P12.13.B Investigating the tumor - immune cell crosstalk inex vivo glioblastoma models

alexandrossfakianakis shared this article with you from Inoreader P12.13.B Investigating the tumor - immune cell crosstalk inex vivo glioblastoma models via # Neuro-Oncology Current Issue Abstract Background Immunotherapy is a promising therapeutic approach to fight cancer by activating the immune system. Multiple immune-based strategies are under development that aim at recruiting or re-activating cellular components of the immune system. While immunotherapies have recently revolutionized cancer therapy, they have shown so far little therapeutic success in glioblastoma patients. To enhance the efficacy of novel strategies, we need to better understand the immunogenic status of glioblastoma cells and their cross-talk with immune cells in different microenvironmental niches. Material and Methods We assessed expression of molecules related to antigen processing and presentation as well as immune checkpoints in patient tumor databases as well as in a series of glioblastoma patient-derived organoids, 3D stem-like cultures and adherent cell lines under varying microenvironmental conditions (varying oxygen levels, inflammation ). We further established an allogenic co-culture protocol for glioblastoma organoids with immune cells isolated from HLA matched donor blood, allowing for the functional assessment of the crosstalk between tumor and immune cells. Results Analysis of a large cohort of patient tumors and patient-derived glioblastoma preclinical models shows inter-patient heterogeneity at the level of components of major histocompatibility complex (MHC)-MHC-II, immune checkpoints. Glioblastoma cells in general express MHC-I machinery, albeit at different levels. MHC-II and immune checkpoints are variably expressed across glioblastoma cells. Different tumor microenvironment conditions, including hypoxia and interferon-γ, impact the expression of immune-related molecules. Upon co-culture, HLA-matched donor-derived T cells integrate well into the core of glioblastoma tumor organoids and display reciprocal crosstalk with tumor cells. Conclusion Assessing antigen presentation and immune cell responses at the functional level are key to improve patient-specific responses to immunotherapies. Advanced glioblastoma organoids incorporating the immune compartment appear as clinically-relevant models for ex vivo efficacy studies. View on Web

Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

P11.74.A Plexiform Neurofibromas prevalence and treatment modalities in a referral comprehensive cancer center

alexandrossfakianakis shared this article with you from Inoreader P11.74.A Plexiform Neurofibromas prevalence and treatment modalities in a referral comprehensive cancer center via # Neuro-Oncology Current Issue 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. View on Web

Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

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 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 via # Neuro-Oncology Current Issue 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 View on Web

Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

PL02.2.A Microglia-specific disruption of sialic acid-Siglec-9/E interactions. A novel immunotherapy against glioblastoma?

alexandrossfakianakis shared this article with you from Inoreader PL02.2.A Microglia-specific disruption of sialic acid-Siglec-9/E interactions. A novel immunotherapy against glioblastoma? via # Neuro-Oncology Current Issue Abstract Background Recently, 'don't eat me'-signals like CD47 have emerged as novel innate immune checkpoints, enabling cancer cells to evade clearance by phagocytes such as monocyte-derived macrophages (MdM) or microglia (MG). Here, we aim at defining the role of inhibitory Siglec-9 in human and its mouse homologue Siglec-E in MG-centered immunotherapy against GBM. Material and Methods We employed a CT-2A orthotopic GBM mouse model with MG specific (Sall1CreERT2 x Sigleceflox) and whole innate-compartment (Cx3cr1CreERT2 x Sigleceflox) spatio-temporal deletion of Siglece. We applied multi-color flow cytometry, transcriptomics and proteomics analysis to decipher the immune response upon Siglece knockout. Results TCGA RNA-sequencing data revealed a significant correlation between high expression of immunoinhibitory SIGLEC9 and poor survival in GBM patients (log-rank p = 0.02). Siglec-E blockade increased murine MG mediated GBM cell in vitro phagocytosis (normalized phagocytosis of 1.00 in isotype vs. 1.76 in anti-Siglec-E antibody, p < 0.001). In the MG specific spatio-temporal deletion of Siglece (Sall1CreERT2 xSigleceflox), we observed high MG-proliferation upon Siglec-E knockout (Ki-67+ MG 1 4.8% in Cre- vs. 34.9% in Cre+, p < 0.0001) accompanied by an enhanced microglial GBM-cell uptake (5.6% in Cre- vs. 12.3% in Cre+, p < 0.001). By extending the Siglece knockout to the MdM compartment in our glioma mouse model (Cx3cr1CreERT2 x Sigleceflox) we observed a significantly prolonged survival in the Cx3cr1Cre+ population (21d in Cre- vs. 27d post-tumor injection in Cre+, p = 0.018), which could be further promoted by combining Siglece knockout with CD47 blockade (30d post-tumor injection in Cre+ + anti-CD47). Unbiased proteomics analysis revealed increased antigen processing and presentation capabilities of Siglece knockout MdMs which was confirmed by ex-vivo OT-1 cross-presentation assays. This bridging of innate and adaptive responses with increased T cell priming upon MdM Siglece knockout was further promoted by addition of anti-PD1 antibody to the combined Siglece knockout and anti-CD47 treatment arm. Animals harboring CT-2A tumors, exhibited a sustained survival benefit under the triple therapy, with 23% of animals experiencing long-term remission, even after tumor re-challenge into the contra-lateral hemisphere. By genetically targeting sialic acids, the ligand for Siglec receptors, on CT-2A cells (GNE-KO), we observed a strong innate and adaptive immune response with increased GBM-cell phagocytosis by MG and MdMs and less exhausted tumor-infiltrating CD8+ T-cells (14.8% in WT vs. 5.9% in GNE-KO, p = 0.003). Conclusion These data identify the sialic-acid-Sigl ec-E pathway as an anti-phagocytic signal in a pre-clinical GBM model, and demonstrate its therapeutic potential in GBM immunotherapy. View on Web

Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

P17.06.B Different dosage of bevacizumab treatment in recurrent IDHwt glioblastoma/IDHmut grade 4 astrocytoma and its impact on outcome

alexandrossfakianakis shared this article with you from Inoreader P17.06.B Different dosage of bevacizumab treatment in recurrent IDHwt glioblastoma/IDHmut grade 4 astrocytoma and its impact on outcome via # Neuro-Oncology Current Issue 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. View on Web

Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

Favipiravir in patients with early mild-to-moderate COVID-19: a randomized controlled trial

alexandrossfakianakis shared this article with you from Inoreader Favipiravir in patients with early mild-to-moderate COVID-19: a randomized controlled trial via Clinical Infectious Diseases Advance Access 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. View on Web

Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

Outcomes of Partial Oral Antibiotic Treatment for Complicated S. aureus Bacteremia in People Who Inject Drugs

alexandrossfakianakis shared this article with you from Inoreader Outcomes of Partial Oral Antibiotic Treatment for Complicated S. aureus Bacteremia in People Who Inject Drugs via Clinical Infectious Diseases Advance Access Abstract Background Staphylococcus aureus represents the leading cause of complicated bloodstream infections among persons who inject drugs (PWID). Standard of care (SOC) intravenous (IV) antibiotics result in high rates of treatment success, but are not feasible for some PWID. Transition to oral antibiotics may represent an alternative treatment option. Methods We evaluated all adult patients with a history of injection d rug use hospitalized from 1/2016 through 12/2021 with complicated S. aureus bloodstream infections, including infective endocarditis, epidural abscess, vertebral osteomyelitis, and septic arthritis. Patients were compared by antibiotic treatment (SOC IV antibiotics, incomplete IV therapy, or transition from initial IV to partial oral) using the primary composite endpoint of death or readmission due to microbiologic failure within 90 days of discharge. Results Patients who received oral antibiotics after an incomplete IV antibiotic course were significantly less likely to experience microbiologic failure or death than patients discharged without oral antibiotics (p < 0.001). There was no significant difference in microbiologic failure rates when comparing patients who were discharged on partial oral antibiotics after receiving at least 10 days of IV antibiotics to SOC regimens (P > 0.9). Conclusion Discharge of P WID with partially treated complicated S. aureus bacteremias without oral antibiotics results in high rates of morbidity and should be avoided. For PWID hospitalized with complicated S. aureus bacteremias who have received at least 10 days of effective IV antibiotic therapy after clearance of bacteremia, transition to oral antibiotics with outpatient support represents a potential alternative if the patient does not desire SOC IV antibiotic therapy. View on Web

Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.