bluuebunny/crossref_metadata_2025_split huggingface dataset:
Biomarkers for Hypoxia, HPVness, and Proliferation from Imaging Perspective
Authors: Sanduleanu Sebastian , Keek Simon , Hoezen Lars , Lambin Philippe 
Published: June 2021

AbstractRecent advances in quantitative imaging with handcrafted radiomics and unsupervised deep learning have resulted in a plethora of validated imaging biomarkers in the field of head and neck oncology. Generally speaking, these algorithms are trained for one specific task, e.g. to classify between two or multiple types of underlying tumor biology (e.g. hypoxia, HPV status), predict overall survival (OS) or progression free survival (PFS), automatically segment a region of interest e.g. an organ at risk for radiotherapy dose or the gross tumor volume (GTV). Despite relatively good performances in external validation cohorts these algorithms still have not found their way into routine clinical practice. The reason this has not happened yet is complex, multifactorial, and can be usually divided into three categories: technical (a part of the algorithm or pre-processing step is not technically sound), statistical (mainly related to selection of subset of relevant biomarkers), and translational (not enough understanding by clinicians, not easily implementable within clinical workflow). We currently foresee that the next artificial intelligence (AI)-driven technique to find its way into clinical practice beside existing techniques (e.g. automatic organ at risk segmentation) will be the automatic segmentation of head and neck gross tumor volumes.
Innovation and Advances in Precision Medicine in Head and Neck Cancer
Authors: Watson Geoffrey Alan , Taylor Kirsty , Siu Lillian L. 
Published: June 2021

AbstractThe clinical utility of precision medicine through molecular characterization of tumors has been demonstrated in some malignancies, especially in cases where oncogenic driver alterations are identified. Next generation sequencing data from thousands of patients with head and neck cancers have provided vast amounts of information about the genomic landscape of this disease. Thus far, only a limited number of genomic alterations have been druggable, such asNTRKgene rearrangements in salivary gland cancers (mainly mammary analogue secretory carcinoma),NOTCHmutations in adenoid cystic cancers,HRASmutations in head and neck squamous cell cancers, and even a smaller number of these have reached regulatory approval status. In order to expand the scope of precision medicine in head and neck cancer, additional evaluation beyond genomics is necessary. For instance, there is increasing interest to perform transcriptomic profiling for target identification. Another advance is in the area of functional testing such as small interfering RNA and drug libraries on patient derived cell cultures. Liquid biopsies to detect specific tumor clones or subclones, or viral sequences such as HPV, are of great interest to enable non-invasive tracking of response or resistance to treatment. In addition, precision immuno-oncology is a tangible goal, with a growing body of knowledge on the interactions between the host immunity, the tumor and its microenvironment. Immuno-oncology combinations that are tailored to immunophenotypes of the host-tumor-microenvironment triad, personalized cancer vaccines, and adoptive cell therapies, among others, are in active development. Many therapeutic possibilities and opportunities lie ahead that ultimately will increase the reality of precision medicine in head and neck cancer.
Mechanisms of Cetuximab Resistance and How to Overcome It
Authors: De Pauw Ines , Boeckx Carolien , Wouters An 
Published: June 2021

AbstractDeregulated or increased signalling of the epidermal growth factor receptor (EGFR) plays an integral role in the development of various cancer types, including head and neck squamous cell carcinoma (HNSCC), making it a compelling drug target. However, after initially promising results of EGFR-targeted therapies, such as the monoclonal antibody cetuximab, it became clear that both intrinsic and acquired therapeutic resistance are major roadblocks in the field of personalised cancer treatments.In order to unravel and overcome resistance to cetuximab, at least two strategies can be adopted.Firstly, therapeutic resistance to anti-EGFR therapy may arise from mechanisms that can compensate for reduced EGFR signalling and/or mechanisms that can modulate EGFR-dependent signalling. In this chapter, we discuss which mechanisms of cetuximab resistance are already known and which ones deserve further investigation. This enhanced knowledge will guide us to rationally design and test novel combination therapies that overcome resistance to EGFR-targeting agents in cancer treatment.Secondly, an urgent need remains to develop novel targeted treatments for single-agent or combined therapy use. In this view, due to the particular mode of activation of the EGFR receptor, involving ligand-induced homo- and heterodimerization of the four HER receptors, an increased inhibition scope of HER receptors most likely results in a more potent blockade of the HER network, preventing premature emergence of resistance and leading to a more pronounced therapeutic benefit. We discuss two multitargeted compounds, being MEHD7945A (duligotuzumab) and afatinib, in this chapter.Despite the huge efforts to unravel the molecular landscape of HNSCC, the main clinically validated target remains EGFR. However, immune checkpoints, like programmed cell death protein 1 (PD-1), are gaining clinical approvals as well. We underscore the importance of adopting rational drug combinations to enhance the therapeutic effect of the EGFR-inhibitor cetuximab and highlight the ongoing search for predictive biomarkers, with the ultimate goal of delivering individualized cancer therapy to HNSCC patients.
Biomarkers for Immune Modulatory Treatment in Head and Neck Squamous Cell Carcinoma (HNSCC)
Authors: Rischin Danny 
Published: June 2021

AbstractImmune checkpoint inhibitors have changed the standard of care for recurrent/metastatic head and neck squamous cell carcinoma (R/M HNSCC). However, only a minority of patients respond, hence the search for predictive biomarkers. Potential predictive biomarkers for immune checkpoint inhibitors discussed in this chapter include (1) Immune checkpoint ligand expression e.g., PD-L1, (2) biomarkers of a T-cell inflamed tumour microenvironment (TME) such as gene expression profiles of activated T cells, (3) biomarkers of tumour neoepitope burden such as tumour mutation burden (TMB) and (4) multidimensional quantitative techniques. At present only PD-L1 expression has been shown to have clinical utility in head and neck cancer. It enriches for populations more likely to respond, but the false positive predictive value remains high. In the pivotal Keynote−048 trial that established a role for pembrolizumab (anti-PD1) monotherapy and pembrolizumab + chemotherapy as treatment options in first-line R/M HNSCC, primary endpoints included overall survival in defined subgroups based on PD-L1 expression. In this trial the combined positive score (CPS) was used which takes into account PD-L1 expression in tumour and immune cells. Based on this trial regulatory approvals for first-line pembrolizumab in R/M HNSCC require assessment of PD-L1 expression using the CPS. Finally we discuss emerging evidence that locoregionally advanced HPV-associated oropharyngeal cancers that have high expression of CD103 positive CD8 T cells have an excellent prognosis and features that suggest increased probability of responding to anti-PD1/PD-L1, raising the possibility of incorporating these immune therapies as part of a de-escalation trial strategy.
The Surgical Approach to Elderly Patients with HNSCC
Authors: Dietz Andreas 
Published: June 2021

AbstractDespite the fact that elderly people are the main incidental and continuously growing patient group with head and neck cancer, prospective trials focusing on special issues regarding head and neck surgery in elderlies are missing. To avoid complications during and after surgery in that patient category, comprehensive evaluation of functional status, comorbidities, performance status, social support and mental condition is mandatory. Regarding functional parameters, cardiac and respiratory conditions play a major role for any primary surgical procedure. Nevertheless, other comorbidities, medication and patients view on self-determination have carefully to be taken into consideration. It has repeatedly been shown that fit elderly individuals may benefit from intensive therapies like reconstructive surgery with microvascular free tissue transfer, concurrent chemoradiotherapy in the locoregionally advanced disease setting, and even from the standard first- and second-line palliative systemic therapies. Since it is well known that tolerance of systemic nonsurgical treatments in elderly people is less and therefore death from noncancer-related causes in that population is higher, moderate surgical procedures can be even more effective regarding quality of life in situations facing higher comorbidities, or functional constraints with limited life expectancy compared to nonsurgical standard approaches. Older people usually are at increased risk of postoperative complications. In particular, organ failure progresses much faster in multiple organ failure. The preoperative clarification of comorbidity for the avoidance of surgical complications is therefore of major importance. Close coordination with anesthesia and rapid postoperative mobilization are essential for this. Decision-making and treatment based on specific assessment in an experienced multidisciplinary team is key.
Living with a Brain AVM: A Quality of Life Assessment
Authors: Orosz Péter , Vadász Ágnes , Veres Dániel Sándor , Berentei Zsolt , Gubucz István , Nardai Sándor , Kis Balázs , Szikora István 
Published: June 2021

AbstractBackground and purpose: Brain arteriovenous malformations (AVM) are uncommon vascular lesions with the risk of hemorrhage, epileptic seizures, neurological deficits, and headache. Comparing the risks of the natural history and that of preventive treatment, a recent study has found observation more beneficial than treatment for unruptured AVMs. This study, however, did not consider the long-term impact of carrying a brain AVM on everyday activities. In this study we analyzed the Quality Of Life (QOL) of patients with untreated AVMs, a measure increasingly used in clinical trials to asses this kind of impact.Methods: We enrolled 36 patients with unruptured, untreated brain AVM from our hospital database and measured their QOL retrospectively using the EQ-5D-5L questionnaire. As a control group we used the results of the Research Report, a nationwide study based on the quality of life of 5534 healthy Hungarians in 2002. Due to the low number of cases, statistical analysis could not be made.Results: Headache proved to be the most common AVM-related sign in our cohort (40%, n = 17), with a female predominance; neurological deficit was detected in 33% (n = 14), while epileptic seizures occurred in 26% (n = 11), more commonly affecting male subjects. Anxiety and discomfort seemed to be the most prevalent influencing factors on QOL, especially in the youngest age group (18–34 years). Female subjects showed a greater dependence than men in all age groups, though males had a more significant impairment in their usual activities. Older patients were affected more significantly in their self-care and usual activities compared with the younger population.Conclusions: Untreated AVMs have a significant negative impact on patients carrying unruptured brain AVMs, as proved by QOL assessment. Beside neurological deficits, this impact should also be considered in the therapeutic decision.
Surgical Simulation with Three-Dimensional Fusion Images in Patients with Arteriovenous Malformation
Authors: Hara Takayuki , Yoshino Masanori 
Published: June 2021

AbstractIn arteriovenous malformation (AVM) surgery, vessel structures should be well evaluated with angiography. However, with conventional angiography, it is sometimes difficult to distinguish each feeder and its feeding territory in the nidus. In this study, we used two software systems to create three-dimensional (3D) fusion images using multiple imaging modalities and evaluated their clinical use. In the AVM patient, data were obtained from 3D rotational angiography, rotational venography, computed tomography (CT), and magnetic resonance imaging (MRI) and superimposed into 3D fusion images using imaging software (iPLAN and Avizo). Virtual surgical fields that were quite similar to the real ones were also created with these software programs. Compared with fusion images by iPLAN, those by Avizo have higher resolution and can demarcate not only each feeder but also its supplying territory in the nidus with different colors.In conclusion, 3D fusion images in AVM surgery are helpful for simulation, even though it takes time and requires special skill to create them.
Surgical Treatment of Unruptured Brain AVMs: Short- and Long-Term Results
Authors: Eliava Shalva , Gorozhanin Vadim , Shekhtman Oleg , Pilipenko Yuri , Kuchina Olga 
Published: June 2021

AbstractUnruptured brain AVMs (bAVMs) remain a controversial subject for practicing neurosurgeons, especially in the light of ARUBA and other observational studies. This retrospective study aims to analyze our experience with unruptured bAVMs to see whether it is beneficial in the long-term and how it corresponds to large literature trials. The study comprised 160 adult patients with unruptured bAVMs surgically treated in Burdenko NMC (Moscow) in 2009–2017. Mean age: 33.4 ± 10лет. Clinical presentations were: seizures in 99 (61.9%), chronical headaches—49 (30.6%), ischemic symptoms—4 (2.5%), asymptomatic in 8 (5%) patients. Spetzler-Martin scale: I—18 pt. (11.3%), II—71 pt. (44.4%), III—60 pt. (37.5%), IV—11 pt. (6.8%). Good outcomes (mRS = 0–2) at discharge were achieved in 149 (93.1%), satisfactory (mRS—3)—9 (5.6%). Follow-up was complete for 97 (60.6%) patients, mean—59.3 (13–108 month). Excellent outcomes (mRS = 0–1) reached in 94.8%. For epilepsy patients, Engel I outcome was found in 50 (84.8%); for chronic headaches, 43 (66.1%) patients reported improvement. Postoperative visual field defects were followed in 22 of 55 (40%), complete recovery was reported in 6 (27%) and partial recovery in 8 (36%) patients. Overall, our results support the conclusion that surgery for low-grade bAVMs (S-M I–II) is a beneficial, low-risk option.
Maximum Nidus Depth as a Risk Factor of Surgical Morbidity in Eloquent Brain Arteriovenous Malformations
Authors: Ryu Bikei , Yamaguchi Koji , Ishikawa Tatsuya , Atsushi Fukui , Matsuoka Go , Eguchi Seiichiro , Kawashima Akitsugu , Okada Yoshikazu , Kawamata Takakazu 
Published: June 2021

AbstractBackground: Eloquent location of a brain arteriovenous malformation (BAVM) is known to increase the surgical risk. Surgical removal of such BAVMs is challenging. Useful indicators for the safe removal of eloquent BAVMs are needed. The aim of this study was to determine the surgical risk factors for these challenging entities.Methods: The authors retrospectively reviewed 29 motor and/or sensory BAVM patients who underwent surgeries. The risk factors for surgical morbidity were analyzed. As a new risk factor, maximum nidus depth, was evaluated.Results: Complete obliteration was achieved in 28 patients (96.6%). Postoperative transient and permanent neurological deteriorations were seen in nine patients (31.0%) and five patients (17.2%), respectively. In univariate analysis, maximum nidus depth (p = 0.0204) and asymptomatic onset (p = 0.0229) were significantly correlated with the total morbidity. In multivariate analysis, only maximum nidus depth was significantly correlated with total morbidity (p = 0.0357; odds ratio, 2.78598; 95% confidence interval, 0.8866–8.7535). The cut-off value for the maximum nidus depth was 36 mm for total morbidity (area under the curve [AUC], 0.7428) and 41 mm for permanent morbidity (AUC, 0.8833). The cutoff value of the maximum nidus size was 30 mm for total morbidity (AUC, 0.5785) and 30 mm for permanent morbidity (AUC, 0.7625). AUC was higher for the maximum nidus depth than it was for the maximum nidus size.Conclusions: Maximum nidus depth was significantly associated with surgical morbidity of eloquent BAVMs. The maximum nidus depth is a novel and a simpler indicator of the risk of surgical morbidity.
Microneurosurgical Management of Posterior Inferior Cerebellar Artery Aneurysms: Results of a Consecutive Series
Authors: Del Maestro Mattia , Luzzi Sabino , Galzio Renato 
Published: June 2021

AbstractAneurysms of the posterior inferior cerebellar artery (PICA) are uncommon. The complex anatomy of PICA and its intimate relationships with medulla, lower cranial nerves, and jugular tubercle makes the surgical treatment of these aneurysms fascinating. The reported is study aimed at a critical review of the overall results of a personal series of PICA aneurysms, treated by the senior author, R. Galzio. Demographics, charts, videos, outcome, and follow-up of a cohort of PICA aneurysms managed in the last 10 years were retrospectively analyzed, focusing only upon those treated with microneurosurgery. Twenty-five patients, harboring a single aneurysm, were operated on. Fifteen aneurysms were ruptured. Nineteen were proximal, all of these being been treated through a far-lateral approach. Trans-condylar or trans-tubercular variants were rarely necessary and however reserved to peculiar cases. Twenty-three aneurysms underwent direct treatment consisting of clip ligation. At 6-month follow-up, 60% of patients had a modified Rankin Score (mRS) of 0–2. Given the high anatomical variability of both PICA and patients’ bony anatomy, a case-by-case meticulous preoperative imaging evaluation is mandatory for the choice of the most suitable and tailored surgical corridor which, in turn, is pivotal to achieve the best outcome.
Earthquake Physical Risk/Loss Assessment Models and Applications: A Case Study on Content Loss Modeling Conditioned on Building Damage
Authors: Akkar S. 
Published: June 2021

AbstractThis paper presents a novel approach to develop content fragility conditioned on building damage for contents used in residential buildings in Turkey. The approach combines the building damage state probabilities with the content damage probabilities conditioned on building damage states to develop the content fragilities. The paper first presents the procedure and then addresses the epistemic uncertainty in building and content fragilities to show their effects on the content vulnerability. The approach also accounts for the expert opinion differences in the content replacement cost ratios (consequence functions) as part of the epistemic uncertainty. Monte Carlo sampling is used to consider the epistemic uncertainty in each model component contributing to the content vulnerability. A sample case study is presented at the end of the paper to show the implementation of the developed content fragilities by calculating the average annual loss ratio (AALR) distribution of residential content loss over the mainland Turkey.
Memoirs of the Fruits of Globalization: The Markets for Chinese Textiles in New Spain by Jean de Monségur
Authors: Fernandez de Pinedo Nadia , Thépaut-Cabasset Corinne 
Published: June 2021

Abstract
A revealing report produced by the French intelligence services of the beginning of eighteenth-century explores the production of luxury and fashion commodities and their distribution on a global scale. According to Jean de Monségur the main competitors in New Spain arrived through China commercial routes. On one hand, we intend to explore if the trade market in Mexico was reflecting or not European fashions, in particular French fashion so in vogue among European elites. On the other hand, some cultural aspects must be taking into account to discern how entangled Europe, Asia and the Americas were in 1700s underlying economic prestige and social status as in Europe. How cultural and symbolic message matters? Was New Spain contributing to develop an emerging hybrid consumer society?
The EU as an Anchor for Turkey’s Macroeconomic and Trade Policy
Authors: Akman Mehmet Sait , Çekin Semih Emre 
Published: June 2021

AbstractEU–Turkey relations have been subject to manifold ups and downs for decades. The EU’s role in Turkey’s domestic transformation has long been a matter of interest to the academic community. This chapter examines to what extent and under what conditions the EU has served as an anchor for the Turkish economy during the last two decades, focusing on the effects of the EU anchor on Turkey’s macroeconomic and trade policy. It finds that maintaining a European anchor after the Helsinki European Council helped Turkey realize much-desired comprehensive macroeconomic reforms, especially during times when the EU anchor was combined with another multilateral anchor. Nevertheless, the EU’s anchor-providing role has not been consistent and amidst changing political circumstances it is no longer considered an ‘elixir’ for the Turkish economy. The establishment of the Customs Union (CU) is revealed to have been a significant driver of the transformation of Turkey’s trade policy. While the trade partnership remains one of the few well-functioning aspects of the volatile bilateral dialogue between the EU and Turkey, the EU’s role in the trade policy arena is diminishing, and the upgrading of the CU remains vital to achieve further momentum and enhance mutual gains.
Current Trends and Future Prospects for EU–Turkey Relations: Conditions for a Cooperative Relationship
Authors: Reiners Wulf , Turhan Ebru 
Published: June 2021

AbstractThis chapter summarizes the key insights derived from a three-dimensional perspective on EU–Turkey relations that combines the analytical lenses of (1) theories and concepts, (2) institutions, and (3) policies. It furthermore reflects upon the different periodizations of the EU–Turkey relationship. On this basis, we offer a systematic survey of the conditions under which cooperative trends in EU–Turkey relations could be (re)invigorated. The analysis shows that despite the high potential for reciprocity inside and outside the accession framework, the relationship currently rests on unfavorable conditions for cooperation on both sides. Important enablers of cooperative behavior—trust, communication, reputation, fairness, enforcement, and common identity—cannot properly operate in the current setup. The chapter puts forward possible means to allow for these enablers to facilitate cooperative behavior in EU–Turkey relations in the future. It concludes by discussing the future trajectory of the relationship and pinpointing avenues for a future research agenda for EU–Turkey studies.
Historical Institutionalism and EU–Turkey Relations: Path Dependence and Critical Junctures in the Accession Process
Authors: Icoz Gülay , Martin Natalie 
Published: June 2021

AbstractThis chapter employs the perspective of historical institutionalism to analyze and explain why Turkey’s EU accession process endures even though it has not significantly progressed since it began. It argues that its temporal approach, the concepts of critical junctures and path dependence help explain the processes of stasis and change inherent within it. The chapter starts with an outline of historical institutionalism and contextualizes its conceptual and theoretical value for the analysis of EU–Turkey relations, arguing that an underlying path dependence in the accession process is the result of security considerations. The chapter continues by identifying several critical junctures which have intervened, and both expedited and hampered the process. The opposition of member states, the Arab Spring, and authoritarian drift within Turkey are important factors in this context. On this basis, the analysis shows how progress achieved has typically been countered by opposition, often related to human rights concerns. As a result, the accession process has stagnated but has endured at the same time as security interests and human rights concerns have balanced each other over time.