\r\n\t
\r\n\tAdditionally, authors are expected to cover the medicinal effect of tea polyphenols viz. catechins, theaflavins and thearubigins which are the major chemical compounds of tea. Green tea contains a higher quantity of catechins as compared to black tea which becomes transformed into more complex compounds (theaflavins and therubigins) during the manufacturing of black tea. Out of many therapeutic uses these bioactive compounds, protection against cardiovascular diseases, atherosclerosis, cancer, gene mutation, and diabetics have been reported and are more promising. This book will also highlight the nutraceuticals of tea. The catechins along with other various bioactive compounds present in tea have many therapeutic properties which attribute to the development of various food products where tea constitutes as an active ingredient. That is why it is important to stress the potential use of tea and their bioactive constituents (catechins, polysaccharides, vitamins, amino acids etc.) in food products with added nutraceutical values. Finally, the contamination of tea and its effect on our health will also be covered. Tea and its food products may contain various types of contaminations which may include toxic heavy metals, pesticides, microorganisms, and environmental pollutants etc. which are present from tea infusion and from residues. These contaminations which are above the regulatory limit may pose a serious threat to public health. Submitted chapters are expected to contain novel information, be informative as well as thought-provoking.
Congenital anomalies are a major cause of stillbirths and neonatal mortality. Taking into consideration that in 2004 WHO estimated an incidence of about 7% in newborns, congenital anomalies are a major cause of morbidity and mortality worldwide.
\nCongenital anomalies can be caused by chromosome abnormalities, single-gene defects, multifactorial inheritance, or epigenetic or nongenetic factors. It is notable that in up to 50% of all cases no apparent identifiable cause can be found. Any microscopically detectable autosomal imbalance, such as trisomy, duplication, deletion, or monosomy, will result in severe structural and developmental abnormality, most of which are lethal conditions. Single-gene defects have been associated with congenital abnormalities that might involve one or more organs and systems with or without an obvious underlying embryological relationship. Multifactorial inheritance accounts for the majority of congenital abnormalities, including isolated malformations, in which genetic factors can clearly be involved.
\nIt should be noted that although malformations are always thought to be congenital, not all congenital abnormalities are “literally” malformations. Anomalies due to an intrinsic, genetic (chromosomal aberration and gene mutation), or multifactorial factor represent approximately 45% of all congenital abnormalities. These are considered primary congenital malformations. Anomalies resulting from the action of an extrinsic factor—chemical, physical, biological agents, and possibly maternal condition—add up 5% of the congenital anomalies identified and are considered secondary congenital anomalies. For the remaining 50% of these abnormalities, the cause is unknown and therefore cannot be included in this classification [1].
\nThe impact of genetic variability on embryogenesis and fetus development established medical genetics as essential for the prevention of congenital anomalies, early detection, and appropriate management. In the past, when dealing with congenital malformations, medical professionals had to face two major issues: a late detection of the anomaly and the lack of an identifiable cause. The act of disease prevention back then was virtually impossible.
\nThough, in the last decade of rapidly progressing genomic technologies, genetic diagnosis tools became widely accessible, playing an important role in both clinical practice and research. The completion of the Human Genome Project has contributed greatly to our understanding of the molecular basis of genetic disorders.
\nThe importance of determining the genetic cause of birth defects lies in the need for appropriate case management and genetic counseling. Genetic counseling is meant to assist parents in making informed decisions. Through counseling, parents learn about the risk of having a newborn with a congenital malformation and the nature of the disorder and its natural history, are advised on available testing for that particular case, and discuss options for risk management and family planning.
\nAll attempts must be made to arrive at as precise a diagnosis as possible by evaluating gestational history for environmental factors, family history for genetic factors, and patient anatomy for clues to embryologic etiopathogenic mechanisms. Evaluating family history for genetic factors, gestational history for environmental factors, and patient phenotype for information on embryologic mechanisms is mandatory to arrive at as precise a diagnosis as possible.
\nGenetic counseling may be hampered by the inaccurate recording of the above mentioned and the inherent uncertainty in interpreting them. Given the incompleteness of available data and the difficulty in interpretation, genetic counseling has a demanding and potentially difficult mission.
\nGenetic counseling is a complex medical act, which aims to help families, individuals, and couples to better understand the familial, medical, psychological, and reproductive consequences of the genetic contribution to specific health conditions. It can be offered both pre- and postnatally.
\nFortunately, most babies are born healthy. However, in some pregnancies, a risk for birth defects or other genetic problems may be identified. Geneticists and genetic counselors provide prenatal genetic counseling services for individuals, couples, or families with a concern about the health of their unborn baby.
\nPrenatal counselling manages cases with risks by understanding prenatal screening and testing options. Increased chance of having a child with a birth defect or genetic condition makes the genetic consultations a necessity. The purpose of genetic counseling is to allow informed decision-making by communicating accurate and complete information and presenting objective diagnostic and therapeutic options [2]. To achieve its goal, information transfer must be made in a clear but neutral way, using simple language, respecting ethical and cultural values.
\n\nPretest counseling. At this stage, the couple will be informed on the objectives of the counseling session regarding the suspicion of congenital anomaly for the pregnancy.
\nThe genetic counselor/geneticist will lay down the alternatives the couple has for following up the pregnancy and explain the possibility and alternatives for testing for identifying the cause of the congenital anomalies identified. The geneticist must take into consideration that accepting to be tested may be influenced by psychosocial factors, such as ethnicity, socio-demographic status, and the presence of the partner during the counseling session [3].
\nIf the couple expresses the desire for prenatal diagnosis, the counselor must present the objectives, benefits, risks, limitations, costs, and alternatives for each of the available screening and/or diagnosis techniques. The patient has the right to accept or refuse a given recommendation. At all times, it must be clear that testing is optional.
\nThe counseling must go beyond making an informed choice for testing and what this step entails, but also preparing the couple for possible outcomes dictated by a positive or negative result.
\n\nPosttest counseling. Posttest counseling must explain thoroughly the significance of the result, the meaning of a positive or negative result, and go over the limitations of each test. It must also suggest other possible confirmatory or complementary tests or alternatives [2] and unconditionally support the patient’s options, respecting the autonomy of his/her choice.
\nOne of the most encumbering tasks of genetic counseling is presenting a family with the fact that their child has a genetic condition or birth defect. Most of the test results face the couple with a termination/no-termination decision.
\nAs part of the informed decision-making process, the couple must be informed in detail on the clinical presentation and prognosis of the disorder identified. This is often problematic in chromosomal disorders: (1) genotypic variability—the phenotype will vary depending on the extent of the genetic defect and (2) phenotypic variability—the evolution of a case can vary greatly, even between carriers of the same type of anomaly.
\nThese questions are perhaps among the most frequent during the counseling session and we will try to answer them briefly below. The probability reoccurrence is called “recurrence risk.” Recurrence risk assessment and counseling is based on a combination of theoretic risk assessment and empiric data. Families and patients should be informed on the assumptions involved and the limitations of such estimates.
\nThis chapter is focused on genetic counseling in congenital anomalies, caused by chromosomal, monogenic, or plurifactorial anomalies, as well as on preimplantation genetic diagnosis.
\nCarrier and aneuploidy screening and diagnostic testing have expanded intensely over the past two decades [2], which is justifiable given the estimate of 5.3% of the neonates affected by a genetic disorder. Despite ultrasound and biochemistry reasons for recommending a prenatal diagnosis, genetic testing in pregnancy is optional. Decisions about undergoing testing should be expressed, consented, and based on individual patient’s values and needs and guided by the geneticist during counseling sessions.
\nCongenital anomalies can be caused by chromosomal, monogenic, and multifactorial disorders [4]; out of which, chromosomal anomalies have a significant impact given their combined frequency of 1 in 153 pregnancies [5] and the reserved prognosis for many of them.
\nAneuploidies are the most frequent chromosomal anomalies. Aneuploidies are numerical disorders (\nFigure 1\n)—the number of chromosomes differs to the normal state, called euploidy. Any of the chromosomes, autosomes, or heterosomes can be affected. Aneuploidies can be complete, involving the whole chromosome, or partial. From a single fertilized egg, more populations of cells of different genotypes can develop—this abnormal situation is called mosaicism. Due to their high incidence, three complete trisomies bear significance for the prenatal diagnosis: trisomy 21 (T21—Down syndrome), 18 (T18—Edwards syndrome), and 13 (T13—Patau syndrome).
\nKaryotype 45,X—monosomy X.
Other chromosomal anomalies are structural, such as deletions, duplications, inversions, insertions, translocations, etc. (\nFigures 2\n and \n3\n). They are rare and require different diagnosis strategies, counseling, and management of the case.
\nKaryotype 45,XX,rob(13;22)(q10;q10)—Robertsonian translocation.
Karyotype 46,XY,t(1;15)(p36.3;q26.1)—reciprocal translocation.
Possible alternatives for screening (“Prenatal Biochemical and Ultrasound Markers in Chromosomal Anomalies”) and diagnosis (“Genomic Testing for Prenatal Clinical Evaluation of Congenital Anomalies”) are presented in detail in different chapters, due to their marked importance in genetic testing and counseling.
\nIn the current section, we aim to cover several genetic counseling concepts in a few hypothetical situations of congenital anomaly with underlying chromosomal cause. Pre- and posttesting counseling are a prerequisite of all genetic counseling, but the genetic consult comprises also of a detailed assessment of medical history, psychosocial assessment, and family history, which we are not focusing on here [3, 6, 7].
\nThe possible mechanism by which the chromosomal anomalies occur is usually due to errors in the cell division cycles: nondisjunction in the maternal meiotic division I, and, less frequently, paternal origin [8] or meiosis II [9].
\nThe etiology is mostly unclear, but the probability of chromosomal anomalies increases with maternal age [4], and this is one of the most common etiological factors. Predisposition to oocyte aneuploidy is also seen in young women, gene expression alteration due to environmental factors and the influence of follicle-stimulating hormone (FSH) being possible culprits [10]. It is yet uncertain if the paternal age contributes to the risk of aneuploidy, if at all [11]. The contribution of different occupational or environmental factors is insufficiently documented.
\nAneuploidies are most frequent causes of mental retardation and pregnancy loss [9]. It comes as no surprise that the chance of reoccurrence is one of the most relevant aspects of genetic counseling.
(a) Complete chromosomal, especially autosomal trisomies, when parents are not carriers of translocations
Recurrence risk in the absence of parent translocations follows the empirical risk—the risk measured in the general population, generally evaluated around 1% for the most common trisomy [12] and increases with age for trisomy 21. For other trisomies, the recurrence risk seems lower. Recurrence rates are rather difficult to estimate in sexual aneuploidies. Subjects with Down syndrome are generally infertile, but they have a significant risk of aneuploidy recurrence in their offspring [13].
(b) Chromosomal trisomies with one of the parents being a carrier of a chromosome 21 translocation
Down syndrome translocations are present in less than 4% of the cases. Translocations can occur de novo. For transmitted translocations, the recurrence risk depended on the affected parent: for instance, depending on the involved translocated chromosomes, if the mother is the balanced carrier, the risk is to that of the father, without any known reason for the discrepancy. A balanced translocation t(21,21) has 100% recurrence risk [14].
(c) Mosaicism
Generally, mosaicism cases have the lowest frequency contributions to the total of the trisomies. Mosaicism can occur de novo in the offspring, but parental germ line mosaicism contributes to the recurrence risk [15]. Reduced mosaic [16], meaning low percentage of modified cell lines, or partial trisomy [17], equivalent with duplication, generally has a better prognosis by comparison with a homogenous complete trisomy, but this is not a rule [18].
\nThe couple must be informed that there is no prophylaxis or treatment to correct the aneuploidy, but genetic counseling can provide the support for medically informed decisions to guide the management of the case.
\nIf the couple wishes to keep a pregnancy with chromosomal disorder, they must be informed on the obstetrical complications that may arise, the life expectancy, and the natural history of the disease neonatally and into adulthood.
\nA trisomy prenatal case, especially 13 or 18, may present with different obstetrical challenges: miscarriage and stillbirth are more frequent than compared to the general population. Structural anomalies of the fetuses lead to a negative prognosis after birth and low life expectancy [19].
\nScreening and diagnosis limitations for trisomy 13 lead to underdiagnosis of this aneuploidy. Genetic counseling should bring into discussion the viable fetuses in the second trimester (60% of the cases), when life expectancy is very hard to predict and there is no longer the alternative to terminate the pregnancy. It is crucial to inform the parents on the neonatal procedures for resuscitation, possibilities to correct certain defects so that the couple is prepared to face the trauma of having a child with lethal defect [20].
\nFor trisomy 18, only 10% of the neonates survive longer than 1 year. Diagnosing this trisomy though genetic testing is essential for decision-making during the neonatal life, where critical emergency interventions and choosing invasive treatments are often required [21].
\nTrisomy 21 has a life expectancy of almost 60 years. Following up, the patient asks for collaborations with multiple medical specialties: cardiological, ENT, ophthalmology, endocrinology, to assess possible complications. During their pediatric life, other interventions are generally symptomatic and similar to their euploid peers [22]. The parents must be prepared though through genetic counseling for the possible difficulties due to motor and cognitive delay. Support in the patient’s lifestyle can also come from nongovernmental associations and patient support groups, e.g., Down Syndrome International (
Very often, genetic congenital anomalies are part of the clinical presentation of monogenic diseases; 7.5% of isolated or syndromic congenital anomalies are caused by monogenic disorders. Congenital anomalies can become obvious prenatally or at birth, and at times, they are noticeable only in later development, but in all cases, it happens between conception and birth.
\nThe diagnosis of a monogenic disease is often established based on a conclusive family history, clinical examination, and pedigree pattern and confirmed through genetic testing.
\nWith a known diagnosis, the risk of recurrence will be estimated according to the inheritance pattern of the disease. When definite diagnosis is not available, all attempts should be made to associate the clinical picture with a specific disease. If successful, precise genetic counseling can be offered. Situations when diagnosis cannot be demonstrated before birth are difficult to manage—the counselor will advise the couple when there is a lack of crucial medical information.
\nShould screening identify congenital anomalies during intrauterine life, couples will be faced with a pressing situation, as anomaly finding does not necessarily imply certain diagnosis. In this case, establishing the diagnosis should be aimed for whenever possible, as the first step in genetic counseling.
\nThere are situations with a known diagnosis and known disease-causing mutation that allow prenatal diagnosis testing. Prenatal invasive diagnosis for monogenic disease running in the family, depending on its severity, should and will be recommended. If diagnosis can be readily established, then the recurrence risk can be calculated. Probability of inheritance based on Mendel’s principles and conditional probability (also known as Bayesian analysis, based on Bayes’ theorem on probability) are used to calculate genetic risk [1].
\nThe risk of expressing a monogenic disease is dependent not only on the pattern of inheritance, but also on other factors such as the incidence of the disease, the presence of other affected members, the penetrance and variable expressivity, ethnicity, and the influence of environmental factors.
\nAn autosomal dominant disease is a condition expressed in both heterozygous, carrying one copy, and homozygous individuals, carrying two copies one from each parent. The disease is caused by a single gene defect located on an autosome. The affected individuals are usually heterozygous, and the homozygous genotype is associated with more severe features or can be lethal. Females and males exhibit the trait in approximately equal proportions and severity of clinical signs is similar between the two sexes. Both sexes are equally likely to transmit the mutation to their offspring. Mostly, the affected offsprings are descendants of an affected heterozygous and a normal parent. On average, half of the children will be heterozygous and express the disease and half will not. Rarely, homozygous are seen in autosomal dominant diseases. This status can be due to a higher frequency of a gene with mild effects, late onset (e.g. Huntington disease) or when both parents are affected (e.g. achondroplasia). Unusually, an affected homozygous parent will transmit the disease to all of his children. On the pedigree, a vertical transmission pattern is observed (\nFigure 4\n), and the disease phenotype is usually seen in one generation after another. The disease does not skip generations: if an individual has an autosomal disease, in most of the cases, one parent must also have it [1, 2].
\nAutosomal dominant inheritance.
Frequently, autosomal dominant disorders involve different organs and systems of the body; however, dominant conditions affecting one organ have been described (e.g., congenital cataract). The capacity of a single gene to affect unrelated organs is called pleiotropy (e.g., Marfan syndrome can affect the skeletal, ocular, and cardiovascular systems; some affected individuals have all features, whereas others may have almost none). In addition, the clinical features in autosomal dominant disorders can show remarkable variation between patients, even between the members of the same family. This difference between individuals is referred to as variable expressivity (e.g., in autosomal dominant polycystic kidney disease, some affected individuals develop renal failure in early adulthood, whereas others have just a few renal cysts that do not significantly influence renal function). Occasionally, the heterozygous and homozygous individuals express identical phenotype (complete dominance) [2, 23].
\nSometimes, a dominant mutation is inherited, but the condition it determines is not expressed. In these cases, the gene has reduced (incomplete)penetrance. The term penetrance is used in monogenic inheritance to indicate the probability of a gene to influence the phenotype. A number of autosomal dominant diseases show an incomplete penetrance (e.g., polydactyly), meaning that a person has the mutation but shows no evidence of a disease. A gene is completely penetrant if each individual who inherited the mutation expresses clinical features (e.g., neurofibromatosis type I) [3].
\nOften, known autosomal dominant conditions are seen in a person without an affected parent. The condition seems to be isolated and no clinical features are detected among other family members. In these cases, the disease can be attributed to a “de novo” mutation and the recurrence risk for siblings is very low. The mutation is found only in a gamete and the mutated gene is transmitted by one of the healthy parents. The percent of cases caused by de novo mutations is influenced by the severity of clinical features or the capability of reproduction. Osteogenesis imperfecta type II is exclusively caused by new mutations, the condition being perinatally lethal. Also, more than 80% of cases with achondroplasia are due to new mutations, and the proportion is significantly lower in polycystic kidney disease. In this case, it is important to know the family history to distinguish isolated cases and rule out incomplete penetrance or variation in expression. The detection of a specific mutation in a proband allows direct testing of the parents to exclude a disease with expression variability. Also, the detection of a specific mutation can help predict the severity of clinical features in some diseases [24].
\n\nGermline mosaicism is another mechanism documented in a number of autosomal dominant diseases such as tuberous sclerosis or osteogenesis imperfecta. Germline mosaicism, also known as gonadal mosaicism, is a condition in which the precursor (germ line) cells to egg and sperm cells are a mixture (mosaic) of two or more genetically different cell lines [1, 2]. The parents do not exhibit any clinical features because the somatic cells are not affected; only a proportion of eggs or sperm cells are carriers of the mutation. Two or more children are affected when there is no family history of disease. This condition is associated with increased recurrence risk for future offspring of a mosaic parent. Because mutation is a rare event, it is unlikely that this would be due to multiple mutations in the same family.
\nAn autosomal recessive disease is a condition expressed only in homozygous individuals with both mutant alleles. The parents of such homozygotes must be at least heterozygous for the disease allele and are usually referred to as carriers for that disorder (\nFigure 5\n). In most cases, the loss-of-function mutation is a process in which mutant allele reduces or removes the function of an enzyme. In the heterozygous state, the normal allele can compensate the mutant one, and in homozygotes or compound homozygotes with both mutant alleles, the disease occurs [1, 2, 4].
\nAutosomal recessive inheritance.
When two carrier parents of the mutant allele are matting, there is a 50% chance for each of them to transmit either the wild-type or the mutant allele. Thus, each of them has a 50% chance to transmit the mutant allele and further 25% of offspring may be homozygous affected. This also means that 50% of the cases the offspring will get one wild-type allele and one mutant allele, resulting in a carrier. If a parent is affected by a recessive disorder and the other is heterozygous there is a 50% chance that the disorder will be transmitted to children, depending on which allele the partner contributes with. All children are carriers when a parent is affected by an autosomal recessive disorder and the other is homozygous wild-type [1, 4].
\n\nConsanguinity is referred to as a couple who have at least a common ancestor, meaning that they are relatives. Finding out that an individual with a genetic disorder is the result of a consanguineous couple is strong evidence for a recessive condition, although not certainty, because there is a greater chance that the parents would have inherited the mutant allele from their common ancestor and passed it down, than the possibility of finding a similar mutation in two unrelated individuals in the general population. In fact, this is true for very rare mutations (e.g., alkaptonuria or xeroderma pigmentosum). In contrast for common autosomal recessive disorders (e.g., cystic fibrosis), the incidence in general population is not significantly lower than in consanguineous marriages. Meaning that the rarer the mutation is in the general population, the more likely that the parents are related (consanguinity) [5].
\nThere are specific recessive disorders for which it is not uncommon that two affected individuals will have children together. Such is the case for individuals with deafness or visual impairment who will benefit from the same social facilities or will be educated together. If the disorder is caused by the same mutation, then all their children would be affected; however, there are studies that show that normal children are born from these couples. The most common explanation is that the parents are homozygous for different genes, both causing deafness, and so the children are heterozygous for both mutations, also known as double heterozygote. This type of genetic heterogeneity is called locus heterogeneity. Heterogeneity can also be found in the same locus, as it would be the case of an affected individual who is heterozygote for both alleles, making him/her a compound heterozygote. Most affected individuals with recessive autosomal inherited disorders are compound heterozygotes, unless that specific mutation is rather common in the general population (as is the case with cystic fibrosis), or he/she is the result of a consanguinity marriage [1].
\nAnother method of assessing recurrence risk is by calculating the genotype frequency, knowing the allele frequency. This is not as straightforward as it would seem because there is the matter of allele distribution in heterozygotes and homozygotes. This can be done by using the Hardy-Weinberg Law, but the population used on has to meet some criteria such as: (a) the population is large and the mattings are random; (b) there is no significant rate of new mutations; (c) there is no selection for any genotype; and (d) there is no significant migration disturbing the endogenous population allele frequency [6].
\nThe presence of both homologous from a pair or chromosomal regions in an offspring coming from the same parent is called uniparental disomy. The uniparental disomy can be caused by an error in meiosis resulting in two different chromosomes coming from the same parent, which is called heterodisomy, or by an error in meiosis II, which will result in identical chromosomes transmitted from the same parent called isodisomy. This abnormality has been reported to be a rare cause for cystic fibrosis, in families where only one parent is heterozygote and the offspring takes both homologous chromosomes with the mutant allele from that parent [1, 4].
\nThis type of inheritance is linked to the genes found on the sex chromosomes. Inheritance patterns for the genes found on X chromosome relates to X-linked inheritance, while for the genes located on Y chromosomes, it is called holandric or Y-linked inheritance. The genes positioned on the X and Y chromosomes are unequally transmitted to males and females.
\n\nX-inactivation is a normal process, which appears in the early development of the embryo. The result is that most of the genes on one of the two X chromosomes in females are inactivated in each cell, ensuring the fact that, similar to males, females have only one functional X chromosome. One of the two chromosomes is randomly inactivated, meaning that approximately half of the cells in females have a functional X chromosome of maternal origin and the other half have the paternal one functional. This process interferes with both dominant and recessive X-linked inheritance as detailed below [5].
\nX-linked dominant inheritance is caused by a dominant mutant allele located on the X chromosome. Hemizygous males and both homozygous and heterozygous females are affected. Males are more likely to be severely affected given the fact that in females one of the X chromosomes will be inactivated (X-inactivation), unless the females are homozygous for that allele.
\nAffected heterozygote offsprings of both sexes have a 50% chance to inherit the mutant allele from an affected mother, which is similar in the autosomal dominant inheritance too (\nFigure 6\n). The difference between the autosomal and X-linked dominant inheritance refers to affected males. All daughters of an affected male will also be affected by inheriting the X chromosome with the mutant allele, whereas male offsprings will inherit the Y chromosome, thus avoiding the disorder. Affected females are twice more frequent than affected males, although females tend to have milder phenotypic manifestations. One example of an X-linked dominant inheritance disorder is the hypophosphatemic rickets [1, 2, 4].
\nX-linked dominant inheritance.
In some cases, affected males with an X-linked dominant disorder are rarely seen, for example, Rett syndrome and incontinentia pigmenti. This is due to the fact that the presence of the mutant allele in male hemizygotes will result in an early embryonic development stop. In other cases, it seems that only females are affected because males are “speared.” An example of a disorder that spares male hemizygotes is X-linked females—limited epilepsy and cognitive impairment. Females appear to be healthy at birth, yet they develop the affection from the second year of life, while males are unaffected their whole life. This disorder is caused by a loss of functional mechanism in the protocadherin gene 19, which is expressed in the neurons. The explanation for this particular case would be that random X-inactivation makes a mosaic expression of this gene in the cells of the central nervous system, which disrupts communications between neurons. In males, the brain is spared this miscommunication between neurons by seemingly a different protocadherin, which compensates the loss of the first [6].
\nX-linked recessive inheritance is caused by a recessive mutant gene located on the X chromosome. Almost all affected individuals are males (hemizygotes), while homozygotes affected females are rarely seen. The clinical features seen in females are mainly due to non-random X-inactivation [4].
\nAll daughters of an affected male (hemizygous) will be carriers (heterozygotes) for a specific disorder, whereas the sons will inherit the Y chromosomes from the father and thus will be unaffected by the disorder. For a female carrying the mutation, there is a 50% chance to transmit the mutant X chromosome to the offspring, as a result 50% of the daughters will be carriers and 50% of the sons will be affected (\nFigure 7\n). For a female to be affected means to inherit the mutant allele from each parent, which is very unlikely to happen, or another option is the presence of only one X chromosome (monosomy X) on which the mutation is present, making her a hemizygous for the allele, like in the case of males. A commonly known X-linked recessive disorder is hemophilia A caused by deficiency of factor VIII, a protein involved in clotting [1, 2, 6].
\nX-linked recessive inheritance.
Sometimes, the females can express the phenotype. The most common situation is represented by a carrier female showing phenotypic features, phenomenon known as manifesting heterozygote. This manifestation is due to X-inactivation, which is not random anymore; rather, it has become unbalanced or skewed. The skewed X-inactivation can be both advantageous when the inactivated X chromosome in all or most cell lines and tissues is the one with the mutation and deleterious when inactivation occurs on the X chromosome containing the wild-type allele. This unbalance can be created through chance alone by selecting mostly one of the X chromosomes, rather than the other, or through different mechanisms like cytogenetic abnormalities (translocation) or removal of the cells containing the mutant allele [6].
\nThe germline mosaicism (gonadal mosaicism) is an important mechanism in assessment of X-linked recessive inheritance risk and it was also seen in autosomal dominant inheritance. Because both male and female gametogenesis can be affected, it should be taken into account when the recurrence risk is assessed in apparently sporadically appeared X-linked disorders like Duchenne muscular dystrophy [1].
\nY-linked inheritance also known as holandric inheritance is caused by genes located on the Y chromosome. This is a rather straightforward type of inheritance as only males have Y chromosome, meaning that a male will transmit the mutant allele and thus the disorder to all his male descendants and none of his female ones.
\nMultifactorial heredity describes a trait whose manifestations are determined by the activity of one or more genes in combination with environmental factors that can trigger, accelerate, or exacerbate the pathological process. Multifactorial diseases present a specific familial disposition, the incidence for close relatives of the affected individual being about 2–4%, unlike diseases determined by the mutations of a single gene (25–50%) [7].
\nThese types of pathologies are classified into two main categories: (1) common diseases of adulthood (coronary disease, hypertension, diabetes, asthma, schizophrenia, etc.), having a prevalence of around 1–5%, and (2) isolated congenital abnormalities of the childhood (e.g. neural tube defects, cleft lip and anterior palate, congenital anomalies of the heart, varus equina), with an incidence of approximately 1–8% in newborns [25].
\nCongenital anomalies, also referred to as congenital abnormalities, congenital malformations, congenital disorders, or birth defects, are conditions of prenatal origin that describe developmental disorders of the embryo and fetus, potentially impacting its health and development [26]. There is a wide array of anomalies including structural and functional conditions that can fall under these headings [3].
\nCongenital anomalies are affecting 1–6% of pregnancies worldwide, making them a leading cause of morbidity and mortality in early life [8, 9, 27, 28]. In high-income countries, a quarter of the infant deaths is due to these anomalies [10, 29, 30]. Mortality in children under 5 years old escalates to 3.3 million [28].
\nThese anomalies can occur in isolation (isolated congenital anomalies) or as a group of defects (multiple congenital anomalies). However, there is no generally accepted system of classification, or even an agreed definition of what constitutes a congenital anomaly [3].
\nImprovements in the sensitivity and availability of prenatal screening have helped decrease the number of children born with congenital anomalies [8, 31]. Even so, when the event arises, the diagnosis and the discussions around pregnancy termination create significant emotional distress [32]. Moreover, parents who have lost a child to a congenital anomaly or families with a preexisting condition will be very concerned about the risk of recurrence in future pregnancies [11].
\nThe role of genetic counseling is to provide guidance and support to the families being affected by these conditions [12, 24], yet the etiology of most congenital anomalies is multifactorial or unknown [33] and so an exact evaluation of the recurrence risk is hard to make for most anomaly groups and subtypes. There are a few population-based studies that offer some information concerning the recurrence risk [13, 14, 34]. All three studies conducted in the 1990s found that a congenital anomaly has twice the risk of occurrence in a future pregnancy if it has already been present, and the risk rises 5- to 12-fold if the same anomaly is present in the subsequent pregnancy [13, 14, 34]. These studies have also limitations, due to small sample size, lack or outdated classification, rendering them less useful. There is also more accurate data available in a recent article [3] that shows that for similar anomalies the recurrence risk for isolated congenital anomalies is 20-fold higher, while for dissimilar anomalies, the recurrence risk is 1.3-fold higher. Also, it was concluded in the article that the absolute recurrence risk varies between 1 in 20 and 1 in 30 [3].
\n\nGeneral recurrence risk. Under these conditions, a number of general principles must be respected for genetic counseling. The empirical risk represents a medium risk for the respective disease in the population of which the proband (index case) is, and so it is possible that in the studied family the average risk is not the same as the real risk.
\nThe overall empirical risk of recurrent fracture or progression for isolated congenital malformations with a frequency of 1–1000 newborns is about 2.5% for common diseases; at a frequency of 1–100, the risk is about 10%.
\nThe risk of recurrence of the condition is influenced by a number of factors:
The degree of kinship with the proband (index case). The risk of recurrence to first-degree relatives is much higher than for other people in the family; for example, the descendants and siblings of a proband with oral cleft have a risk of 3.15 and 2.79%, respectively, and the second- and third-degree relatives have much lower risks, 0.47 and 0.27%, respectively.
The presence of a more severe condition in the proband. If the proband has a unilateral oral cleft, the risk to siblings is 1.9%, and if the proband has bilateral oral cleft, the risk rises to 6.6%.
The presence in the family of several affected individuals. In the case of labia, if two siblings are affected, the risk for the next birth is 10%; if a parent and child are affected, then the risk for another affected child is 14%.
Sex of the proband. The risk increases if in the family there are sick individuals of a certain sex at which the illness is normally less frequent (i.e., developmental dysplasia of the hip in boys and pyloric stenosis in girls).
Consanguinity increases the risk of recurrence because the risk genes are inherited from both sides.
If for certain isolated congenital anomalies there is no information on the empirical risk in a given population, the risks may be recalculated based on the population frequency and the severity of the condition, as well as the number of affected individuals.
\n\nRecurrence risks per pathology. Regarding congenital anomalies of the heart, the recurrence risk is greater on the horizontal line (brotherhood) than on the vertical line for first-degree relatives and it revolves around 2–4%, whereas for second-degree relatives, the risk is reduced, becoming similar to that of the general population [35]. On the other hand, though, if the affected parent is the mother, the recurrence risk is significantly higher than the one for which the father would have been the carrier of the anomaly.
\n\nCleft lip when associated or not with anterior palate represents the most common facial congenital anomaly, being present in over 20% of the cases and also having a positive family history.
\nAt birth, the fact that the child has an affected mother and that she has another affected child increases the prevalence. The recurrence risk for patients that have first-degree relatives with this disease is 32 times greater than in the general population for cleft lip and anterior palate and 56 times greater for anterior palate alone, even though patients with cleft lip have a high familial recurrence of almost 4%.
\nIn regard to neural tube defects, recent studies have pointed that if the proband would be the first affected child in the family then the recurrence risk for the following children would be 3.15%, whereas for the second affected sibling, the risk for recurrence would be around 10–11.76%. Some studies also showed that the risk is higher for female children and for the first and last siblings of a mother.
\n\nCongenital hip dislocation has a 5% recurrence risk if an affected sibling is already present. An increased risk of male probing according to sex ratio (8 males per 1 affected female) is encountered in people affected by this congenital anomaly.
\n\nVarus equina seems to be twice as frequent in girls as in boys, while in families that have one child with this condition, the occurrence risk for the following children is 30 times higher than that of the general population being approximately 7.3%.
\nThe indirect setting, based on family history, of an increased individual risk of the disease will allow for the direct determination by molecular tests of genetic risk factors, possibly specific medical actions of early diagnosis.
\nTo summarize, genetic counseling in isolated congenital anomalies relies on information gathered from population-based studies, on new and future discoveries related to the etiology of these disorders, and other factors such as the degree of kinship with the proband, presence of a more severe condition, more than one individual affected in the same family, or consanguinity for calculating the recurrence risk for the respective condition.
\nGenetic counseling is about guidance and support for the patient and the patient’s family, so a great deal of attention must also be directed toward careful wording when explaining the risk and decisions that need to be made.
\nPreimplantation genetic diagnosis is a multistep procedure that analyzes the genetic material from a single or several cells, with the purpose to avoid a pregnancy affected by a specific disease. The biological samples were obtained during assisted reproductive treatment (ART) by the biopsy of oocyte polar bodies or embryos. PGD requires a multidisciplinary and highly experienced team in ART and genomic evaluation at single-cell level [15, 16].
\n\nIndications for PGD. Usually, PGD is provided to couples at risk of conceiving abnormal offspring with monogenic or chromosomal disorders. Thus, PGD is suitable for couples where one member is affected by a dominant disorder or both are known carriers of mutant alleles for a recessive disease, or one of them carries a balanced chromosome rearrangement that predisposes him/her to transmit and unbalanced chromosomal abnormality, often deletion or duplication [16, 17]. The presence of a gene mutation or chromosomal abnormality in a member or members of a family must be identified before PGD to allow the detection of a particular genetic abnormality before implantation and further the transmission of a specific disorder to children. Only normal embryos are transferred to the uterus to initiate the pregnancy knowing that the embryo is not a carrier for a specific abnormality, thus decreasing the risk of having an offspring affected by a specific genetic disorder. Many of these diseases are associated with an early death or severe mental and congenital abnormalities. The monogenic diseases diagnosed through PGD include autosomal recessive conditions (e.g., β-thalassemia, cystic fibrosis, spinal muscular atrophy, and sickle cell disease), autosomal dominant conditions (Huntington’s disease, myotonic dystrophy, and Charcot-Marie-Tooth disease), or X-linked recessive conditions (fragile X syndrome, Duchenne muscular dystrophy, and hemophilia) [18].
\nPGD is also available to help parents in creating embryos that are human leucocyte antigen (HLA) compatible with a child affected by a severe blood disease, thus the selected sibling serving as a donor. PGD is an appropriate choice for carrier couples who also have infertility problems and plan to use assisted reproductive treatment anyway or for couples with an ethical or religious objection to pregnancy termination. PGD can also be used for the detection of a variety of cancer predispositions (e.g., familial breast cancer) [19, 20].
\n\nBiopsy procedures and genetic analysis technique. Genetic testing can be performed using biological samples obtained by one of the following: polar body, cleavage-stage embryo, or blastocyst biopsy [15, 16].
\nPolar body biopsy. First and second polar bodies are haploid cells produced in the first and, respectively, second meiotic division of oogenesis. The genetic evaluation of both polar bodies is required to precisely establish the genetic status of the oocyte. Because polar bodies are not a part of the zygote, this technique is mainly performed in some countries where embryo biopsy is unauthorized by law. Polar body analysis only provides data about mutations or aneuploidies of maternal origins. The chromosome abnormalities occurring postmeiotically (e.g., mosaicism and polyploidy), limited amount of genetic material, and doubling the number of samples for analysis have made the need to perform this type of biopsy questionable [36, 21].
\nCleavage-stage embryo biopsy. Cleavage-stage biopsy is usually performed on day 3 when early embryo consists of approximately 6–10 cells. At this stage, the cells are still totipotent and are not yet adhering to one another, allowing the extraction of a single blastomere for genetic testing. Limited amount of genetic material and high rates of mosaicism observed in early embryos can lead to misdiagnosis at this stage. The biopsy of two blastomeres was associated with deleterious effects on embryo development and is recommended to be avoided [22, 37].
\nBlastocyst biopsy. The embryo reaches the blastocyst stage on day 5 or 6 after fertilization. The blastocyst contains about 100 cells and comprises the outer trophectoderm and inner cell mass. During blastocyst biopsy, 5–10 trophectoderm cells are retrieved; thus, more material for genetic diagnosis is available. The ethical and safety considerations related to early embryo biopsy are overcome somewhat because the trophectoderm cells will differentiate into trophoblast cells and further go on to form placenta and other extraembryonic tissues, and not participate to form the embryo [15, 23]. Recent studies showed that this type of biopsy has no effect on reproductive capacity of a blastocyst [16, 24]. However, only about 40–50% of preimplantation embryos will reach this stage in vitro. Because the time to obtain a genetic diagnosis is very limited to perform a fresh embryo transfer, mostly frozen embryo transfer is performed after vitrification [15, 16, 36].
\n\nGenetic analysis techniques. After the biological material is available for biopsy, the genetic analysis can be performed. The evaluation is based on only a single cell or very limited genetic material. For fresh embryo transfer, the genetic diagnosis must be done within 24–36 h. The single-gene mutations are detected using molecular genetic methods (PCR, PCR-multiplex, RTqPCR, whole genome amplification, or even next-generation sequencing) and chromosomal abnormalities (e.g., translocation and aneuploidies) by cytogenetic techniques (FISH, array CGH, and SNP array) [16, 25].
\nThe embryo testing using genetic methods with the aim to detect de novo chromosomal aneuploidies is known as preimplantation genetic screening (PGS) [26]. PGS analyzes whether a single cell or a small number of cells biopsied from a preimplantation embryo is euploid before transferring it to the uterus. PGS is not PGD, being mainly offered to couples with advanced maternal age, recurrent implantation failure or recurrent miscarriages, and other conditions associated with high risk for aneuploid embryos in order to increase the success rate of IVF (~30%). PGS can be performed using FISH, multiplex quantitative PCR, or chromosomal microarrays [16, 27, 28].
\n\nGenetic counseling. A clinical genetic consultation provided by a geneticist with practice in ART is required to the couples before starting PGD treatment. Its purpose is to confirm the genetic diagnosis, to evaluate the reproductive status of the couple, and to provide information about the disease, mode of inheritance, recurrence risk, genetic testing, and reproductive options, including PGD [38].
\nGenetic counseling by a qualified geneticist or a certified genetic counselor is recommended to the couples to receive support and appropriate information in a nondirective manner and with no pressure, allowing them to make the best choice. Family history, reason for PGD, what is PGD, alternative reproductive options and side effects of treatment, the limitations of testing, success rates (about 30%), and possible outcome options should be discussed, including an unsuccessful cycle [29, 30].
\nAlso, a multiple birth should be considered when ART is used. Thus, the couple should understand and consider the physical, psychological, and financial impact of treatment [31].
\nAn important part of genetic counseling is to establish the reason for choosing PGD. In most cases, the couples choose PGD to avoid termination of pregnancy due to a genetic disease or to know earliest that the pregnancy is unaffected by a specific genetic abnormality [17]. Other reasons for PGD include a previously affected child or a loss of a child, recurrent abortions, or infertility. When parents are carriers for a recessive disorder, more embryos may be carriers for a mutant allele. The couple must be informed about the genetic status of the embryos and in the absence of a clinical feature in carriers, these can be considered for transfer to increase the number of available embryos. The issue of genetic testing of children for carrier status should be discussed prior to offering prenatal diagnosis to confirm the PGD result.
\nSex selection is not allowed by law in many countries, while in others, it is allowed. Except some recessive X-linked disorders where females may have a mild phenotype, in these cases, the female embryos should be excluded for transfer, and the parents should be able to choose not to know the sex of their embryos.
\nAfter implantation, a new contact with a geneticist is required. Occasionally, when PGD is used, a misdiagnosis can occur; therefore, prenatal diagnosis should be offered. Prenatal diagnosis requires an invasive testing (chorionic villus sampling and amniocentesis) associated with the risk of losing the pregnancy, and many of them may refuse the confirmatory test [29].
\nThe postnatal confirmatory diagnosis from blood is in contrast to recommendations for testing in childhood, which specify that unless there are clinical benefits to testing minors, testing for carrier or late disease conditions should be delayed until the child is old enough to understand the implications and be part of the decision making. In most cases, a successful PGD cycle will result in an ongoing pregnancy and a healthy live born infant. However, a follow-up after birth is recommended.
\nBiomedical ethics is based on applying various principles in order to create a framework of moral analysis that allows the practitioner to make an optimal decision in agreement with the patients’ wishes/needs and their point of view.
\nMedical genetics is one of the medical fields in which, from the very beginning, sensitive ethical issues have been raised; their importance subsequently became more and more undeniable due to technological advances and discoveries in the field (see Human Genome Project, Next Generation Sequence, and Whole Genome/Exome Sequencing).
\nOf all the areas of genetics, prenatal diagnosis raises the most fervent debates and, consequently, ethical dilemmas. It is one of the chapters that are hard to fit in an accurate guide for the clinician, sufficient enough to use and make sure he has done or said what is needed to ensure that the health of the patient and family is protected.
\nThe particularity of this field is derived from the existence of two entities whose rights must be taken into account: on one hand, the “patient,” the unborn fetus at different stages of development at the time of the diagnosis request, and on the other hand, the mother/couple requesting the diagnosis. Although the phrase“on one hand and … on the other side” might seem inappropriate, it still reflects reality, because not always the rights of the patient are on the same side as those of the parents. And here lies the first dilemma: autonomy vs. benefit.
\nIn order to improve medical practice in medical genetics and implicitly in prenatal genetic diagnosis, a set of essential ethical principles was developed to support a clinical decision [32, 35]:
Respecting the autonomy of a person referring to the right of a patient to make his/her own decision without any constraint but at the same time informed by a genetic counseling in a nonlinear and impartial manner, without prejudices.
The “do not harm” obligation and the “doing good” duty reflect on the degree of necessity of the two desires. Obviously, it is desirable to do well (benefit), but in this process, it is much more important to avoid mistakes before getting the right benefit (e.g., presymptomatic testing for early-onset diseases) [33].
Confidentiality protects the patient’s genetic data from various other parts. The data could be provided only with the patient’s consent and only if the doctor considers them relevant. However, the doctor may not respect confidentiality if the genetic data are relevant for the relatives and the patient is not able to properly inform them about familial medical conditions.
Equal access to patients for care and treatment: this concept is the most difficult to apply due to the insufficient resources.
Prenatal diagnosis (PD), and here we will only refer to invasive PD, involves a genetic test that allows the diagnosis of a fetus with a serious genetic disorder (and there is an issue of what “serious” means in the opinion of specialists), followed by communication of the data to parents. The purpose of prenatal genetic testing is exclusively medical and testing criteria should be clearly established [34].
\nWhen PD is recommended, the couple will be informed, regardless of their perspective on abortion because sometimes it can be useful for psychological and medical training for the birth of a child with a congenital anomaly [34]. However, PD is a voluntary decision of the couple who will decide if the suspected condition requires diagnosis testing or termination of the pregnancy.
\nThe distinctiveness of PD consists in this one-sided decision of the pregnant woman whose sentence affects both herself and the unborn child; if a woman is able to make an independent and well-considered decision, she must have the necessary knowledge to act in the context that PD does not only give information about a potential termination of a pregnancy but also it provides information that will prepare the parents for the birth of an affected child.
\nFor this purpose, pretesting counseling is vital, and it will determine not only the risk of the fetus being affected, but also the chances of it being normal, it will inform about the conditions that can be diagnosed and their consequences not only on the fetus but also on the care/treatment options. Furthermore, it will also provide counseling regarding the limits of the test, the possibility of an irrelevant or unexpected result, and the couple’s options after testing.
\nIf a PD is established, the physician should discuss with the pregnant woman about all the possible aspects of the clinical features, including the heterogeneity of the clinical manifestations. The informed choice of the pregnant woman/couple in the diagnosis of a fetus with congenital malformations will be respected and protected without prejudice, giving importance and priority to the family and sociocultural background in which the couple and the future malformed child will spend their lives.
\nIn the case of PD without medical indication, when the testing is only based on pregnancy/couple’s anxiety, it will be done but with a low priority in allocating resources compared to PD associated with medical reasons. The practice of PD testing with the intention of selecting the child’s sex (except for X-linked diseases) is not permitted, as well as the testing of paternity (excepting the pregnancy after an incest or rape) [34].
\nParticularly, the evolution of technology with the implementation of NGS in PD complicates the ethical aspects because, although genetic diagnosis has been improved, the method has some limitations, some of them common with those of the usual methods of PD [35]:
Diagnosing a disease for which there is no treatment.
Neither the severity of the clinical manifestations nor the progression of the disease can always be predicted only by conducting a genetic test.
There are not yet genetic tests established for all genetic diseases.
The results require a complex interpretation because the test provides a lot of data.
No test is 100% safe; the safety is dependent on the disease and the used method.
Laboratory errors sometimes do occur.
Not all pathogenic variants could be detected and interpreted.
The cost of the method is very expensive and not all the patients have financial resources.
In conclusion, ethical aspects surrounding PD are multiple and demanding for both the physician and parents, but using the qualified knowledge of a professional, exposed with much tact and patience, the couple will correctly understand the implications of the problem and their possible solutions/the lack of solutions and will take the best decision based on these aspects and according to their own convictions.
\nFor centuries, the inside of the chest cavity was a no-go area for complex surgical interventions. The problems of an open pneumothorax were already known by the ancient Greek Celsus around the year 30 AD noted: “as soon as the knife really penetrates to the chest, by cutting through the transverse septum, a sort of membrane which divides the upper from the lower parts, the man loses his life at once” [1].
\nAt that time, drainage of an empyema as described by Hippocrates (approx. 460–375 BC) was the only feasible operation [2]. The first report of a successful lung resection is attributed to Roland of Parma in 1499 who resected the herniating part of a lung, days after a penetrating chest trauma [3]. In 1846, general anesthesia with ether had been introduced by William Morton in Boston, an extremely important step in the history of surgery.
\nDuring the mid-nineteenth century, when tuberculosis reached its highest incidence, it was recognized that a state of rigidity of the mediastinum permitted an open pneumothorax. Estlander of Helsingfors was one of the first to describe wide thoracoplasty in order to “rest” a lung affected by tuberculosis (“decostalisation of the chest” in 1879) [4].
\nDuring the late nineteenth century, many experiments were carried out, mainly in animals, aimed at performing lobectomy and pneumonectomy. Usually these experiments were done in stages, the first procedure aiming at creating a state of fixation of the mediastinum. The world still was not ready yet for primary lung resections.
\nFurther in this chapter, a historical overview and an overview of modern surgical techniques for the treatment of lung cancer are outlined. The focus is on the introduction of open surgery as well as the minimally invasive surgery. In addition, a short introduction to upcoming techniques and modalities is given.
\nDuring the late nineteenth century, Joseph Lister, based on Louis Pasteur’s theory of micro-organisms, introduced the concept of asepsis in 1867. Surgeon’s hands, instruments, and surgical wounds were sterilized with 5% carbolic acid (phenol) solution and a mist of phenol was sprayed into the surgical field [5]. This policy led to an extreme reduction of post-operative mortality and for this reason, Lister is regarded as the father of modern surgery. Caroline Hampton, chief nurse and later on the wife of William Halsted, one of the founding fathers of the John’s Hopkins Hospital, developed severe dermatitis due to frequent exposure to phenol and mercuric chloride. This provoked Halsted to ask the Goodyear Company to develop rubber gloves to protect the hands of the surgical team. These became available at the end of 1890 and were soon used throughout the world [6].
\nThe aftermath of the nineteenth century saw the discovery of X-ray by William Konrad Rontgen in 1895. For the first time in mankind, it became possible to identify large tumors in the chest when not shaded by the heart and other mediastinal structures. At the turn of the twentieth century, the major barrier to enable one stage intrathoracic surgery was that of the open pneumothorax. This is remarkable since the anatomist Vesalius in 1543 had extensively studied respiration and already studied tracheotomy and positive pressure ventilation. His ideas would be dormant for about 3.5 centuries [7]. Based on this concept that there should be a pressure difference between the intra-alveolar pressure and the atmospheric pressure, Sauerbruch, still an assistant of von Mikulicz, developed the negative pressure chamber [8]—a genius idea, but quite unpractical. Only two of these operation theaters were built worldwide, one in Germany and the other one in the German Hospital (today the Lenox-Hill hospital) in New York where the surgeon Willy Meyer, emigrated to the USA from Germany in 1884, added a small positive pressure chamber over the patients head in 1909, this was called the super chamber but it was never clinically used [9]. Willy Meyer would become one of the founding fathers of the American Association for Thoracic Surgery (AATS) in 1918.
\nIn the same year, 1909, and also in New York, Meltzer and his son-in-law Auer launched their concept of positive pressure ventilation, using a flexible silk woven tracheal catheter and a continuous stream of air mixed with ether [10]. Their concept was the birth of modern anesthesia. Recognizing that this was an enormous step forward, Meltzer was invited to become the first president of the AATS. In a speech delivered at the founding meeting of the AATS, Willy Meyers stated: “The thorax was the last fortress to be attacked and it has been laid open safely to the surgeon’s knife” [9].
\nLung cancer was a very rare disease in the beginning of the twentieth century. In 1919, Alton Ochsner, as a medical student was invited with his whole class to witness an autopsy of a patient who died of lung cancer. The pathologist announced that no one in that class would ever again see another such case [11]. It took 17 years before Ochsner, who had become a surgeon, saw his second case, followed by 8 other cases in the 6 following months. All of these patients were male and had served as soldiers in World War I and in the line of duty they had taken up the habit of smoking, provoked by mass advertisements promoting smoking. Ochsner was amongst the first surgeons to correlate smoking to the development of lung cancer [12]. With the lung cancer epidemic which started after World War I, the number of patients with potentially resectable lung cancer increased significantly. Two major surgical items had to be settled; should a lung resection for cancer be a lobectomy or a pneumonectomy and what is the best surgical technique? Is it mass hilar ligation or anatomical dissection? The first report on lobectomy for lung cancer was that of Edward Churchill (Boston) in 1932 [13]. One year later, Evarts Graham, while intending to perform a lobectomy, was forced to perform a pneumonectomy because the tumor was very centrally located in the hilum at the origin of the left upper lobe (bronchoplastic procedures such as sleeve resection had not been developed yet) [14]. For a considerably long period, pneumonectomy was regarded as the golden standard for all lung cancer patients. Lobectomy by many was considered inferior and compared with lumpectomy without resection of loco-regional lymph nodes in breast cancer [15]. Only in 1962, a large case series between pneumonectomy and lobectomy were compared showing that lobectomy was equivalent to pneumonectomy as a cancer operation but with a lower rate of complications and mortality [16].
\nWith respect to surgical technique, there was no consensus on hilar control; mass ligation or anatomical dissection and step-by-step control of the hilar structures. Cadaveric studies performed by Blades and Kent in the early 1940s pushed the world toward the latter, later supported by several publications of Boyes on the intrahilar anatomy of the lung segments [10, 17].
\nWith this knowledge, Clement Thomas Price (London, 1947) introduced the concept of parenchyma sparing operations, having done the first anatomical segmentectomy in a lung cancer patient [18]. The first sleeve resection for bronchogenic carcinoma was performed in 1952 [19]. Consequently, it was around the mid-1950s the four main operations in lung cancer as we know today were in the armamentarium of the thoracic surgeon: pneumonectomy, lobectomy, sleeve lobectomy, and segmentectomy.
\nA major step forward was the introduction of double lumen endo-tracheal tube by Carlens in 1949 [20]. With this selective single lung ventilation concept, modern lung surgery is greatly facilitated, particularly, the endoscopic and robotic techniques used nowadays (discussed later in this chapter).
\nDiagnostic techniques were still very primitive in that era compared with today’s standards. Besides standard chest X-ray, there was rigid bronchoscopy, bronchography, planography, and cytology. The concept of staging had to be developed yet. Exploratory thoracotomy in “operable patients” was performed with a very low threshold, not to lose time. Some authors reported up to 50% inoperability [21]. In the Amsterdam University Hospital between 1955 and 1960 in a series of 100 exploratory thoracotomies in patients who were found to be inoperable, 54% of patients had complications and 9 of the 100 patients died due to post-operative complications [22]. In 63% of the cases, mediastinal ingrowth or large irresectable nodes were found. In 23%, there was in growth in heart and/or major vessels, 12% ingrowth into the thoracic wall, 1% in growth in the diaphragm, and 1% pleural carcinomatosis. By far, mediastinal involvement was the leading cause of inoperability. In 1959, Carlens had published his experience with 100 mediastinoscopies [20]. The morbidity of this technique was 2.5% and the mortality was less than 0.5%, way better then exploratory thoracotomy. The Amsterdam team embraced mediastinoscopy and combined this in a series of operable patients with bronchoscopy and on indication diagnostic pneumothorax. Due to the mediastinoscopy findings, the resection rate in Amsterdam rose from 60 to 94% with 12% false positive mediastinoscopies [20]. Years later, in 1984, Griffith Pearson published a landmark paper showing that when positive mediastinal nodes were found, any subsequent lung resection would not cure a patient [23].
\nThe world was waiting for methods to better identify loco-regional progression and distant metastases. Hounsfield, by combining tomography images with the calculating power of a computer, constructed the first computed tomography (CT) scanner, first for brain scans only, but in 1975 he and his team built the first whole body scanner. The computed tomography (CT) scanner was soon to be followed by the magnetic resonance imaging (MRI) scanner in 1977, while the next big step was the combination of positron emission tomography (PET) and CT scanners in 1991. The use of mediastinoscopy has declined after the introduction of ultrasound-guided examinations of the mediastinum and the hilum (endo-esophageal ultrasound (EUS) and endo-bronchial ultrasound bronchoscopy (EBUS)), but is still used on a regular base when the latter techniques fall short.
\nFor decades, postero-lateral thoracotomy has been the preferred entrance for most lung resections (Figure 1A). However, the price of an excellent exposure to the lung hilum came with high percentages of long standing post-operative pain, discomfort, and functional loss.
\nOverview of the surgical approaches for treatment of lung cancer. (A) Postero-lateral thoracotomy, (B) 3 ports, video-assisted thoracic surgery (VATS), (C) uniportal video-assisted thoracic surgery (UVATS), (D) robotic-assisted thoracic surgery (RATS), and (E) endo-bronchial surgery.
The Swedish internist Jacobeus is often positioned as the founding father of thoracoscopy but in fact, it was the British surgeon Francis Richard Cruse who already had published this technique in 1865 [24].
\nThe first thoracoscopic resections were not immediately embraced by the surgical community. Ralph Lewis was the first one to publish a series of 100 lobectomies done thoracoscopically [25]. Lacking experience, tailor-made instruments, and specific endo-staplers, these resections were performed using a mass stapling technique. In Los Angeles, Robert McKenna worked out a standardized approach for video-assisted thoracic surgery (VATS) lobectomy (Figure 1B), working through the hilum from anterior to posterior; in 2006, he published a series of 1100 cases [26].
\nThis provoked surgeons around the world to adapt this technique and today in many hospitals, it is the preferred approach for the majority of cases. In 2019, Eric Lim published the results of the VIOLET trial, a prospective randomized trial between VATS and thoracotomy in lung cancer patients. VATS showing to be superior with respect to major adverse events, less pain on post-operative day 2 and shorter median hospital stay with an equal oncological outcome (number of lymph nodes harvested and upstaged and R-0 resections) [27].
\nStudies on chronic pain (pain for which patients visit a doctor 3 months post-operative), however, did not show a major difference in pain between thoracotomy patients and VATS patients 3–6 months post-operatively [28]. Chronic pain after VATS is often contributed to the insult of multiple intercostal nerves by trocars and instruments. It has to be seen whether the explanation is that simple, however, it moved surgeons to search for even less invasive methods, eventually leading to the concept of uniportal VATS (UVATS), first proposed by Rocco in 2004 [29] (Figure 1C).
\nThere is still no proof that an UVATS approach leads to less pain, discomfort, and loss of functionality compared with multiple port VATS.
\nWith the idea of intercostal nerve damage in mind, surgeons have also explored other VATS-assisted intrathoracic pathways like subxiphoid and cervical approaches [30, 31]. Others are exploring a hybrid approach, combining 5 mm intercostal ports with a subxiphoid approach [32].
\nAlmost parallel with the introduction and evolution of VATS, the world saw the introduction of robotic-assisted thoracic surgery (RATS), first published by Franca Melfi and her team [33] (Figure 1D).
\nUp till now, no significant differences have been shown in complications and outcome between VATS, UVATS, and RATS [34]. The major reason that the introduction of RATS lagged behind in many institutions is a financial reason; it is not cost-efficient. In the meantime, VATS has evolutionized to three-dimensional VATS (3D VATS) and robotic-like instruments have become available for laparoscopic and VATS procedures.
\nDuring the last decade, there is a growing interest in lung parenchyma-sparing resections. This need is more highlighted by the results of the two largest population based national screening studies (NLST, 2011 and NELSON, 2018) showing that discovery and resection of early stage lung cancer through screening programs lead to significantly better survival of patients [35, 36]. The NLST study showed a reduction of 20% in lung cancer mortality for annual screening over 3 years with low-dose CT with a greater benefit for screening in women. The NELSON study showed for screening with low-dose CT, a 26% reduction of lung cancer mortality in high-risk men and up to 61% reduction of lung cancer mortality in high-risk women over a 10-year period. Nowadays, there is a trend toward sub-lobar resection as segmentectomy, making the oncological lung surgery even more challenging. Moreover, this makes the role of peri-operative diagnostic tools as fluorescent indocyanine green (ICG) [37], 3D-CT modalities, and (navigational) bronchoscopy interventions (next section, Figure 1E) indispensable. Because of its anatomical complexity, many surgeons hesitate to perform segmentectomy. For this reason, in 2012, Hiroaki Nomori and Morihito Okada published the book “Illustrated Anatomical Segmentectomy for Lung Cancer” which is an essential book for surgeons starting a segmentectomy program at their centers. In 2019, segmentectomy is mostly performed in countries of Eastern Asia, such as Japan, followed by few centers in the USA and Western Europe.
\nOver the past few decades, imaging modalities such as CT, PET-CT, and standard chest X-ray imaging have played a key role in the non-invasive diagnostic work-up of thoracic disease. In addition, these imaging modalities are an essential part of the preoperative planning process of thoracic surgical procedures. Even though there is a broad range of clinical indications for various thoracic imaging modalities and the information provided by all different modalities is different, the purpose of this section is not to undertake a comprehensive evaluation of the characteristics of these imaging modalities. Specifically, this section will focus on innovative preoperative and intraoperative imaging modalities as a surgical planning and navigation tools and provide a brief overview of new developments in medical imaging, especially in the context of (oncologic) pulmonary resections.
\nIn the setting of oncologic thoracic surgery, a standard chest CT scan can be used to evaluate the extensiveness of disease in terms of pleural, mediastinal, chest wall, or vascular involvement. In addition, the CT scan is used to study the surgical anatomy of the pulmonary artery (and its major branches), pulmonary vein, and bronchial structures when a resection of the lung parenchyma is planned. Due to the establishment and development of more modern multislice CT scanners, it has become easier to detect smaller peripheral tumors. While this has enabled more diagnostic accuracy, it has resulted in an increased clinical use of sublobar anatomic resections. Specifically, in the setting of anatomic segmental pulmonary resections, which are technically and anatomically more demanding and complex, there is a need for more accurate imaging modalities that enables better preoperative knowledge of the surgical anatomy (such as bronchial and vascular anatomy in sublobar/segmental levels). Recently, an increasing number of scientific reports have been published on the use of preoperative three-dimensional (3D)-CT reconstruction as a surgical planning tool before anatomic resection of pulmonary segments or lobes [38, 39, 40, 41, 42]. According to some of these studies, the preoperative use of 3D-CT reconstructed images is feasible and safe and, in some cases, associated with shorter operative time due to better preoperative understanding of surgical anatomy [38, 42]. In order to obtain 3D-CT image reconstructions, different methods are described and various (free open-source) software packets are available [42, 43, 44]. However, there are also limitations regarding the utility of software to reconstruct 3D images of CT scans. For example, the identification and separation of the pulmonary artery and vein may be a challenging and time-consuming process. Moreover, in some cases, a contrast-enhanced CT scan is required to create 3D-simulations, which increases the risks of radiation exposure. In addition, the reconstruction commonly requires technical support and the assistance of radiology and information and communication technology (ICT) experts.
\nOizumi et al. reported a study on the use of 3D reconstruction of multidetector CT (MDCT) images in order to plan and guide pulmonary segmentectomy preoperatively and during surgery [38]. It was noted that after the introduction of 3D-CT reconstruction, the number of (fairly) difficult classified segmentectomies that have been performed increased significantly, suggesting that preoperative 3D-CT simulation contributes fairly to the efficacy of surgical planning of complex segmentectomies. In addition, in a retrospective analysis of patients undergoing thoracoscopic segmentectomy reported by Xue et al., the authors found that when preoperative 3D-CT reconstruction was used to make operation plans, in 19% of the cases, the operation plan was changed due to the results of 3D simulation [42]. The original surgical plan of these cases was changed due to the expectation of an inadequate resection margin distance, based on pre-operative simulation results. This indicates that preoperative 3D simulation not only contributes to technical feasibility and efficacy of surgery, but also to the decision-making process from an oncological point of view.
\nEven though an increasing number of studies on the use of 3D-CT simulation are being published, the majority of them do not report on the differences in parameters of clinical outcome (such as perioperative blood loss, post-operative stay, and conversion rates to thoracotomy) but focus more on technical aspects and feasibility of 3D-simulation and surgery. However, the majority of reports do recognize the following advantages of preoperative 3D-simulation in the context of (sub-)lobar pulmonary resection: (1) classification and identification of anatomical (vascular and bronchial) abnormalities; (2) identification of unsuitable surgical cases for segmentectomy; (3) training of less experienced thoracic surgeons and surgical residents; (4) preoperative estimation of proper surgical resection margin; (5) a step-wise preoperative surgical planning; and (6) intraoperative navigation for identification of anatomical structures [38, 40, 41, 42].
\n3D-CT-mediated preoperative surgical planning and intraoperative guidance of (oncological) pulmonary surgery could contribute significantly to the development of more accurate and safer (sublobar) anatomic resections. In the near future, this technology will become more common in thoracic surgery. However, in order to reach that stage, some (mostly technical) limitations need to be overcome.
\nVirtual reality (VR) is a technology that enables users to interact with a computer-generated virtual 3D interface (Figure 2). More interestingly, in augmented reality (AR), the user is able to overlay aspects of the VR world within the real physical world. Finally, mixed reality (MR) allows users to create a hybrid physical and virtual world and offers the possibility to interact and analyze objects in the physical world by virtual projections [45, 46].
\nAn example of virtual reality application during minimally invasive lung cancer surgery in the operating theater.
Recently, surgical intraoperative navigation as well as preoperative surgical simulation based on VR, MR, and AR have been developed and successfully used in various surgical fields including neurosurgery, liver surgery, kidney surgery, and orthopedic surgery [47, 48, 49, 50, 51]. In contrast to 2D interfaces (e.g. conventional CT scans), VR, MR, and AR enable not only visualization of anatomical structures but also allow interactive manipulation of the digital information (e.g. anatomic structures) provided by (wearable) computer-integrated devices (such as the Microsoft Hololens or the Google Glass). It has been suggested that these new interfaces might have the potential to benefit both the surgeon and the patient. For surgeons, this benefit comes by the way of improved preoperative surgical planning, better and more accurate intraoperative imaging guidance, and a better preoperative awareness of anatomical abnormalities. Patients will potentially benefit from shorter operative time, shorter length of hospital stay, and improved outcomes. Additionally, AR, VR, and MR offer the possibility to simulate surgical situations as well as facilitating training for surgeons and residents. In the field of thoracic surgery, some of these modalities have been used over the past few years in order to train surgical residents and surgeons to master the techniques necessary for minimally invasive lung surgery [52].
\nHowever, only very few reports are available on the use of AR, VR, or MR for surgical planning or intraoperative navigation for lung surgery [53, 54, 55]. Frajhof et al. recently published a study on the use of AR, VR, and MR technology in the preoperative planning of a technically demanding VATS left upper lobectomy [53]. In another study from Rouzé et al., augmented reality was used as a navigation tool in combination with cone beam CT (CBCT) to guide intraoperative localization of pulmonary nodules for wedge resection through VATS. The investigators firstly localized the lesions by CBCT intraoperatively. Subsequently, a 3D reconstruction of the nodule was created by using software. After this, an augmented fluoroscopic 3D image of the pulmonary nodule was projected on a screen in front of the operating table. By this, the surgeon was able to localize the lesion intraoperatively and perform a wedge resection safely [54].
\nInterestingly, also some reports are available on the use of VR 3D reconstruction of the airways, known as virtual bronchoscopy, specifically used as a diagnostic aid tool in the assessment of airway masses and stenosis [56, 57]. Virtual bronchoscopy contributes fairly to the diagnostic process since it enables diagnostic maneuvers, such as assessing bronchial anatomy distally from stenoses, which are not possible with standard flexible bronchoscopy. Moreover, virtual bronchoscopy is a noninvasive method and does not bear any additional risks (e.g. radiation exposure or iatrogenic airway damage) for patients. Despite these advantages, virtual bronchoscopy is not expected to completely replace flexible bronchoscopy due to some limitations. For example, tumor boundaries can be misjudged by intrabronchial secretions that might lead to a false-positive result. Moreover, it has shown not to be sensitive and effective enough for detecting small mucosal abnormalities (e.g. erythema and erosion), dynamic stenoses (caused by, for example, the respiratory cycle or vocal cords), and in differentiating mucus plugs from a mass. Finally, virtual bronchoscopy has the limitation that it does not enable biopsies.
\nIn the past two decades, there has been an increase in the development of innovative technologies to facilitate more accurate, efficient, and safe (minimally invasive) thoracic interventions. Specifically, there have been some reports on the progress of innovative therapeutic modalities that approach lung cancer through other minimally invasive methods than direct surgery. Examples of these therapeutic options are thermal ablation, including radiofrequency ablation (RFA), microwave ablation (MWA), and cryoablation of malignant lung lesions. This section will touch on some of these developments and review some outcomes of thermal ablation therapy.
\nAmongst various thermal ablation therapies, RFA is a well-studied method, especially in the treatment of liver cancer [58, 59]. Due to favorable outcomes in the treatment of liver cancer, specifically hepatocellular carcinoma, the application of this technology to malignant lesions in other organs, including the lungs, has been growing. RFA involves the insertion of a probe inside the affected target tissue. The electrode on the probe generates frictional heat that creates coagulation necrosis of the surrounding (tumor) lung parenchyma. In pulmonary surgery, the use of RFA has been reported in the treatment of various malignant lesions including inoperable lung cancer [60, 61, 62], primary or metastatic pulmonary tumors of less than 3.5 cm in size [63], and stage I-4 non-small cellular lung cancer (NSCLC) not eligible for surgery [64, 65, 66, 67]. Results from retrospective studies on RFA of primary malignant lung lesions have suggested reasonable overall 1-year survival rates ranging from 78 to 94% in patients with early stage lung cancer [66, 68, 69, 70]. A 5-year survival rates have been reported to be significantly lower and in the range of 25–58% [66, 71, 72]. Important prognostic factors in RFA therapy of lung cancer, in terms of survival, are the additional use of targeted systemic therapies, lesions less than 3 cm (diameter), a Charlson comorbidity index (an index of associated comorbidities) >5, and lower stage disease [66, 73].
\nA major drawback of RFA therapy compared with surgical resection is the poor results of local progression control [74]. This limitation might be explained by the fact that in RFA therapy no systematic lymph node dissection is carried out and, additionally, no good method exists to check for local adequate treatment margins. With regard to complications, pneumothorax is one of the most common complications associated with RFA. However, it is most often (>80%) treated conservatively without the need for chest tube drainage [75]. In addition, pleural effusion might develop after RFA, however, similar to pneumothorax, does not often (<5%) require intervention [75]. In summary, RFA therapy seems an effective and relatively safe intervention for treating lung cancer, however, a careful patient selection is necessary. Moreover, more future long-term and large randomized controlled trials are necessary to compare the clinical outcomes between RFA, surgical resection, and other modalities of thermal ablation therapy.
\nMWA involves hyperthermia-mediated ablation of tissue by causing friction between water molecules in the target tissue. By creating a dipole excitation, hyperthermia is generated and coagulation necrosis results in the lesion and surrounding tissue [76, 77]. The placement of the probes is commonly guided by CT/CT-fluoroscopy. MWA has been successfully used to create larger ablation zones than RFA. Compared with RFA, MWA technology is thought to be more effective in creating larger zones of coagulation necrosis due to the elimination of heat loss through heat sink (the loss of heat through blood flow inside the target tissue) [76].
\nStudies and long-term data after MWA as a thermal ablation modality are limited when compared with RFA. In a recent review, Yuan and colleagues reported a meta-analysis of clinical outcomes after RFA and MWA for primary and metastatic pulmonary malignancies [75]. The authors identified 11 studies based on MWA compared with 42 studies based on RFA therapy, all with a retrospective study design. In this meta-analysis, it was demonstrated that RFA seems to be superior to MWA with regard to overall survival (up to 5 years) for both primary and metastatic pulmonary malignancies. However, the authors note that the results of lung metastasis should be interpreted carefully, since small groups of patients were included in the analysis based on only a few retrospective studies. With regard to local tumor progression free survival, RFA and MWA showed similar results. In addition, similar to RFA, MWA is a relatively safe intervention which is not associated with high complication rates. Yuan et al. reported comparable rates of pneumothorax and pleural effusion after ablation by MWA and RFA [75]. Concerning prognostic factors negatively affecting survival and local tumor progression control, more advanced disease stage, tumors >3 cm (diameter), and emphysematous lungs have been identified [78].
\nAn opposite method of hyperthermia induced ablation, termed cryoablation, creates protein denaturation, ischemia, cell rupture, and necrosis through local hypothermia (temperatures < −40°C) [79]. In this technique, compressed argon gas is used to create freezing temperatures that induce local injury to the tissue. Subsequently, helium is used to thaw the tissue. Comparable to MWA, in cryoablation, multiple probes can be used to increase the ablation area in the tissue and placement under the guidance of CT/CT-fluoroscopy. Although cryosurgery is a relatively old ablative technique, use of cryoablation in the context of lung cancer and long-term studies are limited. Besides percutaneous cryoablation, other methods of cryoablative strategies are endo-bronchial (for obstructive intrabronchial tumors) (Figure 1E) and intrathoracic (during surgery). Specific indications for each modality have been reviewed by Niu and colleagues and are beyond the scope of this chapter [80].
\nSince thermal ablation therapies are commonly reserved for patients not eligible for curative surgery, tumor recurrence after radiotherapy or patients who refuse surgery, even though they have resectable lesions, cryoablation is often offered as a therapy to palliate symptoms or to increase survival in advanced disease stage. Consequently, a number of reports have been published on the use of cryoablation for the treatment of medically inoperable NSCLC, advanced stages of NSCLC, and for pulmonary metastasis [80, 81, 82, 83, 84]. Niu et al. reported on a series of 840 patients with NSCLC who received percutaneous cryoablative therapy for various stages of NSCLC ranging from IIa to IV. The reported overall survival was 68, 52, 34, 26, and 17% for 1-, 2-, 3-, 4-, and 5-year, respectively. Local and peripheral recurrence rates were 28.3 and 47.2%, respectively, after a median follow-up of 34 months (range 4–63 months). For patients with less advanced NSCLC, better outcome is reported in terms of overall survival. In 2012, Yamauchi et al. demonstrated a 2-year overall survival of 88% in medically inoperable patients with stage I NSCLC who were treated with percutaneous cryoablation [84]. In addition, Moore and colleagues published a study in which an overall survival rate of 67.8% was reported in patients with stage I NSCLC after 5 years [82].
\nRegarding cryoablation therapy in metastatic lung lesions, studies have also proven the efficacy and safety of percutaneous cryoablation. For example, Yamauchi et al. reported a 3-year progression free survival rate of 59% for patients with metastatic colorectal carcinoma treated with cryoablation [85]. Factors associated with local tumor progression or poor prognosis have been studied by multivariate analyses. Interestingly, most of these factors (e.g. tumor size <3 cm and stage of disease) are comparable to the factors in other modalities of thermal ablation [78, 80]. Regarding the safety profile of cryoablation compared with other modalities of thermal ablation, comparable rates of pneumothorax and pleural effusion are reported in the literature [77, 80]. However, incidental reports of transient recurrent laryngeal nerve neuropraxia have also been documented [86].
\nUntil the late nineteenth century, the inside of the chest cavity was a no-go area for complex surgical interventions. The world still was not ready yet for primary lung resections. To make the lung surgery possible, several giant steps were undertaken: the introduction of aseptic concept by Joseph Lister in 1867, the discovery of X-ray by William Konrad Rontgen in 1895, and the introduction of positive pressure ventilation by Meltzer and Auer in 1909. With the lung cancer epidemic after World War I, the number of patients with potentially resectable lung cancer increased significantly. Surgeons around the world were debating on the preferable resection (lobectomy vs. pneumonectomy) and the best surgical technique: mass hilar ligation versus anatomical dissection. While the first report on lobectomy for lung cancer in 1932, it took almost 30 years to report that lobectomy was the preferred resection for lung cancer surgery. In the same period, the anatomical dissection technique gained wider application. This all together with the discovery of double lumen endo-tracheal tube by Carlens in 1949 paved the way for modern lung resection techniques. The introduction of diagnostic tools as CT, MRI, PET-CT, and later EUS and EBUS facilitated even better tumor localization and mediastinal evaluation decreasing the surgical mortality.
\nThe next major challenge was decreasing the morbidity of thoracotomy: high percentages of long standing post-operative pain, discomfort, and functional loss. The solution led to the development of modern minimally invasive lung surgery. In 2006, Robert McKenna published a standardized approach for VATS lobectomy in a series of 1100 cases leading to global adaptation of VATS for lung surgery. While VATS showing to be superior with respect to major adverse events, less pain on post-operative day 2 and shorter median hospital stay with an equal oncological outcome, studies on chronic pain, however, did not show a major difference in pain between thoracotomy and VATS. This moved surgeons to search for even less invasive methods, eventually leading to the concept of uniportal VATS, first proposed by Rocco in 2004, subxiphoid and cervical approaches, and hybrid approach combining 5 mm intercostal ports with a subxiphoid approach. At the same time, the world witnessed the introduction of RATS by Franca Melfi and her team, however, because of the financial reasons, the introduction of RATS in many centers lagged behind. In the meantime, VATS has evolutionized to 3D-VATS and robotic like instruments have become available for laparoscopic and VATS procedures. Whether all these approaches will lead to reduction of chronic pain is yet to be determined.
\nThe results of major screening programs have shifted the trend of lung resection toward sub-lobar resection as segmentectomy, making the lung surgery even more challenging. Moreover, this makes the role of peri-operative imaging tools as fluorescent indocyanine green (ICG), 3D-CT modalities, and (navigational) bronchoscopy interventions indispensable.
\nThe upcoming VR, AR, and MR enable a more naturalistic 3D presentation of human anatomy in a digital interface. As a diagnostic tool, it can provide physicians with a more realistic view of the patient’s anatomy and might enable diagnostic assessment, preoperative surgical planning, and intraoperative guidance. In addition, it can provide training and learning platform for students, residents, and surgeons. It has already proven its added value for a broad range of surgical procedures; however, AR/VR/MR has not been used widely in thoracic surgery yet. Considering the speed of development of this technology in other areas, it is expected that it will make its way into the world of thoracic surgery in the near future. In this perspective, hybrid operating theaters including 3D-CT and (robotic-assisted) navigational bronchoscopy tools are already on their way. To address this, however, it is essential that thoracic surgeons have an active and open attitude toward the introduction of innovative (digital) applications.
\nWith respect to endo-bronchial interventions, thermal ablation therapy seems to provide an efficacious and safe alternative for surgical therapy of lung cancer and lung cancer metastasis. However, patient’s selection should be carried out with caution and should be personalized for each patient based on type of cancer (e.g. NSCLC), comorbidities, tumor size, and disease stage. Specifically, thermal ablation therapy could offer a palliative or even a life-prolonging treatment option for non-surgical candidates. Hopefully future long-term and larger prospective (randomized controlled) trials will answer the remaining questions. For example, it will be necessary to study the impact of combining thermal ablation therapy with other conventional (e.g. systemic or radiotherapy) therapies for the treatment of lung cancer. In addition, more data are warranted on the determination of the best therapy for incomplete ablations and/or local recurrence of disease. More interestingly, biomarkers or novel imaging techniques to follow-up on ablative therapies are also required, especially since the radiological follow-up of recently ablated lung tissue is very challenging. More data and confirmation of these data are therefore necessary and need to be generated by future multicenter trials.
\nTo conclude, this chapter provides a historical overview and a summary of state-of-the-art surgical techniques in the treatment of lung cancer today. The journey of lung surgery was and is a very challenging one, with major hurdles to overcome. It departed from a “no-go” era, leaving behind the golden standard of pneumonectomy and thoracotomy, to arrive in the current era of minimally invasive and robotic-assisted surgery. The journey continues toward the horizon of non-intubated operations, sub-lobar resections, virtual reality imaging modalities, navigational bronchoscopy interventions, and hybrid procedures. We are heading toward the era of incisionless, natural orifice surgery: an almost science fiction vision, yet nothing is more real.
\nThe contribution of Egied Simons (Simons Productions, Mathenesserdijk 236A, 3026 GL, Rotterdam, The Netherlands) and Chris Hordijk (Medical VR, van Eeghenstraat 98, 1071JL, Amsterdam, The Netherlands) in generating the figures is highly appreciated. We would like to thank Dr. F. Incekara (Departments of Neurosurgery and Radiology, Erasmus Medical Center, Rotterdam, The Netherlands) for his helpful advice.
\nVATS | video-assisted thoracic surgery |
UVATS | uniportal video-assisted thoracic surgery |
RATS | robotic-assisted thoracic surgery |
3D | three-dimensional |
CT | computed tomography scanner |
AATS | American Association for Thoracic Surgery |
MRI | magnetic resonance imaging scanner |
PET | positron emission tomography |
EUS | endo-esophageal ultrasound |
EBUS | endo-bronchial ultrasound bronchoscopy |
ICG | indocyanine green |
ICT | information and communication technology |
MDCT | multidetector computed tomography |
VR | virtual reality |
AR | augmented reality |
MR | mixed reality |
CBCT | cone beam computed tomography |
RFA | radiofrequency ablation |
MWA | microwave ablation |
NSCLC | non-small cellular lung cancer |
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\\n\\n7.8 Governing law: This Publication Agreement and any dispute or claim (including non-contractual disputes or claims) arising out of or in connection with it or its subject matter or formation shall be governed by and construed in accordance with the law of England and Wales. The parties submit to the exclusive jurisdiction of the English courts to settle any dispute or claim arising out of or in connection with this Publication Agreement (including any non-contractual disputes or claims).
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The Corresponding Author (acting on behalf of all Authors) and INTECHOPEN LIMITED, incorporated and registered in England and Wales with company number 11086078 and a registered office at 5 Princes Gate Court, London, United Kingdom, SW7 2QJ conclude the following Agreement regarding the publication of a Book Chapter:
\n\n1. DEFINITIONS
\n\nCorresponding Author: The Author of the Chapter who serves as a Signatory to this Agreement. The Corresponding Author acts on behalf of any other Co-Author.
\n\nCo-Author: All other Authors of the Chapter besides the Corresponding Author.
\n\nIntechOpen: IntechOpen Ltd., the Publisher of the Book.
\n\nBook: The publication as a collection of chapters compiled by IntechOpen including the Chapter. Chapter: The original literary work created by Corresponding Author and any Co-Author that is the subject of this Agreement.
\n\n2. CORRESPONDING AUTHOR'S GRANT OF RIGHTS
\n\n2.1 Subject to the following Article, the Corresponding Author grants and shall ensure that each Co-Author grants, to IntechOpen, during the full term of copyright and any extensions or renewals of that term the following:
\n\nThe aforementioned licenses shall survive the expiry or termination of this Agreement for any reason.
\n\n2.2 The Corresponding Author (on their own behalf and on behalf of any Co-Author) reserves the following rights to the Chapter but agrees not to exercise them in such a way as to adversely affect IntechOpen's ability to utilize the full benefit of this Publication Agreement: (i) reprographic rights worldwide, other than those which subsist in the typographical arrangement of the Chapter as published by IntechOpen; and (ii) public lending rights arising under the Public Lending Right Act 1979, as amended from time to time, and any similar rights arising in any part of the world.
\n\nThe Corresponding Author confirms that they (and any Co-Author) are and will remain a member of any applicable licensing and collecting society and any successor to that body responsible for administering royalties for the reprographic reproduction of copyright works.
\n\nSubject to the license granted above, copyright in the Chapter and all versions of it created during IntechOpen's editing process (including the published version) is retained by the Corresponding Author and any Co-Author.
\n\nSubject to the license granted above, the Corresponding Author and any Co-Author retains patent, trademark and other intellectual property rights to the Chapter.
\n\n2.3 All rights granted to IntechOpen in this Article are assignable, sublicensable or otherwise transferrable to third parties without the Corresponding Author's or any Co-Author’s specific approval.
\n\n2.4 The Corresponding Author (on their own behalf and on behalf of each Co-Author) will not assert any rights under the Copyright, Designs and Patents Act 1988 to object to derogatory treatment of the Chapter as a consequence of IntechOpen's changes to the Chapter arising from translation of it, corrections and edits for house style, removal of problematic material and other reasonable edits.
\n\n3. CORRESPONDING AUTHOR'S DUTIES
\n\n3.1 When distributing or re-publishing the Chapter, the Corresponding Author agrees to credit the Book in which the Chapter has been published as the source of first publication, as well as IntechOpen. The Corresponding Author warrants that each Co-Author will also credit the Book in which the Chapter has been published as the source of first publication, as well as IntechOpen, when they are distributing or re-publishing the Chapter.
\n\n3.2 When submitting the Chapter, the Corresponding Author agrees to:
\n\nThe Corresponding Author will be held responsible for the payment of the Open Access Publishing Fees.
\n\nAll payments shall be due 30 days from the date of the issued invoice. The Corresponding Author or the payer on the Corresponding Author's and Co-Authors' behalf will bear all banking and similar charges incurred.
\n\n3.3 The Corresponding Author shall obtain in writing all consents necessary for the reproduction of any material in which a third-party right exists, including quotations, photographs and illustrations, in all editions of the Chapter worldwide for the full term of the above licenses, and shall provide to IntechOpen upon request the original copies of such consents for inspection (at IntechOpen's option) or photocopies of such consents.
\n\nThe Corresponding Author shall obtain written informed consent for publication from people who might recognize themselves or be identified by others (e.g. from case reports or photographs).
\n\n3.4 The Corresponding Author and any Co-Author shall respect confidentiality rights during and after the termination of this Agreement. The information contained in all correspondence and documents as part of the publishing activity between IntechOpen and the Corresponding Author and any Co-Author are confidential and are intended only for the recipient. The contents may not be disclosed publicly and are not intended for unauthorized use or distribution. Any use, disclosure, copying, or distribution is prohibited and may be unlawful.
\n\n4. CORRESPONDING AUTHOR'S WARRANTY
\n\n4.1 The Corresponding Author represents and warrants that the Chapter does not and will not breach any applicable law or the rights of any third party and, specifically, that the Chapter contains no matter that is defamatory or that infringes any literary or proprietary rights, intellectual property rights, or any rights of privacy. The Corresponding Author warrants and represents that: (i) the Chapter is the original work of themselves and any Co-Author and is not copied wholly or substantially from any other work or material or any other source; (ii) the Chapter has not been formally published in any other peer-reviewed journal or in a book or edited collection, and is not under consideration for any such publication; (iii) they themselves and any Co-Author are qualifying persons under section 154 of the Copyright, Designs and Patents Act 1988; (iv) they themselves and any Co-Author have not assigned and will not during the term of this Publication Agreement purport to assign any of the rights granted to IntechOpen under this Publication Agreement; and (v) the rights granted by this Publication Agreement are free from any security interest, option, mortgage, charge or lien.
\n\nThe Corresponding Author also warrants and represents that: (i) they have the full power to enter into this Publication Agreement on their own behalf and on behalf of each Co-Author; and (ii) they have the necessary rights and/or title in and to the Chapter to grant IntechOpen, on behalf of themselves and any Co-Author, the rights and licenses expressed to be granted in this Publication Agreement. If the Chapter was prepared jointly by the Corresponding Author and any Co-Author, the Corresponding Author warrants and represents that: (i) each Co-Author agrees to the submission, license and publication of the Chapter on the terms of this Publication Agreement; and (ii) they have the authority to enter into this Publication Agreement on behalf of and bind each Co-Author. The Corresponding Author shall: (i) ensure each Co-Author complies with all relevant provisions of this Publication Agreement, including those relating to confidentiality, performance and standards, as if a party to this Publication Agreement; and (ii) remain primarily liable for all acts and/or omissions of each such Co-Author.
\n\nThe Corresponding Author agrees to indemnify and hold IntechOpen harmless against all liabilities, costs, expenses, damages and losses and all reasonable legal costs and expenses suffered or incurred by IntechOpen arising out of or in connection with any breach of the aforementioned representations and warranties. This indemnity shall not cover IntechOpen to the extent that a claim under it results from IntechOpen's negligence or willful misconduct.
\n\n4.2 Nothing in this Publication Agreement shall have the effect of excluding or limiting any liability for death or personal injury caused by negligence or any other liability that cannot be excluded or limited by applicable law.
\n\n5. TERMINATION
\n\n5.1 IntechOpen has a right to terminate this Publication Agreement for quality, program, technical or other reasons with immediate effect, including without limitation (i) if the Corresponding Author or any Co-Author commits a material breach of this Publication Agreement; (ii) if the Corresponding Author or any Co-Author (being an individual) is the subject of a bankruptcy petition, application or order; or (iii) if the Corresponding Author or any Co-Author (being a company) commences negotiations with all or any class of its creditors with a view to rescheduling any of its debts, or makes a proposal for or enters into any compromise or arrangement with any of its creditors.
\n\nIn case of termination, IntechOpen will notify the Corresponding Author, in writing, of the decision.
\n\n6. INTECHOPEN’S DUTIES AND RIGHTS
\n\n6.1 Unless prevented from doing so by events outside its reasonable control, IntechOpen, in its discretion, agrees to publish the Chapter attributing it to the Corresponding Author and any Co-Author.
\n\n6.2 IntechOpen has the right to use the Corresponding Author’s and any Co-Author’s names and likeness in connection with scientific dissemination, retrieval, archiving, web hosting and promotion and marketing of the Chapter and has the right to contact the Corresponding Author and any Co-Author until the Chapter is publicly available on any platform owned and/or operated by IntechOpen.
\n\n6.3 IntechOpen is granted the authority to enforce the rights from this Publication Agreement, on behalf of the Corresponding Author and any Co-Author, against third parties (for example in cases of plagiarism or copyright infringements). In respect of any such infringement or suspected infringement of the copyright in the Chapter, IntechOpen shall have absolute discretion in addressing any such infringement which is likely to affect IntechOpen's rights under this Publication Agreement, including issuing and conducting proceedings against the suspected infringer.
\n\n7. MISCELLANEOUS
\n\n7.1 Further Assurance: The Corresponding Author shall and will ensure that any relevant third party (including any Co-Author) shall, execute and deliver whatever further documents or deeds and perform such acts as IntechOpen reasonably requires from time to time for the purpose of giving IntechOpen the full benefit of the provisions of this Publication Agreement.
\n\n7.2 Third Party Rights: A person who is not a party to this Publication Agreement may not enforce any of its provisions under the Contracts (Rights of Third Parties) Act 1999.
\n\n7.3 Entire Agreement: This Publication Agreement constitutes the entire agreement between the parties in relation to its subject matter. It replaces and extinguishes all prior agreements, draft agreements, arrangements, collateral warranties, collateral contracts, statements, assurances, representations and undertakings of any nature made by or on behalf of the parties, whether oral or written, in relation to that subject matter. Each party acknowledges that in entering into this Publication Agreement it has not relied upon any oral or written statements, collateral or other warranties, assurances, representations or undertakings which were made by or on behalf of the other party in relation to the subject matter of this Publication Agreement at any time before its signature (together "Pre-Contractual Statements"), other than those which are set out in this Publication Agreement. Each party hereby waives all rights and remedies which might otherwise be available to it in relation to such Pre-Contractual Statements. Nothing in this clause shall exclude or restrict the liability of either party arising out of its pre-contract fraudulent misrepresentation or fraudulent concealment.
\n\n7.4 Waiver: No failure or delay by a party to exercise any right or remedy provided under this Publication Agreement or by law shall constitute a waiver of that or any other right or remedy, nor shall it preclude or restrict the further exercise of that or any other right or remedy. No single or partial exercise of such right or remedy shall preclude or restrict the further exercise of that or any other right or remedy.
\n\n7.5 Variation: No variation of this Publication Agreement shall be effective unless it is in writing and signed by the parties (or their duly authorized representatives).
\n\n7.6 Severance: If any provision or part-provision of this Publication Agreement is or becomes invalid, illegal or unenforceable, it shall be deemed modified to the minimum extent necessary to make it valid, legal and enforceable. If such modification is not possible, the relevant provision or part-provision shall be deemed deleted.
\n\nAny modification to or deletion of a provision or part-provision under this clause shall not affect the validity and enforceability of the rest of this Publication Agreement.
\n\n7.7 No partnership: Nothing in this Publication Agreement is intended to, or shall be deemed to, establish or create any partnership or joint venture or the relationship of principal and agent or employer and employee between IntechOpen and the Corresponding Author or any Co-Author, nor authorize any party to make or enter into any commitments for or on behalf of any other party.
\n\n7.8 Governing law: This Publication Agreement and any dispute or claim (including non-contractual disputes or claims) arising out of or in connection with it or its subject matter or formation shall be governed by and construed in accordance with the law of England and Wales. The parties submit to the exclusive jurisdiction of the English courts to settle any dispute or claim arising out of or in connection with this Publication Agreement (including any non-contractual disputes or claims).
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