nerve conduction studies fulfilled definite electrodiagnostic EFNS criteria for CIDP. Sural nerve biopsy reported inflammatory demyelination without infiltration. Systemic chemotherapy (Cyclophosphamide/Vincristine) with intrathecal cytarbine/methotrexate was administered.
Results
Favorable initial, but brief response was noticed for the cranial nerves and gait. He had neurological relap se with gait impossibility. Neuraxis MRI showed no contrast enhancement in the brain but new contrast enhancement of lumbosacral roots. Nerve conduction studies reported severe worsening criteria of CIDP. The PET/CT demonstrated complete response. Five days of methylprednisolone (1gr IV) followed by oral prednisone were prescribed (50 mg qd). However, two weeks later he suffered clinical neurological worsening with respiratory failure. IVIg was started (.4g/kg/day for 5 days) with no improvement; palliative care decision was consented.
Conclusion
We report the case of an adult male with multiple cranial nerve palsy, cerebellar syndrome and refractory rapidly progressive asymmetric polyneuropathy with BPDCN. CIDP in the absence of multiple attempts to demonstrate nervous system infiltration led us to consider this as a paraneoplastic phenomenon refractory to treatment. To our knowledge no CIDP has been reported in this rare disease
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P17.06.B Different dosage of bevacizumab treatment in recurrent IDHwt glioblastoma/IDHmut grade 4 astrocytoma and its impact on outcome

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Abstract
Background
Angiogenesis is one of the most distinctive hallmarks of glioblastoma (GBM). Although bevacizumab did not show to improve overall survival in phase 3 trials, it was approved by FDA and is often prescribed as off-label therapy in the recurrent clinical setting. The aim of this study is to evaluate the difference in terms of survival and safety between the 5 mg/m2 and 10 mg/m2 bevacizumab schedule in recurrent GBM.
Material and methods
All pts treated at Veneto Institute of Oncology from May 2013 to March 2022 were retrospectively reviewed. Major inclusion criteria were: histologically confirmed diagnosis of IDHwt GBM/IDHmut grade 4 astrocytoma (according to the WHO 2021 classification), relapse after first or subsequent line of therapy, treatment with bevacizumab at 5 mg/m2 or/and 10 mg/m2 every 2 weeks until progression/death or unacceptable toxicity. Bevacizumab was admini stered as off-label therapy. The treatment schedule was at physician's discretion. RANO criteria and CTCAE v5.0 were used for response and toxicity assessment.
Results
81 pts were enrolled. From starting bevacizumab the median follow-up was 10.9ms [95% CI 9.8-14.0] and median age was 53ys (range 18-81). 33 (41%) pts received the 5 mg/m2 schedule. Among them, 2 (6%) were IDHmut grade 4, 8 (24%) had ≥65ys and ECOG-PS was 0-1 in 16 (48%) and ≥2 in 17 (51%), respectively. MGMT was methylated in 15 of 30 (50%) evaluable pts. Median number of prior lines of treatment was 2 (range 1-4) and 30% of pts received bevacizumab at first recurrence. 28 (84.9%) pts were evaluable for response: 7 (21%) and 5 (15%) showed PR and SD. 48 pts received the 10 mg/m2 schedule: 5 (10%) were IDHmut grade 4 astrocytoma; 29 (60%) had an ECOG-PS of 0 or 1 and 4 (8%) had ≥65ys, MGMT was methylated in 20 of 44 (45%) evaluable pts. 36 (75%) pts received bevacizumab beyond the second line of therapy. 46 (96%) pts were evaluable for response: 6 (12%) had PR, 19 (39%) SD. mOS from the start of bevacizumab was 7.3ms (95% CI 4.3-6.4), mPFS was 4.4ms [95% CI 3.7 - 6.4]. At univariate analysis, pts who received the 5 mg/m2 or the 10 mg/m2 schedule had a mOS of 5.4 and 7.7ms (p=0.08); mOS for pts with ECOG-PS < or ≥2 was 9.0 and 5.4ms (p=0.04) while mOS for pts with <2 or ≥2 lines of therapy was 4.7 and 7.7ms (p=0.056). Age and type of the tumor were not statistically significant. At multivariate analysis, MGMT methylated status was the only factor statistically associated with OS (HR=0.48, 95% CI, p=0.002) and PFS (HR=0.33, 95% CI, p=0.001), while a number of prior lines of therapy ≥2 (HR=2.07, 95% CI, p=0.02) was significantly associated only with PFS. Grade 3-4 most common adverse events were hypertension (18%) in pts treated with 5 mg/m2 and hypertension (16%) and proteinuria (2%) in pts treated with 10 mg/m2.
Conclusions
Bevacizumab tr eatment with a dosage of 5 mg/m2 and 10 mg/m2 seems to give comparable outcome in terms of survival in recurrent GBM pts. No difference was demonstrated for safety.
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KS05.5.A Alterations in white matter fiber density associated with structural MRI and metabolic PET lesions following multimodal therapy in glioma patients

alexandrossfakianakis shared this article with you from Inoreader
Abstract
Background
In glioma patients, multimodal therapy and recurrent tumor result in local brain tissue changes, characterized by pathologic findings in structural MRI and metabolic PET images. Little is known about these different lesion types' impact on the local white matter fiber architecture and clinical outcome.
Patients and Methods
This study included data from 121 pretreated patients (median age, 52 years; ECOG, 01) with histomolecularly characterized glioma (WHO grade IV glioblastoma, n=81; WHO grade III anaplastic astrocytoma, n=28; WHO grade III anaplastic oligodendroglioma, n=12), who had a resection, radiotherapy, alkylating chemotherapy, or combinations thereof. After a median time of 14 months (range, 1-214 months), post-therapeutic structural and metabolic findings were evaluated using anatomical MRI and O-(2-[18F]fluoroethyl)-L-tyrosine (FET) PET acquired on a 3T hybrid PET/MR scanner. Local fiber densi ty was estimated from tractography based on highangular resolution diffusion-weighted imaging. A cohort of 121 healthy subjects selected from the 1000BRAINS study and matched for age, gender and education served as a control group.
Results
The median volume of resection cavities, contrast-enhancing regions, regions with pathologically increased FET uptake, and T2/FLAIR hyperintense regions amounted to 20.9, 7.9, 30.3, and 53.4 mL, respectively. Compared to the control group, the average local fiber density in these regions was significantly reduced (p<0.001). Resection cavities showed the highest reduction, followed by contrast-enhancing lesions and metabolically active tumors on FET PET (relative fiber density reduction, -87%, -65%, -55%, respectively). The local fiber density was inversely related (p=0.005) to the FET uptake in recurrent tumors. T2/FLAIR hyperintense lesions, either assigned to peritumoral edema in recurrent glioma or radiation-induced gliosis, had a c omparable impact on reducing fiber density (48% and 41%, respectively). The total fiber loss (average fiber loss multiplied by lesion volume) associated with contrast-enhancing lesions (p=0.006) and T2/FLAIR hyperintense lesions (p=0.013) had a significant impact on the general performance status of the patients (ECOG score).
Conclusions
Our results suggest that apart from resection cavities, reduction in local fiber density is greatest in contrast-enhancing recurrent tumors, but total fiber loss induced by edema or gliosis has an equal detrimental effect on the patients' performance due to the larger volume affected.
Funding
Funded by the 1000BRAINS study (INM, Research Centre Juelich, Germany), Horizon 2020 (Grant No. 945539 (HBP SGA3; SC)), and Heinz Nixdorf Foundation.
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Favipiravir in patients with early mild-to-moderate COVID-19: a randomized controlled trial

alexandrossfakianakis shared this article with you from Inoreader
Abstract
Background
Despite vaccination, many remain vulnerable to COVID-19 and its complications. Oral antivirals to prevent COVID-19 progression are vital. Based upon perceived potency and clinical efficacy, favipiravir is widely used to treat COVID-19. Evidence from large randomized controlled trials (RCT) is lacking.
Methods
In this multicenter double-blinded placebo-controlled RCT, adults with early mild-to-moderate COVID-19 were 1:1 randomized to favipiravir or placebo. The study evaluated time to sustained clinical recovery (TT-SCR), COVID-19 progression, and cessation of viral shedding.
Results
Of 1187 analyzed patients across 40 centers, 83.3% were Hispanic, 89.0% unvaccinated, 70.3% SARS-CoV-2 seronegative, and 77.8% had risk factors for COVID-19 progression. The median time from symptom presentation and from positive test to randomization was three and two days, respectively. There was no difference in TT-SCR (median of 7 days for both groups; p = 0.80), COVID-19 progression [11 patients each (1.9% vs. 1.8%); p = 0.96], time to undetectable virus [median = 6 days, 95% CI (6-8) vs. 7 days, 95% CI (6-9)], or in undetectable virus by end of therapy (73.4% vs. 72.3%; p = 0.94). Outcomes were consistent across the analyzed sub-groups. Adverse events were observed in 13.8% and 14.8% of favipiravir-treated and placebo-treated subjects, respectively. Uric acid elevation was more frequent among favipiravir-treated subjects (19.9% vs. 2.8%).
Conclusions
Favipiravir was well tolerated but lacked efficacy in TT-SCR, progression to severe COVID-19, or cessation of viral shedding and should not be used to treat patients with COVID-19.
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