bluuebunny/crossref_metadata_2025 huggingface dataset:
P14.41 Temporal muscle thickness is an independent prognostic marker in patients with progressive glioblastoma: translational imaging analysis of the EORTC-26101 trial
Authors: Furtner J , Genbrugge E , Gorlia T , Bendszus M , Nowosielski M , Golfinopoulos V , Weller M , van den Bent M J , Wick W , Preusser M
Published: September 2019

BACKGROUND

Temporal muscle thickness (TMT) was described as surrogate marker of skeletal muscle mass and prognostic parameter in brain metastasis patients. This study aimed to evaluate the prognostic relevance of TMT in patients with progressive glioblastoma.

MATERIAL AND METHODS

TMT was analyzed on the baseline cranial magnetic resonance (MR) images of 596 patients with progression of glioblastoma after radio-chemotherapy enrolled in the EORTC 26101 trial. An optimal TMT cutoff for overall survival (OS) and progression free survival (PFS) was defined in the training cohort (n=260 patients enrolled in phase 2 part of EORTC 26101). Patients were grouped as “below” or “above” the TMT cutoff and associations with OS and PFS were tested using the Cox model. The findings were validated in a test cohort (n=308 patients enrolled in phase 3 part of EORTC 26101).

RESULTS

An optimal baseline TMT cutoff of 7.2 mm was obtained in the training cohort for both OS and PFS (AUC=0.64). Univariate analyses estimated a hazard ratio (HR) of 0.54 (95% CI:0.42, 0.70, p<0.0001) for OS and a HR of 0.49 (95% CI: 0.38, 0.64, p<0.0001) for PFS for the comparison of training cohort patients above versus below the TMT cutoff. This was confirmed in multivariate testing for OS (HR of 0.54, 95% CI: 0.41, 0.70, p<0.0001) and PFS (HR of 0.47, 95% CI: 0.36, 0.61, p<0.0001) adjusted for the important risk factors with relevance in the trial for OS (Steroid use at baseline, HR of 1.58, 95% CI: 1.19, 2.11, p = 0.002; MGMT Status, HR of 0.51, 95% CI: 0.36, 0.72, p<0.001; maximum diameter ≥ 40mm, HR of 2.49, 95% CI: 1.41, 4.41, p = 0.002; central hemisphere involvement, HR of 1.97, 95% CI: 1.37, 2.84, p<0.001) and PFS (Neurological deficit, HR of 1.44, 95% CI:1.09, 1,92, p = 0.011; Steroid use at baseline, HR of 1.42, 95% CI: 1.08, 1.86, p = 0.011; MGMT status, HR of 0.61, 95% CI: 0.43, 0.87, p = 0.007; Number of target lesion >1, HR of 2.47, 95% CI: 1.38, 4,41, p = 0.002). Similar results were obtained in the validation cohort.

CONCLUSION

TMT is an independent prognostic parameter in patients with progressive glioblastoma. This parameter is easily assessable on routine MR images and may help to better define frail patient populations and thus facilitate patient management by supporting patient stratification for therapeutic interventions or clinical trials.
P14.43 Histone H3F3A and HIST1H3B K27M mutations in pediatric high-grade gliomas: the Florentine experience
Authors: Guidi M
Published: September 2019

Background

Pediatric high- grade gliomas (HGGs) represent a malignancy with a poor survival. The genetic analysis of these entities has identified useful mutations for an improved prognostic framing. The research of mutations in all H3 histone variants (HIST1H3B and H3F3A) could be usefull to define tumors with different prognosis and phenotypes inasmuch they seems to drive two distinct oncogenic programmes.

MATERIALS E METHODS

We performed a retrospective analysis of pediatric HGGs. We evaluated the type of histone H3 mutated and we performed a meta-analysis comparing our results with literature data.

RESULTS

We evaluated 41 cases of pediatric HGGs (median age of patients: 7 years old, range: 0–32):): 32 anaplastic astrocytoma (78,5%), 9 glioblastoma multiforme (25,9%), We have researched the K27M mutations in the distinct histone H3 variants (i.e. HIST1H3B and H3F3A). The mutation H3F3A K27M was found in 6 patients instead HIST1H3B K27 mutations was found in a single patient with GBM. All the patients with H3F3A K27M mutation had a progression disease but without statistical correlation (p:0,07). They had a worse prognosis with a median overall survival of 15,5 months (p: 0.0014) versus wild type patients (not reached). H3.3K27M mutation status is a signiﬁcant predictor of OS with a hazard ratio of 4.499 (p = 0.0001). The patient with HIST1H3B K27 mutation died after first line of therapy.

Conclusions

Due to the low incidence of the mutation HIST1H3B in our series we can’t define the difference with two variants. However, the research of K27M mutation in HGGs has diagnostic and prognostic role. The role of histone H3 mutated could predict the outcome in HGGs patients and it could give us more informations compared to the clinic and radiological characteristic of the tumors.
P14.54 Association of EGFR Expression and Copy Number with Outcome in Depatux-m (ABT-414) Randomized Phase II Study of the EORTC Brain Tumor Group
Authors: van den Bent M J , Gorlia T , Sun Y , Kular R , Looman J , Bain E E , Robberts-Rapp L , Ansell P J , Golfinopoulos V , French P
Published: September 2019

BACKGROUND

Patients with glioblastoma (GBM) have a dismal prognosis and are in desperate need of better therapy than the standard of care (SOC). Epidermal growth factor receptor (EGFR) gene amplification is reported in more than 50% of GBMs as an important target for therapeutic intervention and as a potential predictive biomarker. Depatuxizumab mafodotin (depatux-m, ABT-414) is an antibody-drug conjugate that preferentially binds cells with EGFR active conformation, internalized and releases the cytotoxin, leading to cell death. In the primary analysis we reported a trend (in EORTC 1410; HR: 0.71, 95% CI [0.50–1.02], p = 0.06) at topline analysis which continued to improve with ad hoc follow up (HR of 0.66, 95%CI [0.47–0.93]; p = 0.016) was observed towards improved overall survival (OS) in patients with EGFR amplified (amp) recurrent glioblastoma treated with depatux-m in combination with temozolomide. OS was equivalent in the depatux-m monotherapy and chemotherapy control arms. Here, we evaluate the association of EGFR mRNA expression and EGFR copy number with outcome using the updated efficacy data.

METHODS

Eligible were patients with centrally confirmed EGFR amp GBM at first recurrence after temozolomide chemo-irradiation. Patients were randomized to either a) depatux-m 1.0–1.25 mg/kg combined with temozolomide 150–200 mg/m2 day 1–5 every 4 weeks, b) depatux-m 1.0–1.25 mg/kg monotherapy or c) either temozolomide or lomustine (TMZ/LOM) depending on the time of relapse. Primary endpoint was OS. Long-term follow-up data (24 months follow-up; 237 events) were utilized for this EGFR analysis. The expression level of EGFR was determined using RT-PCR. The absolute copy number of EGFR was determined using next generation sequencing. EGFR mRNA and EGFR copy number were treated as continuous variables and compared to OS using a generalized additive cox proportional hazards model.

RESULTS

The outcome of the long-term follow-up was that when used in combination with TMZ, depatux-m addition resulted in improved OS as compared to TMZ/ LOM control regardless of EGFR expression or absolute copy number of EGFR. In contrast, in depatux-m monotherapy, a trend was observed that depatux-m improved the outcome only at highest expression levels and highest absolute EGFR copy number.

CONCLUSIONS

The long-term follow-up trial results demonstrated that addition of depatux-m to SOC showed a trend to increased survival as compared to SOC alone in EGFR amp patients as determined using Fluorescent in situ hybridization (FISH) analysis. Further retrospective analysis supports this efficacy advantage is observed at all expression and amplification levels. When used in combination with SOC and regardless of the absolute copy number of EGFR, the trend for OS improvement was observed at all expression levels.
P14.55 FOXP2 as a prognostic biomarker in glioblastoma
Authors: Plata-Bello J , Fariña H , Betancor I , Quintero Y , Salido E , Garcia-Marin V
Published: September 2019

Background

FOXP2 is an essential transcription factor for the development of language. It has also a high expression in some neosplasm, with a differential role as a prognostic biomarker. However, the role of FOXP2 in glioblastoma (GBM) has not been studied until now.

AIM

To study the role of FOXP2 as a prognostic biomarker in GBM.

METHODS

This is a retrospective observational case series study in which the expression of FOXP2 has been analyzed at the protein level (immunochemistry, in probes from patients treated in our Center) and at the level of mRNA (RNAseq, in a cohort of GBM patients from The Cancer Genome Atlas [TCGA] database). The expression of some target genes of FOXP2 (RNAseq) has also been studied in the TCGA cohort. Survival analysis using Log-Rank test and COX regression (uni- and multivariate) have been used. The analysis included also other molecular and clinical features of interest in GBM.

RESULTS

At protein level, FOXP2 was expressed in more than 90% of patients, with a mean positivity of 28.33% (SD=32.29). At mRNA level, FOXP2 was expressed in 79% of patients, with a mean expression of 29.72 RPKM (SD=63.77). Patients with a high expression of FOXP2 at protein level showed a worse prognosis than those patients with low expression in both, progression free survival (HR=1.711; p=.034) and overall survival (HR=1.809; p=.014). These associations maintained their significance in multivariate analysis. Nevertheless, no prognostic association was found with mRNA FOXP2 expression. Interestingly, FOXP2 target genes did not show the expected regulation described in previous works. Some of these genes has been involved in oncogenesis.

CONCLUSION

FOXP2 is expressed in many GBM patients. Higher expression of FOXP2 protein may be associated with a worse prognosis, but this has not been confirmed at mRNA. Furthermore, a dysregulation of FOXP2 function may be present in tumoral cells.
P14.59 Post-Market Surveillance Data of the EMEA region indicate good tolerability of TTFields in WHO Grade III Glioma
Authors: Keßler A F , Ritz R
Published: September 2019

BACKGROUND

Despite considerable progress in molecular characterization and evidence for certain regimens, treatment of grade III gliomas is still ambiguous and, with surgery, radiotherapy and chemotherapy, in analogy to grade IV glioma treatment. Tumor treating fields (TTFields) therapy proved to be effective as an additional anti-mitotic treatment in glioblastoma and is available in several countries. While TTFields in grade III glioma are being investigated in several clinical trials, we report an analysis of surveillance safety data in patients with grade III glioma already treated with TTFields in the EMEA region.

METHODS

We reviewed post-marketing surveillance data of the EMEA region. Using the MedDRA body system with system organ class and preferred terms, adverse events reported in the subgroup of patients with grade III glioma treated with TTFields were systematically analysed. Patients with diagnosis of anaplastic astrocytoma and anaplastic oligodendroglioma were included.

RESULTS

This analysis includes 142 patients with grade III glioma treated with TTFields in the EMEA region. Median age was 47 years (range 5–78 years). 64% of the patients reported at least one adverse event. With an incidence of 35%, skin reaction was the most common reported adverse event, none of them were severe. 29 % of the patients reported general disorders, including general health deterioration (15%) and fatigue/malaise (6%). Adverse events related to the nervous system were reported in 26% of patients; seizures were noted in 9% and headache in 7% of patients.

CONCLUSION

The retrospective analysis of available post-market surveillance data of EMEA patients with grade III glioma showed no occurrence of serious adverse events that were associated with TTFields. Skin reaction, as the most commonly reported adverse event, but also other reported adverse events had comparable incidences to the rates observed in the phase III trials for patients with recurrent (EF-11) and newly diagnosed GBM (EF-14). In summary, this analysis identifies no additional safety signals on the use of TTFields in the treatment of patients with grade III glioma. Future results of clinical trials in these indications will give further insight into safety and efficacy in this subgroup.
P14.62 Safety and adverse event profile post-market surveillance analysis of Tumor Treating Fields (TTFields) in EMEA
Authors: Schmidt T , Kebir S , Lazaridis L , Stoppek A , Glas M
Published: September 2019

BACKGROUND

Tumor Treating Fields (TTFields) are established as modality in glioblastoma (GBM) therapy. GBM is the most aggressive brain tumor in adults, constituting approximately 15 % of all primary brain tumors. At diagnosis, a considerable subgroup of GBM patients is ≥65 years of age. The phase 3 EF-14 trial demonstrated a significant improvement of progression free, overall and longterm survival in newly diagnosed GBM (ndGBM) patients by the addition of TTFields compared temozolomide therapy. No treatment limiting systemic adverse events in the EF-14 trial for ndGBM or in the EF-11 trial for recurrent GBM (rGBM) were observable. Here, we present post-market surveillance data from patients in the EMEA region including elderly patients (≥ 65 years) treated with TTFields.

METHODS

Based on the MedDRA body system (system organ class) and preferred terms surveillance data of patients in the EMEA region were assessed. Additionally, surveillance data of patients < 65 as well as ≥ 65 years of age in this region were separately analyzed.

RESULTS

A total of 11,048 patients were treated with TTFields (ndGBM 53.3 %, rGBM 39.5 %, other diagnoses 7.2 %) of whom 2,252 (20.4 %) patients were treated in the EMEA region. 19.6 % of patients treated in this region were ≥65 years of age at the time of TTFields therapy initiation. One or more adverse events were reported by 64 % of EMEA patients < 65 and in 67 % of elderly EMEA patients. The most prevalent adverse event in both age groups was skin reactions, occurring in 30 % of patients < 65 years of age and 33 % elderly patients. Likewise, further adverse events in elderly patients in the EMEA region were comparable to patients younger than 65 years of age, e.g. heat sensation (< 65; ≥ 65: 4 %; 4 %) and general physical health deterioration (14 %; 18 %).

CONCLUSION

These real-life data demonstrate a good safety profile of TTFields in elderly patients as well as in patients < 65. The most frequent registered adverse event was skin reaction, which is in line with the results of the phase 3 EF-11 trial for rGBM and the EF-14 trial for ndGBM patients. In summary, these results from post-marketing surveillance emphasize the safety of TTFields in GBM treatment, particularly in the elderly population.
P14.82 Combining therapy with recombinant human endostatin and cytotoxic agents for recurrent disseminated glioblastoma: a retrospective study
Authors: Zhang J
Published: September 2019

BACKGROUND

The optimal chemotherapeutics of recurrent disseminated glioblastoma has yet to be determined. We analyzed the efficacy and safety of temozolomide (TMZ) and irinotecan (CPT-11) combined with recombinant human endostatin (rh-ES) in patients with recurrent disseminated glioblastoma.

MATERIAL AND METHODS

We retrospectively reviewed 30 adult patients with recurrent disseminated glioblastoma treated with this combination chemotherapy from November 2009 to August 2018. TMZ was given orally 200mg/m2 for 5 days in each 28-day cycle (5/28d). CPT-11 was administrated 125 mg/m2 for patients not receiving enzyme-inducing antiepileptic drugs (EIAEDs) or 340 mg/m2 for patients receiving EIAEDs on day 1 and day 15; rh-ES was administrated 15 mg/d, daily for 14 days of each 28-day treatment cycle.

RESULTS

Primary endpoint was progression-free survival at 6 months (6m-PFS). The 6m-PFS was 23.3%. The median PFS was 3.2 months. The overall survival rate (OS) at 12 months was 28.6%. The median OS was 6.9 months. Six out of 30 (20%) patients demonstrated partial radiographic response and 11/30 (36.7%) remained stable. The PFS of the 6 patients who got partial response was 5.8, 6.3, 6.9, 13.6, 15.8, 16.6 months, respectively, and the median time interval of first response was 4 (range, 2.0–6.6) months. The most common adverse events were hematologic toxicity and gastrointestinal reactions. The Grade ≥3 adverse event was mainly hematologic toxicity. The adverse events were manageable.

CONCLUSION

Rh-ES, in combination with cytotoxic drugs, was an alternative effective regimen with manageable toxicity in treatment of recurrent disseminated glioblastoma.
P14.89 What happens after 15 years? A clinical picture of a cohort of survivors of CNS tumors treated with whole-brain irradiation in a National Cancer Center
Authors: Espírito Santo V L , Passos J , Pimentel T , Nunes J , Costa I , Salgado D
Published: September 2019

BACKGROUND

Radiotherapy (RT) is standard curative treatment for many tumours, specially brain tumours. However, RT causes damage to normal brain tissue due to genetic instability, impairment of synaptic plasticity and increased oxidative stress and inflammation. With improved treatment, patient survival also increased in years, making long-term effect of RT more evident. Late toxicities of RT are well described for pediatric survivors but there is scant literature on late toxicities in adult survivors and, in general, the adult brain is considered less susceptible to radiation damage.

MATERIAL AND METHODS

Retrospective analysis of adult patients treated with whole-brain RT with more than 15 years of follow-up. Clinical charts were reviewed to collect clinical, demographic and outcome data.

RESULTS

From 18 patients found (mean age at diagnosis of 27 years, 13 male/ 5 female), 5 were diagnosed with medulloblastoma, 5 CNS lymphoma, 5 with germinoma, 3 with ependymoma and 1 with teratocarcinoma. Most common presentations were headache (61,1%), seizure (16,7%) and dizziness (16,7%). 5 patients (27,8%) had hydrocephalus at diagnosis. All patients received whole-brain RT (mean 40Gys, varying between 21 to 60Gys), alongside with complete surgical resection in 11 patients (61,1%) and chemotherapy in 10 patients (55,6%). Mean follow-up time was 23,6 years and only 1 patient died due to lymphoma recurrence 16,7 years after the initial diagnosis. During follow-up, all patients had late RT induced changes, leukoencephalopathy in 16 patients (88,9%; mean 8,6 years after RT), ischemic stroke in 9 patients (50,0%; mean 16,0 years after RT), cerebral microbleeds in 14 patients (77,8%; mean 15,4 years after RT), cognitive decline in 12 patients (66,7%; mean 15,8 years after RT), radio-induced meningioma in 3 patients (16,7%; mean 18,1 years after RT) and epilepsy in 2 patients (11,1%; mean 10,5 years after RT). Also 1 patient had neurosensorial loss 14,2 years after RT and another one had subarachnoid haemorrhage due to ruptured aneurysm 19 years after RT.

CONCLUSION

Our results show that late RT induced effects are progressive and irreversible in the adult survivors, in a very similar manner as has been reported in the pediatric survivors. The impact on quality of live is increasing as patients survive longer. RT is still an important tool in neuro-oncology, but its role in curing brain tumors needs further study.
P14.95 Is the pathological-grade relevant in “IDH-wild type, TERT-mutant” diffuse-gliomas? An analysis in 147 patients
Authors: Danyeli A E , Akyerli C B , Dinçer A , Coşgun E , Abacıoğlu U , Pamir M , Özduman K
Published: September 2019

BACKGROUND

Although the word “glioblastoma” still denotes a grade-IV pathology, basic molecular studies have clearly indicated that a significant proportion of lower-grade gliomas harbor genetic alterations typical of glioblastomas. Based on these findings cIMPACT-NOW update 3 has defined an entity called the “diffuse astrocytic glioma, IDH-wildtype, with molecular features of glioblastoma, WHO grade IV”. A TERT-promoter mutation is one of these typical molecular markers of glioblastomas. In this study we analyzed IDH-wild type, TERT-mutant diffuse gliomas of different pathological grades to look for differences in demographic, clinical and survival characteristics.

MATERIAL AND METHODS

147 adult hemispheric diffuse-gliomas with wild-type IDH1/2 and mutant TERT-promoter (C228T or C250T) were retrospectively analyzed. Primary thalamic, cerebellar brainstem or spinal cases were excluded. 126 (86%), 16(11%) and 5(3%) patients were WHO grade IV, III and II respectively. After surgical treatment or stereotactic biopsy all patients underwent chemoradiation. Median follow-up was 16mo (1–110). Tumors of different grades were compared for age, gender, multifocality, gliomatosis pattern, Ki-67 index, progression-free survival and overall-survival.

RESULTS

Mean age at presentation for grade II, III and IV were comparable (58.1, 58 and 58.1; ANOVA, p=0.72). There was a slight male predominance in both lower-grades and WHO-grade IV (M:F ratios 1.625 and 1.74). Mean Ki-67 index was significantly higher in higher grades (0.06, 0.14 and 0.25 for grades II, III and IV; ANOVA, p=0.001). Multifocality was comparable (chi-sq, p=1) in lower-grades (3/21; 14.3%) vs. WHO-grade IV (18/126; 14.3%). Gliomatosis pattern was comparable (chi-sq, p=0.095) in lower-grades (2/21; 9.5%) vs. (3/126; 2.3%). Median recurrence free survival (RFS) was 16 months (0–63) in lower-grades and 8months (1–50) in WHO-grade IV. PFS was significantly different between 3 WHO-grades (Log rank, p=0.007) and also between lower-grades and WHO-grade IV (Log rank, p=0.002). Median overall survival was 26 months(2–110) in lower-grades and 15mo(1–91) in WHO-grade IV. OS was significantly different between 3 WHO-grades (Log rank, p=0.014) and also between lower-grades and WHO-grade IV (Log rank, p=0.007).

CONCLUSION

Increasing pathological grades of hemispheric “IDH-wild type, TERT-mutant diffuse gliomas” have similar demographic and clinical characteristics but incrasing proliferation indices, decrasing progression free survival and shorter overall survival. The findings may be suggesitve of different grades of one common tumor entity.
P14.97 High risk of venous thromboembolism in patients with brain metastases from non-small cell lung cancer
Authors: Mir Seyed Nazari P , Ay C , Steindl A , Gatterbauer B , Frischer J M , Dieckmann K , Widhalm G , Hainfellner J A , Pabinger I , Preusser M , Berghoff A
Published: September 2019

BACKGROUND

Venous thromboembolism (VTE) is a common complication in patients with cancer. In general, patients with metastatic disease are at highest risk. Lung cancer belong to those tumor entities with a particularly high risk of VTE, ranging between 3–13.8%. However, little is known about the VTE rate in lung cancer patients with brain metastases.

MATERIAL AND METHODS

Our study was conducted in the framework of the Vienna Brain Metastasis Registry. Clinical data and VTE events during the course of the disease were recorded via retrospective chart review. In this analysis, non-small cell lung cancer (NSCLC) patients with a resection of brain metastases at the Medical University of Vienna between 2006 and 2010 were included.

RESULTS

In total, 69 NSCLC patients with brain metastases were analyzed. Overall, 69.6% (48/69) patients had an adenocarcinoma, 13% (9/69) a squamous cell carcinoma, 8.7% (6/69) a large cell carcinoma and 8.7% (6/69) other primary tumor histologies. After cancer diagnosis, 20.3% (14/69) patients developed VTE during the course of the disease. Of those, 85.7% (12/14) thromboembolic events occurred after the diagnosis of brain metastases.

CONCLUSION

Based on our data, patients with brain metastases from NSCLC have a very high VTE risk. Further investigations are needed in order to identify patients with distinct VTE risk profiles. Patients at high risk might potentially benefit from primary thromboprophylaxis over the high risk of intracerebral bleeding.
P14.102 Cerebellar atrophy patterns in paraneoplastic cerebellar degeneraiton and spinocerebellar ataxia 1 (SCA1)
Authors: Vialatte de Pémille C , Psimaras D , Adanyegu I , Graus F , Dürr A , Honnorat J , Delattre J , Alentorn A
Published: September 2019

BACKGROUND

Brain and more specifically cerebellar atrophy is a major radiological finding in both Paraneoplastic Cerebellar Degeneration (PCD) with anti-Yo antibodies and Spinocerebellar Ataxia type 1 (SCA1).We sought to analyze the different brain volumetric patterns of cerebellar atrophy in these diseases.

MATERIAL AND METHODS

We performed a retrospective multicentric study (Paris, Lyon, Barcelona reference centres) with either anti-Yo PCD (n=16) or SCA1 (n=17) and 30 healthy subjects paired by age. We used VolBrain and CERES algorithms to obtain the brain and cerebellum segmentation, respectively as well as the cortical thickness. We used a Sparse Canonical Correlation Analysis (SCCAN) and Voxel Brain Morphometry (VBM) with family wise error correction to analyze volumetric differences between the different conditions.

RESULTS

SCA patients were younger than PCD patients (p<0.05, ANOVA). In univariate analysis, most of the atrophic regions (p<0.05) were common between PCD and SCA1 compared to controls. Isolated cortical thickness and grey matter analysis showed predominant atrophy in PCD patients. Multivariate analysis using SCCAN and VBM confirmed these results. We identified a particular atrophy pattern in PCD patients involving lobules III to VII. We observed a more diffuse atrophy distribution in SCA1 patients and a lower cortical atrophy in PCD patients.

CONCLUSION

We described the specific pattern of topographic cerebellar atrophy in PCD and SCA1 patients. The cerebellar atrophy in PCD is mainly localized in the neocerebellum.
P14.118 Carboxypeptidase G2 (CPG2) rescue after high dose methotrexate (hdMTX) chemotherapy for Primary CNS Lymphoma (PCNSL). A French LOC network study
Authors: Garcilazo Y J , Soussain C , Tabouret E , Ahle G , Schimitt A , Waultier A , Blonski M , Liou-Schischmanoff A , Hoang-Xuan K , Houillier C
Published: September 2019

BACKGROUND

CPG2 is an efficient rescue recombinant bacterial enzyme that cleaves MTX into inactive metabolites. As hdMTX is the key agent in PCNSL, delayed MTX excretion (DME), and/or MTX induced nephrotoxicity (MIN) may expose the patients to severe toxicities and prevent the further use of the drug. Little is known on the use of CPG2 and its impact on patient outcome.Objective: To describe the clinical characteristics, indications, risk factors, outcomes of PCNSL patients treated with CPG2.

MATERIAL AND METHODS

Retrospective analysis of patients from the LOC network database with histologically proven PCNSL, aged >18, who received CPG2 following hdMTX.

RESULTS

From 2011 to 2018, 41(3%) of 1236 patients treated with hdMTX used CPG2. Median age: 70 years [46–86], sex ratio M/F 3.6, median KPS 70. Indications of CPG2 were DME (12%), MIN (34%), both (49%). 37/41 (90%) of the patients had either a cardiovascular history (CVH) (76%) or a preexisting chronic kidney disease (CKD) (56%) and 59% had at least one additional risk factor: delayed MTX elimination or renal toxicity in prior cycles (20%), other grade III-IV toxicity (20%), concomitant drugs interfering with MTX excretion (29%), active infection (22%), hypoalbuminemia (59%). Median hdMTX dose was 3 g/m2 [1–3.5], median number of MTX injection received at the time of CPG2: 2[1–6]. At time of the CPG2 administration, median serum creatinine was 185 μmol/l [108–410] and median serum MTX: 25 μmol/l [1–240]. 24% of patients underwent hemodialysis, 76% return to baseline creatinine, in a median of 30 days; no MTX related deaths were reported. Extrarenal grade III-IV toxicities: lymphopenia (46%), neutropenia (22%), mucocutaneous toxicity (15%), thrombopenia (12%), hepatotoxicity (12%), sepsis (12%). Median time to chemotherapy resumption: 26 days (cytarabine-based or hdMTX rechallenge). HdMTX was reintroduced safely in 14 patients (34%) but one. The outcome (ORR, PFS OS) was similar with that expected of patients who would not have had toxicity to MTX.

CONCLUSION

In our study, a small number of patients have received CPG2 regarding the incidence of MIN and DME, probably due to treatment cost. The high frequency of risk factors points out the need of careful attention of this issue and for adapted hdMTX protocol for this vulnerable population. CPG2 treated patients do not have a worse prognosis than expected. A controlled study is warranted to compare the cost/benefit of the management of MIN /DME with or without CPG2.
P14.120 Phase II study of weekly carboplatin in pretreated adult malignant gliomas
Authors: Villani V , Pace A , Vidiri A , Tanzilli A , Sperati F , Terrenato I , Carosi M , Casini B , Maschio M , koudriavtseva T , Cognetti F , Fabi A
Published: September 2019

BACKGROUND

Patients with relapse of recurrent glioma have a poor outcome and limited treatment options. The aim of this study is to investigate the clinical benefit and tolerability of weekly intravenous administration of carboplatin-based monotherapy in adult glioma patients who had progressed from previous chemotherapy lines based on temozolomide and nitrosoureas

MATERIAL AND METHODS

This was a single arm, Phase II study. Eligibility criteria included progressive or recurrent malignant glioma after radiotherapy and chemotherapy-based treatments and Karnofsky Performance Status (KPS) > 60.

RESULTS

Thirty-two patients (median age: 43.5 y) were enrolled to receive weekly carboplatin monotherapy in intravenous mode of administration. The median duration of response was 7.3 months with an overall disease control rate of 31.3%. Median progression-free survival (PFS) was 2.3 months while overall survival (OS) was 5.5 months. Patients achieving clinical benefit exhibited a longer PFS (4.6 vs 1.5 months; p>0.001) and OS (7.9 vs 3.2 months; p=0.041) compared to those not achieving clinical benefit.

CONCLUSION

Our findings show that single agent, weekly, intravenous carboplatin may have a role in the treatment patients with recurrent malignant glioma
P14.122 Integrin α5 is a poor prognostic factor in patients with glioblastoma treated by the Stupp protocol
Authors: Etienne-Selloum N , Prades J , Bello Roufai D , El Azumi F , Boone M , Sevestre H , Trudel S , Coutte A , Desenclos C , Constans J , Chauffert B , Dontenwill M
Published: September 2019

BACKGROUND

Integrin α5β1 was suggested to be involved in glioblastoma (GBM) aggressiveness through preclinical studies and genomic analysis of several cohorts of patients. However, protein expression data are still missing to confirm this hypothesis. Our aim was to investigate the prognostic value of integrin α5 protein expression level in GBM.

MATERIAL AND METHODS

We retrospectively determined the protein expression level of integrin α5 using immunochemistry in tumors from patients treated in 6 French centers. Paraffin sections of GBM were labeled by immunofluorescence and analyzed by confocal microscopy. The corresponding clinical and survival data have been identified and analyzed. The primary end-point was overall survival (OS).

RESULTS

Out of 297 patients newly diagnosed with GBM between 2006 and 2013, 152 met the inclusion criteria (scheduled for initial treatment with the Stupp protocol, age > 18 years) and 95 tumor samples were suitable for immunohistochemical analysis. The median age is 58 years, (64 men, 34 women). Most of patients received macroscopic (43%) or partial (36%) surgery. In univariate analysis using the Log Rank test, high integrin α5 expression level was associated with poor prognosis (PFS: hazard ratio (HR) = 1,696, p=0,0355; OS: HR=1,598, p = 0,0508). Corresponding median OS were 15,6 versus 19,2 months. Similarly, OS was significantly reduced with age (> 60 years), lower resection degree, higher RPA (recursive partitioning analysis) score and non-methylated MGMT (O-6-methylguanine-DNA methyltransferase) promoter. In the subgroup of patients who received the full initial protocol (temozolomide treatment together with radiotherapy and later as adjuvant treatment; n=58) mean OS was strongly reduced when integrin α5 expression level was high (15,6 versus 22,8 months, p=0,0162) suggesting an impact of integrin signaling on temozolomide response in GBM.

CONCLUSION

Our study validates for the first time that the high protein level expression of α5 integrin is associated with poor prognosis in GBM. It also confirms its potential as a therapeutic target and its likely role in resistance to temozolomide as previously shown in preclinical study.
P14.126 radiation-induced optic neuropathy
Authors: Thomas A , Birzu C , Feuvret L , Noël G , Hoang-Xuan K , Savatosky J , Ricard D , Psimaras D
Published: September 2019

BACKGROUND

Optic neuropathy is an inflammation of the optic nerve leading to a rapidly progressive visual loss. Most frequent etiologies are multiple sclerosis, vasculitides, and infections. In the context of tumorous pathology, optic neuropathy can occur due to meningeal infiltration, tumoral compression, or antitumor therapeutics (radiation therapy, some targeted cancer therapies, and checkpoint inhibitors). In the current study, we examine radiation-induced optic neuropathy (RION), which is the most frequent among optic neuropathies caused by antitumor therapeutics.

MATERIAL AND METHODS

We present the cases of 3 patients who experienced RION. For each patient, we collected data on age, type of tumor, date and modalities of radiation-therapy, starting date of visual loss, ophthalmologic description, MRI images, treatment, and clinical and radiological evolution.

RESULTS

The three patients were aged 57 to 68 years old at the time of NORI. They had irradiation between 2013 and 2018. Two patients had proton therapy and one had whole brain irradiation. The visual loss occurred between seven and twelve months after the end of radiation therapy. In all patients the symptoms were bilateral and the loss of vision was rapidly worsened until culminating in almost total blindness. The MRI abnormalities were consistent with retrobulbar optic neuritis. The visual loss remained severe despite the treatment administered. High dose steroids had no clinical effect. Bevacizumab enabled a discrete subjective visual improvement in one patient, but a worsening of visual loss in another. Hyperbaric oxygen therapy had no clinical effect but was undertaken three months after the starting date of visual loss which is probably too late for efficiency. Interestingly one patient was treated with an anti-IL6 antibody (tocilizumab). It was administered in order to avoid fibrosis formation, which is the ultimate condition of the inflammatory process. The rationale is that radiation-induced opening of the bood-brain-barrier and destruction of endothelial and glial cells lead to reparation process through microglia activation. In-vitro studies showed an increased secretion of IL-6 (and other pro-inflammatory cytokines) by the activated microglia. Our patient could not experience benefit from tocilizumab, but the treatment was administered four months after the starting date of visual loss and fibrosis was probably already formed.

CONCLUSION

These cases are consistent with existing literature. The risk is mostly due to the total dose and dose per fraction of the irradiation and the prognosis is very poor with no efficient treatment at the present time. Anti-IL6 antibody could be an interesting treatment if administered at an early stage, but a future prospective clinical trial would be needed to clinically validate this hypothesis.
Discovery of a new pyrimidine synthesis inhibitor eradicating glioblastoma-initiating cells
Authors: Echizenya Smile , Ishii Yukiko , Kitazawa Satoshi , Tanaka Tadashi , Matsuda Shun , Watanabe Eriko , Umekawa Masao , Terasaka Shunsuke , Houkin Kiyohiro , Hatta Tomohisa , Natsume Tohru , Maeda Yoshimasa , Watanabe Shin-Ichi , Hagiwara Shinji , Kondo Toru
Published: September 2019

Background

Glioblastoma-initiating cells (GICs) comprise a tumorigenic subpopulation of cells that are resistant to radio- and chemotherapies and are responsible for cancer recurrence. The aim of this study was to identify novel compounds that specifically eradicate GICs using a high throughput drug screening approach.

Methods

We performed a cell proliferation/death-based drug screening using 10 560 independent compounds. We identified dihydroorotate dehydrogenase (DHODH) as a target protein of hit compound 10580 using ligand-fishing and mass spectrometry analysis. The medical efficacy of 10580 was investigated by in vitro cell proliferation/death and differentiation and in vivo tumorigenic assays.

Results

Among the effective compounds, we identified 10580, which induced cell cycle arrest, decreased the expression of stem cell factors in GICs, and prevented tumorigenesis upon oral administration without any visible side effects. Mechanistic studies revealed that 10580 decreased pyrimidine nucleotide levels and enhanced sex determining region Y–box 2 nuclear export by antagonizing the enzyme activity of DHODH, an essential enzyme for the de novo pyrimidine synthesis.

Conclusion

In this study, we identified 10580 as a promising new drug against GICs. Given that normal tissue cells, in particular brain cells, tend to use the alternative salvage pathway for pyrimidine synthesis, our findings suggest that 10580 can be used for glioblastoma therapy without side effects.

Key Points

1.  Chemical screening identified 10580 as a novel GIC-eliminating drug that targets DHODH, an essential enzyme for the de novo pyrimidine synthesis pathway.

2. Compound 10580 induced cell cycle arrest, apoptosis, and differentiation in GICs.
Risk factors for the development of epilepsy in patients with brain metastases
Authors: Wolpert Fabian , Lareida Anna , Terziev Robert , Grossenbacher Bettina , Neidert Marian C , Roth Patrick , Poryazova Rositsa , Imbach Lukas L , Le Rhun Emilie , Weller Michael
Published: September 2019

Background

Current guidelines do not recommend primary prophylactic anti-epileptic drug (AED) therapy for patients with brain metastases (BM). Yet, subgroups of patients at high seizure risk might still benefit from prophylaxis.

Methods

We identified 799 patients diagnosed with BM by retrospective screening of our electronic chart system. Candidate risk factors for the development of epilepsy were tested by univariate and multivariate Cox regression models.

Results

Epilepsy was diagnosed in 226 of 799 patients (28%). Risk factors for epilepsy in non-operated patients were single BM (P = 0.002, hazard ratio [HR] 3.2, 95% CI: 1.5–6.6) and detection of tumoral hemorrhage (P = 0.008, HR 2.5, 95% CI: 1.3–4.9). Preoperative seizures occurred predominantly in patients with supratentorial BM (P = 0.003, HR 20.78, 95% CI: 2.8–153.4) and lung cancer (P = 0.022; HR 2.0, 95% CI: 1.1–3.6). Postoperative seizures were associated with supratentorial localization (P = 0.017, HR 5.8, 95% CI: 1.4–24.3), incomplete resection (P = 0.005, HR 4.6, 95% CI: 1.6–13.1), and by trend for multiple brain surgeries (P = 0.095, HR 1.9, 95% CI: 0.9–4.0). These risk factors were integrated into a predictive score model for postoperative epilepsy (score sum 0–8). A gradual increase of seizure rates along with higher sum score was confirmed post hoc (score 0 = no seizures; score 8 = 48% seizures). Receiver operating characteristic analysis supported diagnostic accuracy (P = 0.00001, area under the curve = 0.75).

Conclusions

Here we have defined risk profiles for the development of BM-related epilepsy and derived a score which might help to estimate the risk of postoperative seizures and identify individuals at risk who might benefit from primary prophylactic AED therapy.
The soluble form of pan-RTK inhibitor and tumor suppressor LRIG1 mediates downregulation of AXL through direct protein–protein interaction in glioblastoma
Authors: Neirinckx Virginie , Hau Ann-Christin , Schuster Anne , Fritah Sabrina , Tiemann Katja , Klein Eliane , Nazarov Petr V , Matagne André , Szpakowska Martyna , Meyrath Max , Chevigné Andy , Schmidt Mirko H H , Niclou Simone P
Published: September 2019

Background

Targeted approaches for inhibiting epidermal growth factor receptor (EGFR) and other receptor tyrosine kinases (RTKs) in glioblastoma (GBM) have led to therapeutic resistance and little clinical benefit, raising the need for the development of alternative strategies. Endogenous LRIG1 (Leucine-rich Repeats and ImmunoGlobulin-like domains protein 1) is an RTK inhibitory protein required for stem cell maintenance, and we previously demonstrated the soluble ectodomain of LRIG1 (sLRIG1) to potently inhibit GBM growth in vitro and in vivo.

Methods

Here, we generated a recombinant protein of the ectodomain of LRIG1 (sLRIG1) and determined its activity in various cellular GBM models including patient-derived stem-like cells and patient organoids. We used proliferation, adhesion, and invasion assays, and performed gene and protein expression studies. Proximity ligation assay and NanoBiT complementation technology were applied to assess protein–protein interactions.

Results

We show that recombinant sLRIG1 downregulates EGFRvIII but not EGFR, and reduces proliferation in GBM cells, irrespective of their EGFR expression status. We find that sLRIG1 targets and downregulates a wide range of RTKs, including AXL, and alters GBM cell adhesion. Mechanistically, we demonstrate that LRIG1 interferes with AXL but not with EGFR dimerization.

Conclusions

These results identify AXL as a novel sLRIG1 target and show that LRIG1-mediated RTK downregulation depends on direct protein interaction. The pan-RTK inhibitory activity of sLRIG1 warrants further investigation for new GBM treatment approaches.
Photosynthesis Regulation in Response to Fluctuating Light in the Secondary Endosymbiont Alga Nannochloropsis gaditana
Authors: Bellan Alessandra , Bucci Francesca , Perin Giorgio , Alboresi Alessandro , Morosinotto Tomas
Published: September 2019

In nature, photosynthetic organisms are exposed to highly dynamic environmental conditions where the excitation energy and electron flow in the photosynthetic apparatus need to be continuously modulated. Fluctuations in incident light are particularly challenging because they drive oversaturation of photosynthesis with consequent oxidative stress and photoinhibition. Plants and algae have evolved several mechanisms to modulate their photosynthetic machinery to cope with light dynamics, such as thermal dissipation of excited chlorophyll states (non-photochemical quenching, NPQ) and regulation of electron transport. The regulatory mechanisms involved in the response to light dynamics have adapted during evolution, and exploring biodiversity is a valuable strategy for expanding our understanding of their biological roles. In this work, we investigated the response to fluctuating light in Nannochloropsis gaditana, a eukaryotic microalga of the phylum Heterokonta originating from a secondary endosymbiotic event. Nannochloropsis gaditana is negatively affected by light fluctuations, leading to large reductions in growth and photosynthetic electron transport. Exposure to light fluctuations specifically damages photosystem I, likely because of the ineffective regulation of electron transport in this species. The role of NPQ, also assessed using a mutant strain specifically depleted of this response, was instead found to be minor, especially in responding to the fastest light fluctuations.
Pregnancy and undifferentiated connective tissue disease: outcome and risk of flare in 100 pregnancies
Authors: Zucchi Dina , Tani Chiara , Monacci Francesca , Elefante Elena , Carli Linda , Parma Alice , Stagnaro Chiara , Ferro Francesco , Gori Sabrina , Strigini Francesca Anna Letizia , Mosca Marta
Published: September 2019

Objective

UCTD is a systemic autoimmune condition that fails to fulfil the criteria for a definite CTD. Given that there are a lack of studies on links between pregnancy and UCTD, the purpose of this study was to evaluate the risk of disease flares or development of CTD in addition to the risk of adverse pregnancy outcomes in patients with UCTD.

Methods

This is a retrospective study using prospectively collected data for 100 pregnancies in 81 incidences of UCTD treated in a single referral centre.

Results

A total of 11 pregnancies (11%) ended in miscarriage in the first trimester and the remaining 89 (89%) ended with a live birth. Thirteen patients (13%) flared during pregnancy or puerperium and three (3%) suffered major flares that led to the development of SLE with renal involvement. Obstetric complications occurred in 26 of the 89 successful pregnancies (29%), including 1 case (1%) of pre-eclampsia; in some cases, a single pregnancy was affected by more than one complication. There was a significant link between disease flare and both anti-dsDNA-positive antibodies at baseline (P < 0.01) and disease activity at the beginning of pregnancy (P < 0.01).

Conclusion

The impact on pregnancy in the study’s cohort appears to be less serious in UCTD than in other CTDs. Nevertheless, disease flares and obstetric complications can represent a clinical challenge and clinical and serological disease activity would appear to represent important determinants of pregnancy outcomes. Pre-pregnancy counselling and planning as well as close monitoring during pregnancy is therefore essential.
The Effect of an Educational and Interactive Informed Consent Process on Patients With Cervical Spondylotic Myelopathy Caused by Ossification of the Posterior Longitudinal Ligament
Authors: Lee Young-Seok , Cho Dae-Chul , Sung Joo-Kyung , Han Inbo , Kim Chi Heon , Kim Ji-Yoon , Kim Kyoung-Tae
Published: September 2019

Study Design.

Prospective observational cohort study.

Objective.

In this study, an educational and interactive informed consent (EIC) program was proposed for patients with cervical spondylotic myelopathy caused by ossification of the posterior longitudinal ligament (OPLL-CSM) to improve their comprehension level during the informed consent process.

Summary of Background Data.

OPLL-CSM is a slow progressive disease, and it is difficult for patients to understand the disease. Few studies have evaluated very specific programs to improve the informed consent process for these patients.

Methods.

This prospective study evaluated patients with OPLL-CSM who either underwent the proposed EIC process (n = 63) or the standard consent process (n = 124). The standard consent process only included a physician–patient interview. During the EIC process, information was provided regarding OPLL-CSM through information booklets, a video, verbal information, and initial and second physician–patient interviews. After the second physician–patient interview, the patient was requested to answer 14 medical questions to assess their knowledge about OPLL-CSM. The proposed EIC process took approximately 90 minutes. They were asked to report the most useful educational method and the most effective method of reinforcing verbal communication.

Results.

The mean questionnaire scores were higher in the EIC group than in the control group (P < 0.001). Video was selected by 50/63 patients (79.4%) as the most useful EIC process method, and the most effective method of reinforcing verbal communication was video (n = 61; 96.8%). Patients in the EIC group reported having higher satisfaction with surgery (P = 0.024) than did those in the control group.

Conclusion.

The proposed EIC process was shown to result in good patient comprehension and recall regarding OPLL-CSM. Using a video was the most informative and effective reinforcement of verbal communication. The enhanced educational group had better knowledge and improved satisfaction following surgery. The EIC process might help physicians educate and counsel patients regarding OPLL-CSM and its treatment.

Level of Evidence: 2