**4.1.2 Electrical properties**

Four-point (or five-point) probe methods are often applied either to ingots, crystals or pressed pellets to measure resistivity and the size of the Hall effect. This gives information on whether the compound is an insulator, semiconductor, semimetal or metal and upon the type of doping and the mobility in the delocalized bands (if present). Thus, important information is obtained on the chemical bonding in the material.

The impedance spectroscopy is also a very useful method used for electrical properties characterization of perovskite-type materials, especially for bulk ceramic samples.


*Edited by Weibo Cai and Hao Hong*

Proteins are indispensable players in virtually all biological events. The functions of proteins are coordinated through intricate regulatory networks of transient proteinprotein interactions (PPIs). To predict and/or study PPIs, a wide variety of techniques have been developed over the last several decades. Many in vitro and in vivo assays have been implemented to explore the mechanism of these ubiquitous interactions. However, despite significant advances in these experimental approaches, many limitations exist such as false-positives/false-negatives, difficulty in obtaining crystal structures of proteins, challenges in the detection of transient PPI, among others. To overcome these limitations, many computational approaches have been developed which are becoming increasingly widely used to facilitate the investigation of PPIs. This book has gathered an ensemble of experts in the field, in 22 chapters, which have been broadly categorized into Computational Approaches, Experimental Approaches, and Others.

ISBN 978-953-51-0397-4

Protein-Protein Interactions - Computational and Experimental Tools

Photo by Ugreen / iStock


**An Anthropology of** *Singularity***? Pastoral Perspectives for an Embodied Spirituality in the** *Annus virtualis* **and Beyond1**

Jan-Albert van den Berg  *Department of Practical Theology, Faculty of Theology, University of the Free State South Africa*

#### **1. Introduction**

428 Social Sciences and Cultural Studies – Issues of Language, Public Opinion, Education and Welfare

Rogoff, B. (1990). *Apprenticeship in Thinking: Cognitive Development in Social Context*. New

Rogoff, B. (2003). *The Cultural Nature of Human Development*. New York: Oxford University Press. Roth, W-M. (2004). Activity theory and education: An introduction. *Mind, Culture and*

Roth, W-M. (2007). Emotion at work: A contribution to third-generation cultural-historical activity theory. *Mind, Culture and Activity: An International Journal*, 14(1/2). 40-63. Rueda, R., Gallegor, M., & Moll, L. (2000). The last restrictive environment: A place or a

Rydberg, T. & Christiansen, E. (2008). Community and network sites as technology

Senge, P. (1990). *The Fifth Discipline: The art and Practice of the Learning Organization*. New

Scribner, S. (1985). Vygotsky's uses of history. J.V. Wertsch (Ed.). *Culture, Communication, and*

Torenvliet, G. (2003). We can't afford it. The devaluation of a usability term. *Interactions*, 10.

Tuomi-Gröhn, T., Engeström, Y., & Young, M. (2003). From transfer to boundary-crossing

Vygotsky, L. (1987). Thinking and speech. R. W. Rieber & A. S. Carton (Eds.). *The Collected Works of L. S. Vygotsky, Vol 2, The fundamentals of defectology*, New York: Plenum, 122-138. Vygotsky, L. (1994). The socialist alteration of man. R. van der Veer & J. Valsiner (Eds.). *The*

Vygotsky, L. (1998). Pedagogy of the adolescent. R. Rieber (Ed.). *The Collected Works of L. S.*

Vygotsky, L. (1999). Consciousness as a problem in the psychology of behavior. *Undiscovered*

Vygotsky, L. (2004). The historical meaning of the crisis in psychology: A methodological

Walker, D., & Nocon, H. (2007). Boundary-crossing competence: Theoretical considerations and educational design. *Mind, Culture and Activity: An International Journal*, 14(3). 178-195.

Wells, G. (2007). The mediating role of discoursing in activity. *Mind, Culture and Activity: An*

Winograd, T. (Ed.). (1996). *Bringing Design to Software*. New York: Addison Westley.

*Vygotsky: Etudes on the pre-history of cultural-historical psychology,* Vol 8, New York:

investigation. R.W. Rieber & D.K Robinson (Eds.). *The Essential Vygotsky*. New

enhanced learning environments. *Technology, Pedagogy and Education*, 17(3). 207-219.

*Cognition: Vygotskian perspectives*. Cambridge, UK: Cambridge University Press. 119-145.

between school and work as a tool for developing vocational education: An introduction. T. Tuomi-Gröhn & Y. Engeström. (Eds.). *Between School and Work: New Perspectives on Transfer and Boundary-crossing*. Kidlington, UK: Elsevier Science. 1-15. Vince, R. (2004). Action learning and organizational learning: Power, politics and emotions

York: Oxford University Press.

York: Doubleday.

Peter Lang. 251-281.

York: Kluwer Academic. 227-357*.*

Wartofsky, M. (1979). *Models*. Dordrecht: Riedel.

*International Journal*, 14(3). 160-177.

Yaroshevsky, M. (1989). *Lev Vygotsky*. Moscow: Progress.

12-17.

*Activity: An International Journal*, 11(1). 1-8.

in organizations. *Action Learning*, 1(1) 63-78.

*Vygotsky Reader*. Oxford, UK: Blackwell.

Vygotsky, L. (1986). *Thought and Language*. Cambridge, Mass.: MIT Press.

Vygotsky, L. (1997). *Educational Psychology*. Boca Raton: St Lucie Press.

Wertsch, J. (1998). *Mind as Action*. New York: Oxford University Press.

*Vygotsky, Vol 5, Child psychology.* New York: Plenum, 31-184.

context? *Remedial and Special Education*, 21(2), 70-87.

In the award-winning film, "The social network" (2010), the origin, development and farreaching significance of Mark Zuckerberg's *Facebook* are highlighted. In the film, one of the characters, Sean Parker, refers to the Facebook phenomenon as "[t]he true digitalization of real life" (nilesfilmfiles.blogspot.com. 2011:02).

Taking into account that film has developed into an important technological and visual expression of meaning (Graham, 2002; Louw, 2008), it seemed necessary to take note of how the advancement of technology is portrayed. With the accent on possible future developments in "performing the faith" (Swinton & Mowat, 2006, p. 4), as well as on giving expression to the dynamics of life – since life "is about change" (Astley, 2002, p. 21) – the aim of the research was to trace the contours of the "true digitalization of real life" and the pastoral perspectives for an embodied spirituality.

Since we are living in a world where "the spirit of technology pervades the whole of culture" (Schuurman, 2003, p. 13), the challenge of addressing this quest is further demarcated through the acknowledgement of the fact that we currently find ourselves in a world characterised by "the new social structure of the Information Age", which constructs "a culture of virtuality in the global flows that transcend time and space" (Castells, 2006, p. 381). The demands that are made upon our time as a result of this culture of virtuality challenge us to examine "the impact of twenty-first-century technologies – digital, cybernetic and biomedical – upon our very understanding of what it means to be human" (Graham, 2002, p. 1). The contours of this contribution are however not only to be found within the meaning of the present age of virtuality, but also wants to map the considerable scholarly discussion regarding the movement toward a state of posthumanism (Lunceford, 2009). When the term 'posthuman' is used, the condition referred to by writers and intellectuals, "who envision a day when humans will virtually merge with their technology, thereby creating a new and superior posthuman species" (Waters, 2006, p. x), is brought to

1 This is an extensively reworked, updated and edited version of my earlier published article *An embodied spirituality: Perspectives for a bodily pastoral anthropology,* which was published in 2008 in *Acta Theologica.* 28(2):118-132.

An Anthropology of *Singularity*?

*(Graham, 2003, p. 38).*

meaning.

**3. Backspace**

Pastoral Perspectives for an Embodied Spirituality in the *Annus virtualis* and Beyond 431

The foregoing perspectives could possibly be evaluated by making use of perspectives from a dogmatologically informed anthropology (Staley, 2011). However, in contrast to a dogmatological anthropology, a pastoral anthropology focuses on understanding human beings in their recovery (therapy), as well as on accompanying them in their search for meaning in life (Louw, 1999). In a previous research contribution (Van den Berg, 2008), it has already been indicated and confirmed that when perspectives on an "embodied soul" are negotiated for the purposes of pastoral care, these perspectives serve to emphasise, *inter alia*, that identity can be understood in terms of a so-called "bodily identity" (Murphy, 2006, p. 141), thereby accentuating a positive perception and experience of the body (Ganzevoort & Veerman, 2000). The implication of this in a possible description of a pastoral anthropology is thus that corporeality "confronts us with the realities of vulnerability and affliction", and that this very vulnerability "is deeply embedded in our bodily existence" (Van Huyssteen, 2006, p. 320). The implications of these accents will then need to be reevaluated and re-articulated within the developing understanding of singularity, and as part of the world of the *annus virtualis* and beyond, where the possibility of a "transition from *Homo sapiens* to postbiological *Homo cyberneticus*" (Graham, 2002, p. 9) is envisaged.

As the cyberspace visitor would know, it is always possible to re-visit previous domains by using the backspace option. Re-visiting previous domains will hopefully contribute not only towards the evaluation and re-articulation of the possible further development of the current debate, but also towards the opening up of additional space for evolving vistas of

I remember a time when, in the process of rethinking the meaning of anthropology for pastoral care, I reflected on the work of a German anatomist, Gunther von Hagens. During the late 1970s, he developed the so-called plastination technique, revealing inner anatomical structures (Van den Berg, 2008). One of the images portrayed a praying man holding his heart between his hands. To my mind, this image not only depicts the intimate relationship between body and soul, but also metaphorically points to an embodied understanding of spirituality in pastoral care. This insight occurred a few years ago, and at the time I thought that this comprised a new understanding of a bodily spirituality. These days, I find myself in front of the computer, thinking about embodiment in virtuality, where "much human interaction" currently "occurs in a bodiless world" (Herzfeld, 2010, p. 125). As if this were not enough, it is further anticipated that singularity, merging the human being with the machine, will allow "human beings to transcend some of their perceived limitations" (Garner, 2004, p. 16). Understandably, this possible scenario challenges the expectation as to how spirituality will be embodied in an era of singularity. In this regard Dean-Drummond (2005, p. 365) has already pointed out the importance of "[q]uestions about human identity –

such as, who am I? Where do I come from? What does the future hold?"

*The ultimate goal for transhumanism is to attain what is called the 'singularity': a point in the (not too distant) future at which the rising curve of technological progress reaches its peak. According to transhumanists, the singularity will signal a radical qualitative change in the nature of human/machine intelligence – a transition into super intelligence and omnipotence*

mind. Within this broad domain of interest, questions relating to forms of embodiment therefore play an important role in the quest for relevance, especially taking into account that "[t]o enter virtual reality is to cross a threshold where physical and temporal limits are suspended" (Waters, 2006, p. 52).

In the evolving understanding of our age as the *annus virtualis* (Joubert, 2010, p. 48) – and in thinking ahead into the future – the traditional lines of demarcation are being eliminated (Barna, 2011, Kindle edition). A futuristic possibility exists of "scanning our consciousness into computers", enabling us to "enter a virtual existence or swap our bodies for immortal robots and light out for the edges of space as intergalactic godlings" (Time, 2011, p. 27). This links up with Graham's (2003, p. 32) observation that "technological advance is reshaping what it means to be human".

Taking this evolving understanding as a point of departure for a critical reflection on the scientific fields of practical theology and, in particular, pastoral care – as well as futures studies, *inter alia* – the domain of interest is not only reflected upon, but recent and future developments are also taken into account, paving the way for the motivation of an interdisciplinary discourse. The research on which this contribution is based is characterised by a philosophical analysis of relevant concepts leading to theory building. In coherence with the theme of the contribution, the documentation of research is delineated by making use of the metaphor of internet connectivity and associative networks of meaning (Müller & Maritz, 1998) as a possible expression of the "technologization of nature" (Graham, 2002, p 2). Connecting to the internet evokes the expectation of encountering landscapes of meaning – some in the form of old, familiar territories, while others comprise uncharted virtual horizons that await the exploring visitor.

#### **2. Loading**

The term 'loading' evokes the experience of a webpage being downloaded and loading onto the computer screen. A virtual experience is commonly facilitated by connecting to the internet, thereby creating 'cyberspace', which refers in this context to the "symbolic, imagined space between nodes on the network that allows new selves and new worlds to be created" (Garner, 2004, p. 16). In using the metaphor of the internet, I do not wish to imply that this is the only expression of technological advancement. Rather, it is an expression of the current "medium-is-the-message" world (Carr, 2010, p. 1). Graham (2002, p. 4) explains the world of shifting realities:

*Just as the boundaries between humans, animals and machines are eroded, so too are distinctions between the virtual and the real. New digital technologies have reconfigured taken-for-granted patterns of physical space, communication and intimacy.*

My particular approach to the theme of the article is reflected in the understanding that "anthropology is essentially a hermeneutical problem" (Louw, 1999, p. 157). In this approach the emphasis falls on hermeneutical methodology, in which spirituality as a universal human concern in the quest for transcendence and meaning is investigated in terms of a variety of religious traditions and scholarly disciplines (Schneiders, 2005). It is from this point of view that an investigation of the meaning and implications of the futuristic concept of 'singularity' is conducted, in terms of the following definition:

*The ultimate goal for transhumanism is to attain what is called the 'singularity': a point in the (not too distant) future at which the rising curve of technological progress reaches its peak. According to transhumanists, the singularity will signal a radical qualitative change in the nature of human/machine intelligence – a transition into super intelligence and omnipotence (Graham, 2003, p. 38).*

The foregoing perspectives could possibly be evaluated by making use of perspectives from a dogmatologically informed anthropology (Staley, 2011). However, in contrast to a dogmatological anthropology, a pastoral anthropology focuses on understanding human beings in their recovery (therapy), as well as on accompanying them in their search for meaning in life (Louw, 1999). In a previous research contribution (Van den Berg, 2008), it has already been indicated and confirmed that when perspectives on an "embodied soul" are negotiated for the purposes of pastoral care, these perspectives serve to emphasise, *inter alia*, that identity can be understood in terms of a so-called "bodily identity" (Murphy, 2006, p. 141), thereby accentuating a positive perception and experience of the body (Ganzevoort & Veerman, 2000). The implication of this in a possible description of a pastoral anthropology is thus that corporeality "confronts us with the realities of vulnerability and affliction", and that this very vulnerability "is deeply embedded in our bodily existence" (Van Huyssteen, 2006, p. 320). The implications of these accents will then need to be reevaluated and re-articulated within the developing understanding of singularity, and as part of the world of the *annus virtualis* and beyond, where the possibility of a "transition from *Homo sapiens* to postbiological *Homo cyberneticus*" (Graham, 2002, p. 9) is envisaged.

As the cyberspace visitor would know, it is always possible to re-visit previous domains by using the backspace option. Re-visiting previous domains will hopefully contribute not only towards the evaluation and re-articulation of the possible further development of the current debate, but also towards the opening up of additional space for evolving vistas of meaning.


**3. Neurotransmitters in the Enteric Nervous System (ENS)**

The enteric nervous system (ENS) can be considered the body's second brain with more than 100 million neurons of different types. Neural signals may be transmitted from gut to the CNS by neural connection and by humoral mechanisms. The afferent fibers of the gut-brain neural are vagal (parasympathetic) and (ortho)sympathetic. Different sensors respond also to distension of stomach and contractions of the intestine. Chemical stimuli (e.g. spices), gut hormones, neurotransmitters, neuromodulators, cytokines and inflammatory mediators produced by the bacterial flora in the gut-are all important. In the brainstem most afferent vagal fibers terminate on the nucleus tractus solitarius (NTS). There is a viscerotopic repre‐ sentation of different parts of the enteric system in the NTS. The NTS is in connection with hypothalamus and amygdala, which also plays a role in regulation of hunger and satiety. We should not forget the emotional aspects of eating (smell, taste, and situational factors during eating).

Cholecystokinin is secreted by duodenal and jejunal cells after eating food. CCK acts on vagal neurons projecting to the brainstem, giving a signal of satiety inhibiting further need for eating.

Ghrelin is secreted when a person is hungry and it increases appetite. It acts on the hypothal‐ amus stimulating feeding, counteracting the inhibitory effects of leptin.

Leptin is manufactured mainly in fat cells in adipose tissue. Leptin counteracts the effects of neuropeptide Y and inhibits secretion of alpha-MSH (alpha melanocyte-stimulating hormone). Leptin decreases appetite and inhibits food intake contrary to ghrelin.

Alpha-MSH is in the arcuate nucleus in the brain where it acts to suppress appetite. Alpha-MSH may have also some function in the sleep-wake regulation.

Serotonin is an important neurotransmitter in the central nervous system (CNS) with impor‐ tant effects on sleep-wake regulation. Serotonin also has an important role in regulation of the gastrointestinal (GI) function through an interaction with the ENS. Up to 60-90 % of the total body amount of serotonin is in the GI tract, and 2-20% of all enteric neurons express serotonin. Stimulatory receptors include β-adrenoceptors, muscarinic and nicotinic Ach receptors and 5- HT3 receptors. Inhibitory receptors include alpha2-adrenceptors, histamine H3, GABA-B, adenosine A2, and 5-HT4 receptors. In the GI tract 5-HT is eliminated mainly by monoamine oxidase metabolism. [8]

Hypocretin (orexin) was originally considered to be important especially in central control of food intake [9, 10] but it is essential also in control of sleep and wakefulness. There are about 70 000 hypocretin neurons in the lateral hypothalamus. Narcolepsy, a central hypersomnia with excessive daytime sleepiness and cataplexy, is characterized by destruction of the hypocretin neurons. [11, 12] Hypocretin is involved also in energy homeostasis, nociception, reward seeking behavior, and drug addiction. [13-19] In addition to brain, hypocretins are also widely present in the gastrointestinal tract12 where they have a role in regulation of peristaltic GI motility, and in gastric, intestinal and pancreatic secretions. The hypothalamic hypocretin cells are intermingled with MCH neurons. Both hypocretin-and MCH-cells are glucosesensing neurons. Decrease of glucose increases activity of hypocretin neurons and decreases activity of the MCH cells, producing wakefulness. Respectively, increase of glucose decreases activity of hypocretin and increases activity of MCH, producing sleepiness. These interactions explain at least partly the alerting effects of fasting and the observations that eating rapidly absorbing carbohydrates, provoking fast increase of blood glucose, increase sleepiness.


*3.6. Evaluation*

Forecasting performance was evaluated using three performance evaluation metrics, namely, mean absolute error (MAE) [39], RMSE [40], and NRMSE [39]. They are defined as follows:

$$\text{MAE} = \frac{1}{N} \sum\_{i=1}^{N} |\mathcal{G}\_i - y\_i| \tag{1}$$

$$\text{RMSE} = \sqrt{\frac{\sum\_{i=1}^{N} (\mathcal{Y}\_i - y\_i)^2}{N}} \tag{2}$$

$$\text{NRMSE} = \frac{\sqrt{\frac{\sum\_{i=1}^{N} (y\_i - y\_i)^2}{N}}}{\mu} \tag{3}$$

$$\text{NRMSE}(\%) = \frac{\sqrt{\frac{\sum\_{i=1}^{N} (\hat{y}\_i - y\_i)^2}{N}}}{\mu} \ast 100\% \tag{4}$$


**1. Introduction**

The history of integrated factory's steel product usually begins from a preparation of a sinter being one of the main component of a blast-furnace charge. In blastfurnace practice a sinter is a product after high temperature treatment of a mixture of iron ores and their concentrates, fluxing agents (dolomite, lime) and coke breeze. Sintering process takes place in a range of 1200–1300°C and causes partial melting of individual grains of all sinter's components, forming a compact product. The temperature has to be lower than a melting point of the mixture. There are some phase transformations and/or degradation of minerals which accompany the sintering processes. As a result, a mineralogy of a sinter is different than a mineralogy of starting components.

Generally, the mineralogy of sinters can be thought as a mineralogy of two types of compounds: oxides and silicates, including also silicate glass. The presence and the amount of individual minerals depend on the properties of and the conditions of technology (practice). One of the most important factor, characterizing a sinter, is its basicity; the value of this parameter is defined as a ratio of a content of calcium (given as calcium oxide) to a content of silicon (given as silicon dioxide).

The basicity of a sinter is the main reason of diversity in observed mineral composition and – consequently – in properties of the sinter.

The identification of mineral components can be done using various experimental techniques from which the X-ray diffraction seems to be the most important. Every crystalline chemical compound (mineral) produces its own, typical X-ray diffraction pattern which can be used in identification of it in a multiphase mixture. The individual patterns are kept in Powder Diffraction File, updated every year by the International Centre for Diffraction Data and having now (2020) more than 400,000 data of inorganic compounds. In many cases, the data for one particular compound contains also information about crystallography of this compound. It means that a calculation of a theoretical pattern of this compound is possible. In X-ray diffraction method, one can assume that the observed pattern of a multiphase powder mixture is a sum of weighed patterns of individual compounds (minerals). This assumption gives the possibility to apply the Rietveld method to study the multiphase mixtures and to calculate the fractions of individual components of the mixture.

The Rietveld method was presented for the first time in 1967 by H. Rietveld to refine crystallographic structure of a crystalline compound, using neutron diffraction [1, 2]. R. A. Young and D. B. Wiles applied the method to X-ray diffraction in 1981 [3, 4] and the next application to quantitative phase analysis was introduced by Hill and Howard in 1987 [5] and Bish and Howard in 1988 [6]. The crucial advantage of the Rietveld method in studying and quantifying mixtures is the ability to analyze the overlapped reflections. Overlapping is the most important problem in mixtures, especially in the case of low symmetry of constituents. The number of reflections can reach some hundreds in a typical 2Theta range of measurements. There is also another problem – a contribution of intensities of many small reflections to an observed intensity of a background of an experimental X-ray diffraction pattern and consequently some difficulties in refining the background. This is also the case of the presence of amorphous component. This matter was solved in the Siroquant software [7] in which the shape and intensity of the background is not refined but manually removed from a pattern. Owing to the above, the Rietveld method gives the unique opportunity for a precise quantitative description of blast furnace sinters.

The quality of sinter's pieces can be described using different indices which have to be determined by some technical tests and experiments, according to international standards [8].

The tests are carried out in conditions which simulate blast-furnace's conditions in upper part of its shaft. A sample of a sinter of 500 g is placed into a furnace heated up to 500÷550°C and is exposed to a reducing gas for 60 minutes. Then the sinter is cooled in an atmosphere of inert gas and is subjected to tumbling. The disintegration sinter's pieces gives grains of various sizes which are screened to three groups. The following indices, according to International Standard ISO 4696- 1:2007, are determined:

Static resistance to degradation (the ratio of reduced sinter with size larger than 6.3 mm after tumbling test to reduced sinter)

$$RDI - \mathbf{1}\_{\ast \colon \mathbf{3}} = \frac{m\_1}{m\_0} \times \mathbf{100\%} \tag{1}$$

**81**

**Figure 1.**

**1.1 Materials**

*Application of X-Ray Diffraction to Study Mineralogical Dependence of Reduction…*

3.15

0.5

*m* −

Static grindability (the difference between reduced sinter and the sum of reduced sinter with size larger than 6.3 mm, reduced sinter with size larger than 3.15 mm and reduced sinter with size larger than 0.5 mm divided by reduced sinter)

*m* −

of oversize particles remained on a screen of 3.15 mm after tumbling.

quantitative mineral composition of blast furnace sinters on their quality.

were calculated according to the procedure given above.

*Samples of hematite lump ore (a), magnetite concentrate (b) and sinter (c).*

*RDI*

*RDI*

0 12 ( )

− + −= × (2)

− ++ − = × (3)

0 1 100% *m mm*

0 123 ( )

0 1 100% *m mmm*

where: m0 [g] – mass of a sample after reduction before tumbling m1 [g] – mass of oversize particles remained on a screen of 6.3 mm after tumbling m2 [g] – mass

m3 [g] – mass of oversize particles remained on a screen 0.5 mm after tumbling. From technological point of view, the most important index is a static susceptibility to degradation and a question of dependence of its value on a mineralogical composition of a sinter is still to be answered. Previous examinations showed that there was a connection between quantities of mineral components of sinters and their reducibilities [9] and this work is a continuation of studying a dependence of

All sinters were prepared from raw materials which were used in Polish steel plants. There were two kinds of iron ores and three kinds of concentrates of other iron ores (**Figure 1**). Six different mixtures were prepared, each one consisted of different combinations of ores and concentrates but with a planned basicity (**Table 1**). Basicity was calculated as a ratio of calcium content recalculated to CaO to silicon content given as SiO2. Sintering process was carried out in laboratory conditions with application of lime and dolomite in a conventional sinter pot of a diameter of 490 mm [10]. Ten laboratory tests were done for each kind of mixture (**Figure 2**); then three samples characterized by optimal moisture with the highest productivity were selected for further investigations (**Table 2**). The RDI values

*DOI: http://dx.doi.org/10.5772/intechopen.95086*

Static susceptibility to degradation (the difference between reduced sinter and the sum of reduced sinter with size larger than 6.3 mm and reduced sinter with size larger than 3.15 mm divided by reduced sinter)

*Application of X-Ray Diffraction to Study Mineralogical Dependence of Reduction… DOI: http://dx.doi.org/10.5772/intechopen.95086*

$$RDI - \mathbf{1}\_{-3.15} = \frac{m\_0 - \left(m\_1 + m\_2\right)}{m\_0} \times \mathbf{100\%} \tag{2}$$

Static grindability (the difference between reduced sinter and the sum of reduced sinter with size larger than 6.3 mm, reduced sinter with size larger than 3.15 mm and reduced sinter with size larger than 0.5 mm divided by reduced sinter)

$$RDI - \mathbf{1}\_{\text{-0.5}} = \frac{m\_0 - \left(m\_1 + m\_2 + m\_3\right)}{m\_0} \times \mathbf{100\%} \tag{3}$$

where: m0 [g] – mass of a sample after reduction before tumbling m1 [g] – mass of oversize particles remained on a screen of 6.3 mm after tumbling m2 [g] – mass of oversize particles remained on a screen of 3.15 mm after tumbling.

m3 [g] – mass of oversize particles remained on a screen 0.5 mm after tumbling. From technological point of view, the most important index is a static susceptibility to degradation and a question of dependence of its value on a mineralogical composition of a sinter is still to be answered. Previous examinations showed that there was a connection between quantities of mineral components of sinters and their reducibilities [9] and this work is a continuation of studying a dependence of quantitative mineral composition of blast furnace sinters on their quality.

#### **1.1 Materials**

*Iron Ores*

The basicity of a sinter is the main reason of diversity in observed mineral composi-

The identification of mineral components can be done using various experimental techniques from which the X-ray diffraction seems to be the most important. Every crystalline chemical compound (mineral) produces its own, typical X-ray diffraction pattern which can be used in identification of it in a multiphase mixture. The individual patterns are kept in Powder Diffraction File, updated every year by the International Centre for Diffraction Data and having now (2020) more than 400,000 data of inorganic compounds. In many cases, the data for one particular compound contains also information about crystallography of this compound. It means that a calculation of a theoretical pattern of this compound is possible. In X-ray diffraction method, one can assume that the observed pattern of a multiphase powder mixture is a sum of weighed patterns of individual compounds (minerals). This assumption gives the possibility to apply the Rietveld method to study the multiphase mixtures

The Rietveld method was presented for the first time in 1967 by H. Rietveld to refine crystallographic structure of a crystalline compound, using neutron diffraction [1, 2]. R. A. Young and D. B. Wiles applied the method to X-ray diffraction in 1981 [3, 4] and the next application to quantitative phase analysis was introduced by Hill and Howard in 1987 [5] and Bish and Howard in 1988 [6]. The crucial advantage of the Rietveld method in studying and quantifying mixtures is the ability to analyze the overlapped reflections. Overlapping is the most important problem in mixtures, especially in the case of low symmetry of constituents. The number of reflections can reach some hundreds in a typical 2Theta range of measurements. There is also another problem – a contribution of intensities of many small reflections to an observed intensity of a background of an experimental X-ray diffraction pattern and consequently some difficulties in refining the background. This is also the case of the presence of amorphous component. This matter was solved in the Siroquant software [7] in which the shape and intensity of the background is not refined but manually removed from a pattern. Owing to the above, the Rietveld method gives the unique opportunity for a precise quantitative description of blast

The quality of sinter's pieces can be described using different indices which have to be determined by some technical tests and experiments, according to interna-

Static resistance to degradation (the ratio of reduced sinter with size larger than

1

*m* − =× + (1)

0

6.3

1 100% *m RDI*

Static susceptibility to degradation (the difference between reduced sinter and the sum of reduced sinter with size larger than 6.3 mm and reduced sinter with size

The tests are carried out in conditions which simulate blast-furnace's conditions in upper part of its shaft. A sample of a sinter of 500 g is placed into a furnace heated up to 500÷550°C and is exposed to a reducing gas for 60 minutes. Then the sinter is cooled in an atmosphere of inert gas and is subjected to tumbling. The disintegration sinter's pieces gives grains of various sizes which are screened to three groups. The following indices, according to International Standard ISO 4696-

and to calculate the fractions of individual components of the mixture.

tion and – consequently – in properties of the sinter.

**80**

furnace sinters.

tional standards [8].

1:2007, are determined:

6.3 mm after tumbling test to reduced sinter)

larger than 3.15 mm divided by reduced sinter)

All sinters were prepared from raw materials which were used in Polish steel plants. There were two kinds of iron ores and three kinds of concentrates of other iron ores (**Figure 1**). Six different mixtures were prepared, each one consisted of different combinations of ores and concentrates but with a planned basicity (**Table 1**). Basicity was calculated as a ratio of calcium content recalculated to CaO to silicon content given as SiO2. Sintering process was carried out in laboratory conditions with application of lime and dolomite in a conventional sinter pot of a diameter of 490 mm [10]. Ten laboratory tests were done for each kind of mixture (**Figure 2**); then three samples characterized by optimal moisture with the highest productivity were selected for further investigations (**Table 2**). The RDI values were calculated according to the procedure given above.

**Figure 1.** *Samples of hematite lump ore (a), magnetite concentrate (b) and sinter (c).*

#### **Table 1.**

*The planned basicity values of each kind of mixtures.*

#### **Figure 2.**

*The experimental site for sintering iron ores and waste products in Sie*ć *Badawcza* Ł*ukasiewicz - Instytut Metalurgii* Ż*elaza.*

**Table 2.**

*The RDI values of the chosen sinters.*


**5. Selection Criteria Based on the Addition of AFP and/or DCP Serum Level Measurements to HCC Morphology**

AFP is considered a marker of HCC differentiation and vascular invasion; thus, the measurement of its serum levels pre-LT has been proposed as a potential tool to identify HCC patients with a higher risk of tumor recurrence and poor post-LT survival who should be excluded from transplantation [48]. The limitations of this approach became immediately evident, since it was very difficult to apply AFP measurement in a standardized and reproducible timeframe. For example, in deceased donor liver transplantation, the date of the transplant is never predictable. Thus, the optimal time interval between transplantation and AFP measurement that would make it a predictive marker of recurrence was unclear [19]. Instead of adopting cutoff values of AFP, an interesting approach is to consider multiple AFP measurements to calculate a trend in the increase or decrease in its serum levels. Patients experiencing an increase in serum AFP > 15 ng/mL/month had a higher frequency of waitlist dropout or significantly worse post-LT survival than those with a lower (≤15 ng/mL/month) increase in AFP (54% vs. 94%) [49]. These results suggest that the variations in AFP serum levels, rather than the last AFP level available before LT, may be more accurate in predicting post-LT outcome. [50]. This concept is incorporated to increase the accuracy of the assessment of tumor downstaging before LT. For example, a rapid increase in AFP serum levels after a presumed successful downstaging, assessed by radiologic imaging, should be considered a predictor of poor post-transplant outcome.

A very attractive way to select in patients beyond MC at baseline those with a higher risk of HCC recurrence is to add AFP serum levels to the morphologic characteristics of HCC [51]. The Toronto criteria [21] were developed assuming that all patients with HCC may have acceptable post-LT survival independent of the number and/or size of the nodules if HCC was confined to the liver, well differentiated at histology, and without macrovascular invasion. These criteria identified AFP serum levels > 400 IU/mL at the time of transplant as an independent predictor of worse 5-year disease-free survival. The Toronto criteria were subsequently validated, confirming that AFP serum levels before LT were strongly associated with post-LT survival and HCC recurrence [52].

Similar results, combining the morphology and histology of HCC with AFP serum levels, have been obtained in China, where the Hangzhou criteria were developed [22]. These criteria selected HCC patients for LT in the absence of portal vein tumor invasion and with either HCC ≤ 8 cm in diameter or with HCC ≥ 8 cm in diameter but with concurrent AFP serum levels < 400 ng/mL and histological grade I or II. Patients fulfilling the Hangzhou criteria experienced 1- and 3-year survival rates very similar to those reported in patients transplanted within the MC. The combination of AFP serum levels and morphologic characteristics of the tumor also inspired European authors to expand the MC for selecting patients with HCC for LT. Toso et al. [53] evaluated a large cohort of 6000 European LT patients and demonstrated that the subgroup of recipients who presented a total tumor volume (TTV) of ≤115 cm3 and AFP serum levels ≤ 400 ng/mL experienced a lower risk of HCC recurrence and better survival after LT. It should be highlighted that these expanded criteria were more effective than both the Milan and UCSF criteria in selecting patients with a low risk of HCC recurrence for LT. The TTV-AFP criteria were subsequently validated in cohorts of patients in countries outside Europe and in Canada [23]. A further model that combined AFP serum levels and morphologic characteristics of HCC, known as the AFP model, was proposed by the Liver Transplantation French Group [24]. The AFP model merges AFP serum levels and the size and the number of nodules, attributing different scores for each variable. Tumor sizes of 0, 1, or 4 points were assigned if the largest tumor diameter was ≤3 cm, 3–6 cm, or >6 cm, respectively. Moreover, 0 or 2 points were assigned if the number of nodules was ≤3 or ≥4. Regarding the AFP serum levels, 0, 2, or 3 points were assigned if AFP serum levels were ≤100, 100–1000, or >1000 ng/mL, respectively. The maximum score sum of the AFP model is 9. Patients may be divided into low risk of HCC

recurrence if the final score is up to 2 points and high risk of HCC recurrence if the final score is ≥3. A very innovative observation of the study was that in patients presenting AFP serum levels > 1000 ng/mL, 3 points are attributed, irrespective of the number or size of nodules; thus, they may be immediately considered at high risk of HCC recurrence. The AFP model was validated in different countries and in living donor liver transplantation, confirming its clinical utility in stratifying the recurrence risk of HCC after LT in a better way than MC [54–57]. The Metroticket 2.0 model [25], developed in Italy, was based on the measurement of the sum of the number and size of nodules and the log10 AFP level. Recipients with AFP levels < 200 ng/mL and with the sum of the number and size of tumors (in centimeters) not exceeding 7 presented a post-LT survival probability of 70%, which was comparable to that observed in patients transplanted within MC. To maintain this excellent clinical outcome in the presence of AFP levels of 200–400 ng/mL, the sum of the number and size of tumors should be reduced to ≤5, and if AFP levels are 400–1000 ng/mL, the sum of the number and size of tumors should be further reduced to ≤4. This model outperformed the original MC, UCSF, and AFP French models in identifying patients with excellent 5-year post-LT survival.

The results obtained by combining the morphological characteristics of the tumor and the AFP values made it possible to develop selection criteria for LT that definitively exceeded those of Milan. These models introduced many innovations to more accurately select patients with HCC for LT. First, these selection criteria made it possible to offer LT to many patients with HCC who would have been excluded by application of the MC, assuring excellent post-transplant survival. Second, the calculation of both the size and number of nodules and the AFP serum levels appears simple and available in every context, making these models applicable in different geographical contexts and with all types of patients. Third, these models may be used "dynamically", in addition to the assessment of the HCC response to neoadjuvant treatments, to more accurately select patients who will undergo tumor downstaging before LT.

The interest in measuring DCP serum levels was derived from the observation that some HCCs expressed normal levels of AFP but increased levels of DCP. These subtypes of HCCs present a poor grade of differentiation and frequent MVI [58,59]. The combination of morphological characteristics of HCC (up to 10 nodules ≤ 5 cm in diameter) and DCP serum levels (≤400 mAU/mL) are the key elements included in the Kyoto criteria [26,60,61]. Patients beyond MC who fulfilled the Kyoto criteria at the time of LT had similar post-LT prognoses in terms of survival and HCC recurrence compared to those within MC [60]. In the context of living donor liver transplantation, the Kyushu criteria [62] that are considered suitable for LT patients with any number of HCC < 5 cm in diameter and DCP serum levels < 300 mAU/mL were developed. These criteria appeared more accurate for predicting HCC recurrence than both the Kyoto and UCSF criteria but only when living donation was considered [63,64].

Another interesting way to construct a prediction model of post-LT clinical outcome in patients with HCC beyond MC is to combine DCP and AFP serum levels. Starting from this assumption, the MoRAL model was developed in living donor liver transplant patients exceeding the MC [27]. Both AFP and DCP serum levels were significantly associated with the time elapsed from transplantation to HCC recurrence. In the group of recipients exceeding the MC, a MoRAL score ≤ 314.8 was predictive to select patients with significantly longer (66.3%) 5-year recurrence-free and overall (82.1%) survival. In contrast, the group of recipients fulfilling the MC but with a MoRAL score > 314.8 showed a higher risk of HCC recurrence and lower post-LT survival than patients beyond MC with a low MoRAL score. A retrospective study evaluating the combination of DCP and AFP serum levels in predicting clinical outcome in liver transplant patients outside the MC was also conducted in the United States [65]. In this study, AFP and DCP serum levels ≥ 250 ng/mL and ≥7.5 ng/mL, respectively, were predictive of more frequent HCC recurrence. When AFP and DCP were combined with MC, the hazard ratio of HCC recurrence risk increased from 2.6 for patients beyond MC to 8.6 when AFP serum levels were ≥250 ng/mL and to

7.2 when DCP serum levels were ≥7.5 ng/mL. The encouraging results deriving from the use of DCP as post-transplant survival as well as post-transplant HCC recurrence predictor should be analyzed with caution. It should be emphasized that more than 90% of the published papers related to DCP have been produced in Asian countries and refer to living donor liver transplanted patients for liver diseases mainly related to HBV infection [66]. Thus, solid data on the role of DCP in conditioning the clinical outcome of patients with HCC transplanted with deceased donors and with liver diseases due to nonviral etiologies are still lacking. Considering these limitations, among all biological markers that have been studied, AFP remains the only one that has proven useful in predicting the clinical outcome in patients transplanted for HCC. The prognostic models of post-transplant survival that incorporate pre-LT AFP serum levels and HCC morphological characteristics remain the most widely used to accurately select patients beyond MC for LT. In addition, the evaluation of AFP serum level variations induced by locoregional therapies and HCC downstaging modalities is becoming the most promising strategy to select patients to be transplanted with HCC beyond the MC with even greater accuracy.

#### **6. Selection Criteria Based on the Response of HCC to Bridging and Downstaging Treatments**

A very innovative approach to select patients for LT presenting at baseline beyond the MC is to evaluate the characteristics of tumor response after LRT and consider it a surrogate marker of biological HCC aggressiveness and of the risk of recurrence [19]. When LRT is used to control tumor growth with the aim of reducing the risk of waiting list dropout, it may be considered a "bridge" treatment to LT. The efficacy of LRT in reducing waiting list dropout has been demonstrated if the waiting time for LT is at least 6 months [67]. Patients whose tumor progression occurs despite LRT within 6 months have a worse post-LT outcome than those who achieved treatment response or the stability of HCC following LRT [49,68,69]. These observations suggest that the response to LRT might be influenced not only by the treatment modality but also, more importantly, by the biological behavior of the tumor.

The term "downstaging" is used by attributing the possibility of LRT decreasing the baseline tumor burden until it meets the criteria for LT (ideally within MC) and to assure acceptable post-LT outcomes [36]. This concept was derived from some studies suggesting that post-LT outcomes in patients successfully downstaged to the MC were comparable with those observed in transplanting patients with MC at presentation [70,71]. The potential explanation of these findings is that a close correlation exists between successful downstaging and better explant histologic characteristics of the tumor [70–72].

As indicated by the Barcelona Clinic Liver Cancer (BCLC) staging system [73], among the LRT modalities that may be employed to perform downstaging of HCC, transarterial chemoembolization (TACE) is the most commonly utilized. Transarterial radioembolization (TARE) and ablative techniques may be often proposed [74].

It should be emphasized that there are important potential safety concerns of TACE and TARE in generating hepatic decompensation. In accordance with the guidelines for TACE [3], it has been strongly suggested that only patients with preserved liver function (Child–Pugh score A/B and bilirubin ≤ 3 mg/dL) should be considered for downstaging procedures [75]. Although TACE is the recommended first-line treatment for downstaging objectives in most studies [75–77], TARE may be considered an alternative treatment to TACE, particularly in larger HCCs, where the results are encouraging. However, this treatment modality requires further studies to confirm its real utility as a downstaging procedure [78]. The major limitation of downstaging protocols is that they can be applied only in a subgroup of patients who present simultaneously compensated cirrhosis complicated with HCC but cannot be applied in patients with decompensated cirrhosis with HCC.

A very challenging issue will soon be the potential role of neoadjuvant treatments combining systemic drugs such tyrosine kinase and checkpoint inhibitors in downstaging protocols [79]. In a recent clinical trial, the combination of atezolizumab plus bevacizumab in the treatment of unresectable HCC was able to induce a complete and partial response to therapy in 18% and 71% of treated patients, respectively [80]. These results open the critical question of whether systemic treatments may be adopted in combination and/or sequentially with traditional LRT to increase the chances of obtaining successful HCC downstaging.

A further critical element that must be considered in the application of downstaging procedures is the objective measurement of the treatment response. The modified Response Evaluation Criteria in Solid Tumors (mRECIST) were developed for the assessment of treatment response by measuring tumor shrinkage. These criteria divided the rate of response to treatment into four categories: (1) complete response (CR—disappearance of arterial enhancement in tumor(s), (2) partial response (PR—a minimum 30% reduction in the sum of diameters of viable tumors compared with baseline), (3) stable disease (SD—not meeting PR or progressive disease), and (4) progressive disease (PD—an increase of at least 20% in the sum of diameters of viable tumors compared with baseline or the appearance of new lesions) [81]. The usefulness of the mRECIST criteria in the evaluation of response to LRT after downstaging protocols in patients with HCC has been confirmed both in those within and beyond the MC. In a small series of 33 patients presenting HCC outside the MC who underwent LT after downstaging performed by TACE, the 5-year survival was significantly higher in those who achieved CR (94.4%) than in those who had PR (45.4%) and SD (50%). These significant differences were explained by a progressive increase in HCC recurrence rates from patients with CR (15.5%) to those with SD (50%) to those with PR (53.3%) [82]. Similar results were obtained in the study performed by Kim et al., which evaluated HCC recipients within and beyond MC after the TACE procedure [83]. The 5-year HCC recurrence rate was 5.3% in patients who achieved CR or PR after TACE compared with 17.6% in those who achieved SD or PD. It should be noted that although the mRECIST criteria are sufficiently detailed, they may not be systematically adopted among different transplant centers, such that the results obtained by LRT may not be comparable [19].

In addition to the quality of the response to LRT, the duration of response is increasingly used as a surrogate marker to identify HCC with more aggressive behavior. Starting from this assumption, many liver transplant centers adopted the strategy to "ablate and wait" to assess the type and duration of response to LRT [9]. It has been suggested that the success of downstaging should be assessed, demonstrating the absence of tumor progression during an observation period of at least 3 months after the procedure. A successful downstaging procedure allows the selection of candidates with more favorable tumor biology and better post-LT survival [84]. This strategy avoided early post-LT recurrences, as demonstrated in patients with HCC beyond MC transplanted after short waiting times [85]. Thus, the guidelines of both the American and European associations for the study of the liver are concordant in recommending the adoption of LRT in patients with HCC beyond MC and the consideration of those who achieved successful downstaging for at least 3–6 months as suitable candidates for LT [3–86].

The question at this time is what the baseline and the final burdens of HCC obtained after successful downstaging that may be considered sufficient to perform LT should be. In the United States, the UCSF downstaging protocol [70] has recently been employed as a national policy both for the graduation of urgency to transplantation and to try to answer this question. In this protocol, the baseline selection criteria for patients with HCC who may benefit from LRT downstaging procedures before LT were as follows: a single HCC ≤ 8 cm in diameter; up to three lesions < 5 cm in diameter; or up to five nodules, all of them <3 cm in diameter, but in any case with a total tumor diameter < 8 cm. Retrospectively analyzing the UNOS database, the 3819 liver transplanted patients with HCC were divided as always within the MC or achieved UNOS downstaging criteria (UNOS-DS). The 3-year post-LT survival was 83.2% in patients always within MC and 79.1% in those fulfilling UNOS-DS. Moreover, the 3-year HCC recurrence rate was 6.9% in recipients who were always within MC and 12.8% for those within UNOS-DS. A very interesting issue that emerged from this

study was that AFP serum levels ≥ 100 ng/mL were the only independent predictor of post-LT HCC recurrence in downstaged groups [87].

To date, only one randomized clinical trial (the XXL trial) has evaluated the clinical outcome of patients presenting at baseline with HCC beyond MC who were successfully downstaged by means of LRT and subsequently transplanted compared with those who received only LRT [88]. This study was conducted in Italy and enrolled 74 patients with HCC beyond the MC, without macrovascular invasion or extrahepatic spread, with a 5-year expected post-LT survival of at least 50% (estimated by Metroticket calculator [37]) and preserved liver function (Child–Pugh classes A5–B7). All patients initially underwent tumor downstaging with LRT or systemic therapies, according to a multidisciplinary decision. After an observation period of 3 months, during which treatment with sorafenib was allowed, patients presenting CR or PR, assessed by means of the mRECIST criteria, were randomly assigned (1:1) to LT or to continue LRT or systemic treatments (control group). Of note, in patients with baseline AFP values ≥ 400 ng/mL, a radiological tumor response was confirmed only in case of a parallel percentage decrease in AFP concentrations. In contrast, in patients with AFP serum levels < 400 ng/mL at recruitment, an increase in AFP concentrations above that cutoff value at the end of the downstaging phase or during the observation period was considered tumor progression, independent of radiological assessment. The primary endpoints of the study were the evaluation of 5-year tumor-eventfree survival and overall survival. The first result of the study was that 29/74 (39.1%) of the patients dropped out before randomization; thus, only 45 (60.9%) patients were finally included in the study (23 underwent LT, and 22 maintained LRT or systemic treatments). Despite the high rate of dropout, after a median follow-up of 71 months, a significantly higher 5-year tumor-event-free survival was observed in the LT group (76.8%) than in the control group (18.3%). Regarding the 5-year overall survival, the figures were quite similar, indicating a better overall survival in the LT group (77.5%) than in the control group (31.2%). Tumor progression was the main cause of death in both groups, while in the LT group, HCC recurrence was detected in 22% of cases. The results of this study provide additional evidence to previous results demonstrating comparable post-LT outcomes in patients with HCC beyond the MC who underwent successful downstaging within the MC and in those who underwent LT fulfilling the MC at presentation. A further very important message from this study is that different schedules of LRT and systemic treatments may be employed in patients with HCC beyond the MC to achieve successful and durable downstaging to permit them to be suitable for LT.

#### **7. Conclusions**

LT must be considered the best treatment option for patients with unresectable HCC [89]. Since the number of donors is insufficient to satisfy all requests for transplantation for HCC, it is essential to perform careful selection of transplant candidates. For approximately 25 years, MC have been the benchmark for offering patients with HCC the opportunity for transplantation, but as recently demonstrated, they excluded a subset of patients who could have benefited from LT. For this reason, several other more extended selection criteria to offer LT to an increasing number of patients with HCC have been evaluated. In the beginning, many of the expanded criteria evaluable in the pre-LT period were based on the morphological characteristics of the tumor as the original strategy adopted for constructing the MC. Subsequently, the addition of biological markers, predominantly AFP serum levels, to the morphological characteristics of the tumor emerged as the more solid and reproducible criteria for patient selection beyond the MC for LT, assuring excellent post-LT outcomes. Downstaging HCC to MC by means of LRT and/or systemic therapies is becoming a valid and increasingly utilized method of patient selection for LT. Adopting this approach, the surrogates of tumor biology can be assessed, such as the response rate to LRT and its maintenance for a sufficient time during the waiting list before transplant. The measurement of AFP serum levels or AFP slope during or after downstaging protocols can be considered a further important option to identify those patients at higher risk of

HCC recurrence that should be excluded from LT. It appears clear that the risk of failure of successful downstaging is related to both the tumor burden and to AFP serum levels at baseline.

It is important to highlight that the selection of HCC patients for LT by means of the expanded criteria may be difficult to adopt in areas of the world with severe organ shortages. In these areas, the selection criteria based on the utility principle that assures the maximum post-transplant survival, such as the MC, will remain preponderant, rather than expanded criteria that could reduce access to LT for patients with better post-LT prognosis [67–90]. This justified that not all liver transplant centers around the world adopt the same criteria to select patients with HCC for LT [3–74]. Each country developed, based on its scientific experiences, some selection criteria for transplanting patients with HCC beyond MC. A common thread that links the various selection criteria adopted in different countries is to consider the morphological characteristics of the tumor (number and size of nodules) and the values of some biological markers, mainly AFP, as main determinants of the selection process. In the United States and in Europe, the concept to not necessarily set a baseline HCC limit size to consider patients potentially transplantable, except for the presence of macrovascular invasion or extrahepatic spread, appears to be more accepted. Thus, the downstaging process will probably become the main selection tool for LT, enabling clinicians to postpone the transplantation decision from tumor presentation to the assessment of final response to LRT [91]. The effectiveness of downstaging procedures should be considered as having brought the tumor back within the MC for a period of at least 3–6 months before enlisting [84].

In summary, to try to answer the key questions reported in the introduction, the following proposals can be suggested: (a) it seems proven that in the absence of macrovascular invasion and extrahepatic spread, no upper limit of tumor burden beyond MC should be established "a priori" to determine transplant eligibility for HCC; (b) to justify a policy to transplant patients with HCC beyond MC at presentation, the minimal expected 5-year post-LT survival probability, estimated by Metroticket calculator, should be at least 50% [37]; (c) the response to neoadjuvant LRT and/or systemic treatments in addition to the dynamic evaluation of AFP serum levels are expected to replace conventional morphological criteria for selecting patients with HCC for LT in the near future.

**Author Contributions:** Conceptualization, P.T.; methodology, E.F. (Elisa Fumolo); data curation, E.F. (Ezio Fornasiere), D.B.; writing—original draft preparation, P.T., E.F. (Elisa Fumolo), E.F. (Ezio For-nasiere), and D.B.; writing—review and editing, P.T. All authors have read and agreed to the published version of the manuscript.

**Funding:** This research received no external funding.

**Institutional Review Board Statement:** Ethical review and approval were waived for this study due to the fact that it refers to a review of the scientific literature in the field.

**Informed Consent Statement:** Not applicable.

**Conflicts of Interest:** The authors declare no conflict of interest.

### **References**