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Developing A Universal Religion/Religions' Origins/Assumptions

No one knows just how religious beliefs and practices began, but Sara Blaffer Hardy suggests mutual childcare may have been important. since "It only requires a couple to conceive a child, but a whole village to raise it to maturity".

The emergence of agriculture and the domestication of animals around seven thousand years ago i(n about the fifth millennium B.C.E) are generally acknowledged as the impetus for the emergence of the first large-scale, complex urban societies. These societies, which appeared almost simultaneously around 4000 B.C.E in both Egypt and Mesopotamia, used stone tools, but within 500 years stone tools and weapons gave way to bronze. With bronze manufacture came a revolution in warfare.

Along with weapons, emerged military discipline, tactical skills and strategic planning, particularly relating to the optimization of available manpower by training, sanitation and the strict avoidance of those foods likely to cause digestive discomfort or diarrhea. Religions tend to enforce absolute self-discipline by imposing the belief that unseen observers are monitoring our every thought and action in order to reward or punish us for all eternity after our demise, so that - but only for obedient believers - death need not be feared, and may even be welcomed for those 'fortunate enough' to killed 'heroically' in battle.

A plausible explanation for modern religious belief is that like all animals, actions and habits that were effective in promoting survival and prosperity in the past have evolved  from previous  generations. The ideas and customs of men and women who have been successful would therefore similarly have been passed on to their offspring as 'truths'. Parents tend impose their beliefs as assumptions that serve inhibit questioning or experimentation which might prove be hazardous.

Everyone makes thousands of minor assumptions every day, and normally these all transpire unnoticed. We get up, dress, eat, do chores, go to work, return home, prepare a meal, and so on, continuously making subconscious assumptions that determine the way we act. For example, we assume that other people will behave in much the same way as they always have—and they do. We assume that the bus will arrive, that stores and offices will open, that we still have a job to go to—and we are usually right. Any incorrect suppositions we might make are generally inconsequential, and corrections are easily, and mostly subconsciously, made.

We make assumptions because we can never know all there is to know about any facet of our lives, or about any object or event we encounter. Our true state of ignorance is seldom apparent to us, but our lack of knowledge makes itself known every time there is an important decision to be made, one whose consequences might seriously affect us, or the lives of those we love, for instance. On these occasions we quickly discover how little we really know. Anyone considering marriage or buying a house for the first time, for example, knows this feeling. At such times we may temporarily be unable to make a decision, for fear of the consequences were we to make a “wrong” choice. When such feeling arise, we spend much time gathering and evaluating information, trying all the time to replace assumptions with accurate knowledge. Thus, although we rarely notice that every decision we make has its fringe of assumptions, such is the case.

Early humans would have faced exactly the same difficulty. They knew even less than we do about the true state of most affairs, and making assumptions would have been the only way they could have made decisions. And—just as happens to the assumptions we make—after a while many of the useful assumptions they made would have become indistinguishable from facts.

Since we humans are born of into a society consisting of parents, grandparents and various experts, and that children tend to learn from wise elders, the assumption that there was some ancient, all-wise ancestor or progenitor of mankind is not unreasonable. Claiming some special relationship to this assumed omnipotent wisdom provided a powerful mechanism of social control which allows the sophisticated human organization required to develop ancient empires and modern civilization.For example, monarchs claiming divine intervention or inspiration delivering them victory or a  'bridge' (pontiff in Roman times) whose inspiration is divine and thus infallible.

It is a rather modern (Age of Enlightenment) idea that Oscar Wilde encapsulated: ''To Assume makes an ASS out of yoU and ME!

 * Return to Religions' Origins, Introduction
 * ../Ancient Assumptions/


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Developing A Universal Religion/Religions' Origins/Ancient Assumptions

Traces of the assumptions made by early men and women still exist in tangible form today. Two in particular are important to the theme of this book and will be examined: our ancestors assumed that they would experience life after death, and they assumed that gods existed.

 * Return to Religions' Origins, Introduction
 * ../Life After Death/

license: Creative Commons - Attribution Share-Alike - https://creativecommons.org/licenses/by-sa/4.0/


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Developing A Universal Religion/Religions' Origins/Life After Death

The earliest evidence yet discovered that our ancestors believed in some kind of life after death is to be found in graves of the Neandertals (who lived from about 200,000 to about 25,000 y.a.). Careful arrangement of the deceased, as well as accompanying flint implements together with broken animal bones (likely to have come from food buried with the body), suggest that these accoutrements were considered to be needed by the dead. (Neandertal cave artwork depicting burial rituals also supports the premise that they assumed a life after death.)

At least as early as 30,000 y.a., Cro-Magnon followed more complex rituals. They buried their dead in sewn clothing, covered them with ornaments and bead decorations, and surrounded them with tools, weapons and food. One grave, 28,000 years old, in Sungir, Russia, contains the body of a sixty year old man wearing bracelets and necklaces, and dressed in a tunic sewn with hundreds of mammoth-ivory beads; he was accompanied by rich grave goods.

For some as yet unknown reason, ornamenting the dead with red pigment has also been a long-lasting and widespread custom. The skeleton of a young man some 25,000 years old, discovered in a cave in South Wales, was covered with red ochre and accompanied by a shell necklace, ivory beads and bracelets. Ornamentation continued until at least 6,500 y.a., for the head of one of seventeen Stone Age bodies (dated to that age and found in a cemetery at Bøgebakken, Denmark) was surrounded by red ochre. Burial customs such as these and others provide strong evidence that early man believed in the existence of some kind of afterlife, for which the body needed to be prepared and provisioned.

Burial rituals increased in complexity during the Neolithic Age (9,000–5,000 y.a.), to the extent of including animal sacrifices, cremation, entombment in stone chambers roofed with huge boulders and body preservation. The Chinchorro culture of northern Chile conducted extremely elaborate burial rituals, as is readily evidenced by mummified bodies dating back 9,000 years. The head, hands and feet were removed, the body was skinned and soft tissue excavated, and the skull was packed with a mixture of grass, hair and ashes. The skin was then reapplied, the whole body plastered with an ash paste and then painted black and red. It is inferred from this elaborate practice that some intense religious assumption (one that sooner or later may well have metamorphosed into a belief) must have prompted such effort.

A different form of evidence suggesting early Homo had the intellectual ability to invent assumptions is to be found in several now-European countries where Cro-Magnon left rock drawings and engravings in caves. These sketches illustrate their prowess in hunting large herds of animals (and the skeletons of hundreds of early horses found in sites frequented by Cro-Magnon show how successful these pursuits were). Such hunting strategies require abstract thought, organization and planning, and from this it is deduced that they had a language complex enough to be able to conduct a discussion of options and to manage assumptions.

Another item occasionally shown in cave drawings, and of significance to this discussion, is a figure in clothing associated with shamans or medicine men. These figures appear to have a significant role in the behaviours being depicted in the drawings. Shamans are traditionally involved in caring for the dead, and their thoughts and practices would certainly influence ideas held by clan members.

The accepted conclusion from this kind of evidence is that our ancestors assumed that an afterlife existed—that they actualized the concept of an afterlife thousands of years before the same notion was incorporated into the religions of early Egyptians and, later, into many of ours. This suggests that when describing “heaven” today we are not simply repainting a vision first drawn by prophets or theologians—we are actually maintaining or embroidering a Neandertal assumption. Of course, we don’t say that we are describing an assumption, but such is its origin. And our belief in an afterlife remains an assumption because there is no credible evidence that an afterlife actually exists, whether for the Neandertals, the Pharaohs, or for any modern-day human.

 * Return to Religions' Origins, Introduction
 * ../The Existence Of Gods/


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Developing A Universal Religion/Religions' Origins/The Existence Of Gods

Man must have assumed thousands of years ago that the inexplicable behaviour of some or even many aspects of the world was due to the presence of powerful gods.

We can understand why it was necessary to believe in gods. Prior centuries of rational thinking about practical matters (how best to take advantage of an animal’s behaviour when hunting, for example) had led naturally (if only subconsciously) to the realization that everything that happens has a cause. It was therefore only logical to conclude that something must cause such events as thunder and lightning to occur, or the sun to rise always in the east.

It was entirely rational for our ancestors to ask what could possibly give rise to such phenomena. But the true explanations lay far beyond their ability to comprehend all those thousands of years ago.

Written records tell us how the Greeks later solved this problem. They assumed that such events were caused by some kind of invisible beings who lived behind the clouds, occasionally amusing themselves by teasing or playing jokes upon those who lived on Earth below. Today, we might think that this was an extraordinary fantasy to dream up, but what, in ancient times, other than some supernatural beings, could explain the occurrence of such impressive events?

The hidden existence of powerful entities was not an unreasonable assumption for even very early humans to make. Living in caves and huts, they were low in nature’s hierarchy. There were many dangerous and more powerful animals lying in wait. Numerous awe-inspiring events took place daily that could not be explained. Mysterious illnesses and sudden inexplicable deaths occurred. Thunder filled the air for miles around, but lightning struck only certain spots seemingly randomly chosen. The sun, on the other hand, followed a routine—it moved across the sky in an orderly manner, regularly disappeared at night, only to rise again the next day. And eclipses—how could such rare incidences possibly be explained?

It was logical and sensible to assume that one or more mighty beings lived out of sight above, and that they contrived such events. This explanation so admirably solved many profound mysteries that, once put forward, it must have seemed the obvious answer and been immediately accepted. It seems certain that H. sapiens would have assumed gods existed almost as soon as they could form such a concept.

Moreover, in addition to being an explanation, this assumption had practical applications. It suggested ways men and women could act, if and when they needed to influence, praise or placate the behaviour of those who ruled from the skies above.

There is a great deal of evidence that magical rites with appeasement objectives were practised in many primitive societies. Early authorities, skilled in catering to capricious gods, devised and carried out often fanciful rituals. When the incantations and methods of these experts worked, when rain fell or eclipses ended, their reputation grew. When their best efforts were to no avail, someone or something else could easily be blamed.

The craft of such specialists continues today. Nearly all religions employ functionaries with similar roles, intermediaries who communicate the wishes of (and direct penitence to) a god. Their roles have remained roughly the same, but the communicants’ rituals and ceremonial customs have changed because, over time, humans have modified their beliefs about what is the “correct,” or “moral,” way to behave (for example, we no longer hold that human sacrifices are necessary).

 * Return to Religions' Origins, Introduction
 * ../Beliefs/


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Developing A Universal Religion/Religions' Origins/Beliefs

Assumptions can be indistinguishable from facts. A scientist might seek them out, but most of us would not. It would be impossible to sort one’s general knowledge into facts and assumptions, and we treat them as if they were identical. Both are accepted as being correct until proven wrong, used as long as they are useful, then forgotten when their utility is spent.

This is what has happened to early man’s assumptions that gods exist. Gods were taken for granted from at least as early as 5,000 BC. Their behaviours were discussed, subtle differences noted and character variations identified. Each deity became distinct, recognizable, understandable, named and worshiped by a few or by many; some because they created a fear that had to be calmed, others because they were loved. Assumptions had become indistinguishable from beliefs.

This early belief in many gods is still visible in Hindu communities. Colourful images of gods are displayed all over India, beckoning as clearly today as they did thousands of years ago. These deities are venerated and consulted in much the same manner as monotheists behave toward their one god. Some modern Hindus state that the images seen should be considered reminders that the one true god exists in many forms; others do not feel the situation is this simple, preferring to believe in the existence of many deities, each possessing different powers. However, the nature of Hindu belief is not the issue here; the point to note is that most of humankind once believed in the existence of many gods. Our shift to predominantly believe in a single creator is a relatively recent happening.

The belief in several gods (several dozens of gods, in some societies) gave rise to complex theologies, with many stories chronicling the interactions of multifaceted god-personalities to be memorized and taught to the next generation. It would have been fairly obvious to anyone, anytime, that monotheism is a much simpler belief. One supreme god could replace much confusion. Over centuries past there must have been many intelligent visionaries who argued in favour of a single supreme being.

We know a lot about one such idealist—Amaenhotep IV, a family-oriented Pharaoh who was married to a powerful wife (Queen Nefertiti) and who ruled Egypt for seventeen years, 1300 years before Christ was born. Amaenhotep changed his name to Akhenatom in support of monotheism, and ordered all to worship the one sun-god, Atom. This practice didn’t last long however; shortly after his death it was stopped by traditionalist priests who persuaded his successor (the boy-king Tutankhamen) to revert to polytheism.

Judaism was the first religion of modern significance to successfully institutionalize the belief that there is only one god. Christianity and Islam later adopted this concept, and have since conveyed their message to billions. Furthered by numerous persuasive practices (crusades, conquests, missionaries, inquisitions, torture, trials and burnings, to name a few), this lengthy battle for simplification (and influence over the minds of people) affected many over the centuries. Over time it remodelled nations, as they changed their laws to accommodate changes in beliefs.

Today (as noted in Some Major Religions) the majority of the world’s population take for granted the existence of one god. Most prefer not to consider this just an assumption, first conceived to account for any number of seemingly mysterious events, then employed to explain how the universe and life began. The assumption remains in vogue because it is useful; it authenticates the purpose many refer to (see Moral Decisions) when making decisions about how to live their lives. The assumption or belief that a god created the universe does not, of itself, also mean that the universe (or anything within it) exists for a reason, or to meet some purpose.

It is entirely possible to believe that the initiating god lives or lived outside of time, or inhabits a universe completely detached from ours—thoughts not at all foreign to some of our religions, nor to some scientists. Such a creator could have fabricated our universe from either of these positions and long since forgotten that he (read He, She, It, or even a multi-faceted Entity for “he”) had done so. The originating god even may have decided long ago that he had nothing else to do, and ceased being.

Alternatively, he could have been acting whimsically at the time, and be quite unconcerned subsequently about what is happening within his creation. (This is one way to resolve the concern of some regarding how a benevolent god could permit the existence of evil, but an unacceptable explanation to many, particularly those who, for reasons of their own, want a judgmental god.) Or, he may be just sitting back, not interfering, observing how events in this universe play out, prior to deciding how to create an improved one. In other words, once we assume the existence of a god, with absolutely no factual knowledge about such an entity, we can attribute to it any properties we wish. Anything can be claimed to be god’s will (as demonstrated by the innumerable, often incongruous, religious declarations sometimes proclaimed on television or the radio), and any action can be justified (as evidenced through statements made by some religious terrorists following their appalling actions).

The whole idea of a god seem rather pointless when viewed in this manner; furthermore this perspective completely misses the concept’s major value: belief in a god-given purpose allows our minds to make moral decisions, and acting upon these decisions delivers meaning to our lives. Any other belief of equal or greater significance would do as much.

 * Return to Religions' Origins, Introduction
 * ../Leaders/


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Developing A Universal Religion/Religions' Origins/Leaders

A belief in a god or gods is not a religion. Religions add visions of purpose, ideals, behavioural criteria, rewards, punishments, and much more, to their core belief. (In other words, religions weave and maintain aspects of their followers’ mental environments discussed in Problem Environments.) Many of the most critical of these ideas stem from the religion's founder. To understand how one person can conceive such notions then convince others that they are true, we must first discuss leadership.

Contrary to popular impression, leaders are plentiful in this world. Many lead for just a short time, but others retain their leadership quality for years. Most guide only a family, a work group, or perhaps one friend, but some lead multitudes.

Social conditions elicit leaders—recall the French and Russian revolutions, India in the 1920s (and on), Germany in the 1930s, or South Africa more recently, for example. Individuals within, or emotionally close to, suffering communities feel driven to change conditions and metamorphose into leaders as they become captivated by powerful ideals. Leadership skills strengthen as these ideals are expressed. Think of Jesus, Muhammad, Gandhi, and Mandela, or Churchill, Hitler and Stalin. Each held fast to an imagined ideal of some kind, their view of how society should be, a future to strive for, a dream of a better world.

All leaders have a vision of an enhanced future. A vision is critical because this is what leaders lead toward—their own mental image of a superior state of affairs. These visions can develop slowly, as perhaps for Genghis Khan; or in a blinding flash, as perhaps for Joan of Arc; or in intermittent surges, as perhaps for many parents.

Religious leaders differ from others in one important aspect: they credit a Supreme Being with providing the insights they convey. Moses, Jesus, Muhammad, Joan of Arc, and a multitude of saints and lesser religious leaders attributed the words they spoke to their God. Clearly they did so because they believed this to be true. But skeptics might be forgiven for thinking otherwise, reasoning that the vision expressed may have come from the visionary's “conversion” or “revelation” (terms introduced in Moral Decisions and further discussed in Reformations, Conversions And Revelations), events that were possibly an outcome of their own desire to improve conditions.

Please note that I'm not suggesting that religious leaders or founders do not believe in a God. Almost certainly all do, and many also believe that their God sometimes speaks to, or through, them. What I am stating, however, is that believing that their visions and words come from God does not necessarily make it so. They believe them to be authentic—that is what makes them convincing leaders. Their ideas can be entirely false, but as long as they believe them to be true, the strength of their convictions can convince and convert others.

This raises an important issue. What creates these beliefs? What happens in the minds of religious leaders to convince them that they are God's emissaries? The logical answers to these questions will be provided in the next chapter.

 * Return to Religions' Origins, Introduction
 * ../Summary/


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Developing A Universal Religion/Religions' Origins/Summary

Experience has taught us that everything has a beginning, and this causes us to think that the universe, too, must once have begun. The earliest origin-explanation was that it was created by a god, an interpretation based upon the assumption that such an entity exists.

This explanation has two great advantages over our modern understanding: it is simple, and it is easily understood. However, it also has two great disadvantages: it tells us nothing about the universe and it does not help us to understand cosmological behaviour. If we want to understand reality, then we must work from what we know rather than from what we assume.

Religious founders and leaders rarely state why a god created the universe. But they always attribute purpose to our existence, and they always teach us to live in a manner that demonstrates we value attainment of this purpose. Living to attain this purpose, we are told, presents problems; these, just like all of our everyday problems, can only be solved by understanding the environment that holds the conditions to be met (as we saw in Problem Environments). This is why each religion’s environment is described and explained, and why their God’s criteria or commandments, the existence of a judgement day, heaven and hell, and so on, are detailed. In explaining such things, these leaders all (except, perhaps, a few) confidently believe that they are carrying out the instructions of a higher Being.

A belief in any purpose creates a mind that can make decisions with the clarity of vision and the certainty of conviction. A strong belief in any leader’s vision creates an ardent proselyte. However, belief only makes the believed-in concept real to the believer. It cannot make it true in the real world, for the real world is quite unaffected by what its inhabitants think. And it often cannot make it true to others, where many may simply adopt the views of the local majority to avoid arousing trouble for themselves.

Over the centuries we have significantly added to the belief we started with—that a god simply created the universe. Many of us now infer that this god has a purpose in mind, that humans are intimately linked to this purpose, and that God periodically intervenes in our lives. We have made these assumptions because we cannot solve moral problems or make moral decisions (i.e., obtain peace of mind) without first holding (or, for many, actually believing) that our existence has purpose. Directing our daily activities toward accomplishing valued purposes gives us the comfort of feeling that our lives are meaningful.

But some beliefs prevent us from thinking logically about what surely must be important in life—the way we act when living. Behaviour blinded by benighted belief can have terrible consequences, as acts of terrorism regularly demonstrate.

 * Return to Religions' Origins, Introduction
 * Revelations And Conversions, Introduction

(A postscript to this chapter titled ../../Rationality In Science And Religion is to be found at the end of this part.)


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Formal Logic/Preliminaries/Sets

= Sets=

Presentations of logic vary in how much set theory they use. Some are heavily laden with set theory. Though most are not, it is nearly impossible to avoid it completely. It will not be a very important focal point for this book, but we will use a little set theory vocabulary here and there. This section introduces the vocabulary and notation used.

Sets and elements
Mathematicians use 'set' as an undefined primitive term. Some authors resort to quasi-synonyms such as 'collection'.

A set has elements. 'Element' is also undefined in set theory. We say that an element is a member of a set, also an undefined expression. The following are all used synonymously:

 * x is a member of y
 * x is contained in y
 * x is included in y
 * y contains x
 * y includes x

Notation
A set can be specified by enclosing its members within curly braces.

 * $$\{1, 2, 3\}\,\!$$

is the set containing 1, 2, and 3 as members. The curly brace notation can be extended to specify a set using a rule for membership.

 * $$\{x : x = 1 \text{ or } x = 2 \text{ or } x = 3\}\,\!$$ (The set of all x such that x = 1 or x = 2 or x = 3)

is again the set containing 1, 2, and 3 as members.

 * $$\{x : x \text{ is a positive integer}\}\,\!$$, and

 * $$\{1, 2, 3, \ldots\}\,\!$$

both specify the set containing 1, 2, 3, and onwards.

A modified epsilon is used to denote set membership. Thus

 * $$x \in y\,\!$$

indicates that "x is a member of y". We can also say that "x is not a member of y" in this way:

 * $$x \notin y\,\!$$

Characteristics of sets
A set is uniquely identified by its members. The expressions

 * $$\{x: x\ \mathrm{is\ an\ even\ prime}\}\,\!$$
 * $$\{x: x\ \mathrm{is\ a\ positive\ square\ root\ of}\ 4\}\,\!$$
 * $$\{2\}\,\!$$

all specify the same set even though the concept of an even prime is different from the concept of a positive square root. Repetition of members is inconsequential in specifying a set. The expressions

 * $$\{1,\ 2,\ 3\}\,\!$$
 * $$\{1,\ 1,\ 1,\ 1,\ 2,\ 3\}\,\!$$
 * $$\{x: \mathrm{x\ is\ an\ even\ prime\ or}\ x\ \mathrm{is\ a\ positive\ square\ root\ of}\ 4\ \mathrm{or}\ x = 1\ \mathrm{or}\ x = 2\ \mathrm{or}\ x = 3\}\,\!$$

all specify the same set.

Sets are unordered. The expressions

 * $$\{1,\ 2,\ 3\}\,\!$$
 * $$\{3,\ 2,\ 1\}\,\!$$
 * $$\{2,\ 1,\ 3\}\,\!$$

all specify the same set.

Sets can have other sets as members. There is, for example, the set

 * $$\{\{1,\ 2\}, \{2,\ 3\},\ \{1,\ \mathrm{George\ Washington}\}\}\,\!$$

Some special sets
As stated above, sets are defined by their members. Some sets, however, are given names to ease referencing them.

The set with no members is the empty set. The expressions

 * $$\{\}\,\!$$
 * $$\varnothing\,\!$$
 * $$\{x: x \ne x\}\,\!$$

all specify the empty set. Empty sets can also express oxymora ("four-sided triangles" or "birds with radial symmetry") and factual non-existence ("the King of Czechoslovakia in 1994").

A set with exactly one member is called a singleton. A set with exactly two members is called a pair. Thus {1} is a singleton and {1, 2} is a pair.

ω is the set of natural numbers, {0, 1, 2, ...}.

Subsets
A set s is a subset of set a if every member of s is a member of a. We use the horseshoe notation to indicate subsets. The expression

 * $$\{1,\ 2\} \subseteq \{1,\ 2,\ 3\}\,\!$$

says that {1, 2} is a subset of {1, 2, 3}. The empty set is a subset of every set. Every set is a subset of itself. A proper subset of a is a subset of a that is not identical to a. The expression

 * $$\{1,\ 2\} \subset \{1,\ 2,\ 3\}\,\!$$

says that {1, 2} is a proper subset of {1, 2, 3}.

Power sets
A power set of a set is the set of all its subsets. A script 'P' is used for the power set.

 * $$\mathcal{P}\{1,\ 2,\ 3\} = \{\varnothing,\ \{1\},\ \{2\},\ \{3\},\ \{1,\ 2\},\ \{1,\ 3\},\ \{2,\ 3\},\ \{1,\ 2,\ 3\}\}\,\!$$

Union
The union of two sets a and b, written a ∪ b, is the set that contains all the members of a and all the members of b (and nothing else). That is,

 * $$a \cup b = \{x: x \in a\ \mathrm{or}\ x \in b\}\,\!$$

As an example,

 * $$\{1,\ 2,\ 3\}\ \cup\ \{2,\ 3,\ 4\} = \{1,\ 2,\ 3,\ 4\}\,\!$$

Intersection
The intersection of two sets a and b, written a ∩ b, is the set that contains everything that is a member of both a and b (and nothing else). That is,

 * $$a \cap b = \{x: x \in a\ \mathrm{and}\ x \in b\}\,\!$$

As an example,

 * $$\{1,\ 2,\ 3\}\ \cap\ \{2,\ 3,\ 4\} = \{2,\ 3\}\,\!$$

Relative complement
The relative complement of a in b, written b \ a (or b − a) is the set containing all the members of b that are not members of a. That is,

 * $$b \setminus a = \{x: x \in b\ \mathrm{and}\ x \notin a\}\,\!$$

As an example,

 * $$\{2,\ 3,\ 4\} \setminus \{1,\ 3\} = \{2,\ 4\}\,\!$$

Ordered sets, relations, and functions
The intuitive notions of ordered set, relation, and function will be used from time to time. For our purposes, the intuitive mathematical notion is the most important. However, these intuitive notions can be defined in terms of sets.

Ordered sets
First, we look at ordered sets. We said that sets are unordered:

 * $$\{a,\ b\} = \{b,\ a\}\,\!$$

But we can define ordered sets, starting with ordered pairs. The angle bracket notation is used for this:

 * $$\langle a,\ b\rangle\ \ne\ \langle b,\ a\rangle\,\!$$

Indeed,

 * $$\langle x,\ y\rangle\ =\ \langle u,\ v\rangle\ \mbox{if and only if}\ x = u\ \mbox{and}\ y = v\,\!$$

Any set theoretic definition giving ⟨a, b⟩ this last property will work. The standard definition of the ordered pair ⟨a, b⟩ runs:

 * $$\langle a,\ b\rangle\ =\ \{\{a\},\ \{a,\ b\}\}\,\!$$

This means that we can use the latter notation when doing operations on an ordered pair.

There are also bigger ordered sets. The ordered triple ⟨a, b, c⟩ is the ordered pair ⟨⟨a, b⟩, c⟩. The ordered quadruple ⟨a, b, c, d⟩ is the ordered pair ⟨⟨a, b, c⟩, d⟩. This, in turn, is the ordered triple ⟨⟨⟨a, b⟩, c⟩, d⟩. In general, an ordered n-tuple ⟨a1, a2, ..., an⟩ where n greater than 1 is the ordered pair ⟨⟨a1, a2, ..., an-1⟩, an⟩.

It can be useful to define an ordered 1-tuple as well: ⟨a⟩ = a.

These definitions are somewhat arbitrary, but it is nonetheless convenient for an n-tuple, n ⟩ 2, to be an n-1 tuple and indeed an ordered pair. The important property that makes them serve as ordered sets is:

 * $$\langle x_1,\ x_2,\ ...,\ x_n\rangle\ =\ \langle y_1,\ y_2,\ ...,\ y_n\rangle\ \mathrm{if\ and\ only\ if}\ x_1 = y_1,\ x_2 = y_2,\ ...,\ x_n = y_n\,\!$$

Relations
We now turn to relations. Intuitively, the following are relations:

 * x < y
 * x is a square root of y
 * x is a brother of y
 * x is between y and z

The first three are binary or 2-place relations; the fourth is a ternary or 3-place relation. In general, we talk about n-ary relations or n-place relations.

First consider binary relations. A binary relation is a set of ordered pairs. The less than relation would have among its members ⟨1, 2⟩, ⟨1, 3⟩, ⟨16, 127⟩, etc. Indeed, the less than relation defined on the natural numbers ω is:

 * $$\{\langle x,\ y\rangle: x \in \omega,\ y \in \omega,\ \mathrm{and}\ x < y\}\,\!$$

Intuitively, ⟨x, y⟩ is a member of the less than relation if x < y. In set theory, we do not worry about whether a relation matches an intuitive concept such as less than. Rather, any set of ordered pairs is a binary relation.

We can also define a 3-place relation as a set of 3-tuples, a 4-place relation as a set of 4-tuples, etc. We only define n-place relations for n ≥ 2. An n-place relation is said to have an arity of n. The following example is a 3-place relation.

 * $$\{\langle 1,\ 2,\ 3\rangle,\ \langle 8,\ 2,\ 1\rangle,\ \langle 653,\ 0,\ 927\rangle\}\,\!$$

Because all n-tuples where n > 1 are also ordered pairs, all n-place relations are also binary relations.

Functions
Finally, we turn to functions. Intuitively, a function is an assignment of values to arguments such that each argument is assigned at most one value. Thus the + 2 function assigns a numerical argument x the value x + 2. Calling this function f, we say f(x) = x + 2. The following define specific functions.

 * $$f_1(x) = x \times x\,\!$$
 * $$f_2(x) =\ \mathrm{the\ smallest\ prime\ number\ larger\ than}\ x\,\!$$
 * $$f_3(x) = 6 / x\ \!$$
 * $$f_4(x) =\ \mathrm{the\ father\ of\ x}\,\!$$

Note that f3 is undefined when x = 0. According to biblical tradition, f4 is undefined when x = Adam or x = Eve. The following do not define functions.

 * $$f_5(x) = \pm \sqrt{x}\,\!$$
 * $$f_6(x) =\ \mathrm{a\ son\ of\ x}\,\!$$

Neither of these assigns unique values to arguments. For every positive x, there are two square roots, one positive and one negative, so f5 is not a function. For many x, x will have multiple sons, so f6 is not a function. If f6 is assigned the value the son of x then a unique value is implied by the rules of language, therefore f6 will be a function.

A function f is a binary relation where, if ⟨x, y⟩ and ⟨x, z⟩ are both members of f, then y = z.

We can define many place functions. Intuitively, the following are definitions of specific many place functions.

 * $$f_7(x,\ y) = x + y\,\!$$
 * $$f_8(x,\ y,\ z) = (x + y) \times z\,\!$$

Thus ⟨4, 7, 11⟩ is a member of the 2-place function f7. ⟨3, 4, 5, 35⟩ is a member of the 3 place function f8

The fact that all n-tuples, n ≥ 2, are ordered pairs (and hence that all n-ary relations are binary relations) becomes convenient here. For n ≥ 1, an n-place function is an n+1 place relation that is a 1-place function. Thus, for a 2-place function f,

 * $$\langle x,\ y,\ z_1\rangle\ \in f\ \mathrm{and}\ \langle x,\ y,\ z_2\rangle\ \in f\ \mathrm{if\ and\ only\ if}\ z_1 = z_2\,\!$$

title: Formal Logic/Preliminaries/Sets


text:
User talk:Sideris~enwikibooks

Automatically create and post a PDF of a WikiBook.
Are you really going to write some script to automagically convert to PDF and post the book to wikibooks? That sounds like a nice idea. There must be a page for discussing just that sort of thing. But I cannot find it. --SV Resolution 00:07, 19 August 2005 (UTC)

Your account will be renamed
Hello,

The developer team at Wikimedia is making some changes to how accounts work, as part of our on-going efforts to provide new and better tools for our users like cross-wiki notifications. These changes will mean you have the same account name everywhere. This will let us give you new features that will help you edit and discuss better, and allow more flexible user permissions for tools. One of the side-effects of this is that user accounts will now have to be unique across all 900 Wikimedia wikis. See the announcement for more information.

Unfortunately, your account clashes with another account also called Sideris. To make sure that both of you can use all Wikimedia projects in future, we have reserved the name Sideris~enwikibooks that only you will have. If you like it, you don't have to do anything. If you do not like it, you can pick out a different name.

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Renamed
 This account has been renamed as part of single-user login finalisation. If you own this account you can |log in using your previous username and password for more information. If you do not like this account's new name, you can choose your own using this form after logging in: . -- Keegan (WMF) (talk) 05:29, 19 April 2015 (UTC)

title: User talk:Sideris~enwikibooks


text:
Radiation Oncology/Breast/Prevention

Prevention trials

 * Breast Cancer Prevention Trial (NSABP P-1), 1998 (1992-7)
 * 13000+ pts. Tested the hypothesis that tamoxifen could be used for breast cancer prevention. Enrolled high risk women who were 1) age 60 or older, 2) age 35-59 with a 5-year predicted risk of cancer of at least 1.66% (by Gail model), or 3) history of LCIS. Randomized to placebo vs tamoxifen 20 mg x 5 yrs.
 * PMID 9747868 Full text, 1998 — "Tamoxifen for prevention of breast cancer: report of the National Surgical Adjuvant Breast and Bowel Project P-1 Study." Fisher B et al. J Natl Cancer Inst. 1998 Sep 16;90(18):1371-88.
 * Reduced risk of invasive breast cancer by 49% (43.4 vs 22 per 1000). 56% reduction for pts with LCIS and 86% for atypical hyperplasia. Reduced non-invasive breast cancer by 50%. No difference in ER-negative tumors. Risk of endometrial cancer RR=2.53.  No decrease in ischemic heart disease events.  Decrease in bone fractures.
 * PMID 16288118, 2005 — "Tamoxifen for the prevention of breast cancer: current status of the National Surgical Adjuvant Breast and Bowel Project P-1 study." Fisher B et al. J Natl Cancer Inst. 2005 Nov 16;97(22):1652-62.
 * 7-yr f/u. Reduce rate of invasive cancer by 43% (42.5 vs 24.8 per 1000). Reduced non-invasive cancer by 37%. Reduced osteoporotic fractures by 32%.

 * STAR: Study of Tamoxifen and Raloxifene (NSABP P-2) (1999-2004)
 * Randomized to tamoxifen 20 mg or raloxifene 60 mg x 5 yrs. Entry criteria similar to BCPT except pre-menopausal women not allowed.
 * Target goal: 22,000 women.
 * PMID 16754727, 2006 — "Effects of Tamoxifen vs Raloxifene on the Risk of Developing Invasive Breast Cancer and Other Disease Outcomes: The NSABP Study of Tamoxifen and Raloxifene (STAR) P-2 Trial." Vogel VG et al. JAMA. 2006 June 21;295:2727-2741.
 * Raloxifene as effective as Tamoxifen in reducing risk of invasive breast cancer. Lower risk of thromboembolic events and cataracts. Higher risk of non-invasive cancer (but N.S.). Other effects are similar.
 * Quality of life: PMID 16754728, 2006 — "Patient-Reported Symptoms and Quality of Life During Treatment With Tamoxifen or Raloxifene for Breast Cancer Prevention: The NSABP Study of Tamoxifen and Raloxifene (STAR) P-2 Trial." Land SR et al. JAMA. 2006 Jun 21;295:2742-2751.

 * IBIS-1 Internation Breast Cancer Intervention study, 2002
 * Similar to Breast Cancer Prevention Trial. Risk reduction of 32%. This is thought to be less than that in BCPT because there was less atypical hyperplasia in this trial.
 * PMID 12243915 — "First results from the International Breast Cancer Intervention Study (IBIS-I): a randomised prevention trial." Cuzick J et al. Lancet. 2002 Sep 14;360(9336):817-24.

 * Prophylactic Mastectomy (Hartmann, et al. NEJM 1999, 340, 77)·
 * Mayo Clinic data suggest a 90% reduction in risk of developing breast cancer
 * 639 moderate and high risk women underwent prophylactic mastectomy 1960 - 1993
 * this only applies to patients at moderate - high risk of developing breast by the Gail model
 * PMID 9887158

Raloxifene

 * PMID 16837684 - Risk-Benefit Profiles of Raloxifene for Women (Editorial) (Stefanick ML, NEJM 2006 Jul 13; 355(2):190-192)
 * RUTH: Raloxifene Use for the Heart (raloxifene 60mg in post-menopausal women at risk or with CHD)
 * CHD: no impact
 * BCA: -44% = 1.2 fewer cases per 1000 women/year
 * vertebaral fxs: -35% = 1.3 fewer cases per 1000 women/year
 * venous thromboembolism +44% = 1.2 excess cases per 1000 women/year
 * fatal stroke +49% = 0.7 excess cases per 1000 women/year
 * Conclusion : raloxifene BCA benefit probably not worth the risk in women at risk for CHD
 * Women's Health Initiative (postomenpausal women at average risk for BCA [trial placebo group], using raloxifene stats from RUTH)
 * BCA: 1.7 fewer cases per 1000 women/year
 * Conclusion : raloxifiene BCA benefit minimal in "average risk" postmenopausal women, given the risk
 * Breast Cancer Prevention Trial (tamoxifen in post-menopausal women at risk for BCA)
 * BCA: -49% = 3.3 fewer cases per 1000 women/year
 * STAR: Study of Tamoxifen and Raloxifene (women at high risk for BCA)
 * no placebo group; similar rates of invasive BCA => comparable efficacy of tamoxifen and raloxifene => ~3.3 fewer cases per 1000 women/year)
 * Editorial conclusion Raloxifene efficacy at preventing BCA vs. causing thromboembolism/stroke depends on level of BCA risk. It is probably not worth it for "average risk" post-menopausal women.

Guidelines

 * ASCO Clinical Practice Guideline
 * 2009 - PMID 19470930 link — "American Society of Clinical Oncology Clinical Practice Guideline Update on the Use of Pharmacologic Interventions Including Tamoxifen, Raloxifene, and Aromatase Inhibition for Breast Cancer Risk Reduction." (Visvanathan K, J Clin Oncol. 2009 Jul 1;27(19):3235-58.)

Prophylactic Breast Irradiation

 * Israel BRCA1/2 (2007-2017) -- control (no RT) vs contralateral breast RT
 * Randomized Phase II. 162 patients, BRCA1/2 positive, early stage BCA, who declined contralateral mastectomy. Arm 1) no contralateral RT (control) vs Arm 2) Contralateral RT
 * 2019 PMID 30475942 -- "Prophylactic irradiation to the contralateral breast for BRCA mutation carriers with early-stage breast cancer" (Evron E, Ann Oncol. 2019 Mar 1;30(3):412-417.doi: 10.1093/annonc/mdy515.). Median F/U 4.8 years
 * Outcome: Contralateral BCA control 12% vs RT 2% (p=0.01). Median 2.7 years vs 7.7 years
 * Conclusion: Among BRCA carriers treated for early BCA, contralateral breast RT reduces contralateral breast cancers, and delays their onset

 * Columbia; 2007 PMID 17971581 -- "Reducing second breast cancers: a potential role for prophylactic mammary irradiation." (Brenner DJ, J Clin Oncol. 2007 Nov 1;25(31):4868-72.)
 * Suggestion of a potential benefit of low dose (17-22 Gy) ipsilateral (in case of APBI) and/or contralateral prophylactic breast irradiation

title: Radiation Oncology/Breast/Prevention


text:
User:Daniel Mayer

w:en:user:maveric149 (sysop), meta:user:Daniel Mayer (sysop, steward), wikimedia:user:Daniel Mayer (Wikimedia CFO)

title: User:Daniel Mayer


text:
Radiation Oncology/Cachexia

Treatment
These medications treat the loss of appetite and weight loss but do not treat the cachexia itself.

Medications:
 * Corticosteroids:
 * Stimulate appetite, but effect lasts only for 4-8 weeks, and does not lead to weight gain.
 * Dronabinol (Marinol)
 * Stimulates appetite but does not clearly lead to weight gain
 * Megestrol (Megace)
 * Most potent
 * Anabolic steroids: nandrolone, fluoxymesterone, oxandrolone (increases lean tissue mass)

Nutritional supplements:
 * Boost, Ensure, etc.
 * Boost (Website) - 240 Cal per 8 oz can. Boost Breeze - 160 Cal (8 oz).
 * Boost Plus - 360 Cal (8 oz)
 * Boost High Protein - 240 Cal (8 oz), 15 g protein
 * Ensure (Website) - 250 Cal (8 oz).
 * Ensure Plus - 350 Cal (8 oz)
 * Ensure High Protein - 230 Cal (8 oz)
 * ProSure - Website
 * eicosapentaenoic acid (an omega-3 fatty acid) + protein + calories.
 * Provides 300 Cals (17 g protein) per can.
 * Use 2 cans per day.
 * Does not require prescription.
 * Juven - Website
 * HMB (beta-hydroxy-beta-methylbutyrate), arginine and glutamine.
 * Use: 2 servings per day (one packet per serving). Provides 150 Cal/day (75 Cal/pkg).
 * Does not require prescription

Exercise:
 * Weight training

Studies
Randomized:

Corticosteroids vs Megesterol
 * Mayo, 1999 (1992-96) - PMID 10506633 — "Randomized comparison of megestrol acetate versus dexamethasone versus fluoxymesterone for the treatment of cancer anorexia/cachexia." Loprinzi CL et al. J Clin Oncol. 1999 Oct;17(10):3299-306.
 * 475 pts. Similar efficacy for decadron (0.75 mg qid) and megace (800 mg qd = 5x160), but differing toxicities.

title: Radiation Oncology/Cachexia


text:
Radiation Oncology/NHL

Official Guidelines Overview Randomized Evidence

B-cell T-cell Either Cutaneous
 * Diffuse large B-cell lymphoma
 * Follicular lymphoma
 * Chronic lymphocytic leukemia / Small lymphocytic lymphoma (CLL/SLL)
 * Nodal marginal zone lymphoma
 * MALT lymphoma (extranodal marginal zone)
 * Mantle cell lymphoma
 * Burkitt lymphoma
 * NK/T cell lymphoma
 * Anaplastic large cell lymphoma (ALCL)
 * Lymphoblastic lymphoma
 * Mycosis fungoides (T-cell)
 * Cutaneous anaplastic large cell lymphoma (T-cell)
 * Cutaneous B-cell lymphoma

Treatment:
 * Aggressive
 * Specific sites
 * Radioimmunotherapy
 * Proton Therapy
 * CNS Metastases

title: Radiation Oncology/NHL


text: Template:Radiation Oncology/NHL:TOC

title: Template:Radiation Oncology/NHL:TOC


text:
Radiation Oncology/NHL/Follicular

Overview

 * Accounts for ~22% of NHLs (2nd most common after DLBCL)
 * Incidence increasing at ~4% per year
 * Mean age at diagnosis 60
 * Less common in Asians and Blacks; more common with "Western" lifestyle
 * Presenting symptoms: painless peripheral adenopathy, which can wax and wane in size
 * Malignancy grades defined by proportion of centroblasts (large cells)
 * Grade 1-3a: various proportion of centroblasts - indolent
 * Grade 3b: all centroblasts - aggressive (behaves like DLBCL, and should be treated as such)
 * Extent of disease at diagnosis
 * Stage I: 10-15%
 * Stage II: 85-90%
 * Frequently have extranodal involvement: bone marrow, spleen, liver in about 1/3 to 1/2.
 * B symptoms: ~20%
 * Clinical course is variable
 * Some with indolent clinical course and late relapses over many years
 * Others with rapid disease progression, often with transformation to aggressive lymphoma and early death
 * Median survival 10 years. Considered incurable.
 * Histologic transformation to aggressive (DLBCL) in ~25%

Pathology

 * Arise from germinal center B-cells
 * Mixture of centrocytes (small cleaved cells) and centroblasts (large cells)
 * Grade 1: 0-5 large cells per hpf (used to be classified as follicular small-cleaved cell)
 * Grade 2: 6-15 large cells per hpf (used to be classified as follicular mixed small-cleaved and large cell)
 * Grade 3a: >15 large cells per hpf, but centrocytes present
 * Grade 3b: >15 large cells per hpf, no centrocytes (used to be classified as follicular large cell)
 * Two variants, relationship to typical follicular lymphoma controversial
 * Cutaneous follicle center lymphoma
 * Diffuse follicle center lymphoma.

Rappaport classification: nodular poorly differentiated lymphocytic, nodular mixed Working Formulation: follicular small cleaved, follicular mixed

 * One model of disease development (based on PMID 17301308 and PMID 17043145 below)
 * t(14;18) translocation occurs in healthy persons after activation (after undergoing Ig class-switch recombination during germinal-center response to antigenic stimulation)
 * t(14;18) translocation results in bcl-2, a re-arranged gene whose product blocks apoptosis
 * These cells are not naive (as previously thought) but capable of responding to an exogenous stimulus (such as virus or auto-antigen)
 * A clone of t(14;18) can be detected in >50% of healthy persons, and persists >3 years. These may be memory B cells, circulating after initial stimulation
 * In rare cases, can see pronounced peripheral blood B lymphocytosis (often secondary to infection), with clonal expansion of t(14;18)
 * Further events may lead to transformation. These may be oncogenic events ("hits") or may be related to stimulation via IgM receptors by T-cells. Predictive gene-array data at time of diagnosis suggest that random acquisition of oncogenic events does not play a large role in determining survival. Rather, it seems to be driven by B-cell interactions with non-malignant environment
 * Can see in-situ follicular lymphoma, with histologically abnormal follicles, on LN biopsy. This may progress to overt follicular lymphoma, but may remain benign
 * Further, there appear 2 separate disease processes (PMID 15548776): indolent (~75% of cases, with median survival of >10 years) and aggressive (~25% of cases, with median survival ~4 years). This gene-array modelling agrees with Stanford watchful waiting outcome (PMID 15024027)
 * This two-disease model, may be driven by mutually exclusive pathways:
 * 1) -6q/+1q
 * 2) duplication(18), +7/+8
 * Depending on the environmental interplay, lymphoma may regress spontaneously
 * t(14;18) in normal persons can therefore be seen as an early marker of lymphoma risk

 * St. Bartholomew, 2007 (UK) PMID 17278262 -- "Transformation of follicular lymphoma to diffuse large B-cell lymphoma proceeds by distinct oncogenic mechanisms." (Davies AJ, Br J Haematol. 2007 Jan;136(2):286-93.)
 * Gene expression profiles of 20 patients who transformed (pre- and post- biopsies)
 * Conclusion: Two separate mechanisms; one via high proliferation characterised by presence of known oncogenic abnormalities, and second with similar behavior to the existing FL

 * Netherlands, 2007 PMID 17200149 -- "Gene-expression and immunohistochemical study of specific T-cell subsets and accessory cell types in the transformation and prognosis of follicular lymphoma." (Glas AM, J Clin Oncol. 2007 Feb 1;25(4):390-8.)
 * Gene level: highly uniform by gene arrays. Cell level: high discrimination by IHC for transformation phenotype
 * By ICH, 2 cell populations: "cold" and "activated". Activated much more likely to transform to aggressive (DLBCL) lymphoma
 * Conclusion: FL is an immunologically functional disease, highly uniform at time of diagnosis, but where interaction between the tumor cells and the environment determines clinical aggressiveness

 * Marseille, 2006 (France) PMID 17043145 -- "Follicular lymphoma-like B cells in healthy individuals: a novel intermediate step in early lymphomagenesis." (Roulland S, J Exp Med. 2006 Oct 30;203(11):2425-31.)
 * A new model for development of follicular lymphoma proposed

 * NCI, 2004 PMID 15548776 -- "Prediction of survival in follicular lymphoma based on molecular features of tumor-infiltrating immune cells." (Dave SS, N Engl J Med. 2004 Nov 18;351(21):2159-69.)
 * Gene expression profiles. 191 biopsy specimens, 95 used for supervised expression patterns, 96 validating set
 * Two signatures constructed for survival prediction: quartilies median survival 13.6, 11.1, 10.8, and 3.9 years
 * Discriminant gene expression: non-malignant tumor-infiltrating cells
 * Conclusion: 75% of cases indolent disease with >10 year survival, 25% cases aggressive disease with 4 year survival

Natural history

 * Stanford, 2005 - PMID 15024027 — "Stage I and II Follicular Non-Hodgkin’s Lymphoma: Long-Term Follow-Up of No Initial Therapy." Advani R et al. J Clin Oncol. 2004 Apr 15;22(8):1454-9.
 * Retrospective. Follicular small cleaved and follicular mixed. 43 pts with therapy deferred at least 3 months after diagnosis and minimum follow-up of 1 year.
 * Median follow-up 86 months. 63% had not been treated. Median time to treatment was 22 months. 4 of 16 transformed to higher grade. Survival at 5, 10, and 20 years was 97%, 85%, and 22%.
 * Conclusion: Delayed therapy is appropriate in selected pts.

Prognostic Factors

 * FLIPI 2: Follicular Lymphoma International Prognostic Index Update (2012) PMID: 19652063 — "Follicular lymphoma international prognostic index 2: a new prognostic index for follicular lymphoma developed by the international follicular lymphoma prognostic factor project." Federico et al. J Clin Oncol. 2009 Sept 20;27(27).

FLIPI2: The following factors were found to be predictive of outcome in patients with follicular lymphoma:

Age                                                                  > 60

Largest diameter of largest involved node       > 6 cm

bone marrow involvement

β2-microglobulin                                              > upper limit normal

serum hemoglobin level                                   < 12 g/dl

Low risk   = 0 risk factors,            5 year PFS 79.5%

int risk      = 1-2,                                              51.2%

High risk  = 3-5,                                              18.8%

 * FLIPI: Follicular Lymphoma International Prognostic Index - basically an adaptation of the IPI (which is used for aggressive lymphomas) for low grade lymphomas.
 * Abstract — "Follicular lymphoma international prognostic index." Solal-Celigny P et al. Blood. 2004 Sep 1;104(5):1258-65.

 * MD Anderson, 1984 Follicular large cell lymphoma - PMID 6376721 Full text, 1984 (1973-81) — "Follicular large cell lymphoma: analysis and prognostic factors in 62 patients." Kantarjian HM et al. J Clin Oncol. 1984 Jul;2(7):811-9.

 * GELA, 1999 (France) (1986-95) - PMID 10561315 — "Low-grade stage III-IV follicular lymphoma: multivariate analysis of prognostic factors in 484 patients--a study of the groupe d'Etude des lymphomes de l'Adulte." Decaudin D et al. J Clin Oncol. 1999 Aug;17(8):2499-505.
 * 284 pts treated on two Phase III trials. Stage III-IV.
 * 3 factors significant on multivariate analysis: B symptoms, age > 60, at least 3 nodal sites > 3 cm. IPI score was prognostic, but very few pts had high IPI scores.

Ongoing trials:
 * SWOG S0016 - phase III. CHOP vs CHOP + Rituxan (R-CHOP) vs CHOP + I131-tositumomab (Bexxar) for newly diagnosed follicular NHL. CHOP alone arm closed to accrual early (Dec 2002).

Management Overview

 * For Stage I-II, radiotherapy is standard. However, long-term data from Stanford suggest that in select patients, active surveillance may be a reasonable approach
 * For advanced disease, treatment is deferred until the patient becomes symptomatic. Randomized trials of chemotherapy showed no survival advantage to early treatment thus far

Watchful Waiting

 * Stanford, 2005 - PMID 15024027 — "Stage I and II Follicular Non-Hodgkin’s Lymphoma: Long-Term Follow-Up of No Initial Therapy." (Advani R et al. J Clin Oncol. 2004 Apr 15;22(8):1454-9.)
 * Retrospective. Indolent follicular (follicular small cleaved and follicular mixed). 43 patients with therapy deferred at least 3 months after diagnosis and minimum follow-up of 1 year. Median follow-up 7.2 years.
 * Outcome: 63% not treated. 10-year OS: 85%, 15-year OS: 58%. Estimated median OS 19 years
 * Progression: 16 patients (8 progression, 4 transformation to aggressive). If progression, median time to treatment 22 months. Median time to transformation 7.8 years
 * Conclusion: Delayed therapy is appropriate in selected patients

RT alone

 * Stanford, 1996 (1961-94) - PMID 8648385 — "Is radiotherapy curative for stage I and II low-grade follicular lymphoma? Results of a long-term follow-up study of patients treated at Stanford University." Mac Manus MP et al. J Clin Oncol. 1996 Apr;14(4):1282-90.
 * Retrospective. Stage I-II. RT was involved field, extended field, TLI, or STLI.
 * Median f/u 7.7 yrs. 10-yr OS 64%. MS 13.8 yrs. 10-yr RFS 44%. Pts are unlikely to relapse after 10 years.

RT dose

 * UK FORT (2006 - 2011) -- 24 Gy vs 4 Gy
 * Randomized, multinstitutional 43 centers in UK. 614 patient, age >18, follicular or marginal zone lymphoma, both radical and palliative intent. Arm 1) 24/12 vs Arm 2) 4/2 (4 Gy in 2 fractions)
 * Long-term update 2021 PMID 33539729 — "4 Gy versus 24 Gy radiotherapy for follicular and marginal zone lymphoma (FoRT): long-term follow-up of a multicentre, randomised, phase 3, non-inferiority trial." Hoskin P, et al. Lancet Oncol. 2021 Mar;22(3):332-340.
 * pending...
 * 2014 PMID 24572077 — "4 Gy versus 24 Gy radiotherapy for patients with indolent lymphoma (FORT): a randomised phase 3 non-inferiority trial." (Hoskin PJ, Lancet Oncol. 2014 Apr;15(4):457-63. doi: 10.1016/S1470-2045(14)70036-1. Epub 2014 Feb 24.). Median F/U 2.2 years
 * Outcome: Local progression 24 Gy 7% vs 4 Gy 22%. Time to local progression in 4 Gy worse than 24 Gy (HR 3.4, SS).
 * Acute grade 3-4 toxicity: 24 Gy 3% vs 4 Gy 1%
 * Conclusion: 24 Gy in 12 fraction is more effective for indolent lymphoma. However, 4 Gy remains a useful alternative for palliative treatment

 * UK Multicenter -- 45-45 Gy vs 24 Gy
 * Randomized dose-finding for NHL (primarily follicular and marginal zone). RT involved region. Randomized to 40-45 Gy versus 24 Gy in 12 fractions (indolent) or 30 Gy in 15 fractions (aggressive).
 * 2011 PMID 21664710 — "Reduced dose radiotherapy for local control in non-Hodgkin lymphoma: a randomised phase III trial." (Lowry et al. Radiother Oncol. 2011 Jul;100(1):86-92.)
 * Median f/u 5.6 yrs. Progression-free and overall survival equivalent between low- and high-dose arms. No difference of in-field progression (HR 1.09 in indolent, and HR 0.98 in aggressive)
 * Toxicity: No difference but trend toward reduced toxicities in low dose arms
 * Conclusion: 24 Gy in 12 fractions effective for indolent NHL, and 30 Gy in 15 fractions for aggressive NHL

 * Florida, 1999 PMID 10348285 -- "The impact of radiotherapy dose and other treatment-related and clinical factors on in-field control in stage I and II non-Hodgkin's lymphoma." (Kamath SS, Int J Radiat Oncol Biol Phys. 1999 Jun 1;44(3):563-8.)
 * See also page at: Radiation_Oncology/NHL/Treatment_high_grade
 * 285 pts w/ Stage I-II NHL (72 low grade, 92 intermediate to high grade, 21 unclassified). 159 treated w/ RT alone, 126 combined modality. 95 treatment failures with 12 in-field failures. Most failures occurred in contiguous non-irradiated areas.
 * Conclusion: "Our analysis suggests that the overwhelming problem in the treatment of non-Hodgkin's lymphoma is not in-field failure but, rather, failure in contiguous unirradiated sites. A dose of 20-25 Gy may be sufficient for small-volume LGL of the orbit. A dose of 30 Gy is sufficient for LGL in general"

Chemo-RT

 * MD Anderson, 2003 (1984-1992) PMID 12775737 -- "Long-term follow-up of a prospective study of combined modality therapy for stage I-II indolent non-Hodgkin's lymphoma." (Seymour JF, J Clin Oncol. 2003 Jun 1;21(11):2115-22.)
 * Prospective. 102 patients, Stage I-II low grade (follicular 83%, bulky >5cm 24%, Stage II 52%). Treated with risk-adapted COP-Bleo/CHOP-Bleo and RT 30-40 Gy IF. Median F/U 10 years
 * 10-year outcome: OS 82% (follicular 80%); DFS 76% (follicular 72%). After relapse, 10-year survival 46%
 * Toxicity: acute 10% hospitalization, long term 12 malignancies (4 in RT fields)
 * Conclusion: CMT better DFS and OS than previously reported RT alone

Rituxan-based

 * PMID 15483015 — "Prolonged clinical and molecular remission in patients with low-grade or follicular non-Hodgkin's lymphoma treated with rituximab plus CHOP chemotherapy: 9-year follow-up." Czuczman MS et al. J Clin Oncol. 2004 Dec 1;22(23):4711-6.
 * CHOP + Rituxan

Radiation

 * Heidelberg; 2010 PMID 20331739 -- "Clinical outcome of patients with follicular lymphoma and bulky disease after Rituximab-CHOP immunochemotherapy with and without consolidating radiotherapy." (Fabienne M, Eur J Haematol. 2010 Mar 16. [Epub ahead of print])
 * Retrospective. Subset analysis of RCT evaluating number of Rituximab cycles with CHOP x6. 42 patients with bulky disease, protocol specified IRFT but some did not receive it (62% IFRT, 38% no RT). Median F/U 5 years
 * Outcome: Relapse RT+ 46% (50% within original bulk) vs RT- 56% (NS). 6-year PFS 52% vs 48% (NS), 6-year OS 80% vs 73% (NS)
 * Conclusion: In patients treated with CHOP-R, no difference in control regardless if IFRT was used

Rituxan

 * Multi-national -- CVP vs R-CVP
 * Randomized. 321 patients, CD20+ Stage III-IV folicullar lymphoma requiring therapy. Arm 1) cyclophosphamide, vincristine, prednisone (CVP) vs. Arm 2) CVP, rituximab (R-CVP)
 * 2008 PMID 18662969 -- "Phase III study of R-CVP compared with cyclophosphamide, vincristine, and prednisone alone in patients with previously untreated advanced follicular lymphoma." (Marcus R, J Clin Oncol. 2008 Oct 1;26(28):4579-86. Epub 2008 Jul 28.) Median F/U 4.4 years
 * Outcome: 4-year OS CVP 77% vs. R-CVP 83% (SS); median TTF (SS) CVP 7 months vs. R-CVP 27 months (SS). Improvement regardless of FLIPI, IPI, B-symptoms, or bulky disease
 * Conclusion: Adding Rituximab to CVP improves all outcome measures, including OS

 * Multi-national -- Zevalin consolidation
 * Randomized trial of 414 pts with stage III/IV follicular lymphoma with a CR or PR after first line induction therapy. Allowed a variety of first line therapies, CVP, CHOP, CHOP-like, fludarabine, rituximab.
 * 2008 PMID 18854568 -- "Phase III trial of consolidation therapy with yttrium-90-ibritumomab tiuxetan compared with no additional therapy after first remission in advanced follicular lymphoma." (Morschhauser F, J Clin Oncol. 2008 Nov 10;26(32):5156-64.) Median f/u 3.5 yrs.
 * Patients randomized to zevalin vs no further treatment.
 * A significant increase in PFS was seen with zevalin (36.5 vs 13 months). Benefit for treatment was zevalin was seen regardless of initial CR or PR.

Ongoing trials:
 * SWOG S0016
 * Bulky stage II, Stage III-IV, previously untreated.
 * Randomized to: 1) CHOP, 2) CHOP + Rituxan, 3) CHOP + I-131 Tositumomab (Bexxar).

Palliation

 * Standard treatment: Limited fields to 20 Gy in 10 fractions
 * Low dose treatment: Limited fields to 4 Gy in 2 fractions (2x2)
 * Initially evaluated because:
 * There is no clear dose-response relationship in localized low-grade NHL
 * Low-dose (1.5-2.0 Gy) fractionated TBI resulted in long-term survival in advanced disease patients
 * Good long-term control in patients who stopped treatment for convenience after 5-7 Gy
 * However, a randomized trial (FoRT) shows that the low dose RT regimen is inferior to 24 Gy in 12 fractions
 * Response rate is ~80-90%, with CR rate ~50-60%, and good local long-term control
 * Response is rapid, typically within a week. Median time-to-progression is >1 year in recurrent/chemo refractory patients
 * Gene-expression profiling showes strong p53-mediated induction of apoptotic pathways
 * For spinal cord compression, consider one of the standard (8/1 or 20/5 or 30/10) regimens

Low dose RT
Randomized:
 * FoRT - 24/12 vs 4/2
 * Randomized, non-inferiority trial. 548 pts (614 treatment sites) with FL or MZL requiring either palliative or radical RT. Closed early (short of 650 treatment sites). FL in 86%, MZL in 14%. Curative in 40%, palliative in 60%. Stage I-II in 63%, Stage III-IV in 37%. Prior chemo in 33%, prior RT in 24%.
 * 2012 ASTRO #LBA 3 PDF -- "FoRT: A Phase 3 Multi-Center Prospective Randomized Trial of Low Dose Radiation Therapy for Follicular and Marginal Zone Lymphoma" (Hoskin P, Int J Radiat Oncol Biol Phys Vol. 85, Issue 1, Page 22)
 * Median f/u 22.8 mo. Response rate: 24 Gy - 81% overall, 60.3% CR; 4 Gy - 74.1%, 44.3% CR (SS). Local progression free survival rate at 2 yrs: 93.7% (24 Gy) vs 80.4% (4 Gy). No OS difference.
 * Toxicity: limited in both arms -- Acute G3+ in 8 pts vs 5 pts; Late G3+ in 9 pts vs 6 pts. No overall difference in QOL.
 * Conclusion: "While 4 Gy in 2 fractions can be effective in the palliative setting, it is significantly inferior to 24 Gy in 12 fractions which should remain the schedule of choice for curative radiation therapy in follicular or marginal zone lymphoma."

Non-randomized:

 * Review: France, 2010 PMID 20970029 -- "Localized low-dose radiotherapy for follicular lymphoma: history, clinical results, mechanisms of action, and future outlooks." (Ganem G, Int J Radiat Oncol Biol Phys. 2010 Nov 15;78(4):975-82.)

 * Amsterdam
 * 2007 PMID 17483295 -- "In vivo p53 response and immune reaction underlie highly effective low-dose radiotherapy in follicular lymphoma." (Knoops L, Blood. 2007 Aug 15;110(4):1116-22.)
 * Microarray gene-expression profiling of biopsies pre- and post- low-dose RT
 * Outcome: Major induction of p53 target genes involved in cell-cycle arrest and apoptosis, as well as macrophage activation and TH1 immune response
 * Conclusion: Radiation-induced p53 apoptotic response, not immunologically silent
 * 2005 PMID 16039113 -- "Effective palliation by low dose local radiotherapy for recurrent and/or chemotherapy refractory non-follicular lymphoma patients." (Haas RL, Eur J Cancer. 2005 Aug;41(12):1724-30.)
 * Retrospective. 71 non-follicular lymphoma patients (SLL/CLL 23, marginal zone 18, mantle cell 17, DLBCL 13), 177 symptomatic sites. Bulky disease 73%. Low dose IFRT 4 Gy in 2 fractions.
 * Outcome: Response rate 87% (48% CR). Median time-to-local progression 1.8 years. At time of death, 70% without in-field progression
 * Prognostic factors: none identified
 * Conclusion: Low dose RT valuable in relapsed/chemo refractory disease, both indolent and aggresive lymphoma
 * 2003 PMID 12829665 -- "High response rates and lasting remissions after low-dose involved field radiotherapy in indolent lymphomas." (Haas RL, J Clin Oncol. 2003 Jul 1;21(13):2474-80.)
 * Phase II. 109 patients and 304 symptomatic sites (98 follicular, 9 MALT, 2 lymphoplasmocytoid). Bulky disease (>5cm) 52%. Median 2 prior chemo regimens. Treated with 4 Gy in 2 fractions involved field
 * Outcome: Response rate 92% (CR 61%). Median time-to-progression 1.2 years, to local progression 2 years. If CR time to local progression 3.5 years
 * Conclusion: Low dose IFRT valuable in recurrent low-dose lymphoma

 * Denmark; 2002 (1997-99) - PMID 12459371 — "Phase II study of palliative low-dose local radiotherapy in disseminated indolent non-Hodgkin's lymphoma and chronic lymphocytic leukemia." Johannsson J et al. Int J Radiat Oncol Biol Phys. 2002 Dec 1;54(5):1466-70.
 * Phase II. Low dose RT. 22 pts with "indolent" lymphoma or CLL (13 with follicular, 7 with CLL, 1 SLL, 1 other). Treat 2 Gy x 2 = 4 Gy.
 * Outcome: Response rate 87% (CR in 65%, PR in 22%). For pts with CLL, response rate 71%. Median duration of response 22 months.
 * Conclusion: Low dose RT is effective for palliation.

 * Gustave Roussy; 2001 (1987-1998) PMID 11516864 -- "A high and sustained response rate in refractory or relapsing low-grade lymphoma masses after low-dose radiation: analysis of predictive parameters of response to treatment." (Girinsky T, Int J Radiat Oncol Biol Phys. 2001 Sep 1;51(1):148-55.)
 * Retrospective. 48 patients with low-grade lymphoma, most advanced disease previously treated with chemo. 135 tumor sites (80% nodal, 20% extranodal) treated with 4 Gy in 2 fractions.
 * Outcome: Response rate 81% (CR 57%). 2-year FFLP 56%
 * Predictors: tumor <=5cm (51% vs. 27%), less pretreatment chemo (96% vs. 48%), age <=65
 * Conclusion: Low-dose RT efficient, particularly prior to chemotherapy

 * Le Mans; 1994 (France) PMID 8194839 -- "Potential role for low dose limited-field radiation therapy (2 x 2 grays) in advanced low-grade non-Hodgkin's lymphomas." (Ganem G, Hematol Oncol. 1994 Jan-Feb;12(1):1-8.)
 * Prospective. 27/37 patients, 22 with Stage III/IV disease. 19 patients one course of LD RT only, 8 patients subsequent boost LD RT. Limited field RT 4 Gy in 2 fractions
 * Outcome: Response 89% (CR 37%); if 2+ LD RT courses, CR was 75%
 * Toxicity: minimal
 * Conclusion: Low dose limited field RT shows high proportion of responses

Reviews

 * JCO 2005 - PMID 16155025 — "Treatment Strategies in Follicular Lymphomas: Current Status and Future Perspectives." Hiddemann W et al. Journal of Clinical Oncology, Vol 23, No 26 (September 10), 2005: pp. 6394-6399.

 * CTO 2014 - "Radiotherapy of Follicular Lymphoma: Updated Role and New Rules" Yahalom J. Current Treatment Options in Oncology (2014) 15:262 DOI 10.1007/s11864-014-0286-4

title: Radiation Oncology/NHL/Follicular


text:
Radiation Oncology/NHL/Overview

Classification

 * Historically several systems, both in USA and Europe
 * WHO classification is used today

WHO classification

 * B-cell neoplasms
 * Precursor B-cell neoplasms
 * Precursor B-lymphoblastic leukemia/lymphoma (precursor B-cell acute lymphoblastic leukemia)
 * Mature (peripheral) B-cell neoplasms
 * B-cell chronic lymphocytic leukemia / small lymphocytic lymphoma
 * B-cell prolymphocytic leukemia
 * Lymphoplasmacytic lymphoma
 * Splenic marginal zone B-cell lymphoma
 * Hairy cell leukemia
 * Plasma cell myeloma/plasmacytoma
 * Extranodal marginal zone B-cell lymphoma of MALT type
 * Nodal marginal zone B-cell lymphoma
 * Follicular lymphoma
 * Mantle cell lymphoma
 * Diffuse large B-cell lymphoma
 * Burkitt lymphoma / Burkitt cell leukemia
 * T-cell and NK-cell neoplasms
 * Precursor T-cell neoplasm
 * Precursor T-lymphoblastic lymphoma/leukemia (precursor T-cell acute lymphoblastic leukemia)
 * Mature (peripheral) T/NK-cell neoplasms
 * T-cell prolymphocytic leukemia
 * T-cell granular lymphocytic leukemia
 * Aggressive NK-cell leukemia
 * Adult T-cell lymphoma/leukemia (HTLV1+)
 * Extranodal NK/T-cell lymphoma, nasal type
 * Enteropathy-type T-cell lymphoma
 * Hepatosplenic gamma-delta T-cell lymphoma
 * Subcutaneous panniculitis-like T-cell lymphoma
 * Mycosis fungoides / Sezary syndrome
 * Anaplastic large cell lymphoma, T/null cell, primary cutaneous type
 * Anaplastic large cell lymphoma, T/null cell, primary systemic type
 * Peripheral T-cell lymphoma, not otherwise characterized
 * Angioimmunoblastic T-cell lymphoma

Translocations

 * Lymphoma cells generally do not exhibit significant microsatellite instability (unlike many solid tumors)
 * Chromosomal translocations are a hallmark of lymphomatous disorders
 * t(8;14) - Burkitt's lymphoma (c-myc)
 * t(11;14) - mantle cell lymphoma (bcl-1)
 * t(11;18) - MALT lymphoma
 * t(14;18) - follicular lymphoma (bcl-2)

mnemonic: The common ones (on exams anyway) have 14 in common. The 11 sits on top of 14 (they're in sequence) like something sitting on a mantle. The 8 in Burkitt's resembles the bilaterally swollen neck lymph nodes like you typically see in a picture of a child with Burkitt's. The 8 (18) of follicular resembles two little follicles stuck together to form the 8. The oddball one is MALT which doesn't have the 14.

Epidemiology

 * USA - 59,000 cases/yr (in 2006)

 * ILSG, 1997 PMID 9166827 -- "A clinical evaluation of the International Lymphoma Study Group classification of non-Hodgkin's lymphoma. The Non-Hodgkin's Lymphoma Classification Project." ([No authors listed], Blood. 1997 Jun 1;89(11):3909-18.)
 * Multinational. 1403 cases at 9 sites around the world classified by 5 pathologists

 * Pediatric (based on Cancer, DeVita, 7th edition, 2005)

Staging

 * Uses the Ann Arbor classification, which was developed for Hodgkin's lymphoma.
 * Since disease spread in non-Hodgkin's lymphoma differs from that in Hodgkin's lymphoma, in which spread occurs to adjacent nodal groups in a stepwise fashion, the Ann Arbor classification which relies on nodal staging is not as predictive for NHL.

International Prognostic Index
Risk factors:
 * LDH greater than normal
 * Age > 60
 * Performance status ECOG 2 or worse
 * Extranodal sites of disease (more than 1)
 * Stage III or IV
 * Mnemonic: LAKES (LDH,age,Karnofsky,Extranodal,Stage)

Risk groups:
 * Low - 0 or 1 risk factors
 * Low intermediate - 2
 * High intermediate - 3
 * High - 4 or 5

Prognosis:
 * Low risk: 87% CR and 73% OS at 5 years
 * High risk: 44% CR and 26% OS

Based on pts with aggressive lymphomas treated with doxorubicin-based combination chemotherapy. It is also useful in indolent lymphomas and T-cell lymphomas. These factors independently predict complete response to therapy, relapse-free survival, and overall survival.

 * From PMID 8141877 Full text — "A predictive model for aggressive non-Hodgkin's lymphoma. The International Non-Hodgkin's Lymphoma Prognostic Factors Project." N Engl J Med. 1993 Sep 30;329(14):987-94.

Modifications
Age-Adjusted International Prognostic Index: Developed for pts younger than 60. Uses tumor stage, performance status, and LDH (but not extranodal sites or age). Assigned score of 0 to 3 based on number of risk factors and assigned same labels (low, low int, high int, or high).

Reference: PMID 8141877 Full text - "A predictive model for aggressive non-Hodgkin's lymphoma. The International Non-Hodgkin's Lymphoma Prognostic Factors Project." N Engl J Med. 1993 Sep 30;329(14):987-94.
 * 1982-1987. 3273 pts. Allowed diffuse mixed, diffuse large-cell, or large-cell immunoblastic histologies from the Working Formulation (overlaps with intermediate and high grade but doesn't include all subtypes). Also allowed Kiel and Rappaport. Pts were treated on Phase II-III study. All received combination chemo consisting of doxorubicin. Evaluated potential prognostic factors: sex, age, tumor stage, performance status, B symptoms, sites of involvement, number of extranodal sites, size of tumor, LDH, albumin, and beta-2-microglobulin. Complete information obtained in 1872 pts.

Miller's Stage-Modified IPI:
 * (LDH, Age > 60, Performance Status, Stage II). Doesn't include extranodal.
 * Used for Stage I-II pts.
 * Low 0-1, Intermediate 2, High 3-4
 * 5-yr PFS: Low 77%, Int 60%, High 34%
 * 5-yr OS: Low 82%, Int 71%, High 48%
 * PMID 9647875 (1998)

NCCN IPI:
 * Rituximab era
 * PMID 24264230 (2014) -- "An enhanced International Prognostic Index (NCCN-IPI) for patients with diffuse large B-cell lymphoma treated in the rituximab era." (Zhou Z,Blood. 2014 Feb 6;123(6):837-42.)

Survival
Estimates from AJCC staging manual, 6th edition:
 * Follicular lymphoma: 2-year OS 85%, 5-year 70%. FFS (failure free survival) 2-year 65%, 5-year 45%.
 * Diffuse large B-cell lymphoma: 2-year OS 60%, 5-year 50%. FFS 2-year 50%, 5-year 45%.
 * Mantle cell lymphoma: 2-year OS 60%, 5-year 25%. FFS 2-year 30%, 5-year 10%.
 * Small lymphocytic lymphoma: 2-year OS 70%, 5-year 50%. FFS 2-year 50%, 5-year 30%.

Response Assessment

 * Lugano Classification
 * 2014 PMID 25113753 -- "Recommendations for initial evaluation, staging, and response assessment of Hodgkin and non-Hodgkin lymphoma: the Lugano classification." (Cheson DB, J Clin Oncol. 2014 Sep 20;32(27):3059-68.)

 * International Harmonization Project on Lymphoma
 * 2007 PMID 17242396 -- "Revised response criteria for malignant lymphoma." (Cheson BD, J Clin Oncol. 2007 Feb 10;25(5):579-86.)

 * SPD = sum of the product of the diameters

 * 2007 PMID 17242397 -- "Use of positron emission tomography for response assessment of lymphoma: consensus of the Imaging Subcommittee of International Harmonization Project in Lymphoma." (Juweid ME, J Clin Oncol. 2007 Feb 10;25(5):571-8.)
 * PET after Chemotherapy/chemoimmunotherapy: at least 3 weeks, preferably 6-8 weeks
 * PET after Radiotherapy/Chemoradiotherapy: 8-12 weeks

Molecular diagnosis

 * See also: List of chromosomal translocations

 * Burkitt lymphoma - t(8;14) / c-myc translocation, Ki-67 > 90%, CD10+ and/or BCL-6+, CD19+ or CD20+
 * Usually BCL-2 and t(14;18) negative.
 * Follicular lymphoma - t(14;18), most common translocation in lmphoma / bcl-2 translocation. Is CD10+
 * Mnemonic: "F is for follicular and fourteen"
 * Mantle cell lymphoma - t(11;14), bcl-1, CD15-, cyclin D1
 * MALT lymphoma - t(11;18)
 * Diffuse large B-cell lymphoma - bcl-6 (is favorable)
 * Anaplastic lymphoma - CD30+, Ki-1

Radiation technique

 * See also: Radiation_Oncology/Hodgkin

Involved field
 * CALGB guidelines (done for Hodgkin's disease) - PMID 12078908 Full text (2002) — "The involved field is back: issues in delineating the radiation field in Hodgkin's disease." Yahalom J et al. Ann Oncol. 2002;13 Suppl 1:79-83.
 * Boundaries of the involved fields.

Whole-Abdomen
 * Washington University, 1994 (1978-1990) PMID 8029434 -- "Non-Hodgkin lymphoma: whole-abdomen irradiation as an adjuvant to chemotherapy." (Valicenti RK, Radiology. 1994 Aug;192(2):571-6.)
 * Retrospective. 39 patients with abdominal NHL treated with modified whole-abdomen RT. 34 adjunct to chemo, 5 primary
 * Toxicity: treatment terminated in 4 patients, interrupted in 19. Four Grade 3-4 late toxicities
 * Conclusion: Whole-abdomen RT is safe adjunct in high risk for intraabdominal failure

Reviews

 * 1985: PMID 2579725 Full text -- "The role of radiation therapy in the management of the non-Hodgkin's lymphomas." (Hoppe RT, Cancer. 1985 May 1;55(9 Suppl):2176-83.)

title: Radiation Oncology/NHL/Overview


text:
Chess Opening Theory/1. e4/1...e5/2. f4

= King's Gambit = White attacks Black's pawn on e5 with their f-pawn, but the pawn on f4 is attacked and undefended. A gambit is an opening that involves a sacrifice of material (chess pieces, usually pawns) for positional gain. In the case of the King's Gambit, White seeks to tempt Black's pawn away from the centre onto f4, which would give White the freedom to play d4 and e5. The move d4 will not only gain centre space but will also uncover an attack by the c1-bishop on Black's f4-pawn, and Black will have to make further non-developing moves to retain the pawn on f4.

Unfortunately for White, after Black accepts the gambit with:
 * 2...exf4,

White cannot yet play 3.d4. This is because the move 2.f4 also weakens the e1-h4 diagonal, and 2...exf4 weakens it further by controlling the g3 square. Black can therefore respond with 3...Qh4+! and since White cannot play 4. g3 due to the Black pawn on f4, White's king is forced out to the second rank in the opening, leaving Black with a better position (diagram left). 2...exf4 is considered best in high-level chess, but Black must defend accurately.

It's also possible for Black to decline the gambit, with one of the following moves:
 * 2...Bc5 is the usual way of doing so, taking advantage of the fact that Black's e-pawn isn't really threatened (3.fxe5?? gets hit by 3...Qh4+! again). Black makes sure that White won't be able to play d4 or to castle kingside without going to some considerable effort to shift the bishop from its new diagonal.
 * 2...d5 gives the position a different flavour. Normally Black only manages to get in one of the moves e5 or d5 this early in the opening, but since 2.f4 did nothing to prevent 2...d5, why not play it now? Since it attacks the undefended e-pawn, Black will still get to take one of White's pawns if they want to.
 * Black could also reasonably play 2...Nc6, a variation that is rarely explored, or even 2...d6 (The Archaic Defense), which often transposes to either the Fischer Defense of the King's Gambit, or to the 2...Nc6 lines.
 * Even 2...c6!? intending d5 is possible because 3. fxe5?? Qh4+ 4. Ke2 Qxe4+ 5. Kf2 Bc5+, and black has a winning attack, so white is forced to settle with 3. Nf3.
 * 2... Nf6 is the Petrov's Defense of the King's Gambit Declined. This is just fine for black.
 * 2... f5?! is the Panteldakis Countergambit. It is considered dubious with best play, and white gets an advantage, but white must be careful. In the game Kennaugh vs Shirazi, the game continued 3. exf5 e4?! 4. Qh5+ Ke7 5. d3 Nf6! 6. Qg5?!, and black went on to win a wild game.
 * 2... Qh4+?! is the Keene Defense, but this just loses a tempo to 3. g3, and white is already better.
 * 2... Qf6?! doesn't really help black either.
 * 2... c5 is the Mafia Defense.
 * 2... g5? is the Zilbermints Double Countergambit.

Theory table
1.e4 e5 2.f4

title: Chess Opening Theory/1. e4/1...e5/2. f4


text:
Radiation Oncology/Epidemiology/Worldwide

 * Global cancer statistics: 2002 1999

Resources for statistics

 * Global Cancer Statistics - published in Ca Cancer J Clin
 * Search for publications
 * GLOBOCAN data, produced by IARC (International Agency for Research on Cancer)
 * Latest: PMID 21296855 published 2011 (2008 data)

 * Global Cancer Facts & Figures - American Cancer Society
 * Website
 * Latest: 2nd edition (2008 data)

Summary

 * In 2002, there were estimated to be 10.9 million new cases of cancer, 6.7 million deaths, and 24.6 million persons living with cancer.

Incidence

 * 1st - Lung - 1.35 million (in 2002)
 * 2nd - Breast - 1.15 million (in 2002)
 * 3rd - Colon and rectum - 1.02 million cases (in 2002)
 * 4th - Stomach - 934,000 cases (in 2002)
 * 5th - Liver - 626,000 (in 2002)
 * 9th - Bladder - 357,000 (in 2002)

Incidence - Women

 * 1st - Breast - 1.15 million (in 2002)
 * 2nd - Cervix

Deaths

 * 1st - Lung - 1.18 million (in 2002)
 * 2nd - Stomach - 700,000 (in 2002)
 * 3rd - Liver - 598,000 (in 2002)
 * 4th - Colon and rectum - 529,000 (in 2002)
 * 5th - Breast - 411,000 (in 2002)
 * -?- - Bladder - 145,000 (in 2002)

Deaths - Women

 * 1st - Breast - 411,000 (in 2002)
 * 2nd - Cervix


text:
Radiation Oncology/Epidemiology

Cancer Epidemiology and Survival

Cancer Epidemiology

 * USA
 * Worldwide
 * China
 * Taiwan
 * Cancer epidemiology
 * By cancer site
 * List of most commons
 * Survival data
 * Cancer screening
 * Cancer prevention

Known/Probable Human Carcinogens
IARC MONOGRAPHS ON THE IDENTIFICATION OF CARCINOGENIC HAZARDS TO HUMANS

 * /Group 1: Carcinogenic to humans (120 agents)
 * /Group 2A: Probably carcinogenic to humans (88 agents)
 * /Group 2B: Possibly carcinogenic to humans (313 agents)
 * /Group 3: Not classifiable as to its carcinogenicity to humans (499 agents)

Radiotherapy Epidemiology

 * Sweden; 2003 PMID 14596502 -- "A prospective survey of radiotherapy practice 2001 in Sweden." (Moller TR, Acta Oncol. 2003;42(5-6):387-410.)

Global Oncology

 * JCO Global Oncology - ASCO Journals
 * Global Oncology | Global Health | JAMA | JAMA Network

title: Radiation Oncology/Epidemiology


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|← Back to

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Radiation Oncology/Epidemiology/USA

 * American Cancer Society
 * 2009 PMID 19474385 -- "Cancer statistics, 2009." (Jemal A, CA Cancer J Clin. 2009 Jul-Aug;59(4):225-49. Epub 2009 May 27.)
 * 2008 PMID 18287387 -- "Cancer statistics, 2008." (Jemal A, CA Cancer J Clin. 2008 Mar-Apr;58(2):71-96. Epub 2008 Feb 20.)
 * 2007 PMID 17237035 -- "Cancer statistics, 2007." (Jemal A, CA Cancer J Clin. 2007 Jan-Feb;57(1):43-66.)
 * 2006 PMID 16514137 -- "Cancer statistics, 2006" (Jemal A, CA Cancer J Clin. 2006 Mar-Apr;56(2):106-30.)
 * 2005 PMID 16514137 -- "Cancer statistics, 2005" (Jemal A, CA Cancer J Clin. 2005 Jan-Feb;55(1):10-30.)

Survival

 * SEER data, 2007 (1998-2003) PMID 17664474 -- "Recent major progress in long-term cancer patient survival disclosed by modeled period analysis." (Brenner H, J Clin Oncol. 2007 Aug 1;25(22):3274-80.)
 * 5- and 10-year relative survival evaluated, as a ratio of survival with disease over expected survival in population without disease

Pediatric

 * SEER Incidence Rates (2002-2006)

title: Radiation Oncology/Epidemiology/USA


text:
Neapolitan/pronouns

Subject personal pronouns
Subject personal pronouns are pronouns that replace and indicate the person performing an action.

Demonstrative pronouns
Demonstrative pronouns replace nouns once they are able to be understood from their context.

Note: chisto/chesta/cheste/chist'/chest' can be shortened to 'sto/'sta/'ste/'st'.

Reflexive pronouns
Napoletano/Pronomi

title: Neapolitan/pronouns


text:
Neapolitan/nouns

Capitalization
Almost all nouns in Neapolitan are lower case. The exceptions to this are the names of people and places.

Noun gender
There are three genders of Neapolitan nouns: masculine, feminine and neuter. They take the following articles ("the"): (For more information about articles, see the Neapolitan/articles page.)

Generally, masculine and neuter nouns end in o and feminine nouns end in a

Also, nouns which begin with the letter a tend to be feminine.

Plurals
A given noun's gender is not as clearly evident in Neapolitan as it is in Italian. Most masculine nouns end in o, most feminine nouns end in a. Most but not all. Not all nouns change endings in the plural, vowels at the end of words are often indistinct in any case so may not be much help. Feminine nouns tend to double the first consonant when they are plural, but once again not always. The best way to determine the gender of a noun is by its article or by the endings on any modifiers it may have, for example: 'o cunto, masculine; 'a lavannara, feminine; 'e cunti masculine plural; 'e llavannare feminine plural.

The plural is occasionally formed by changing the body of the word itself. This primarily happens in words already ending in e to begin with, for example 'o guaglione masc. singular becomes 'e guagliune and 'o cazone masc. singular becomes 'e cazune.

The neuter case is apparent by its characteristic doubling of the initial consonant. It is reserved for:
 * abstract concepts- 'o mmale (evil), 'o nniro (the color black)
 * classes/genres of things- 'o ffolk (folk music)
 * elements and minerals- 'o ffiero (iron), 'o cchiummo (lead)
 * foodstuffs- 'o llatte (milk), 'o ccafè (coffee)
 * adjectival nouns- 'o mmericano (the American), 'o bbrutto (the ugly)
 * noun forms of past participles- 'o ccuótto (the cooked), 'o mmuórto (the deceased)
 * nouns derived from verbal infinitives- 'o vvevere (drink).

Napoletano/Sostantivi

title: Neapolitan/nouns


text:
Wikijunior:Ancient Civilizations/Vedic

What country did they live in?
The Vedic people lived in about 3000 BC in what is present day India and Pakistan. The civilization was established from the plains of the Ganges River (India) to the Indus River (India-Pakistan)The people who developed vedic civilization are known as Aryans. The notable contribution of the Aryans can be traced from their litreature, which is well known as vedic litreature. such an ancient and varied litreature is not to be found in any other part of the world. the life of the earliest Aryan is represented in the Rigveda which was composed in 1500 B.C.

What did their buildings look like?
The early Vedic people led a nomadic lifestyle, meaning that they moved from place to place. Later, as agriculture became more important, they began to settle down. They lived in huts made of straw and later built houses out of wood.The early vedic Aryans lived in the valleys of Sindhu, Jhelum, Chenab, Ravi, Bias, Sutlej and Saraswatirivers in the northwest of the Indian subcontinent.

What did they eat?
Dinner might have been warm tasty wheat bread served with barley or rice. It would appear they were very good farmers. They grew barley, peas, melons, wheat, and dates. Farms raised cotton and kept herds of sheep, pigs, zebus (a kind of cow), and water buffalo. Fish were caught in the river with fish hooks! Each town had a large central storage building for grain. Crops were grown, and the harvest stored centrally, for all in the town to enjoy.

What did they wear?
At first,in very ancient times clothing was made out of animal skin. Later cotton, silk and other different plant based yarns and gold, silver and copper threads were used.

Clothing generally consisted two pieces of fabric, one wrapped around the upper body, and the other wrapped around the lower body. Men wore different types of pants, Dhotis, loin cloths and different varieties of shirts, scarves and stoles. A wide range of headdress and turbans were used.

Women had a greater choice in clothing. They also wore dhotis and sometimes wore turbans too. When the dhoti was worn, it was also worn with a blouse (choli), and a scarf. Also available to wear was the sari, a length of fabric wrapped around the body with the loose end thrown over the shoulder. Cholis were worn with saris. Finally, gold and other precious stones worn by men and women have been found. There were a wide range of ornaments for both men and women. A wide range of accessories were used by both men and women including handbags and shoulder bags.

The people used to dress according to their age, profession, and social status.

What did their writing look like?
The Vedic people wrote in Sanskrit. The Rig Ved, the oldest of the four Veds (see below), was composed in what is known as Vedic Sanskrit before writing was introduced to India. Later, writing was introduced, and classical Sanskrit began to emerge.

The Sanskrit language is one of the world's oldest languages, and is related to many modern-day languages in the Indo-European group of languages. These languages, including English, have words that are related to Sanskrit words. Here are some of these words:

What religious practices did they follow?
The early Aryans were worshipers of the forces of nature which they considered as their deities. the chief deities were Varun, Agni, Usha and Aditya. the idea of 'Ekam Sat' [god is one and one alone] formed the basis of their religion that God is omnipresent. the universe is emanated from the 'sat'.Worship of God by any name and in any form ultimately reaches the 'Ekam Sat'.Tolerance is deeply rooted in Indian psyche. The Vedic religion was the source of some of the world's oldest religions, including Hinduism, Buddhism, Sikhism, and Jainism. The religion was centered around the Brahmins (priests), who made sacrifices to the gods, took care of the religious needs of society and maintained the temples. Priests were given a very important place in society. They were guided by the Vedas, a collection of sacred "revealed" texts containing mantras, hymns, and sections on meditation, mysticism, and philosophy. There are four vedas - Rig, Yajur, Sama and Atharvana.

People worshiped with the help of the Brahmins. They performed sacrifices and chanted verses. They prayed for children (especially male children), cattle, and wealth.

Some rituals and sacrifices included:
 * The drinking of Soma, a drink made by pressing juice from the stalks of a certain mountain plant. The exact plant is unknown.
 * Fire rituals, such as:
 * The Agnihotra, a ritual involving prayer to Agni, the fire god.
 * The Agnicayana, a ritual which takes twelve days to perform, during which a great bird-shaped altar is built out of more than a thousand bricks.
 * The Agnistoma or fire sacrifice.
 * The Ashvamedha.
 * The Purushamedha or human sacrifice.
 * Rituals concerning demonology and magic.

The main gods of the Vedic religion were Indra[king of Gods], Agni (fire), and Soma. Lesser gods included Varuna[god of rain], Surya (the Sun), Mitra, and Vayu (the wind). Goddesses included Ushas (the dawn), Prithvi (the Earth) and Aditi. Rivers, especially the Sarasvati, were also considered goddesses.

Are some of them famous even today?
Perhaps the most famous of the Vedic people is a grammarian by the name of Pānini. He was born around 5 BCE. He is known for formulating the 3,959 rules of Sanskrit morphology (the study of the structure of word forms) known as the Aṣṭādhyāyī. Among Western linguists (people who study languages), he has a reputation of perfectly describing these rules. In fact, computer scientists have used these rules to teach computers the Sanskrit language! The grammars used to describe programming languages, called Backus-Naur form grammars, are very similar to Pānini's grammar rules.

According to some traditions, the mathematician Pingala was the younger brother of Pānini. He was the first mathematician to describe a binary numeral system, the Fibonacci series and Pascal's triangle. Perhaps the most famous would be Aryabhatta, who is credited with the discovery of "zero", without which, no major scientific or mathematical breakthrough would have been possible. A series of books called Vedic Mathematicsa has been published which show how to use formulas that lead to short methods of calculations which in modern mathematics are complicated. The Vedas contain knowledge in all branches of science.

Hinduism
The influence of the Vedic people can be seen in Hinduism, which arose from the ancient Vedic religion. It is not possible to place a date on the actual origin of Hinduism. The practices and traditions that have culminated into what is today known as Hinduism are estimated by some scholars to have begun from 3102 BC to 1300 BC. It can be said with some justification that Hinduism is the world's oldest religion. Hinduism of today is essentially the "Sanatana Dharma" of the Vedic times - the philosophy of how to lead the proper, productive, useful life. The name Hindu is in fact a more recent artifact, the result of the interactions with and invasions by East Asian, Central Asian and European warrior clans. More generally, it is thought that the name "Hindu" was used by ancient outsiders to describe the peoples east of the "Sindhu" river which flows through the present-day Punjab regions of India and Pakistan.

Hindus (people who follow Hinduism), believe in Dharma, Karma, and Moksha. Very simply, Dharma is a way of life - to align the human body, mind, and soul in harmony with nature. Karma literally translates to action. Vedic and post-vedic philosophy places tremendous importance on Karma, because that is the only thing that a person has control over. Karma is the sum of everything a person has done in his or her life. The concept of karma is similar to the concept of reaping what you sow. Good deeds result in good results, while bad deeds yield bad results. Moksha is liberation from the cycle of death and rebirth. The word Moksha is used to describe the final goal of all intelligent life - merging one's essential spirit (atman) to become one with the universal spirit (Brahman).

Hindus also believe in the gods and goddesses of the Vedic people. Even though there have been many influences on Hinduism and the underlying philosophies over the ages, it is believed that the Sanatana Dharma has essentially continued the same way it was in Vedic times.

In the early Aryan age the four vedas: Rigveda, Yajurveda, Samaveda and athrvanaveda were composed. Rig veda is the first book composed. In the later Vedic age the great epics, Ramayana and Mahabharatha were written.

Caste System
The Vedic people categorized people's roles in society into four categories - the four "varnas". The four categories were the labor class (Shudra), merchant class (Vaishya), warrior class (Kshatriya) and the priestly class (Brahmin). Over time this categorization led to misinterpretation and exploitation and became what is today called the Hindu caste-system.

The Brahmins became the highest caste. They were the priests and holy men. Next were the Kshatriyas, the warriors and rulers. The Vaishyas were the merchants and businessmen. Last were the Shudras, the servants and labourers. In addition to the above four castes, those who performed "unclean" jobs, were deemed to be outside the caste system and were the "untouchables" - those within the caste system did not have direct contact with them. Mahatma Gandhi called them harijans - children of God. They today call themselves dalits - the oppressed.

The caste system was originally based on division of labour, but over time was used to control religious and social life as well. Although the caste system is now outlawed in India, its effect is still felt in daily life. Discrimination against lower castes still exists, and many dalits still live in poverty. However, the Indian government has set up programs to educate them and help them out of poverty.

The importance of cows
Just as they were sacred to the Vedic people, cows are also sacred to Hindus. In Hinduism, all animals are held sacred and the cow especially so. Thus Hindus don't eat the meat of the cow. There is a regional holiday called Mattu Pongal (literally Cow Pongal in Tamil), which is a thanksgiving day for cows. In addition, there is a tradition which holds that a divine cow named Kamadhenu - the giver of countless boons - is considered to be the mother of all Hindu Gods..

Sanskrit
The ancient language of the Vedas is still taught in Indian Schools. The roots of most of the modern north-Indian languages, including Hindi, Bengali and Gujarati, lie in Sanskrit.

Although there is no community of native speakers today, Sanskrit hymns are still used in most Hindu rituals. Sanskrit is still the spoken language in the town of Mattur in Shimoga District, Karnataka State in India. Even languages from the South-India like Malayalam originated from Sanskrit and Tamil influence. Spoken Sanskrit scholars are becoming extinct, but an organisation called Samkritha Bharathi is slowly reviving the language, with its free Sanskrit camps and classes.

title: Wikijunior:Ancient Civilizations/Vedic


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Biblical Studies/Bible Topics/Anger

Be ye angry and sin not: let not the sun go down on your wrath: Neither give place to the devil. Ephesians 4. 26 - 27.

The crux of the matter --as far as anger is concerned is that it's an emotion that can be provoked in us by the actions of others or our response to situations around us. Emotions are a part of our soul (mind, will & emotions) and created by Almighty God. However, if not properly managed, anger can be very destructive. Anger is an emotional sign that tells us that something is wrong. It's okay to be angry, it's what we do with that anger that can get us into trouble! That is why Paul acknowledges that we will get angry on occasion. We must deal with the cause of the anger. Allowing it to linger could give room for the devil to manipulate us.

"Love or die"

title: Biblical Studies/Bible Topics/Anger


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Talk:Game Maker Programming

New Naming Policy
Hello,

I see you did some new entries into the Programming Book. I like to suggest that you read Naming policy.

--Krischik 09:22, 19 August 2005 (UTC)

Merger
Although Game maker follows the naming convention better this book has more information. Also it shouldn't take alot of work to bring this book up to the naming convention. Klingoncowboy4 22:12, 29 August 2006 (UTC)
 * The merge was already proposed in reverse, I've now completed it as no objections existed. --Panic (talk) 08:13, 26 January 2010 (UTC)

Category
i think this should me put into the game maker category. -->>antome-)-)-) 18:46, 14 November 2007 (UTC)

title: Talk:Game Maker Programming