Survival Outcomes Associated With First-Line Procarbazine, CCNU, and Vincristine or Temozolomide in Combination With Radiotherapy in IDH-Mutant 1p/19q-Codeleted Grade 3 Oligodendroglioma.

PURPOSE: Patients with IDH-mutant 1p/19q-codeleted grade 3 oligodendroglioma (O3IDHmt/Codel) benefit from adding alkylating agent chemotherapy to radiotherapy (RT). However, the optimal chemotherapy regimen between procarbazine, 1-(2-Chloroethyl)-3-cyclohexyl-1-nitrosourea (CCNU), and vincristine (PCV) and temozolomide (TMZ) remains unclear given the lack of randomized trial data comparing both regimens. METHODS: The objective was to assess the overall survival (OS) and progression-free survival (PFS) associated with first-line PCV/RT versus TMZ/RT in patients newly diagnosed with O3IDHmt/Codel. We included patients with histologically proven O3IDHmt/Codel (according to WHO criteria) from the French national prospective cohort Prise en charge des OLigodendrogliomes Anaplasiques (POLA). All tumors underwent central pathological review. OS and PFS from surgery were estimated using the Kaplan-Meier method and Cox regression model. RESULTS: 305 newly diagnosed patients with O3IDHmt/Codel treated with RT and chemotherapy between 2008 and 2022 were included, of which 67.9% of patients (n = 207) were treated with PCV/RT and 32.1% with TMZ/RT (n = 98). The median follow-up was 78.4 months (IQR, 44.3-102.7). The median OS was not reached (95% CI, Not reached [NR] to NR) in the PCV/RT group and was 140 months (95% CI, 110 to NR) in the TMZ/RT group (log-rank P = .0033). On univariable analysis, there was a significant difference in favor of PCV/RT in both 5-year (PCV/RT: 89%, 95% CI, 85 to 94; TMZ/RT: 75%, 95% CI, 66 to 84) and 10-year OS (PCV/RT: 72%, 95% CI, 61 to 85; TMZ/RT: 60%, 95% CI, 49 to 73), which was confirmed using the multivariable Cox model adjusted for age, type of surgery, gender, Eastern Cooperative Oncology Group performance status, and CDKN2A homozygous deletion (hazard ratio, 0.53 for PCV/RT, 95% CI, 0.30 to 0.92, P = .025). CONCLUSION: In patients with newly diagnosed O3IDHmt/Codel from the POLA cohort, first-line PCV/RT was associated with better OS outcomes compared with TMZ/RT. Our data suggest that the improved safety profile associated with TMZ comes at the cost of inferior efficacy in this population. Further investigation using prospective randomized studies is warranted.

Clinical and radiological response of Maffucci related enchondromas to mutant IDH1 inhibitor Ivosidenib.

Ollier Disease (OD) and Maffucci syndrome (MS) is a rare bone disorder that affects the growth and development of the bones, with an estimated prevalence of 1 in 100,000 people. It is associated with somatic mosaicism of isocitrate dehydrogenase-1 (IDH1) or 2 (IDH2) pathogenic variants. Ivosidenib is indicated for the treatment of acute myeloid leukemia and locally advanced or metastatic cholangiocarcinoma and is currently investigated in low-grade glioma with a susceptible isocitrate dehydrogenase-1 (IDH1) pathogenic variant, but its effects in patients with OD or MS are unknown. We here report the first case of a patient with MS who was treated with Ivosidenib for recurrent IDH-1 mutated glioma. Besides the stabilization of the tumor size, the patient observed significant improvement in his enchondromas that became stiffer, with reduced pain, and significant modification of the mineralization of the enchondromas observed on X-rays. This first case report provides hope for the medical management of patients suffering because of OD or MS. Future clinical research is urgently needed to evaluate long-term benefit risk profile of IDH inhibitors in these rare diseases.

BRAF and MEK inhibitor targeted therapy in papillary craniopharyngiomas: a cohort study.

OBJECTIVE: Targeted therapy (TT) with BRAF/MEK inhibitors has emerged as a potential treatment in papillary craniopharyngiomas (PCPs). However, standardized data on large cohorts are lacking. Our study aimed to assess real-life efficacy and safety of BRAF/MEK inhibition in patients with PCPs. DESIGN: Retrospective French multicenter study involving BRAF V600E-mutated PCP patients, treated with BRAF/MEK inhibitor combination dabrafenib and trametinib, from April 2019 to July 2023. METHODS: Objective response and clinical and safety outcomes were assessed after 3 months and at the last available follow-up during TT. RESULTS: Sixteen patients (8 females, mean age 50.5 ± 15.75 years), receiving either neoadjuvant therapy (NEO) for non-resectable tumors (n = 6), post-surgical adjuvant therapy (ADJ; n = 8), or palliative therapy (PAL) following failure of multimodal treatment (n = 2), were included.At the last follow-up (mean 7.6 ± 5.3 months), 12 patients showed subtotal response, 3 exhibited partial response, and 1 maintained stable disease. Mean volume reduction was 88.9 ± 4.4%, 73.3 ± 23.4%, and 91.8 ± 4.3% in the NEO, ADJ, and PAL groups, respectively.Targeted therapy resolved headaches in 5/5 patients and visual impairment in 6/9; 2/3 patients had improved neurological symptoms, 1/4 presented weight loss, and 2/14 recovered endocrine function.Targeted therapy was well-tolerated in 62.5% of cases; adverse events led to treatment discontinuation in 5 patients and definitive discontinuation in 3 cases. CONCLUSIONS: In this study, 94% of patients showed partial response or better to TT. Adverse events were acceptable. Further research is needed to establish standardized protocols; however, these results advocate for a NEO approach in invasive PCPs.

The Role of Radiotherapy, Chemotherapy, and Targeted Therapies in Adult Intramedullary Spinal Cord Tumors.

Intramedullary primary spinal cord tumors are rare in adults and their classification has recently evolved. Their treatment most frequently relies on maximal safe surgical resection. Herein, we review, in light of the WHO 2021 classification of central nervous system tumors, the knowledge regarding the role of radiotherapy and systemic treatments in spinal ependymomas, spinal astrocytomas (pilocytic astrocytoma, diffuse astrocytoma, spinal glioblastoma IDH wildtype, diffuse midline glioma H3-K27M altered, and high-grade astrocytoma with piloid features), neuro-glial tumors (ganglioglioma and diffuse leptomeningeal glioneuronal tumor), and hemangioblastomas. In spinal ependymomas, radiotherapy is recommended for incompletely resected grade 2 tumors, grade 3 tumors, and recurrent tumors not amenable to re-surgery. Chemotherapy is used in recurrent cases. In spinal astrocytomas, radiotherapy is recommended for incompletely resected grade 2 astrocytomas and grade 3 or 4 tumors as well as recurrent tumors. Chemotherapy is indicated for newly diagnosed high-grade astrocytomas and recurrent cases. In hemangioblastomas not amenable to surgery, radiotherapy is an effective alternative option. Targeted therapies are playing an increasingly important role in the management of some intramedullary primary spinal cord tumor subtypes. BRAF and/or MEK inhibitors have demonstrated efficacy in pilocytic astrocytomas and glioneuronal tumors, belzutifan in von Hippel-Lindau-related hemangioblastomas, and promising results have been reported with ONC201 in diffuse midline glioma H3-K27M altered.

Value of Spinal Cord Diffusion Imaging and Tractography in Providing Predictive Factors for Tumor Resection in Patients with Intramedullary Tumors: A Pilot Study.

This pilot study aimed to investigate the interest of high angular resolution diffusion imaging (HARDI) and tractography of the spinal cord (SC) in the management of patients with intramedullary tumors by providing predictive elements for tumor resection. Eight patients were included in a prospective study. HARDI images of the SC were acquired using a 3T MRI scanner with a reduced field of view. Opposed phase-encoding directions allowed distortion corrections. SC fiber tracking was performed using a deterministic approach, with extraction of tensor metrics. Then, regions of interest were drawn to track the spinal pathways of interest. HARDI and tractography added value by providing characteristics about the microstructural organization of the spinal white fibers. In patients with SC tumors, tensor metrics demonstrated significant changes in microstructural architecture, axonal density, and myelinated fibers (all, p < 0.0001) of the spinal white matter. Tractography aided in the differentiation of tumor histological types (SC-invaded vs. pushed back by the tumor), and differentiation of the spinal tracts enabled the determination of precise anatomical relationships between the tumor and the SC, defining the tumor resectability. This study underlines the value of using HARDI and tractography in patients with intramedullary tumors, to show alterations in SC microarchitecture and to differentiate spinal tracts to establish predictive factors for tumor resectability.

The biological significance of tumor grade, age, enhancement, and extent of resection in IDH-mutant gliomas: How should they inform treatment decisions in the era of IDH inhibitors?

The 2016 and 2021 World Health Organization 2021 Classification of central nervous system tumors have resulted in a major improvement in the classification of isocitrate dehydrogenase (IDH)-mutant gliomas. With more effective treatments many patients experience prolonged survival. However, treatment guidelines are often still based on information from historical series comprising both patients with IDH wild-type and IDH-mutant tumors. They provide recommendations for radiotherapy and chemotherapy for so-called high-risk patients, usually based on residual tumor after surgery and age over 40. More up-to-date studies give a better insight into clinical, radiological, and molecular factors associated with the outcome of patients with IDH-mutant glioma. These insights should be used today for risk stratification and for treatment decisions. In many patients with IDH-mutant grades 2 and 3 glioma, if carefully monitored postponing radiotherapy and chemotherapy is safe, and will not jeopardize the overall outcome of patients. With the INDIGO trial showing patient benefit from the IDH inhibitor vorasidenib, there is a sizable population in which it seems reasonable to try this class of agents before recommending radio-chemotherapy with its delayed adverse event profile affecting quality of survival. Ongoing trials should help to further identify the patients that are benefiting from this treatment.

Characteristics of H3K27M-mutant diffuse gliomas with a non-midline location.

PURPOSE: Diffuse midline gliomas (DMG) with H3K27 alterations (H3K27M-DMG) are a highly aggressive form of brain cancer. In rare cases, H3K27 mutations have been observed in diffuse non-midline gliomas (DNMG). It is currently unclear how these tumors should be classified. Herein, we analyze the characteristics of DNMG with H3K27M mutations. METHODS: We reviewed the clinical, radiological and histological characteristics of all patients with an H3K27M mutated diffuse glioma diagnosed in our institution, between 2016 and 2023, to identify cases with a non-midline location. We then performed a molecular characterization (DNA methylation profiling, whole genome and transcriptome sequencing or targeted sequencing) of patients with an H3K27M-mutant DNMG and reviewed previously reported cases. RESULTS: Among 51 patients (18 children and 33 adults) diagnosed with an H3K27M diffuse glioma, we identified two patients (4%) who had a non-midline location. Including our two patients, 39 patients were reported in the literature with an H3K27M-mutant DNMG. Tumors were most frequently located in the temporal lobe (48%), affected adolescents and adults, and were associated with a poor outcome (median overall survival was 10.3 months (0.1-84)). Median age at diagnosis was 19.1 years. Tumors frequently harbored TP53 mutations (74%), ATRX mutations (71%) and PDGFRA mutations or amplifications (44%). In DNA methylation analysis, H3K27M-mutant DNMG clustered within or close to the reference group of H3K27M-mutant DMG. Compared to their midline counterpart, non-midline gliomas with H3K27M mutations seemed more frequently associated with PDGFRA alterations. CONCLUSION: DNMG with H3K27M mutations share many similarities with their midline counterpart, suggesting that they correspond to a rare anatomical presentation of these tumors. This is of paramount importance, as they may benefit from new therapeutic approaches such as ONC201.

Olaparib in recurrent isocitrate dehydrogenase mutant high-grade glioma: A phase 2 multicenter study of the POLA Network.

Background: Based on preclinical studies showing that IDH-mutant (IDHm) gliomas could be vulnerable to PARP inhibition we launched a multicenter phase 2 study to test the efficacy of olaparib monotherapy in this population. Methods: Adults with recurrent IDHm high-grade gliomas (HGGs) after radiotherapy and at least one line of alkylating chemotherapy were enrolled. The primary endpoint was a 6-month progression-free survival rate (PFS-6) according to response assessment in neuro-oncology criteria. Pre-defined threshold for study success was a PFS-6 of at least 50%. Results: Thirty-five patients with recurrent IDHm HGGs were enrolled, 77% at ≥ 2nd recurrence. Median time since diagnosis and radiotherapy were 7.5 years and 33 months, respectively. PFS-6 was 31.4% (95% CI [16.9; 49.3%]). Two patients (6%) had an objective response and 14 patients (40%) had a stable disease as their best response. Median PFS and median overall survival were 2.05 and 15.9 months, respectively. Oligodendrogliomas (1p/19q codeleted) had a higher PFS-6 (53.4% vs. 15.7%, P = .05) than astrocytomas while an initial diagnosis of grade 4 astrocytoma tended to be associated with a lower PFS-6 compared to grade 2/3 gliomas (0% vs 31.4%, P = .16). A grade 2 or 3 treatment-related adverse event was observed in 15 patients (43%) and 5 patients (14%), respectively. No patient definitively discontinued treatment due to side effects. Conclusions: Although it did not meet its primary endpoint, the present study shows that in this heavily pretreated population, olaparib monotherapy was well tolerated and resulted in some activity, supporting further PARP inhibitors evaluation in IDHm HGGs, especially in oligodendrogliomas.

TARGET: A phase I/II open-label multicenter study to assess safety and efficacy of fexagratinib in patients with relapsed/refractory FGFR fusion-positive glioma.

Background: Oncogenic FGFR-TACC fusions are present in 3-5% of high-grade gliomas (HGGs). Fexagratinib (AZD4547) is an oral FGFR1-3 inhibitor with preclinical activity in FGFR-TACC+ gliomas. We tested its safety and efficacy in patients with recurrent FGFR-TACC + HGGs. Patients and Methods: TARGET (NCT02824133) is a phase I/II open-label multicenter study that included adult patients with FGFR-TACC + HGGs relapsing after ≥1 line of standard chemoradiation. Patients received fexagratinib 80 mg bd on a continuous schedule until disease progression or unacceptable toxicity. The primary endpoint was the 6-month progression-free survival rate (PFS6). Results: Twelve patients with recurrent IDH wildtype FGFR-TACC + HGGs (all FGFR3-TACC3+) were included in the efficacy cohort (male/female ratio = 1.4, median age = 61.5 years). Most patients (67%) were included at the first relapse. The PFS6 was 25% (95% confidence interval 5-57%), with a median PFS of 1.4 months. All patients without progression at 6 months (n = 3) were treated at first recurrence (versus 56% of those in progression) and remained progression-free for 14-23 months. The best response was RANO partial response in 1 patient (8%), stable disease in 5 (42%), and progressive disease in 6 (50%). Median survival was 17.5 months from inclusion. Grade 3 toxicities included lymphopenia, hyperglycaemia, stomatitis, nail changes, and alanine aminotransferase increase (n = 1 each). No grade 4-5 toxicities were seen. A 32-gene signature was associated with the benefit of FGFR inhibition in FGFR3-TACC3 + HGGs. Conclusions: Fexagratinib exhibited acceptable toxicity but limited efficacy in recurrent FGFR3-TACC3 + HGGs. Patients treated at first recurrence appeared more likely to benefit, yet additional evidence is required.

Predictors of Progression in a Series of 81 Adult Patients Surgically Managed for an Intracranial Hemangioblastoma: Implications for the Postoperative Follow-Up.

The aim was to identify predictors of progression in a series of patients managed for an intracranial hemangioblastoma, in order to guide the postoperative follow-up modalities. The characteristics of 81 patients managed for an intracranial hemangioblastoma between January 2000 and October 2022 were retrospectively analyzed. The mean age at diagnosis was of 48 ± 16 years. Eleven (14%) patients had von Hippel-Lindau disease. The most frequent tumor location was the cerebellar hemispheres (n = 51, 65%) and 11 (14%) patients had multicentric hemangioblastomas. A gross total resection was achieved in 75 (93%) patients. Eighteen (22%) patients had a local progression, with a median progression-free survival of 56 months 95% CI [1;240]. Eleven (14%) patients had a distant progression (new hemangioblastoma and/or growth of an already known hemangioblastoma). Local progression was more frequent in younger patients (39 ± 14 years vs. 51 ± 16 years; p = 0.005), and those with von Hippel-Lindau disease (n = 8, 44% vs. n = 3, 5%, p < 0.0001), multiple cerebral locations (n = 3, 17% vs. n = 2, 3%, p = 0.02), and partial tumoral resection (n = 4, 18% vs. n = 1, 2%, p = 0.0006). Therefore, it is advisable to propose a postoperative follow-up for at least 10 years, and longer if at least one predictor of progression is present.

Marizomib for patients with newly diagnosed glioblastoma: A randomized phase 3 trial.

BACKGROUND: Standard treatment for patients with newly diagnosed glioblastoma includes surgery, radiotherapy (RT), and temozolomide (TMZ) chemotherapy (TMZ/RT→TMZ). The proteasome has long been considered a promising therapeutic target because of its role as a central biological hub in tumor cells. Marizomib is a novel pan-proteasome inhibitor that crosses the blood-brain barrier. METHODS: European Organisation for Research and Treatment of Cancer 1709/Canadian Cancer Trials Group CE.8 was a multicenter, randomized, controlled, open-label phase 3 superiority trial. Key eligibility criteria included newly diagnosed glioblastoma, age > 18 years and Karnofsky performance status > 70. Patients were randomized in a 1:1 ratio. The primary objective was to compare overall survival (OS) in patients receiving marizomib in addition to TMZ/RT→TMZ with patients receiving the only standard treatment in the whole population and in the subgroup of patients with MGMT promoter-unmethylated tumors. RESULTS: The trial was opened at 82 institutions in Europe, Canada, and the U.S. A total of 749 patients (99.9% of the planned 750) were randomized. OS was not different between the standard and the marizomib arm (median 17 vs. 16.5 months; HR = 1.04; P = .64). PFS was not statistically different either (median 6.0 vs. 6.3 months; HR = 0.97; P = .67). In patients with MGMT promoter-unmethylated tumors, OS was also not different between standard therapy and marizomib (median 14.5 vs. 15.1 months, HR = 1.13; P = .27). More CTCAE grade 3/4 treatment-emergent adverse events were observed in the marizomib arm than in the standard arm. CONCLUSIONS: Adding marizomib to standard temozolomide-based radiochemotherapy resulted in more toxicity, but did not improve OS or PFS in patients with newly diagnosed glioblastoma.

REVOLUMAB: A phase II trial of nivolumab in recurrent IDH mutant high-grade gliomas.

BACKGROUND: Novel effective treatments are needed for recurrent IDH mutant high-grade gliomas (IDHm HGGs). The aim of the multicentric, single-arm, phase II REVOLUMAB trial (NCT03925246) was to assess the efficacy and safety of the anti-PD1 Nivolumab in patients with recurrent IDHm HGGs. PATIENTS AND METHODS: Adult patients with IDHm WHO grade 3-4 gliomas recurring after radiotherapy and ≥ 1 line of alkylating chemotherapy were treated with intravenous Nivolumab until end of treatment (12 months), progression, unacceptable toxicity, or death. The primary endpoint was the 24-week progression-free survival rate (24w-PFS) according to RANO criteria. RESULTS: From July 2019 to June 2020, 39 patients with recurrent IDHm HGGs (twenty-one grade 3, thirteen grade 4, five grade 2 with radiological evidence of anaplastic transformation; 39% 1p/19q codeleted) were enrolled. Median time since diagnosis was 5.7 years, and the median number of previous systemic treatments was two. The 24w-PFS was 28.2% (11/39, CI95% 15-44.9%). Median PFS and OS were 1.84 (CI95% 1.81-5.89) and 14.7 months (CI95% 9.18-NR), respectively. Four patients (10.3%) achieved partial response according to RANO criteria. There were no significant differences in clinical or histomolecular features between responders and non-responders. The safety profile of Nivolumab was consistent with prior studies. CONCLUSIONS: We report the results of the first trial of immune checkpoint inhibitors in IDHm gliomas. Nivolumab failed to achieve its primary endpoint. However, treatment was well tolerated, and long-lasting responses were observed in a subset of patients, supporting further evaluation in combination with other agents (e.g. IDH inhibitors).

Repeated blood-brain barrier opening with a nine-emitter implantable ultrasound device in combination with carboplatin in recurrent glioblastoma: a phase I/II clinical trial.

Here, the results of a phase 1/2 single-arm trial (NCT03744026) assessing the safety and efficacy of blood-brain barrier (BBB) disruption with an implantable ultrasound system in recurrent glioblastoma patients receiving carboplatin are reported. A nine-emitter ultrasound implant was placed at the end of tumor resection replacing the bone flap. After surgery, activation to disrupt the BBB was performed every four weeks either before or after carboplatin infusion. The primary objective of the Phase 1 was to evaluate the safety of escalating numbers of ultrasound emitters using a standard 3 + 3 dose escalation. The primary objective of the Phase 2 was to evaluate the efficacy of BBB opening using magnetic resonance imaging (MRI). The secondary objectives included safety and clinical efficacy. Thirty-three patients received a total of 90 monthly sonications with carboplatin administration and up to nine emitters activated without observed DLT. Grade 3 procedure-related adverse events consisted of pre syncope (n = 3), fatigue (n = 1), wound infection (n = 2), and pain at time of device connection (n = 7). BBB opening endpoint was met with 90% of emitters showing BBB disruption on MRI after sonication. In the 12 patients who received carboplatin just prior to sonication, the progression-free survival was 3.1 months, the 1-year overall survival rate was 58% and median overall survival was 14.0 months from surgery.

Aggressive pituitary tumors and carcinomas: medical treatment beyond temozolomide.

Aggressive pituitary tumors are a subset of pituitary neoplasms, characterized by unusually fast growth rate, invasiveness and overall resistance to optimized standard treatment. When metastases are present, the term pituitary carcinoma is employed. After failure of standard treatments, current guidelines recommend first-line temozolomide monotherapy. However, a significant number of patients do not respond to temozolomide, or experience disease progression following its discontinuation; in these latter cases, re-challenge with temozolomide is generally advised, although the reported outcomes have been less satisfactory. Although no alternative therapies have been formally recommended after temozolomide failure, growing evidence regarding potential second- or third-line therapeutic strategies has emerged. In the present work, we reviewed the available evidence published up to April 2023 involving the most relevant therapies employed so far, namely immune checkpoint inhibitors, bevacizumab, peptide radionuclide receptor therapy, tyrosine kinase inhibitors and mTOR inhibitors. For each treatment, we report efficacy and safety outcomes, along with data regarding potential predictors of response. Overall, immune checkpoint inhibitors and bevacizumab are showing the most promise as therapeutic options after temozolomide failure. The former showed better responses in pituitary carcinomas. Peptide radionuclide receptor therapy has also showed some efficacy in these tumors, while tyrosine kinase inhibitors and mTOR inhibitors have exhibited so far limited or no efficacy. Further studies, as well as an individualized, patient-tailored approach, are clearly needed. In addition, we report an unpublished case of a silent corticotroph pituitary carcinoma that progressed under dual immunotherapy, and then showed stable disease under a combination of lomustine and bevacizumab.

Use of 5-ALA fluorescence-guided surgery versus white-light conventional microsurgery for the resection of newly diagnosed glioblastomas (RESECT study): a French multicenter randomized phase III study.

OBJECTIVE: Only one phase III prospective randomized study, published in 2006, has assessed the performance of 5-aminolevulinic acid (5-ALA) fluorescence-guided surgery (FGS) for glioblastoma resection. The aim of the RESECT study was to compare the onco-functional results associated with 5-ALA fluorescence and with white-light conventional microsurgery in patients with glioblastoma managed according to the current standards of care. METHODS: This was a phase III prospective randomized single-blinded study, involving 21 French neurosurgical centers, comparing 5-ALA FGS with white-light conventional microsurgery in patients with glioblastoma managed according to the current standards of care, including neuronavigation use and postoperative radiochemotherapy. Randomization was performed in a 1:1 ratio stratified by institution. 5-ALA (20 mg/kg) or placebo (ascorbic acid) was administered orally 3-5 hours before the incision. The primary endpoint was the rate of gross-total resection (GTR) blindly assessed by an independent committee. Patients without a confirmed pathological diagnosis of glioblastoma or with unavailable postoperative MRI studies were excluded from the per-protocol analysis. RESULTS: Between March 2013 and August 2016, a total of 171 patients were assigned to the 5-ALA fluorescence group (n = 88) or to the placebo group (n = 83). Twenty-four cases were excluded because the WHO histological criteria of grade 4 glioma were not met. The proportion of GTR was significantly higher in the 5-ALA fluorescence group (53/67, 79.1%) than in the placebo group (33/69, 47.8%; p = 0.0002). After adjustment for age, preoperative Karnofsky Performance Scale score, and tumor location, GTR was still associated with 5-ALA fluorescence (OR 4.13 [95% CI 1.94-8.79]). The mean 7-day postoperative Karnofsky Performance Scale score (≥ 80% in 49/71, 69.0% [5-ALA group]; 50/71, 70.4% [placebo group], p = 0.86) and the proportion of patients with a worsened neurological status 3 months postoperatively (9/68, 13.2% [5-ALA group]; 9/70, 12.9% [placebo group], p = 0.95) were similar between groups. Adverse events related to 5-ALA intake were rare and consisted of photosensitization in 4/87 (4.6%) patients and hepatic cytolysis in 1/87 (1.1%) patients. The 6-month PFS (70.2% [95% CI 57.7%-79.6%] and 68.4% [95% CI 55.7%-78.1%]; p = 0.39) and 24-month OS (30.1% [95% CI 18.9%-42.0%] and 37.7% [95% CI 25.8%-49.5%]; p = 0.89) did not significantly differ. In multivariate analysis, GTR was an independent predictor of PFS (hazard ratio 0.56 [95% CI 0.36-0.86], p = 0.008) and OS (hazard ratio 0.65 [95% CI 0.42-1.01], p = 0.05). The use of 5-ALA FGS generates a significant extra cost of 2732.36€ (95% CI 1658.40€-3794.11€). CONCLUSIONS: The authors found that 5-ALA FGS is an easy-to-use, cost-effective, and minimally time-consuming technique that safely optimizes the extent of resection in patients harboring glioblastoma amenable to a large resection.

Zotiraciclib (TG02) for newly diagnosed glioblastoma in the elderly or for recurrent glioblastoma: The EORTC 1608 STEAM trial.

BACKGROUND: Zotiraciclib (TG02) is an oral multi-cyclin dependent kinase (CDK) inhibitor thought to inhibit tumor growth via CDK-9-dependent depletion of survival proteins such as c-MYC and MCL-1 which are frequently overexpressed in glioblastoma. METHODS: EORTC 1608 (NCT03224104) (STEAM) had a three parallel group (A,B,C) phase Ib, open-label, non-randomized, multicenter design in IDH wild-type newly diagnosed glioblastoma or anaplastic astrocytoma. Groups A and B explored the maximum tolerated dose (MTD) of TG02 in elderly patients, in combination with hypofractionated radiotherapy alone (group A) or temozolomide alone (group B), according to O6-methylguanine DNA methyltransferase promoter methylation status determined centrally. Group C explored single agent activity of TG02 at first relapse after temozolomide chemoradiotherapy with a primary endpoint of progression-free survival at 6 months (PFS-6). Tumor expression of CDK-9, c-MYC and MCL-1 was determined by immunohistochemistry. RESULTS: The MTD was 150 mg twice weekly in combination with radiotherapy alone (group A) or temozolomide alone (group B). Two dose-limiting toxicities were observed at 150 mg: one in group A (grade 3 seizure), one in group B (multiple grade 1 events). Main toxicities included neutropenia, gastrointestinal disorders and hepatotoxicity. PFS-6 in group C was 6.7%. CDK-9, c-MYC and MCL-1 were confirmed to be expressed and their expression was moderately cross-correlated. High protein levels of MCL-1 were associated with inferior survival. CONCLUSIONS: TG02 exhibits overlapping toxicity with alkylating agents and low single agent clinical activity in recurrent glioblastoma. The role of CDK-9 and its down-stream effectors as prognostic factors and therapeutic targets in glioblastoma warrants further study.

A Multicenter Randomized Bioequivalence Study of a Novel Ready-to-Use Temozolomide Oral Suspension vs. Temozolomide Capsules.

BACKGROUND: Temozolomide (TMZ) oral suspension (Ped-TMZ, KIZFIZO®) is being developed for the treatment of relapsed or refractory neuroblastoma, a rare cancer affecting infants and young children. The study assessed the safety and the bioequivalence of this novel pediatric formulation with existing TMZ oral capsules. METHODS: In vitro dissolution profiles and the bioequivalence were evaluated following the European Medicines Agency "Guidelines on the investigation of Bioequivalence". The phase I, multicenter, randomized, open-label, crossover, single-dose bioequivalence study enrolled 36 adult patients with glioblastoma multiforme or lower-grade glioma. Each patient received 200 mg/m2 Ped-TMZ suspension and TMZ capsules (Temodal®) on 2 consecutive days, with the order being randomly assigned. Fourteen blood samples were collected up to 10 h post-dosing. Bioequivalence was assessed by comparing the 90% confidence interval for the ratio of the geometric means of maximum TMZ plasma concentration (Cmax) and the area under the curve (AUCt). Other endpoints included further pharmacokinetic parameters and safety. RESULTS: Both formulations exhibited a fast in vitro dissolution profile with more than 85% of TMZ dissolved within 15 min. For the bioequivalence study, thirty patients completed the trial as per the protocol. The ratio of Ped-TMZ/TMZ capsule geometric means (90% CI) for AUCt and Cmax were 97.18% (95.05-99.35%) and 107.62% (98.07-118.09%), respectively, i.e., within the 80-125% bioequivalence limits. No buccal toxicity was associated with Ped-TMZ liquid formulation. CONCLUSIONS: This study showed that Ped-TMZ oral suspension and TMZ oral capsule treatment are immediate release and bioequivalent medicines. There were also no unexpected safety signals or local toxicity (funded by ORPHELIA Pharma; ClinicalTrials.gov number, NCT04467346).

First evidence of anti-VEGF efficacy in an adult case of adamantinomatous craniopharyngioma: Case report and illustrative review.

BACKGROUND: Craniopharyngioma (CP) is a neurosurgical challenge, due to location and to the substantial risk of morbidity associated with surgical resection. Recent advances in molecular research have identified a mutation signature in papillary craniopharyngiomas: BRAF V600E. This has led to targeted therapy, yielding positive results. Despite numerous studies of the pathophysiology of adamantinomatous craniopharyngioma, treatment options for molecular-based therapy are still lacking. The objective of our study was to provide an illustrative review of the literature on possible molecular targets in adamantinomatous craniopharyngioma and to report the case of a patient harboring an adamantinomatous craniopharyngioma deemed unsuitable for surgical resection, in which an anti-VEGF antibody was used to achieve tumor control. CASE REPORT: An 84-year-old-man was referred to our department with a history of visual loss caused by recurrent infundibular adamantinomatous craniopharyngioma. A first surgical attempt to reduce the cystic portion of the tumor compressing the optic pathway failed. Due to rapid worsening of visual function, adjuvant therapy with bevacizumab was initiated before radiotherapy. RESULTS: Neuroradiological and ophthalmological follow-up showed a decrease in tumor volume and improvement in visual function as early as 6 weeks after commencing therapy. These results were confirmed 3 months after commencement of chemotherapy. Radiotherapy was scheduled for long-term tumor control. CONCLUSIONS: To the best of our knowledge, our case is the first in the literature in which targeted therapy using anti-VEGF was successfully used as a single agent to treat adamantinomatous craniopharyngioma, with favorable outcome in terms of tumor shrinkage and clinical improvement. These preliminary results may open new perspectives for the management of adamantinomatous craniopharyngioma. Validation of this approach requires additional clinical evidence.