bluuebunny/crossref_metadata_2025_split huggingface dataset:
P14.64 PriCoTTF Trial: A phase I/II trial of TTFields prior and concomitant to radiotherapy in newly diagnosed glioblastoma
Authors: Kebir S , Pierscianek D , Proescholdt M , Hau P , Grosu A , Krex D , Sure U , Scheffler B , Stuschke M , Glas M 
Published: September 2021

Abstract

BACKGROUND
TTFields therapy is applied at 200 kHz by arrays that are placed at the patients’ scalp. In the phase 3 EF-14 trial, survival rates were significantly improved when adding tumor-treating fields (TTFields) to adjuvant temozolomide-based chemotherapy in patients with newly diagnosed glioblastoma (nGBM). In preclinical studies, the combination of TTFields and radiotherapy synergistically impaired proliferation and growth of glioblastoma cells. Here, we present the PriCoTTF trial, which is enrolling nGBM patients and will assess the safety and efficacy of TTFields initiated prior and concomitant to radiochemotherapy.

MATERIAL AND METHODS
Following surgery and complete wound-healing, TTFields therapy is initiated in adult nGBM patients. TTFields therapy continues throughout radiochemotherapy and adjuvant chemotherapy for a total of approximately 9 months. During radiotherapy, the arrays - through which TTFields is delivered - remain on the patients’ scalp. Totally, thirty-three patients are planned to be enrolled in two treatment arms. In arm A, 20 patients receive normo-fractionated radiotherapy, whereas in the elderly arm, arm B, 13 patients receive hypo-fractionated radiotherapy. Concomitant and adjuvant chemotherapy follow institutional standards and interdisciplinary tumor conference recommendations.

RESULTS
The primary endpoint of this trial is safety and tolerance that will be gauged by a set of pre-specified treatment-limiting toxicities. Secondary endpoints include the frequency of adverse events, progression-free survival (PFS), and overall survival (OS). The trial is currently enrolling patients at four sites in Germany. At the time of abstract submission, 9 patients enrolled in Arm B. Patient recruitment for arm A has been completed with 20 patients enrolled. We will present initial practical experiences as well as preliminary safety and tolerance data.

CONCLUSION
There is a biological rationale for combining TTFields and radiotherapy to further improve survival of GBM patients. In the presented phase I/II trial, the safety and efficacy of TTFields initiated prior and concomitant to RT in nGBM will be assessed. In addition, initial efficacy data (phase II) may serve as a rationale for a putative randomized phase III trial.
P14.86 Predictive value of MGMT promoter (pMGMT) methylation status on pseudoprogression (PsP) and survival analysis in Glioblastoma (GBM) patients: a retrospective single institutional analysis
Authors: Interno’ V , De Santis P , Stucci L , Porta C 
Published: September 2021

Abstract

BACKGROUND
Glioblastoma is the most common and aggressive primary brain tumor. Conventional therapies, such as maximal extension of surgery followed by radiotherapy (RT) and chemotherapy with Temozolomide (TMZ) have not resulted in major improvements in terms of patients’ outcome, overall survival (OS) still remaining poor. In this context, radiological response assessment after radiotherapy remains challenging due to the potential effect of radionecrosis, often mimicking tumor progression. Differentiation between PsP and true progression is required to avoid further unnecessary surgeries, or the premature discontinuation of TMZ. It is known that pMGMT methylated patients respond better to chemotherapy than unmethylated counterpart, so, tumor cells necrosis can be enhanced in this setting. The aim of the study is to observe the correlation between pMGMT methylation status with the incidence of PsP in GBM patients at the first radiological evaluation after RT.

MATERIALS AND METHODS
Patients with histologically diagnosis of GBM from 2017 to 2021 and availability of pMGMT methylation status were enrolled. PsP was radiologically defined at first brain MRI after RT in case of increasing size of the enhancing component and of peritumoral oedema that remain stable or decrease after antioedema therapy, such as a clinical improvement was observed.

RESULTS
We analysed 55 GBM patients, 35 (64%) displayed pMGMT methylation whereas 20 (36%) resulted pMGMT unmethylated. PsP was evident in 29 patients (53%), all of them showed methylation of pMGMT. In our analysis, none of pMGMT unmethylated patients experienced PsP. Regarding survival outcome for pMGMT methylated patients, our analysis shows a mPFS of 8.7 (95% CI: 5–10) months versus 9.3 (95%CI: 4.6–12.3) months in methylated and unmethylated respectively (p=0.87).

CONCLUSIONS
Methylation status of pMGMT showed to be predictor of PsP in GBM patients. If validated, this information could be very useful to guide clinicians in differentiating PsP from true progression. To date, our survival analysis regarding PFS showed no statistical difference among methylated patients with respect to the presence or absence of PsP. Thus, PsP seems not to be a marker of responsiveness to common treatment. Further data are needed to validate our results.
P15.02 Loss of Williams Syndrome Transcription Factor (WSTF) leads to improved temozolomide sensitivity in human glioblastoma cells irrespective of MGMT expression
Authors: Sarnow K , Schwab S G , Rio O , Mukherjee J , Bjerkvig R , Johannessen T A 
Published: September 2021

Abstract

BACKGROUND
The prognosis for newly diagnosed adult glioblastoma multiforme (GBM) patients is poor even after standard therapy with a median survival of approximately 14–15 months. The DNA repair protein O 6 -methylguanine-DNA methyltransferase (MGMT) efficiently counteracts formation of the most lethal DNA adducts by temozolomide (TMZ) chemotherapy, and is thus associated with poor outcome in GBM patients. Williams Syndrome Transcription Factor (WSTF) has previously been suggested to regulate the DNA damage response pathway (DDR) in both an indirect (through chromatin remodeling together with SMARCA5 in the WICH complex) and direct manner (by phosphorylating H2AX at Tyr142). However, whether WSTF has any role in the development of resistance against chemotherapy through its ability to regulate the DDR in GBMs, is so far not known. In this study, we investigated whether loss of WSTF sensitizes different MGMT-proficient and -deficient GBM cell lines to TMZ treatment.

MATERIAL AND METHODS
We generated WSTF knockout clones from both MGMT-proficient (LN18, T98G) and -deficient GBM cell lines (U-251) using CRISPR/Cas9 gene-editing technology with lentiviral vectors. The PCR-based screening results combined with the T7 endonuclease mismatch assay for bi-allelic monoclonal knockouts were verified via sequencing and immunoblotting to identify candidate knockout clones. For each cell line, three knockout clones were chosen for further investigation. Colony formation assays were performed to determine the survival ability in response to TMZ treatment. Statistical analysis was performed using two-way ANOVA.

RESULTS
WSTF knockout clones showed a significant decrease in colony formation after TMZ-treatment compared to the corresponding WSTF-expressing control groups (non-target single guide RNA) (LN18: Clone 59 vs control: p= 0.0456, T98G: All three studied clones vs control: p &lt;0.0001, U-251: Clone 7/35.1/70.2 vs control: p &lt;0.0001/p= 0.0107/p= 0.0119). Furthermore, two out of three clones of T98G and U-251 (T98G Clone 13 and 128 vs control, p &lt;0.0001, U-251 Clone 7 vs control, p= 0.0062; clone 70.2, p= 0.0052) showed significantly reduced plating efficiency compared to control cells.

CONCLUSION
WSTF is an important factor in both MGMT de- and proficient GBM cell lines for response against TMZ chemotherapy. The loss of WSTF leads to a significantly increased TMZ sensitivity in clinically relevant concentrations for all the studied cell lines. Ongoing studies are investigating the underlying mechanisms and potential alterations in the DDR pathway caused by WSTF loss.
P16.05 Implementation of a novel ex-vivo brain slice model to study human glioblastoma and glioma-associated microglia
Authors: Flüh C , Nanvuma C , Huang Y , Motta E , Kuhrt L , Yuan Y , Xia P , Lubas M , Schnauss M , Hu F , Synowitz M , Kettenmann H 
Published: September 2021

Abstract

BACKGROUND
Glioblastoma multiforme is a highly malignant brain tumor with a devastating prognosis. Resection followed by radio-chemotherapy leads to an overall survival of only 15 months. Up to 40% of the tumor mass consist of tumor-associated microglia and macrophages (TAMs). These cells were shown to promote tumor growth and invasiveness in many murine glioma models. The interaction between TAMs and tumor cells is crucial for tumor progression and includes several known pathways. Still, murine glioma models only partially mirror the human tumor microenvironment. Several known genes, which are highly upregulated in human glioma and TAMs are only expressed in human tissue and not in mice. To further investigate some of these genes, we aimed at establishing a humanized ex-vivo brain slice model, in which human TAMs and human glioma cells can be studied in a standardized manner.

MATERIAL AND METHODS
We used 250 micrometer thick murine brain slices, which were depleted of intrinsic microglia by applying clodoronated liposomes. Next, we inoculated human glioma cells (originating from the cell lines mCherryU87, mCherryU251MG, mCherryLN229 and several patient derived cells lines) with or without human microglia derived from induced pluripotent stem cells (iPSCs). Slices were cultivated for 7 to 14 days. Next, we performed a detailed analysis of microglia morphology (sphericity, cell body volume, process length and branching pattern) and tumor volume.

RESULTS
Clodronation efficacy was high, depending on duration of treatment and length of cultivation. iPSCs and tumor cells integrated into the slice very well. The presence of tumor cells led to an increased sphericity of iPSC-dervied microglia and to an increased cell body volume. Branching pattern and process length did not differ between both conditions. Tumor volume was significantly larger when iPSC-derived microglia were present. This was found in various glioma cells lines and also in patient derived cells.

CONCLUSION
The newly established humanized ex-vivo brain slice system was shown to be feasible. The method successfully allows to study the interaction between human TAMs and tumor cells. Microglia foster tumor growth not only in murine glioma models, but also in a human paradigm. The humanized ex-vivo brain slice model therefore is the optimal basis to study the role human-specific genes in TAM-glioma interaction.
Discourse, Language, and Grand Strategy
Authors: Kornprobst Markus , Traistaru Corina-Ioana 
Published: September 2021

Abstract
This chapter discusses linguistic approaches to grand strategy. Although hints of the importance of language abound in the existing literature, rationalist contributions very much included, an explicitly linguistic perspective addressing grand strategy is relatively new. Yet it makes three important contributions: First, it reminds is that grand strategy—linkages across representations of environment, identity, interest, and means—are intersubjective categories that do not exist independently from language. Second, all kinds of actors can be holders of grand strategy. States are not the only ones. Third, actors make, remake, and unmake convergences on grand strategies in communicative encounters. Processes of justification feature prominently. Since linguistic approaches are still newcomers to the study of grand strategy, many research avenues await further exploration. These pertain to comparing grand strategies held by different (kinds of) actors, exploring productive overlaps of linguistic and other perspectives, and addressing the inescapable normative side of studying grand strategy in responsible fashion.
Rhetoric, Legitimation, and Grand Strategy
Authors: Goddard Stacie E. 
Published: September 2021

Abstract
Scholars associated with diverse research traditions have increasingly agreed that legitimacy is significant in the formulation and operation of grand strategy. Despite the field’s embrace of legitimacy, scholars of international relations have shown less interest in the role of legitimation—the public justification of policy—in creating and sustaining grand strategies. This oversight is puzzling. Grand strategy only becomes legitimate when leaders articulate the reasons why policies are justifiable, and only if audiences accept those claims. Empirically, moreover, leaders devote substantial time, energy, and resources to justifying their strategy to audiences at home and abroad. To overlook legitimation is to overlook much of global politics. This chapter makes the case for treating legitimation as central to the study of grand strategy. It explains what legitimation is, why it matters, and how it drives grand strategy at every stage, from the articulation of national interest, to the interpretation of threat, to the selection of instruments. The essay concludes with challenges to the legitimation of grand strategy in contemporary international politics.
Diplomacy and Grand Strategy
Authors: Sending Ole Jacob 
Published: September 2021

Abstract
Grand strategy can be said to reflect a certain agentic hubris, as if states operate in an environment that is known and controllable. Diplomacy, by contrast, is typically associated with a set of tasks—negotiation, communication, representation—that reflect agentic constraints. Building on the editors’ reflection on grand strategy as an unattainable yet regulative ideal for the conduct of foreign policy, I discuss how grand strategy is integral to states’ presentation of themselves as sovereign—as having a level of control over their environment. The argument falls in three parts: part one introduces grand strategy and diplomacy as core terms. Part two discuss how diplomacy and grand strategy is defined and discussed, highlighting different readings of grand strategy, and introducing an institutional perspective on diplomacy. Part three moves on to reflect on whether grand strategy is a necessary illusion for states to uphold to demonstrate agency vis-à-vis internal and external audiences, and how particular elements of “grand strategy” live on as informal yet defining features of a state’s diplomacy.
The Grand Strategies of Small States
Authors: Wivel Anders 
Published: September 2021

Abstract
This article discusses the nature, opportunities and limitations of small state grand strategy. It identifies the similarities and differences between the grand strategies of small states and great powers and unpacks the nature of traditional defensive small state grand strategies hiding and shelter-seeking as well as more recent offensive, influence-seeking small state grand strategies under the heading of smart state strategy. The article argues that while small state grand strategy remains tied to national security and is formulated in the shadow of great power interests, a changing security environment creates both the need and opportunity for small states to use their weakness instrumentally for maximizing interests. The likelihood of success depends on a pragmatic political culture and the willingness and ability to prioritize goals and means to utilize their nonthreatening small state status in “smart” or “entrepreneurial” policies.
City States in the Later Medieval Mediterranean World
Authors: Lantschner Patrick 
Published: September 2021

Abstract
This article offers a comparative study of city states in the Christian and Islamic spheres of the later medieval Mediterranean world, with a particular focus on Italy, Syria and al-Andalus. Medieval city states are not usually associated with the Islamic world, but rather with a narrative that has foregrounded the exceptional nature of European cities in world history, especially the famous city republics in Northern and Central Italy, and the role that city states played in the formation of European states. Yet city states were a phenomenon that could be observed across urbanized regions of the Mediterranean world where cities turned into important political arenas in the context of sustained political fragmentation. City states are best approached as political systems that were characterized by brittle regimes and experienced high levels of political volatility: they often lacked a clear boundary between the ‘inside’ and ‘outside’ of city states and were characterized by the multiple political organizations that crystallized in, and fought hard to control, urban political space. The most commonly shared type of political organization in city states was the urban lordship, but city-based lords usually found themselves in intense competition with elite-based collective associations, families and factions, and popular political organizations.
Private Equity and the Resolution of Financial Distress
Authors: Hotchkiss Edith S , Smith David C , Strömberg Per 
Published: September 2021

Abstract
We examine the role private equity (PE) sponsors play in the resolution of financial distress of portfolio companies. PE-backed firms have higher leverage and default at higher rates than other companies borrowing in leveraged loan markets. But, PE-backed firms restructure more quickly, avoid bankruptcy court more often, and liquidate less often compared to other highly leveraged firms experiencing financial distress. PE owners are also more likely to retain control post-restructuring, often by infusing capital as firms approach distress. While default frequencies are higher among PE-backed firms, PE investors appear to manage financial distress at lower cost compared to other owners. (JEL G23, G32, G33)
Calcium pyrophosphate crystal deposition in a cohort of 57 patients with Gitelman syndrome
Authors: Chotard Emilie , Blanchard Anne , Ostertag Agnès , Latourte Augustin , Gailly Gilles , Frochot Vincent , Lioté Frédéric , Bousson Valérie , Richette Pascal , Bardin Thomas , Vargas-Poussou Rosa , Ea Hang Korng 
Published: September 2021

Abstract

Objective
Gitelman syndrome (GS) is the most frequent salt-wasting genetic tubulopathy and a source of hypokalaemia and hypomagnesemia. Chondrocalcinosis (CC) is a frequent feature of GS. The aim of our study was to determine the prevalence, distribution patterns, clinical phenotypes and risk factors for CC in GS.

Methods
This prospective study of a cohort of 57 patients with GS included a systematic screening for CC by peripheral joint radiography, cervical spine CT and joint US. The prevalence of cervical C1–C2 CC by CT was compared between 33 GS patients and sex- and age-matched controls. Clinical and biochemical features were analysed to identify factors associated with CC.

Results
Mean (s.d.) age of patients was 46.5 (12.4) years, 66.7% were women and 93.0% carried SLC12A3 mutations. Mean serum magnesium level was 0.60 (0.30) mmol/l. CC was observed in 79% of patients, with the highest prevalence at the cervical spine (81.8%) followed by the knee (52.6%), wrist (50.9%), ankle (38.6%), TM joint (36.4%), shoulder (33.3%), hip (22.8%), elbow (14.0%) and sclerochoroid (12.1%). Prevalence of CC at the C1–C2 level was higher in the GS cohort than control group (72.7% vs 9.1%) (adjusted odds ratio 21.0, 95% CI 2.8, 156.1, P = 0.003). Independent factors associated with CC were low serum magnesium level and age.

Conclusion
GS was associated with widespread CC, favoured by aging and hypomagnesemia. The C1–C2 level was the most affected site. Follow-up of this unique cohort will help understanding the clinical consequences of CC, especially the precise characterization of pyrophosphate arthropathy.
Plasma exchange therapy in refractory inflammatory myopathy with anti-signal recognition particle antibody: a case series
Authors: Zhang Hao , Sun Yue , Liu Honglei , Cheng Xiaobing , Ye Junna , Hu Qiongyi , Jia Jinchao , Wang Mengyan , Liu Tingting , Zhou Zhuochao , Yang Chengde , Chi Huihui , Teng Jialin , Su Yutong 
Published: September 2021

Abstract

Objectives
To explore the efficacy of plasma exchange (PE) therapy in refractory idiopathic inflammatory myopathy (IIM) patients with positive anti-signal recognition particle (SRP) antibody.

Methods
Nine refractory IIM patients with positive anti-SRP antibody were enrolled, who received PE therapy at Ruijin Hospital from October 2017 to December 2020. The clinical manifestations, laboratory tests, chest CT and lower extremity MRI images before and after PE therapy were compared. The treatment response was evaluated by the 2016 ACR/EULAR myositis response criteria.

Results
A total of 88.9% (8/9) of subjects had achieved improvement by 3 weeks after PE therapy, with 55.6% (5/9) minimal improvement and 33.3% (3/9) moderate improvement. There were statistically significant improvements between baseline and after PE therapy at 3 weeks on the core set measures: physician global activity, patient global activity, HAQ, manual muscle testing (MMT), extramuscular disease activity, and muscle enzymes activity including creatine kinase (CK), lactate dehydrogenase (LDH), aspartate transaminase (AST), except for alanine transaminase (ALT). Moreover, the chest CT showed regression of ground glass opacities and irregular linear opacities after PE therapy in four patients with interstitial lung disease. The MRI images of lower extremity in four patients showed reduction of muscle oedema after the therapy.

Conclusion
PE therapy is effective for refractory IIM patients with positive anti-SRP antibody. It should be considered as an alternative treatment for those patients who are resistant to the combined therapy of glucocorticoids and immunosuppressive agents.
New developments in osteoarthritis pharmacological therapies
Authors: Ghouri Asim , Quicke Jonathan G. , Conaghan Philip G. 
Published: September 2021

AbstractOA is an increasingly common, painful condition with complex aetiology and limited therapies. Approaches to expanding our therapeutic armamentarium have included repurposing existing therapies used for other rheumatological conditions, modifying existing OA preparations to enhance their benefits, and identifying new therapeutics. HCQ and low-dose MTX have been unsuccessful in improving hand OA pain or reducing structural progression. Anti-IL-6 and anti-GM-CSF also did not improve symptoms in hand OA trials, but IL-1 remains an intriguing target for large-joint OA, based on reduced joint replacements in a post hoc analysis from a large cardiovascular disease trial. The peripheral nociceptive pathway appears an attractive target, with mAbs to nerve growth factor and IA capsaicin demonstrating efficacy; tropomyosin receptor kinase A inhibitors are at an earlier stage of development. Limited evidence suggests pharmacological therapies can modify cartilage and bone structural progression, though evidence of synchronous symptom benefits are lacking.