bluuebunny/crossref_metadata_2025 huggingface dataset:
P09.04.B The importance of treatment tolerability for people with glioma: registry review and qualitative findings from the COBra Study
Authors: Baddeley E , Retzer A , Sivell S , Seddon K , Bulbeck H , Nelson A , Adams R , Grant R , Watts C , Aiyegbusi O , Rivera S , Kearns P , Dirven L , Calvert M , Byrne A
Published: September 2022

Background

Gliomas are the commonest form of primary brain tumour, accounting for 80% of malignant brain tumours. Gliomas represent a heterogeneous group of cancers with variable outcomes, traditionally graded from I to IV (least to most aggressive). The poor prognosis of some glioma patients and high symptom burden has led to a growing emphasis on their quality of survival. Maintaining cognitive function, physical function and other health-related quality of life aspects throughout the disease trajectory are key considerations, particularly for patients with aggressive forms of glioma. It is therefore important that glioma intervention studies collect data aligned with patient priorities that enables assessment of the net clinical benefit of treatments and facilitates informed decision-making. In particular, and of increasing recognition, is the importance of monitoring the incidence of adverse events during and after the course of an intervention, and understanding their impact upon patients, and patients’ own assessment of, tolerability.

Material and Methods

A trial registry review, a systematic review of the qualitative literature and semi-structured interviews with patients and caregivers were undertaken. Outcomes were extracted from these sources to formulate a longlist during the development of a core outcome set for glioma interventional trials (the COBra study).

Results

The registry review (n=91), systematic review (n=21) and semi-structured interviews (n=19) identified many important outcomes and concepts, one of which was tolerability. Tolerability, adverse events, toxicity or safety was reported to be collected as an outcome in 46 trials. Outcomes related to tolerability were identified from 7 articles included in the systematic review. Themes related to tolerability emerged from the qualitative interviews. These included tolerability of side effects of treatment; trade-offs of side effects versus potential benefits in deciding on, and willingness to, undertake further treatment; and self-directed strategies for coping.

Conclusion

There is a growing acknowledgement of the importance of treatment tolerability in the wider field of cancer research. In glioma research specifically, its significance is yet to be reflected in outcomes collected in trials. Our qualitative findings indicate tolerability is of high significance to patients and those close to them. Participants reported how their preconceptions and experience of tolerability influenced treatment decisions and treatment uptake. However, outcomes related to tolerability were collected in just over half of trials in our sample. Tolerability and items relating to the patients’ experience of adverse events should be collected and reported in trial findings to reflect patients’ priorities and enable informed treatment decisions.
P09.05.A Caregiver café in a neuro-oncological context
Authors: Mathiasen M , Bang Rasmussen C , Piil K
Published: September 2022

Background

Caregivers to patients with primary brain tumors often play a vital role in the direct care and support of the patient. Great responsibility is placed on their shoulders to manage practicalities during the cancer trajectory. Caregivers are asked to carry out procedures, report patient-related evaluations, coordinate care and treatment and deliver proper information to the healthcare providers. Hence, they tend to neglect their own physical and emotional needs as they priorities other tasks including financial issues, household and work while coping with family adjustment. Caregivers of patients with brain tumors experience a high level of burden and distress. It is shown in literature that caregiver interventions can reduce caregiver burden, distress and anxiety, and improve coping, relationships and physical functioning

Aim: The aim of this study is to offer caregivers to join a caregiver café at the neuro-oncological department to 1) relax, meet and support each other, (2) be provided with information and answers to their questions, and (3) be recommended appropriate caregiver services.

Material and Methods

This is a user-based sequential three phase project. Applying a co-creation process with informal caregivers we first investigate their preferences, needs and considerations in relation to establishing a caregiver café. A user survey consisting of demographic characteristics and five study-specific and open-ended questions are conducted. Secondly, a project protocol with the design, content and practical planning will be outlined and presented for the patient/relative-user panel at the oncological department. After the final adjustment, a feasibility testing will take place in phase three.

Results

This three-phase project rest on a sequential project development, and findings from one phase will led to the detailed adjustment in the next. Due to its nature of following a participatory design we consider the results to be highly relevant to the users of health-care services. Results from phase I and II is ready to be presented in autumn 2022 including the preliminary results of the feasibility study (recruitment, adherence, safety etc).

Conclusion

Nurses working within neuro-oncology are e.g responsible for providing support, information and education for family caregivers. This project may inspire other nurses to carry out similar initiatives in clinical practice. Thereby we seek to strengthen the evidence on how, what and when the caregivers’ needs and concerns are best addressed with innovative solutions.

Acknowledgement

We like to thank the nurses at the neuro-oncology department, Rigshospitalet for their valuable input and for their participating with the user survey.
P10.14.A Caught in a trap: Silk fibroin, hyaluronic acid, and heparin sponges to capture residual glioblastoma cells
Authors: Ferreira N H , Molina-Pena R , Najberg M , Roy C , Roncali L , Avril S , Mansor M H , Boury F , Alvarez-Lorenzo C , Garcion E
Published: September 2022

Background

Recurrent glioblastoma (GBM) is today inevitable, even using an aggressive treatment protocol (surgery, radiotherapy, and chemotherapy). It mostly occurs within 2 cm of the resection cavity due to the invasion ability of GBM cells. The aim of this work is to test and qualify a local integrative approach using a nano-based chemokine-cancer cell trap concept to lure the residual GBM cells by releasing chemoattractive molecules and, ultimately, confine and kill them in a biomimetic nanostructured polymeric scaffold.

Material and Methods

The stromal cell-derived factor 1α (SDF-1α) was used here as a chemoattractant due to its synergy with the CXCR4 receptor, and the correlation of this axis to the migration of infiltrating GBM cells. Freeze-dried sponges (20 to 140μm/pore size) composed of silk fibroin (SF), hyaluronic acid (HA), and heparin (hep) charged with SDF-1α was evaluated as a GBM cell trap. First, the cytocompatibility and biodegradability of the sponges were evaluated both in vitro and vivo. Secondly, molecular and functional responses of GBM cells to SDF-1α treatment were evaluated using U87MG-CXCR4+ cells, that constitutively and stably expressed both the CXCR4 receptor and RFP, as reporters. To assess the cell migration in response to the SDF-1α gradient in vitro, transwell, under-agarose, and agarose drop assays were used. U87MG-CXCR4+ spheroids were cultivated in the sponges to verify the hosting capacity of the scaffolds. Finally, syngeneic and xenogeneic models were developed to evaluate the bioperformance of the sponges in vivo.

Results

SF-HA-hep sponges presented low cytotoxicity and complete biodegradation after 4 months of implantation. Histological analysis revealed only local reaction, as an immune response in the short-term study, but no signs of acute inflammation or fibrotic process were found at the resection cavity-brain margin in the long-term study, demonstrating fine tolerability in vivo. Relevant molecules involved in chemotaxis (Akt, Erk, and Paxillin) were activated upon treatment with SDF-1α. U87MG-CXCR4+ cells were directionally attracted to the SDF-1α-loaded sponges, and also a larger neurosphere infiltration area was observed in these sponges compared to controls. Preliminary observations have shown cell clusters detached from the main tumor mass towards the cavity with the implanted SDF-1α-loaded sponge. This may be indicative of chemoattraction, as DAPI correlated with Ki67 staining in the migration front. Further analyses including CXCR4, CD44, paxillin, and galectin-1 immunolabeling will be performed to confirm this hypothesis.

Conclusion

Overall, the results showed that the sponges are biocompatible and the SDF-1α suitable to use as a chemoattractant for GBM cells. This strategy can be used to overcome the treatment resistance in GB, and potentially be transferred to the clinic in the future.
P10.19.B An immunotoxin targeting CD317 for the treatment of glioblastoma
Authors: Gramatzki D , Weiss T , Hänsch L , Silginer M , Rushing E J , Roth P , Gramatzki M , Peipp M , Weller M
Published: September 2022

Background

CD317 is an interferon-inducible cell surface receptor expressed in several solid cancer types. HM1.24-ETA’ is a small immunotoxin with a CD317 single-chain variable fragment (svFv) antibody fused to a truncated version of Pseudomonas aeruginosa exotoxin A (ETA’) that is explored as a novel therapeutic approach in CD317-expressing tumors.

Material and Methods

CD317 mRNA expression in human gliomas and its association with survival was analyzed using the database of the Cancer Genome Atlas (TCGA). CD317 protein levels in human gliomas were assessed by immunohistochemistry. CD317 mRNA expression was assessed by RT-PCR and CD317 protein levels by flow cytometry in 13 human glioma cell lines in vitro. Efficacy of HM1.24-ETA’ was analyzed in acute cytotoxicity assays in vitro. Finally, HM1.24-ETA’ was evaluated in the intracranial human LN-229 glioma xenograft nude mouse model after intravenous injection.

Results

Interrogation of the TCGA database showed that increased CD317 mRNA expression correlated with grade of malignancy among isocitrate dehydrogenase (IDH) wildtype and IDH-mutant gliomas. Enhanced CD317 mRNA expression was associated with inferior survival in glioblastoma and astrocytoma, IDH-mutant, WHO grade 4. Immunohistochemistry confirmed CD317 overexpression in human glioblastoma compared to lower grade astrocytomas. CD317 was expressed heterogeneously on mRNA and protein levels in glioma cell lines in vitro. HM1.24-ETA’ induced acute cytotoxicity in CD317-positive glioma cells in vitro. CD317 expression and susceptibility to HM1.24-ETA’-induced cell death were enhanced by interferon-β. HM1.24-ETA’ prolonged survival in the LN-229 xenograft nude mouse model.

Conclusion

These data define CD317 as a novel target for treatment of human gliomas with immunoconjugates.
P11.14.A Systematic review of phase III trials in newly diagnosed glioblastoma 2005-2021
Authors: Oster C , Lazaridis L , Feldheim J , Schmidt T , Kleinschnitz C , Kebir S , Glas M
Published: September 2022

Background

Despite a plethora of studies since the EORTC/NCIC trial in 2005, glioblastoma (GBM) prognosis remains poor. We here identify and compare glioblastoma phase III trials in terms of efficacy and baseline characteristics in an attempt to summarize the experience of the past 16 years.

Methods

A systematic literature search using PubMed and ClinicalTrials.gov was conducted to provide an overview of clinically relevant GBM phase III trials (years 2005-2021) of adult patients younger than 70 years of age. Search results were screened according to predefined inclusion criteria and either excluded or included in further analysis on study design, baseline characteristics, and survival results.

Results

Eleven trials from the literature and clinical trial database fulfilled the search criteria. Among these trials, a total of three GBM phase III trials reported overall survival (OS) benefit, including the EORTC/NCIC study (NCT00006353), EF-14 (NCT00916409) and CeTeG/NOA09 (NCT01149109). All three studies demonstrate similar hazard ratios, which translate into risk reduction of about 40%. Furthermore, low toxicity profile and mostly preserved quality of life were attributed to the treatments tested. Looking at the study designs, eight out of eleven trials were open label randomized trials, including all of the positive ones, and only three negative trials employed treatment blinding and a placebo control. Canonical baseline characteristics (extent of resection, age, gender, MGMT promoter methylation status) did not significantly differ between positive and negative trials. IDH mutation status was analyzed in only two trials, each showing a small percentage of IDH-mutant tumors only.

Conclusion

This analysis on GBM phase III trials conducted between 2005 and 2021 revealed that the majority of trials did not show a significant improvement in overall survival. CeTeG/NOA-09 and EF-14 are the only two studies with positive overall survival outcome since the EORTC/NCIC trial in 2005.
P11.36.A Could a transcriptome profile predict local control for glioblastoma?
Authors: Antelo G , Valduvieco I , Comas S , Serrano S , Molero J , Balañá C , Villà S , Moreno S , Mollà M , Gomà C
Published: September 2022

Background

Glioblastoma (GB) is the most frequent and aggressive primary brain tumor in adults. The standard of care is surgery followed by radiotherapy in combination with temozolomide. GB molecular subtypes (Classical [CL], Mesenchimal [MES] and Proneural [PN]) have been correlated with prognosis. In the preclinical setting, CL and MES glioma stem-like initiating cells have also been shown to be more radioresistant than PN subtype. If confirmed in patients, the molecular subtype could predict the specific benefit of adjuvant treatment. The aim of this work is therefore to investigate whether GB molecular profiles are associated with treatment resistance in vivo.

Material and Methods

We analyzed the spatiotemporal pattern of recurrence (progression-free survival [PFS] and local control) in 37 GB patients treated with adjuvant radiotherapy (30 x 2 Gy, following EORTC contouring guidelines) plus temozolomide in the context of a multi-centric study. Relapse was defined following the RANO criteria (gadolinium enhanced area on MRI T1 sequence) and classified into 3 groups: in-field relapse (Dmean > 57 Gy), out-of-field relapse (Dmean < 48 Gy) and not-defined relapse (no follow-up MR data or marginal relapse). We used three different classification algorithms (SVM, K-Nearest Neighbor and single sample gene set enrichment analysis) for the transcriptomic classification of tumor samples, and we only assigned a molecular profile when all three classifications agreed, otherwise we called it Mixed profile. Patients with a not-defined spatial pattern of recurrence were included in the PFS analysis, but excluded from the local control analysis.

Results

The transcriptomic classification resulted in 14 CL, 1 MES, 9 PN and 13 Mixed. Median PFS after radiotherapy was 6 months, with a mean follow-up of 11 months. No differences in PFS were found between CL, PN and Mixed groups (the single MES case was excluded). Local control was analyzed in 24 patients (10 CL, 4 PN, 10 Mixed). Non- statistically significant differences were found between PN/Mixed and CL subtypes, with a median in-field relapse-free survival of 6.9 months (PN), 6.3 months (Mixed) and 4.7 months (CL).

Conclusion

Although there is no difference in PFS among GB molecular subtypes, these results suggest that the Classical subtypes seem to relapse faster inside the radiotherapy field. This would suggest a higher radioresistance compared to Proneural and Mixed subtypes, in agreement with preclinical data. Due to the low number of patients these differences are statistically non-significant, but they provide the rationale for further investigation in a larger patient cohort. Grant: Marató -TV3
P11.39.B An unusual case of astroblastoma in adult: a case report and review of the literature
Authors: Bernardes L d , José Santos A , Novaes de Rezende Batistella G , Silva Catito M , Martini Pazini A , Neri Andrade T , Gutierres Gambirasio B , Silva Fernandes N , Henriques Coronatto L , Caroline Freitas Barboza I
Published: September 2022

Background

Astroblastoma is an uncommon glial neoplasm of controversial histogenesis, clinical behavior and response to treatment yet to be understood. It usually appears in the cerebral hemisphere of young patients, preferably in the frontal and parietal lobes. Histologically, its characteristics overlap with high-grade gliomas, making the differential diagnosis between these entities complex. Clinical, radiological, histopathological correlations and, if necessary, genetic tests (MN1 Rearrangement) are essential for an accurate diagnosis.

Material and Methods

We present a case report based on data collected retrospectively from electronic medical records.

Results

A 63-year-old male with a 3-month history of headache and one episode of mental confusion. In the neurological exam, language alteration was noted and the other systemic exams were normal. Magnetic resonance imaging of the brain revealed an intra-axial expansive formation involving the insula, superior and middle temporal gyrus, left portion of brainstem, with lobulated contours and heterogeneous, solid-cystic appearance with intermingled hematic foci. The solid portion had heterogeneous contrast enhancement and foci of gross calcification. The lesion was resected and the postoperative MRI showed no residual tumor lesion. Histopathological evaluation showed an extensive pattern of perivascular pseudorosettes of astrocytic cells with broad processes radiating to central vessels, in addition to frequent foci of hyalinization. Immunohistochemistry showed positive staining with antibodies to glial fibrillary acidic protein (GFAP), vimentin and S100 protein, in addition to membranous positivity for epithelial membrane antigen (EMA). The Ki-67 index was 20%. Based on these data, the diagnosis of NOS astroblastoma was established. Four months after resection, imaging follow-up displayed enhancement of the surgical cavity, suggestive of local recurrence. The patient underwent three-dimensional conformal radiotherapy with a total dose of 6000cGy in 30 sessions, followed by adjuvant chemotherapy with temozolomide.The patient did not have tumor recurrence until the last follow-up made 16 months after surgery.

Conclusion

This is an atypical case of an extremely rare glial tumor of the central nervous system, since most patients with astroblastoma range from 3 months to 40 years (median: 15 years), which makes the diagnosis challenging.
P11.48.A Primary CNS lymphoma after CLIPPERS: a case series
Authors: Doubrovinskaia S , Sahm F , Thier M C , Bendszus M , Wick W , Seliger C , Kaulen L D
Published: September 2022

Background

Few cases of primary CNS lymphoma(PCNSL) following a diagnosis of chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids (CLIPPERS) are reported in the literature. Here we explore implications of this sequel for CLIPPERS follow-up and PCNSL outcome.

Material and Methods

A systematic review and meta-analysis of previously described cases in the MEDLINE database was performed in compliance with PRISMA guidelines. Clinical, radiological and pathological characteristics were summarized. Overall survival was estimated using the Kaplan-Meier method.

Results

In addition to a case from our institution, nine cases were previously described in the literature. Eight patients fulfilled diagnostic criteria for ‘definite’ CLIPPERS whereas two cases were diagnosed with ‘probable’ CLIPPERS. Male-to-female ratio was 9:1. Median interval from CLIPPERS to PCNSL diagnosis was 4.5 months. All patients had received immunosuppressive therapy including methylprednisone in all and azathioprine or cyclophosphamide in most cases. On MRI, appearance of a larger lesion (>3mm) with peripheral contrast enhancement was noted in the most cases upon PCNSLdiagnosis. Whereas Epstein-Barr virus was not detected in biopsy specimen upon CLIPPERS diagnosis, it was identified in the majority of samples upon PCNSL diagnosis. Treatmentfor PCNSL included high-dose methotrexate basedchemotherapy in most cases, however median overall survival was poor (5.5 months).

Conclusion

Interval from CLIPPERS to PCNSL diagnosis was short and may mandate close clinical and radiological follow-up, specifically within the first two years after CLIPPERS diagnosis. Characteristics of PCNSL following CLIPPERS resemble other immunodeficiency-related PCNSL. Outcome was inferior and may reflect late diagnosis or brainstem localization.
P12.15.B Astrocyte immunometabolic regulation of the glioblastoma microenvironment drives tumor pathogenicity
Authors: Perelroizen R , Philosof B , Budick-Harmelin N , Chernobylsky T , Rotem K , Ron A , Shimon D , Tessler A , Adir O , Gaoni-Yogev A , Meyer T , Madi A , Ruppin E , Mayo L
Published: September 2022

Background

Malignant brain tumors are the cause of a disproportionate level of morbidity and mortality among cancer patients, an unfortunate statistic that has remained constant for decades. Despite considerable advances in the molecular characterization of these tumors, targeting the cancer cells has yet to produce significant advances in treatment. An alternative strategy is to target cells in the glioblastoma microenvironment, such as tumor associated astrocytes. Astrocytes control multiple processes in health and disease, ranging from maintaining the brain's metabolic homeostasis, to modulating neuroinflammation. However, their role in glioblastoma pathogenicity is not well understood.

Material and Methods

Immunocompetent mice were implanted with murine glioma cell lines and the role of astrocyte in the tumor pathogenicity was analyzed, and further investigated using in-vitro co-cultures.

Results

Here we report that depletion of reactive astrocytes regresses glioblastoma and prolongs mouse survival. Analysis of the tumor-associated astrocyte translatome, revealed that astrocytes initiate transcriptional programs that shape the immune and metabolic compartments in the glioma microenvironment. Specifically, their expression of CCL2 and CSF1 governs the recruitment of tumor-associated macrophages and promotes a pro-tumorigenic macrophage phenotype. Concomitantly, we demonstrate that astrocyte-derived cholesterol is key to glioma cell survival, and that targeting astrocytic cholesterol efflux, via ABCA1, halts tumor progression. In summary, astrocytes control glioblastoma pathogenicity by reprogramming the immunological properties of the tumor microenvironment and supporting the non-oncogenic metabolic dependency of glioblastoma on cholesterol.

Conclusion

These findings suggest that targeting astrocyte immunometabolic signaling may help treat this uniformly lethal brain tumor.
P13.02.B Fully automated segmentation and volumetric measurement of intracranial meningioma using deep learning
Authors: Kang H , Witanto J N , Pratama K , Lee D , Choi K , Choi S , Kim K , Kim M , Kim J , Kim Y , Park S , Park C
Published: September 2022

Background

Most intracranial meningiomas are small, asymptomatic, and incidentally found tumors. Since the growth of meningioma is the principal indication of treatment, accurate and rapid measurement of the volume of intracranial meningiomas is essential in clinical practice to determine the growth rate of the tumor. It could be useful for the management of meningiomas given their increasing incidence and the wait-and-see policy currently in use for asymptomatic meningiomas. The aim of this study was to develop and validate a computational model for fully automated meningioma segmentation and volume measurement on contrast-enhanced MR scans using deep learning.

Material and Methods

The retrospectively collected axial contrast-enhanced T1-weighted section images from patients diagnosed with meningioma were manually segmented and used to construct automatic segmentation models with six U-Net- and nnU-Net-based architectures. The performance of each model was evaluated with the Sørensen-Dice similarity coefficient (DSC) with internal (IVS) and external validation sets (EVS), each consisting of 100 independent MRI examinations.

Results

A total of 12,909 section images from 459 patients were applied for the training (median age 58 [52-66] [IQR]; 385 women [83.9%]). The median tumor volume of the training set was 2.36 cm3. A 2D nnU-Net showed the highest median DSCs of 0.922 and 0.893 for the IVS and EVS, respectively. The nnU-Nets achieved superior performance in meningioma segmentation than the U-Nets. The DSCs of the 2D nnU-Net for small meningiomas less than 1 cm3 were 0.769 and 0.780 with the IVS and EVS, respectively.

Conclusion

We successfully developed a fully automated and accurate volumetric measurement tool for meningioma using nnU-Net. The volumetry performance for small meningioma was significantly better than that achieved in previous studies. The results of this study are clinically applicable and are expected to be of great use in the management of monitored meningioma patients.
P13.04.B Dissecting high-grade glioma immune infiltration in samples from fluorescence-guided surgery: digital pathology with automated image analysis
Authors: Lang A , Jeron R L , Kiesel B , Mischkulnig M , Bergmeister-Berghoff A S , Ricken G , Wöhrer A , Rössler K , Lötsch-Gojo D , Rötzer-Pejrimovsky T , Hainfellner J A , Höftberger R , Widhalm G , Erhart F
Published: September 2022

Background

Fluorescence-guided surgery with 5-aminolevulinic acid (5-ALA) is a widely used technique to conduct maximum safe resection of high-grade gliomas (HGG). 5-ALA accumulates in malignant tumor tissue where it is metabolized to Protoporphyrin IX (PpIX), an agent with fluorescence properties. It helps neurosurgeons to distinguish between tumor-infiltrated tissue and healthy brain parenchyma. Even though fluorescence-guided surgery is clinically well established, the biological properties of different fluorescence levels are not comprehensively studied yet. A relevant current gap in that respect is the pattern of immune cell infiltration in fluorescent versus non-fluorescent tissue samples. In light of future research, reliable, standardized histopathology methods that allow high-throughput analysis are desirable and digital pathology with automated image analysis is an attractive option to explore.

Material and Methods

128 formalin-fixed paraffin-embedded (FFPE) tissue blocks of 39 patients who underwent fluorescence-guided surgery of a HGG were included. Samples were selected based on their documented 5-ALA fluorescence intensity status (strong, vague, negative). Microtome-cut sections of the tissue were stained with antibodies against CD8, CD68, CD163 and FOX P3, representing immune cell populations of specific interest (cytotoxic T cells, glioma-associated macrophages, regulatory T cells). A total of 512 stained slides were then available for assessment. In addition to a classical, semi-quantitative analysis by two independent human reviewers, the immune infiltration intensity was measured via automated image analysis with the digital pathology software QuPath Version 0.3.2.

Results

Across all stained FFPE samples CD68 showed the overall highest intensity, followed by CD163. CD8 and FoxP3 showed generally lower average intensities. In 5-ALA negative and positive high-grade glioma samples the immune cell infiltration pattern was the same. Quantitative automatic digital pathology correlated well with the classical human histopathological analysis for the majority of markers evaluated.

Conclusion

We successfully explored and established novel digital pathology technologies for the study of immune cell infiltration patterns in neurooncology, specifically in the context of fluorescence-guided resection. Leveraging this platform could allow parallelized and high-throughput analysis of immune cell infiltration also in other contexts.
P14.02.A Serum neurofilaments correlate with axonal loss in paclitaxel-induced peripheral neurotoxicity
Authors: Velasco R , Marco C , Mariotto S , Stradella A , Hernández J , Argyriou A A , Ferrari S , Bruna J
Published: September 2022

Background

Paclitaxel-induced peripheral neuropathy (PIPN) is a dose-limiting axonal polyneuropathy. Nerve conduction studies (NCS) are unique for the assessment of axonal impairment in PIPN. Neurofilaments (NFs), constituent of the neuronal cytoskeleton, are emerging as axonal damage biomarker. To date, the association between changes in NCS and NfL quantification across paclitaxel treatment in breast cancer patients has not been specifically addressed.

MATERIAL AND METHODS: Prospective longitudinal measurement of sNfL levels and NCS in 27 chemotherapy-naïve breast cancer patients before (V0) and after completion (V1) of 12 cycles of weekly paclitaxel-based therapy.

Results

Serum NfL levels (in pg/mL) increased over the course of treatment in the whole of patients (T0: 18,509 +/- 12,886 vs T1:255,805 +/- 194,165, p<0.001). The increase in sNfL levels at T1 showed a significant moderate correlation with the percentage of decrease in the amplitude of the sural (ρ = 0.6205 (p=0.0035), radial (r=0.6134, p=0.005)), ulnar (ρ = 0.6298 (p=0.005)) and peroneal motor (ρ = 0.5676, p=0.024)) nerve in NCS across treatment.

Conclusion

sNfL levels increase proportionally to the degree of paclitaxel-induced neuroaxonal damage, revealing being a promising blood biomarker able to detect the severity of large nerve fiber degeneration and, therefore, improving the diagnostic accuracy in PIPN.
P15.14.B Radionecrosis versus progression in brain tumors: results of a promising MRI tools
Authors: Bellu L , Navarria P , Clerici E , Pessina F , Politi L , Savini G , Lillo S , Marzo M , Scorsetti M
Published: September 2022

Background

Distinguish between radiation necrosis (RN) and tumor progression, in patients with irradiated primary or metastatic brain tumors, is a diagnostic challenge. Also the use of new MRI sequences, like diffusion, perfusion-weighted and spectroscopy, or PET with new amino acid tracers, is not always able to differentiate these two entities.To overcome this crucial problem, encouraging results have been obtained using the analysis of delayed contrast extravasation MRI to calculate high resolution maps, called “treatment response assessment maps” (TRAMs). Aim of this exploratory analysis is to assess TRAM ability in differentiate between radiation effect and tumor progression in a small cohort of brain tumor patients treated with radiation therapy (RT).

Material and Methods

Thirty-four patients irradiated for primary and metastatic brain tumors were evaluated. 12 patients have primary brain tumors, 22 patients have brain metastases from different solid tumors. Distinguish by histological subtypes and type of treatment, the 12 patients with primary brain tumors were: 8 glioblastoma, 2 anaplastic astrocitoma, 1 pleomorphic xanthoastrocytoma WHO grade II, and 1 anaplastic xanthoastrocytoma WHO grade III, treated with surgery followed by RT and concomitant and\or adjuvant chemotherapy with temozolomide. Among brain metastatic patients, primary tumor was: 18 non-small cell lung cancer, 2 malignant melanoma, 1 breast cancer and 1 renal cell carcinoma. All of them were treated with stereotactic radiosurgery at the dose of 20-24Gy in 1fraction, or with hypofractionated stereotactic radiotherapy at the dose of 27-30Gy in 3fractions. All images were uploaded and elaborate into the image workstation ([Brainlab AG, Olof-Palme-Straße 9, 81829 Munich]). TRAMs were calculated by subtracting T1 MRI images acquired 5 minutes after contrast injection from the T1 MRI images acquired 60-105 minutes later. On TRAMs, radiation effects appeared as red areas whereas persistent tumoral lesion appeared as blue areas.

Results

From February 2021, 34 patients have been evaluated, in a prospective study, with this novel MRI modality. During their follow-up, 13patients (38%) showed a clinicoradiologic suspicion of a persistent tumoral lesion or progressive disease, and 21 (62%) a suspicion of RN. For 14patients a brain MET-PET has been performed. TRAMs analysis have shown a fair agreement with clinicoradiologic diagnosis, perfusion-weighted MRI, and PET imaging. Moreover, 7 patients underwent surgical resection, with histopathological confirm of persistent disease in 4 and radionecrosis in 3.

Conclusion

These preliminary results show the ability of TRAMs evaluation in distinguish between RN and progressive disease. The recruitment of new patients continues, and further evaluations are ongoing to evaluate sensitivity and positive predictive value of TRAMs analysis.
P17.09.A Regorafenib and Re-irradiation: analysis of clinical outcomes and toxicities in patients with recurrent glioblastomas
Authors: Fiorelli S , Campisi G , Angelicone I , De Giacomo F , Ricciardi C , De Sanctis V , Ascolese A , Osti M
Published: September 2022

Background

Glioblastoma is the most common and aggressive primary brain tumor in adults.The aggressiveness and poor prognosis related to this disease join to the limited available treatment options. The current standard of care involves surgical resection followed by concomitant radiotherapy and chemotherapy. At recurrence, no standard treatment exists and there are no guidelines to facilitate decisions in the recurrent setting. Available options include re-operation, re-irradiation, systemic therapy, alone or in combination. In recent years, immunotherapy strategies have revolutionized the treatment of many cancers, increasing the hope for GBM therapy. Regorafenib (Stivarga) is an inhibitor of several kinases involved in the mechanisms that regulate neoangiogenesis processes, through the inhibition vascular endothelial growth factor (VEGF) receptors and the modifications of the tumor microenvironment; specifically, Regorafenib binds and stabilizes PSAT1 (phosphoserine aminotransferase 1). The dual regulatory mechanism underlying PSAT1-induced autophagy arrest accounts for the superior anti-GBM effect of Regorafenib compared with Temozolomide.

Material and Methods

15 patients with documented disease progression after surgery followed by RT and TMZ were assigned to receive regorafenib (REG) 160 mg once daily for the first 3 weeks of each 4-week cycle. All patients received prior radiation therapy (RT) to a median dose of 60 Gy (range 40.05 -60). Median time to retreatment after prior RT was 16 months (range 14-33). Tumor volumes ranged from 81.7 cm3 to 422.4 cm3 (CTV) and from 112.7 cm3 to 422.4 cm3 (PTV).3 patients (20%) received concomitant reirradiation with a radiation dose of 37.5 Gy in 15 fractions of 2.5 Gy.

Results

the median follow-up was 9.5 months (range 5-22). The overall survival and the progression-free survival rates were 53,8 %, and 46,6 % respectively at 2 years. In 53% the symptoms were stable. Only one patient developed late toxicity: acute pancreatitis (Grade I) regressed on interruption of Regorafenib. No other neurological deficits occurred during follow-up. At last follow up 60% of patients were alive.

Conclusion

we report our experience with Regorafenib, administered in patients with rapid progression after the end of postoperative radio chemotherapy treatment. Regorafenib might be a new potential treatment option for recurrent glioblastoma: it was well tolerated also in cases of combined treatment with reirradiation and appeared effective. Other studies will be necessary to evaluate and confirm the role of Regorafenib in glioblastoma patients and the potential effectiveness of the combined therapeutic strategy: Regorafenib-reirradiation.
Getting With the Times: A Review of Peripartum Infections and Proposed Modernized Treatment Regimens
Authors: Pek Zachary , Heil Emily , Wilson Eleanor
Published: September 2022

This article provides a review of peripartum infections, including intra-amniotic infection, postpartum endometritis, and postabortal infections. We present a case of postabortal infection to frame the review. The microbiology, pathogenesis, risk factors, diagnosis, and treatment of peripartum infections are reviewed, and a critical appraisal of the literature and available guidelines is provided. There is a focus on discussing optimal antimicrobial therapy for treating these infections.
Millimeter methanol emission in the high-mass young stellar object G24.33+0.14
Authors: Hirota Tomoya , Wolak Pawel , Hunter Todd R , Brogan Crystal L , Bartkiewicz Anna , Durjasz Michal , Kobak Agnieszka , Olech Mateusz , Szymczak Marian , Burns Ross A , Aberfelds Artis , Baek Giseon , Brand Jan , Breen Shari , Byun Do-Young , Caratti o Garatti Alessio , Chen Xi , Chibueze James O , Cyganowski Claudia , Eislöffel Jochen , Ellingsen Simon , Hirano Naomi , Hu Bo , Kang Ji-hyun , Kim Jeong-Sook , Kim Jungha , Kim Kee-Tae , Kim Mi Kyoung , Kramer Busaba , Lee Jeong-Eun , Linz Hendrik , Liu Tie , MacLeod Gordon , McCarthy Tiege P , Menten Karl , Motogi Kazuhito , Oh Chung-Sik , Orosz Gabor , Sobolev Andrey M , Stecklum Bringfried , Sugiyama Koichiro , Sunada Kazuyoshi , Uscanga Lucero , van den Heever Fanie , Volvach Alexandr E , Volvach Larisa N , Wu Yuan Wei , Yonekura Yoshinori
Published: September 2022

In 2019 September, a sudden flare of the 6.7 GHz methanol maser was observed toward the high-mass young stellar object (HMYSO) G24.33+0.14. This may represent the fourth detection of a transient mass accretion event in an HMYSO after S255IR NIRS3, NGC 6334I-MM1, and G358.93−0.03-MM1. G24.33+0.14 is unique among these sources as it clearly shows a repeating flare with an 8 yr interval. Using the Atacama Large Millimeter/submillimeter Array (ALMA), we observed the millimeter continuum and molecular lines toward G24.33+0.14 in the pre-flare phase in 2016 August (ALMA Cycle 3) and the mid-flare phase in 2019 September (ALMA Cycle 6). We identified three continuum sources in G24.33+0.14, and the brightest source, C1, which is closely associated with the 6.7 GHz maser emission, shows only a marginal increase in flux density with a flux ratio (Cycle 6$/$Cycle 3) of 1.16 ± 0.01, considering an additional absolute flux calibration uncertainty of $10\%$. We identified 26 transitions from 13 molecular species other than methanol, and they exhibit similar levels of flux differences with an average flux ratio of 1.12 ± 0.15. In contrast, eight methanol lines observed in Cycle 6 are brighter than those in Cycle 3 with an average flux ratio of 1.23 ± 0.13, and the higher excitation lines tend to show a larger flux increase. If this systematic increasing trend is real, it would suggest radiative heating close to the central HMYSO due to an accretion event which could expand the size of the emission region and/or change the excitation conditions. Given the low brightness temperatures and small flux changes, most of the methanol emission is likely to be predominantly thermal, except for the 229.759 GHz (8−1–70 E) line known as a class I methanol maser. The flux change in the millimeter continuum of G24.33+0.14 is smaller than in S255IR NIRS3 and NGC 6334I-MM1 but is comparable with that in G358.93−0.03-MM1, suggesting different amounts of accreted mass in these events.
Therapeutic applications of nanomedicine in metabolic diseases by targeting the endothelium
Authors: Hou L , Zhang M , Liu L , Zhong Q , Xie M , Zhao G
Published: September 2022

The endothelial cells not only constitute the barrier between the blood and interstitial space, but also actively regulate vascular tone, blood flow and the function of adjacent parenchymal cells. The close anatomical relationship between endothelial cells and highly vascularized metabolic organs suggests that the crosstalk between these units is vital for systemic metabolic homeostasis. Here, we review recent studies about the pivotal role of endothelial cells in metabolic diseases. Specifically, we discuss how the dysfunction of endothelial cells directly contributes to the development of insulin resistance, type 2 diabetes mellitus, atherosclerosis and non-alcoholic fatty liver disease via communication with parenchymal cells. Furthermore, although many biological macromolecules have been shown to ameliorate the progression of metabolic diseases by improving endothelial function, the low solubility, poor bioavailability or lack of specificity of these molecules limit their clinical application. Given the advantages in drug delivery of nanomedicine, we focus on summarizing the reports that improving endothelial dysfunction through nanomedicine-based therapies provides an opportunity for preventing metabolic diseases.
Mindfulness-based stress reduction to improve depression, pain and high patient global assessment in controlled rheumatoid arthritis
Authors: Gaboury Isabelle , Dobkin Patricia L , Gendron Françoise , Roberge Pasquale , Beaulieu Marie-Claude , Carrier Nathalie , Dagenais Pierre , Roux Sophie , Boire Gilles
Published: September 2022

Objective

The aim was to improve distressing patient-reported outcomes (PROs) that persisted in RA patients with clinically controlled inflammation (controlled RA).

Methods

In a pragmatic pilot study, we offered mindfulness-based stress reduction (MBSR), a group intervention, to controlled RA patients who had high (≥16) Centre for Evaluation Studies depression (CES-D) scores and/or patient general assessment of disease activity (PGA) at least 2/10 larger than evaluator general assessment (EGA) (PGA-EGA: Delta). Evaluations before, 6 and 12 months after MBSR included CES-D, PGA, modified HAQ, simple disease activity index (SDAI), anxiety (general anxiety disorder 7; GAD-7), coping strategies (coping with health injuries and problems; CHIP), sleep disturbance and pain. Facilitators and obstacles to recruitment and participation were identified. A subset of patients was interviewed for qualitative analysis of their experience.

Results

Out of 306 screened patients, 65 were referred, 39 (60%) agreed and 28 (43%) completed MBSR. Anticipated burden, timing and frequency of group meetings, commuting issues, age extremes and co-morbidities were barriers to participation. Up to 12 months after MBSR, anxiety, depression, emotion-oriented coping, sleep and function significantly improved. Nonetheless, no significant impact was observed on pain, PGA, Delta or SDAI. The interviews revealed that benefits, including integration of effective coping strategies, were maintained.

Conclusion

We addressed MBSR feasibility issues and selection of outcomes in controlled RA patients with distressing PROs. For patients who chose to participate in MBSR, lasting benefits were evident for anxiety, depression, sleep and function. Larger studies are required to evaluate the weaker impact of MBSR on RA-related pain and PGA.
Promoting effect of a calcium-responsive self-assembly β-sheet peptide on collagen intrafibrillar mineralization
Authors: Li Zhongcheng , Ren Qian , Han Sili , Ding Longjiang , Qin Xi , Hu Die , He Ting , Tian Tian , Lu Ziqian , Zhang Linglin
Published: September 2022

Recently, a de novo synthetic calcium-responsive self-assembly β-sheet peptide ID8 (Ile-Asp-Ile-Asp-Ile-Asp-Ile-Asp) has been developed to serve as the template inducing hydroxyapatite nucleation. The aim of this study was to evaluate the effect of ID8 on intrafibrillar mineralization of collagen making full use of its self-assembly ability. The mineralization experiments were carried out in vitro on both bare Type I collagen and fully demineralized dentin samples. The calcium-responsive self-assembly of ID8 was revealed by circular dichroism spectrum, 8-anilino-1-naphthalenesulfonic acid ammonium salt hydrate assay, attenuated total reflection Fourier transform infrared spectrum (ATR-FTIR) and transmission electron microscope (TEM). Polyacrylic acid (450 kDa) with a concentration of 100 μg ml−1 was selected as the nucleation inhibitor based on the determination of turbidimetry and TEM with selected area electron diffraction (TEM-SAED). The results showed that collagen intrafibrillar mineralization was significantly promoted with the pretreatment of self-assembly ID8 detected by TEM-SAED, SEM, X-ray diffraction and ATR-FTIR. The pretreatment of collagen utilizing self-assembly ID8 not only enhanced intermolecular hydrogen bonding but also contributed to calcium retention inside collagen and significantly increased the hydrophilicity of collagen. These results indicated that peptides with self-assembly properties like ID8 are expected to be potential tools for biomimetic mineralization of collagen.
Semi-3D cultures using Laminin 221 as a coating material for human induced pluripotent stem cells
Authors: Nakashima Yoshiki , Yoshida Shinsuke , Tsukahara Masayoshi
Published: September 2022

It was previously believed that human induced pluripotent stem cells (hiPSCs) did not show adhesion to the coating material Laminin 221, which is known to have specific affinity for cardiomyocytes. In this study, we report that human mononuclear cell-derived hiPSCs, established with Sendai virus vector, form peninsular-like colonies rather than embryonic stem cell-like colonies; these peninsular-like colonies can be passaged more than 10 times after establishment. Additionally, initialization-deficient cells with residual Sendai virus vector adhered to the coating material Laminin 511 but not to Laminin 221. Therefore, the expression of undifferentiated markers tended to be higher in hiPSCs established on Laminin 221 than on Laminin 511. On Laminin 221, hiPSCs15M66 showed a semi-floating colony morphology. The expression of various markers of cell polarity was significantly lower in hiPSCs cultured on Laminin 221 than in hiPSCs cultured on Laminin 511. Furthermore, 201B7 and 15M66 hiPSCs showed 3D cardiomyocyte differentiation on Laminin 221. Thus, the coating material Laminin 221 provides semi-floating culture conditions for the establishment, culture and induced differentiation of hiPSCs.
Functional biomaterials for tendon/ligament repair and regeneration
Authors: Tang Yunkai , Wang Zhen , Xiang Lei , Zhao Zhenyu , Cui Wenguo
Published: September 2022

With an increase in life expectancy and the popularity of high-intensity exercise, the frequency of tendon and ligament injuries has also increased. Owing to the specificity of its tissue, the rapid restoration of injured tendons and ligaments is challenging for treatment. This review summarizes the latest progress in cells, biomaterials, active molecules and construction technology in treating tendon/ligament injuries. The characteristics of supports made of different materials and the development and application of different manufacturing methods are discussed. The development of natural polymers, synthetic polymers and composite materials has boosted the use of scaffolds. In addition, the development of electrospinning and hydrogel technology has diversified the production and treatment of materials. First, this article briefly introduces the structure, function and biological characteristics of tendons/ligaments. Then, it summarizes the advantages and disadvantages of different materials, such as natural polymer scaffolds, synthetic polymer scaffolds, composite scaffolds and extracellular matrix (ECM)-derived biological scaffolds, in the application of tendon/ligament regeneration. We then discuss the latest applications of electrospun fiber scaffolds and hydrogels in regeneration engineering. Finally, we discuss the current problems and future directions in the development of biomaterials for restoring damaged tendons and ligaments.