Optimizing BPNN Algorithm by Improving Genetic Algorithm

GA–BPNN–PID uses the genetic algorithm to optimize the weight and threshold of BPNN so that the optimized BPNN can better realize the function output. Although the GA–BPNN–PID control method is larger than the traditional method, the optimized BPNN weight and threshold can provide better control effect for the liquid manure spraying control algorithm. Both simulation and platform tests have verified that the algorithm has small overshoot, good stability, short rise time, and can better achieve the effect of precise spraying.

In this study, optimizing the BPNN has three parts: determination of the BPNN composition, optimization via genetic algorithm, then prediction by BPNN. The corresponding processes are illustrated in Figure 7. The structure of BPNN was determined according to the input and output parameters. In this study, the input was vehicle speed and the outputs were Kp, Ki, Kd. According to the above input and output data, we set the BPNN structure as 1-6-3, that is, the input layer had 1 node, the hidden layer had 6 nodes, and the output layer had 3 nodes, with a total of 19 weights and 9 thresholds. Therefore, the individual coding length of the genetic algorithm was 28. The BPNN prediction used a genetic algorithm to obtain the initial weight and threshold assignment of the optimal individual to the network. Finally, the prediction function was output after training. The GA–BPNN–PID structure diagram is shown in Figure 8.

The essential factors of BPNN optimized using genetic algorithm t included the initial population, fitness function, select action, crossover operator, and revisited mutations.

The genetic algorithm majorization main theory of the BPNN–PID dominant algorithm involved optimizing the initial value as well as the threshold of BPNN using a genetic algorithm, such that BPNN optimization could better forecast function export. Simultaneously, genetic algorithm optimization of the BPNN input state was used to reduce the network output and was insensitive to the system import, which was likely lag. The corresponding stages were as below:

**Figure 7.** Flow chart of GA–BPNN.

**Figure 8.** GA–BPNN–PID structure diagram.

$$Y = k \left[ \sum\_{i=1}^{n} abs(O\_i - h\_i) \right] \tag{18}$$

where n is the quantity of network export panel points, *oi* is the BPNN's desired export of the ith panel point, *hi* is the forecast export of the ith panel point, and k is a ratio.

(3) The choice manipulation of a genetic algorithm is the choice policy according to the fitness proportion. The choice percentage *pi* of every personality i was such that (Equation (19)):

$$\mathcal{g}\_i = \frac{k}{G\_i}; p\_i = \frac{\mathcal{G}\_i}{\sum\_{j=1}^{N} G\_i} \tag{19}$$

where *Gi* is the fitness price of personality i. Before individual selection, the reciprocal of the fitness proportion was calculated. The factor is k, and N is the amount of the personality in the population.

(4) In the light of optimizing the population initialization process, real number coding was adopted according to the individual; therefore, a real number crossover valve was adopted for the crossover operation. The overlapping operation of the k-th chromosome *bk* as well as c-th chromosome *bc* at position j is as below (Equation (20)):

$$b\_{kj} = b\_{ij}d + b\_{kj}(1 - b); \\ b\_{cj} = b\_{kj}d + b\_{cj}(1 - d) \tag{20}$$

where *d* is a stochastic digit among (0–1).

(5) In the mutation operation, the j-th gene *bij* of i-th personality was chosen with mutation. The mutation operation method was as below (Equation (21)):

$$b\_{ij} = \begin{cases} (b\_{ij} - b\_{\max}) \cdot G(f) + b\_{ij} & r \ge 0.5\\ (b\_{\min} - b\_{ij}) \cdot G(f) + b\_{ij} & r < 0.5 \end{cases} \tag{21}$$

where *bmax* is the top margin of gene *bij*, *bmin* is the bottom margin of gene *bij*; *g*(*f*) = *r*2(1 − *f* / *fmax*), *r*2 is the stochastic digit, and f is the present iteration digit. *Fmax* are the maximum evolution times, and r is stochastic digit among [0–1]. Its control principle is exhibited in Figure 9.

**Figure 9.** GA–BPNN–PID control schematic diagram.


**6. Preoperative checklist**

The preoperative evaluation concludes with a review of all pertinent studies and information obtained from investigative tests.

	- **•** Careful review of the patient's medications is important.
	- **•** The aim is to judiciously give medications that control the patient's illnesses and at the same time minimizing the risk associated with anesthetic and other drugs interactions.
	- **•** In general, patients taking cardiac drugs, pulmonary drugs or anticonvulsants, antihypertensives, or psychiatric drugs are advised to take their medications with sips of water on the morning of operation.
	- **•** Parenteral medications are used if the patient remains NPO for any significant period postoperatively.

Hypoxemia at rest is the prerequisite for the diagnosis. Medical management is disappointing,

Malnutrition is common with liver impairment and is a risk factor for mortality following LT. Nutritional supplementation has not been proven to affect outcome. The total amount of calories provided should be at least 30-35 kcal/kg/day. Adults can receive daily 1-2 g protein/ kg of dry body weight. Patients should take daily multivitamin and other supplements as needed. Specific fat-soluble vitamin supplements are provided if a deficiency is present.

The preoperative period can be extremely stressful. Declining health, uncertainty about the results, and inability to continue working and participating in daily activities may increase the risk of depression and/or anxiety. Patients with chronic HCV have a greater incidence of depression and anxiety. Patients who experience significant psychological distress have

The preoperative evaluation concludes with a review of all pertinent studies and information

**1.** Informed consent after discussion with the patient and family members regarding the indication for the anticipated surgical procedure, as well as its risks and proposed benefits

**3.** Antibiotic prophylaxis: The appropriate antibiotic is chosen before surgery and adminis‐

**•** The aim is to judiciously give medications that control the patient's illnesses and at the same time minimizing the risk associated with anesthetic and other drugs interactions.

**•** In general, patients taking cardiac drugs, pulmonary drugs or anticonvulsants, antihypertensives, or psychiatric drugs are advised to take their medications with sips

**•** Parenteral medications are used if the patient remains NPO for any significant period

and liver transplant is advocated as the treatment of choice.

**5.12. Malnutrition**

16 Recent Advances in Liver Diseases and Surgery

**5.13. Psychosocial stress**

increased complications.

**6. Preoperative checklist**

obtained from investigative tests.

**5.** Revision of medications

postoperatively.

**2.** Review the need for β-blockade, DVT prophylaxis

**4.** Preoperative mechanical bowel cleansing, whenever indicated

**•** Careful review of the patient's medications is important.

tered before the skin incision is made

of water on the morning of operation.


**6. Conclusion**

Molecular markers have facilitated the studies of genetics, taxonomy and evolution of plants delivering breakthrough in scientific knowledge. New possibilities of genetic manipulation emerged, directly benefiting the plant breeding.

The selection methods were largely enhanced by the use of molecular markers, and the success of marker-assisted selection depends on the degree of association between him and

Molecular Markers: Assisted Selection in Soybeans 175

Ashkenazi, V., Chani, E., Lavi, U., Levy, D., Hillel, J. & Veilleux, R.E. (2001) Development of

Autrique, E., Nachit, M.M., Monneveux, P. Tanksley, S.D. & Sorrells, M.E. (1996) Genetic

Bachman, M.S., Tamulonis, J.P., Nickell, C.D. & Bent, A.F. (2001) Molecular markers linked

Barbosa Neto, J.F. (1998) Seleção assistida por marcadores moleculares. In: *Marcadores moleculares em plantas*, Milach, S.C.K., pp.75-80. UFRGS, Porto Alegre. Bateson, W. & Punnett, R.C. (1905) Experimental studies in the physiology of heredity.

Benchimol, L.L., Lanza, L.L.B., Souza, J.R. & Souza, A. P. (2005) Microsatellite-assisted

Brondani, R.P.V., Brondani, C., Tarchini, R. & Grattapaglia, D. (1998) Development,

Brunel, D. (1994) A microsatellie marker in Helianthus annuus L. *Plant Molecular Biology*,

Carvalho, G.A., Sediyama, T., Marin, A.L.A., Barros, E.G. & Moreira, M.A. (2002)

Colombari FIlho, J. M., Geraldi, I. O. & Barona, M. A. A. (2010) Heterose e distâncias

<http://www.scielo.br/scielo.php?script=sci\_arttext&pid=S1413-705420100004000

Concibido, V.C., Lange, D.A., Denny, R.L., Orf, J.H. & Young, N.D. (1997) Genome mapping

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microsatellite markers in potato and their use in phylogenetic and fingerprinting

diversity in durum wheat based on RFLPs, morphological traits and coefficient of

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the characteristic of interest: the greater the association, the lower the chance of recombination between the marker and gene controlling the trait, with a higher selection efficiency. The use of molecular markers presents several advantages over morphological markers: lack of phenotypic analysis, which has high cost and difficulty in performing; no need for special environments (drought and inoculation with pathogens); allows for subjective evaluations (performance organoleptic); there is no destruction of the plant evaluated; allowing the early identification of features found only in advanced stages of plant development.

In plant breeding, there are some challenges, and obtain individuals with the gene combination desirable for the features of interest, presented as one. Two factors are involved in resolving the issue: the existence of variability and the selection process. The identification of individuals requires an efficient method and skill of the investigator.

Molecular markers may help in the selection process for individuals as well as in the process of reviewing the existing diversity. The applications follow some peculiarities and the challenge of reducing costs is a objective to be achieved.

The advantages and limitations of these tools were described in the chapter and serve as a basis for further studies and investigated. The speed in the generation of new knowledge requires much intellectual and financial investment from the professionals working in the field of molecular marker-assisted selection.


2.1 Packaging of wastewaters from olive mills

The samples of water were placed in 30 L bottles and were transported to the laboratory. The samples of OMWW were kept at 20°C for the later use. The research process developed in the laboratory for processing OMWWs is comprised of the steps described below.


**Clinical Presentation of Neuroblastoma**

## Josef Malis

Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/55921

#### **1. Introduction**

Neuroblastoma is a cancer of the peripheral sympathetic nervous system, derived from embryonic neural crest cells (a neuroendocrine tumor) and is one of the few cancers known to undergo spontaneous regression from an undifferentiated state to a benign tumor.

Neuroblastoma is the most common extracranial solid tumor in children, accounting for 7% to 8% of all childhood cancers. The prevalence is about 1 case per 7,000 live births. This incidence is fairly uniform throughout the world, at least for industrialized nations. Neuro‐ blastoma is slightly more common in boys than in girls, with a male-to-female sex ratio of 1.1 to 1 in most large studies [1]. While it accounts for 7% of all childhood malignancies, neuro‐ blastoma accounts for 10% of childhood cancer mortality. Neuroblastoma is a pediatric neoplasm that is the most common cancer diagnosed during infancy. POG and CCG institu‐ tions from 1986 to 2001 showed a median age at diagnosis of about 19 months. In this cohort, 36% were infants, 89% were younger than 5 years, and 98% were diagnosed by 10 years of age. The distribution of cases by age shows that this is a disease of infancy and early childhood, with the highest number of cases diagnosed in the first month of life [2].

#### **2. Current outcome**

Patients with low- and intermediate-risk NBL have an overall survival rate exceeding 90% with a trend toward minimization of therapy [3,4,5]. Standard therapy for patients with highrisk NBL involves multi-agent chemotherapy induction, surgery and external beam radio‐ therapy, myeloablative consolidation with autologous hematopoietic stem cell recue and biologic agents, including the recent demonstration that GD2- directed immunotherapy combined with cytokines significantly improves survival. Despite these achievements, 50% of

© 2013 Malis; licensee InTech. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. © 2013 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

patients with newly diagnosed high-risk disease, and less than 10% of patients whose disease recurs, will survive [6].

outcome. The International Neuroblastoma Response Criteria (INRC) provide a common basis for disease response comparisons across clinical trials [13]. Importantly, the INRC has limitations with respect to definitions of metastatic site response not measurable using anatomical imaging (bone and bone marrow). A National Cancer Institute-sponsored inter‐ national meeting was held in 2012 to develop updated consensus response guidelines. Response components of a revised INRC will includeprimary tumor dimensions using anatomic imaging, and metastatic disease assessment using 123I-MIBG imaging and quanti‐

Clinical Presentation of Neuroblastoma http://dx.doi.org/10.5772/55921 5

**Stage 1:** Localized tumor with complete gross excis ion, with or without microscopic residual disease;

**Stage 2A:** Localized tumor with incomplete gross excision; representative ipsilateral nonadherent lymph

**Stage 4:** Any primary tumor with dissemination to distant lymph nodes, bone, bone marrow, liver, skin,

**Stage 4S:** Localized primary tumor (as defined for stage 1, 2A, or2B), with dissemin ation limited to skin, liver

**Ipsilateral tumor extension within two body compartments Neck-chest, chest-abdomen, abdomen-pelvis**

**Stage 2B:** Localized tumor withor without komplete gross excision, with ipsilateral nonadherentlymph nodes positive for tumor. Enlarged contralateral lymph nodes must benegative microscopically **Stage 3:** Unresectable unilateral tumor infiltrating across the midline, with or without regional lymph node

removed with the primary tumor may be positive)

and/or other organs (except as defined for stage 4S)

and/or bone marrow (limited to infants <1 year of age)

Tumor encasing carotid and/or vertebral artery and/or internal jugular vein

Tumor encasing subclavian vessels and/or vertebral and/or carotid artery

**Table 1.** International Neuroblastoma Staging System

Tumor extending to base of skull Tumor compressing the trachea

Tumor encasing brachial plexus roots

Tumor compressing the trachea

Neck

Cervico-thoracic junction

nodes negative for tumor microscopically

representative ipsilateral lymph nodes negati ve for tumor microscopically (nodes attached and

involvement; or localized unilateral tumorwith contralateral regional lymphnode involvement; or midline tumor with bilateral extensit by infiltration (unresectable) or by lymph node involvement

fication of bone marrow disease.

#### **3. General remarks**

Neuroblastoma is very often called "enigmatic tumor" for its broad spectrum of clinical presentation, biological features and prognosis varying from clinically incidence benign to unresectable or metastic disease with very poor outcomes. Neuroblastomas can arise any‐ where throughout the sympathetic nervous system, most common primary site is adrenal gland, followed by abdominal (extraadrenal), thoracic, cervical, and pelvic sympathetic ganglia. Neuroblastoma metastasizes to lymph nodes, bone marrow, bones (long bones, flat bone soft the scull, orbits), liver, and skin, rarely to lungs or brain. Widespread bone and bone marrow disease causes bone pain, which can lead to limping, or irritability in a younger child. There may be bone marrow replacement and symptoms such as anemia, bleeding, or infection. Skin involvement is seen almost exclusively in infants with INSS stage Ms (4S) tumors and is characterized by a variable number of nontender, bluish subcutaneous nodules.

Constitutional symptoms associated with disseminated disease may include failure to thrive and fever, the latter observed most often in the presence of extensive bone metastases [7]

Regional lymph node metastases are noted in up to 35% of patients with apparently localized tumors and 30% of patients with stage M (4) and Ms (4S) disease also have regional lymph node involvement. Spread of tumor to lymph nodes outside the cavity of origin is considered to be INSS stage 4 disease, but these patients may have a better outlook if there is no bone marrow, cortical bone, or other parenchymal organ involvement. [8,9]

Most primary tumors occur within the abdomen (65%), although the frequency of adrenal tumors is slightly higher in children (40%) compared with infants (25%). Infants also have more thoracic and cervical primary tumors. A primary tumor cannot be found in about 1% of patients.

#### **4. Staging and stratification**

The for decades used surgical-pathologic International Neuroblastoma Staging System (INSS) – Table 1 [10] has been recently replaced by the International Neuroblastoma Risk Group Staging System (INRGSS) [11]. The INRGSS uses radiologic features to distinguish locore‐ gional tumors (Table 2) that do not involve local structures (INRGS L1) from locally invasive tumors (INRGS L2), exhibiting image defined risk factors (Table 3) [12]. Stages M and MS refer to tumors that are widely metastatic or have an INSS 4 and 4s pattern of disease, respectively. Neuroblastoma is classified into low-, intermediate-, or high-risk categories based upon clinical and biological features, with risk category correlating with outcome. The recently proposed INRG classification defines similar cohorts that will be used to assess clinical trial outcome. The International Neuroblastoma Response Criteria (INRC) provide a common basis for disease response comparisons across clinical trials [13]. Importantly, the INRC has limitations with respect to definitions of metastatic site response not measurable using anatomical imaging (bone and bone marrow). A National Cancer Institute-sponsored inter‐ national meeting was held in 2012 to develop updated consensus response guidelines. Response components of a revised INRC will includeprimary tumor dimensions using anatomic imaging, and metastatic disease assessment using 123I-MIBG imaging and quanti‐ fication of bone marrow disease.

**Table 1.** International Neuroblastoma Staging System

#### **Ipsilateral tumor extension within two body compartments**

#### **Neck-chest, chest-abdomen, abdomen-pelvis**

#### Neck

patients with newly diagnosed high-risk disease, and less than 10% of patients whose disease

Neuroblastoma is very often called "enigmatic tumor" for its broad spectrum of clinical presentation, biological features and prognosis varying from clinically incidence benign to unresectable or metastic disease with very poor outcomes. Neuroblastomas can arise any‐ where throughout the sympathetic nervous system, most common primary site is adrenal gland, followed by abdominal (extraadrenal), thoracic, cervical, and pelvic sympathetic ganglia. Neuroblastoma metastasizes to lymph nodes, bone marrow, bones (long bones, flat bone soft the scull, orbits), liver, and skin, rarely to lungs or brain. Widespread bone and bone marrow disease causes bone pain, which can lead to limping, or irritability in a younger child. There may be bone marrow replacement and symptoms such as anemia, bleeding, or infection. Skin involvement is seen almost exclusively in infants with INSS stage Ms (4S) tumors and is

Constitutional symptoms associated with disseminated disease may include failure to thrive and fever, the latter observed most often in the presence of extensive bone metastases [7]

Regional lymph node metastases are noted in up to 35% of patients with apparently localized tumors and 30% of patients with stage M (4) and Ms (4S) disease also have regional lymph node involvement. Spread of tumor to lymph nodes outside the cavity of origin is considered to be INSS stage 4 disease, but these patients may have a better outlook if there is no bone

Most primary tumors occur within the abdomen (65%), although the frequency of adrenal tumors is slightly higher in children (40%) compared with infants (25%). Infants also have more thoracic and cervical primary tumors. A primary tumor cannot be found in about 1% of

The for decades used surgical-pathologic International Neuroblastoma Staging System (INSS) – Table 1 [10] has been recently replaced by the International Neuroblastoma Risk Group Staging System (INRGSS) [11]. The INRGSS uses radiologic features to distinguish locore‐ gional tumors (Table 2) that do not involve local structures (INRGS L1) from locally invasive tumors (INRGS L2), exhibiting image defined risk factors (Table 3) [12]. Stages M and MS refer to tumors that are widely metastatic or have an INSS 4 and 4s pattern of disease, respectively. Neuroblastoma is classified into low-, intermediate-, or high-risk categories based upon clinical and biological features, with risk category correlating with outcome. The recently proposed INRG classification defines similar cohorts that will be used to assess clinical trial

characterized by a variable number of nontender, bluish subcutaneous nodules.

marrow, cortical bone, or other parenchymal organ involvement. [8,9]

recurs, will survive [6].

4 Neuroblastoma

**3. General remarks**

patients.

**4. Staging and stratification**

Tumor encasing carotid and/or vertebral artery and/or internal jugular vein

Tumor extending to base of skull

Tumor compressing the trachea

#### Cervico-thoracic junction

Tumor encasing brachial plexus roots

Tumor encasing subclavian vessels and/or vertebral and/or carotid artery

Tumor compressing the trachea

#### 6 Neuroblastoma

#### Thorax

Tumor encasing the aorta and/or major branches

Tumor compressing the trachea and/or principal bronchi

Lower mediastinal tumor, infiltrating the costo-vertebral junction between T9 and T12

**5. Sporadic and familiar neuroblastoma**

**6. Associated conditions**

**7. Clinical presentation**

**8.1. Head and neck**

type I, or Beckwith-Wiedemann syndrome

Most neuroblastomas occur sporadically; around 1-2% are familial and associated with multiple primary tumours, usually occurring at <18 months of age. Familial disease has the same diverse clinical behaviour as somatic neuroblastoma, ranging from aggressive progres‐ sion to spontaneous regression.11 Within the last 10 years significant advances have been in the understanding of hereditary neuroblastoma, with germline mutations in two genes ALK and paired homeobox 2b gene PHOX2B accounting for the majority of cases, which may present in the neonatal period. ALK mutations are now known to be the most now known common cause of hereditary neuroblastoma, and in familial neuroblastoma [14,15,16]

Clinical Presentation of Neuroblastoma http://dx.doi.org/10.5772/55921 7

Neuroblastoma can be associated with several inborn conditions, like Hirschsprung disease, congenital central hypoventilation syndrome (CCHS or Ondine's curse), neurofibromatosis

The presenting signs and symptoms of neuroblastoma are highly variable with a broad spectrum. Presenting symptoms of neuroblastoma depend on the location of the primary tumor, presence of metastatic lesions, systemic symptoms from catecholamine secretion.

Unilateral palpable mass developing in infants or in preschool age children, rarely are

Horners syndrome (ptosis, miosis, anophthalmos, anhydrosis). This syndrome is unilateral, Tatli reported a 28 old child with bilateral prosis [18]. Primary cervical neuroblastoma are ussually non agressive and thein prognosis is very good. But some are fatal - extremely rare case described Güzelmansur et al. – diagnosed prenatally with progression to brain. [19]

Orbit and eye exophthalmoses, periorbital ecchymoses (raccoon eyes), palpable masses, edema of conjunctiva, papilledema, strabismus, anisocoria. The periorbital ecchymoses can be present in about 20% of disseminated neuroblastoma. This clinical findings is related to obstruction of the palpebral ond orbita vessels by metastatic lesions within orbital bones. Frequently these

Weight loss and fever are present at advanced stages neuroblastoma.

**8. Anatomical site of the primary tumour**

diagnosed in newborn mimicking cervical teratoma. [17]

#### Thoraco-abdominal

Tumor encasing the aorta and/or vena cava

#### Abdomen/pelvis

Tumor infiltrating the porta hepatis and/or the hepatoduodenal ligament

Tumor encasing branches of the superior mesenteric artery at the mesenteric root

Tumor encasing the origin of the coeliac axis, and/or of the superior

#### mesenteric artery

Tumor invading one or both renal pedicles

Tumor encasing the aorta and/or vena cava

Tumor encasing the iliac vessels

Pelvic tumor crossing the sciatic notch

Intraspinal tumor extension whatever the location provided that:

More than one third of the spinal canal in the axial plane is invaded and/or the perimedullary leptomeningeal spaces are not visible and/or the spinal cord signal is abnormal

#### Infiltration of adjacent organs/structures

Pericardium, diaphragm, kidney, liver, duodeno-pancreatic block, and mesentery

#### Conditions to be recorded, but not considered IDRFs

Multifocal primary tumors

Pleural effusion, with or without malignant cells

Ascites, with or without malignant cells

**Table 2.** Image-defined risk factors (IDRFs)

**Table 3.** International Neuroblastoma Risk Group Staging System

#### **5. Sporadic and familiar neuroblastoma**

Most neuroblastomas occur sporadically; around 1-2% are familial and associated with multiple primary tumours, usually occurring at <18 months of age. Familial disease has the same diverse clinical behaviour as somatic neuroblastoma, ranging from aggressive progres‐ sion to spontaneous regression.11 Within the last 10 years significant advances have been in the understanding of hereditary neuroblastoma, with germline mutations in two genes ALK and paired homeobox 2b gene PHOX2B accounting for the majority of cases, which may present in the neonatal period. ALK mutations are now known to be the most now known common cause of hereditary neuroblastoma, and in familial neuroblastoma [14,15,16]

#### **6. Associated conditions**

Thorax

6 Neuroblastoma

Thoraco-abdominal

Abdomen/pelvis

mesenteric artery

Tumor encasing the aorta and/or major branches

Tumor encasing the aorta and/or vena cava

Tumor invading one or both renal pedicles Tumor encasing the aorta and/or vena cava

Tumor encasing the iliac vessels

Infiltration of adjacent organs/structures

Conditions to be recorded, but not considered IDRFs

Multifocal primary tumors

**Table 2.** Image-defined risk factors (IDRFs)

**M**: Distant metastatic disease (expect stage MS)

compartment

Pelvic tumor crossing the sciatic notch

Intraspinal tumor extension whatever the location provided that:

Pleural effusion, with or without malignant cells

**L2**: Locoregional tumor with presence of one or more image-defined risk factors

**Table 3.** International Neuroblastoma Risk Group Staging System

Ascites, with or without malignant cells

Tumor compressing the trachea and/or principal bronchi

Lower mediastinal tumor, infiltrating the costo-vertebral junction between T9 and T12

Tumor infiltrating the porta hepatis and/or the hepatoduodenal ligament

Tumor encasing the origin of the coeliac axis, and/or of the superior

Tumor encasing branches of the superior mesenteric artery at the mesenteric root

More than one third of the spinal canal in the axial plane is invaded and/or the perimedullary

**L1**: Localized tumor not involving vital structures as defined by the list of image-defined risk factors and confined to one body

**MS**: Metastatic disease in children younger than 18 months with metastases confined to skin, liver, and/or bone marrow

leptomeningeal spaces are not visible and/or the spinal cord signal is abnormal

Pericardium, diaphragm, kidney, liver, duodeno-pancreatic block, and mesentery

Neuroblastoma can be associated with several inborn conditions, like Hirschsprung disease, congenital central hypoventilation syndrome (CCHS or Ondine's curse), neurofibromatosis type I, or Beckwith-Wiedemann syndrome

#### **7. Clinical presentation**

The presenting signs and symptoms of neuroblastoma are highly variable with a broad spectrum. Presenting symptoms of neuroblastoma depend on the location of the primary tumor, presence of metastatic lesions, systemic symptoms from catecholamine secretion. Weight loss and fever are present at advanced stages neuroblastoma.

#### **8. Anatomical site of the primary tumour**

#### **8.1. Head and neck**

Unilateral palpable mass developing in infants or in preschool age children, rarely are diagnosed in newborn mimicking cervical teratoma. [17]

Horners syndrome (ptosis, miosis, anophthalmos, anhydrosis). This syndrome is unilateral, Tatli reported a 28 old child with bilateral prosis [18]. Primary cervical neuroblastoma are ussually non agressive and thein prognosis is very good. But some are fatal - extremely rare case described Güzelmansur et al. – diagnosed prenatally with progression to brain. [19]

Orbit and eye exophthalmoses, periorbital ecchymoses (raccoon eyes), palpable masses, edema of conjunctiva, papilledema, strabismus, anisocoria. The periorbital ecchymoses can be present in about 20% of disseminated neuroblastoma. This clinical findings is related to obstruction of the palpebral ond orbita vessels by metastatic lesions within orbital bones. Frequently these children are investigated for an abuse or a trauma (basal skull fractures) [20,21]. Usually further systemic symptoms are present – weight loss, fever.

bifurcation or just beyond. When neuroblastoma arises these small organs, normally not visible on radiographs, then it could cause compression of bowel or urine bladder

Clinical Presentation of Neuroblastoma http://dx.doi.org/10.5772/55921 9

Paraspinal tumors in the thoracic, abdominal, and pelvic regions are able to invade the spinal canal through the neural foramina ( dumbbell tumor) causing spinal cord compression and cause symptoms related to compression of nerve roots and spinal cord. The range of sympto‐ matology includes subacute or acute paraplegia, bladder or bowel dysfunction, or less

Up to 2% of patients present with opsoclonus and myoclonus (OMS) (myoclonic jerking and random eye movements). Often have localized disease and a good long-term prognosis*.* Opsoclonus and myoclonus syndrome is manifested by rapid and chaotic eye movements, ataxia, and myoclonia. Most children with this syndrome have a favorable outcome with respect to their tumor, as this syndrome is correlated with an immune-mediated antitumor

Autonomous tumor secretion of vasoactive intestinal peptide (VIP) is another paraneoplastic syndrome (Kerner-Morrison Syndrome) that is rarely associated with neuroblastoma. VIP secretion can cause abdominal distension and intractable secretory diarrhea with associated hypokalemia ; these symptoms usually resolve after removal of the tumor. chronic watery diarrhea preceded the diagnosis of the tumor; these patients were considered to have ''Primary

Regional lymph node metastases are noted in 35% of patients with apparently localized

The most common sites for hematogenous spread are: bones (skull, long bones, ribs, verte‐

Pain and limping, sphenoid bone and retrobulbar tissue involvement causes orbital ecchymoses swelling and proptosis (raccoon face), infants present as irritable and fussy. Bone marrow involvement may result in pancytopenia. Respiratory distress may occur in young babies with Stage IVS (Ms) disease - due to enlarged liver. Skin or subcutaneous nodules are seen almost only in infants. These nodules are non-tender, bluish and mobile

NBL is associated with lymphatic and hematogenous metastatic disease.

bras),bone marrow, liver, skin and rarely brain or lungs. Signs and symptoms of metastatic neuroblastoma include:

(constipation, enuresis) [23].

commonly radicular pain.

host response [24].

VIP secreting NTs.''

tumors.

**10. Metastatic disease**

**9. Paraneoplastic syndrome**

Opsoclonus also known as dancing-eye syndrome, presents in early childhood with opsoclo‐ nus (rapid, multidirectional, conjugate eye movements) usually associated with myoclonus, ataxia, and behavioral changes such as irritability and sleep problems.– opsoclonus-myoclonus syndrome (OMS) [22]

Chest Upper thoracic tumours: Primary thoracic tumors present as symptomatic masses or can be discovered incidentally when chest radiographs are obtained to evaluate patients for other reasons. High thoracic and cervical masses can be associated with Horner syndrome, which consists of unilateral ptosis, myosis, and anhydrosis. Occasionally, large thoracic tumors are associated with mechanical obstruction and resultant superior vena cava syndrome.

Lower thoracic tumours: usually no symptoms, usually accidental discovery on chest X-ray or thoracic CT performed for other reasons.

#### **8.2. Abdominal neuroblastoma**

About 60% of primary neuroblastomas arise in the abdomen, two thirds of them are from the adrenal glands (adrenal neuroblastoma), one third are from paravertebral ganglion (extraa‐ drenal neuroblastoma). Only about one tenth of neuroblastoma are detected as an abdominal mass during a routine examination. The mass is ussually fixed,and firm.

Symptoms: abdominal pain or fullness, abdominal mass, or rarely intestinal obstruction, enlarged and/or displaced liver and spleen. Massive involvement of the liver with metastatic disease is particularly frequent in infants with stage Ms (4S) and may result in respiratory compromise (Pepper Syndrome). Occasionally, the size of primary or metastatic abdominal tumors can result in compression of venous and lymphatic drainage from the lower extremi‐ ties, leading to scrotal and lower extremity edema. Rarely, patients will experience reninmediated hypertension because of compromise of renal vasculature.

Hypertension, tachycardia, flushing, and sweating are uncommon symptoms because epinephrine is rarely released from most neuroblastomas, since they lack the enzyme necessary for synthesis.

Only about one tenth of neuroblastoma are detected as an abdominal mass during a routine examination. The mass is ussually fixed,and firm.

Spontaneous rupture from hemorrhage into the tumor occurs very rarely and only in rapidly growing tumors.

There is a small subgroup of abdominal neuroblastomas arising near to the aortic bifurca‐ tion (commonly called organ of Zuckerkandl, O. Z.) to assess their biologic outcome and problems in diagnosis and therapy. The organ of Zuckerkandl comprises of a small mass of chromaffin cells derived from neural crest located along the aorta, beginning cranial to the superior mesenteric artery or renal arteries and extending to the level of the aortic bifurcation or just beyond. When neuroblastoma arises these small organs, normally not visible on radiographs, then it could cause compression of bowel or urine bladder (constipation, enuresis) [23].

Paraspinal tumors in the thoracic, abdominal, and pelvic regions are able to invade the spinal canal through the neural foramina ( dumbbell tumor) causing spinal cord compression and cause symptoms related to compression of nerve roots and spinal cord. The range of sympto‐ matology includes subacute or acute paraplegia, bladder or bowel dysfunction, or less commonly radicular pain.

## **9. Paraneoplastic syndrome**

children are investigated for an abuse or a trauma (basal skull fractures) [20,21]. Usually further

Opsoclonus also known as dancing-eye syndrome, presents in early childhood with opsoclo‐ nus (rapid, multidirectional, conjugate eye movements) usually associated with myoclonus, ataxia, and behavioral changes such as irritability and sleep problems.– opsoclonus-myoclonus

Chest Upper thoracic tumours: Primary thoracic tumors present as symptomatic masses or can be discovered incidentally when chest radiographs are obtained to evaluate patients for other reasons. High thoracic and cervical masses can be associated with Horner syndrome, which consists of unilateral ptosis, myosis, and anhydrosis. Occasionally, large thoracic tumors are associated with mechanical obstruction and resultant superior vena

Lower thoracic tumours: usually no symptoms, usually accidental discovery on chest X-ray or

About 60% of primary neuroblastomas arise in the abdomen, two thirds of them are from the adrenal glands (adrenal neuroblastoma), one third are from paravertebral ganglion (extraa‐ drenal neuroblastoma). Only about one tenth of neuroblastoma are detected as an abdominal

Symptoms: abdominal pain or fullness, abdominal mass, or rarely intestinal obstruction, enlarged and/or displaced liver and spleen. Massive involvement of the liver with metastatic disease is particularly frequent in infants with stage Ms (4S) and may result in respiratory compromise (Pepper Syndrome). Occasionally, the size of primary or metastatic abdominal tumors can result in compression of venous and lymphatic drainage from the lower extremi‐ ties, leading to scrotal and lower extremity edema. Rarely, patients will experience renin-

Hypertension, tachycardia, flushing, and sweating are uncommon symptoms because epinephrine is rarely released from most neuroblastomas, since they lack the enzyme necessary

Only about one tenth of neuroblastoma are detected as an abdominal mass during a routine

Spontaneous rupture from hemorrhage into the tumor occurs very rarely and only in rapidly

There is a small subgroup of abdominal neuroblastomas arising near to the aortic bifurca‐ tion (commonly called organ of Zuckerkandl, O. Z.) to assess their biologic outcome and problems in diagnosis and therapy. The organ of Zuckerkandl comprises of a small mass of chromaffin cells derived from neural crest located along the aorta, beginning cranial to the superior mesenteric artery or renal arteries and extending to the level of the aortic

mass during a routine examination. The mass is ussually fixed,and firm.

mediated hypertension because of compromise of renal vasculature.

examination. The mass is ussually fixed,and firm.

systemic symptoms are present – weight loss, fever.

thoracic CT performed for other reasons.

**8.2. Abdominal neuroblastoma**

syndrome (OMS) [22]

8 Neuroblastoma

cava syndrome.

for synthesis.

growing tumors.

Up to 2% of patients present with opsoclonus and myoclonus (OMS) (myoclonic jerking and random eye movements). Often have localized disease and a good long-term prognosis*.* Opsoclonus and myoclonus syndrome is manifested by rapid and chaotic eye movements, ataxia, and myoclonia. Most children with this syndrome have a favorable outcome with respect to their tumor, as this syndrome is correlated with an immune-mediated antitumor host response [24].

Autonomous tumor secretion of vasoactive intestinal peptide (VIP) is another paraneoplastic syndrome (Kerner-Morrison Syndrome) that is rarely associated with neuroblastoma. VIP secretion can cause abdominal distension and intractable secretory diarrhea with associated hypokalemia ; these symptoms usually resolve after removal of the tumor. chronic watery diarrhea preceded the diagnosis of the tumor; these patients were considered to have ''Primary VIP secreting NTs.''

#### **10. Metastatic disease**

NBL is associated with lymphatic and hematogenous metastatic disease.

Regional lymph node metastases are noted in 35% of patients with apparently localized tumors.

The most common sites for hematogenous spread are: bones (skull, long bones, ribs, verte‐ bras),bone marrow, liver, skin and rarely brain or lungs.

Signs and symptoms of metastatic neuroblastoma include:

Pain and limping, sphenoid bone and retrobulbar tissue involvement causes orbital ecchymoses swelling and proptosis (raccoon face), infants present as irritable and fussy. Bone marrow involvement may result in pancytopenia. Respiratory distress may occur in young babies with Stage IVS (Ms) disease - due to enlarged liver. Skin or subcutaneous nodules are seen almost only in infants. These nodules are non-tender, bluish and mobile - called the "blueberry muffin sign".

#### **Acknowledgements**

This work was supported by the project for the conceptual development of research organi‐ zation 00064203.

[9] Brodeur GM, Pritchard J, Berthold F, et al. Revisions of the international criteria for neuroblastoma diagnosis, staging, and response to treatment. J Clin Oncol

Clinical Presentation of Neuroblastoma http://dx.doi.org/10.5772/55921 11

[10] Monclair T, Brodeur GM, Ambros PF, et al. The International Neuroblastoma Risk Group (INRG) staging system: An INRG Task Force report. J Clin Oncol 2009;27:298–303].

[11] Cecchetto G, Mosseri V, De Bernardi B, et al. Surgical risk factors in primary surgery for localized neuroblastoma: The LNESG1 study of the European International Soci‐ ety of Pediatric Oncology Neuroblastoma Group. J Clin Oncol 2005;23:8483–8489.

[12] Dubois SG, London WB, Zhang Y, et al. Lung metastases in neuroblastoma at initial diagnosis: a report from the International Neuroblastoma Risk Group (INRG)

[13] Mosse YP, Laudenslager M, Longo L, et al. Identification of ALK as a major familial

[14] Chiarle R, Voena C, Ambrogio C, Piva R, Inghirami G. The anaplastic lymphoma

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Aug 4

e388 -e394

#### **Author details**

Josef Malis\*

Dept. of Pediatric Oncology, University Hospital Motol and Charles University, Prague, Czech Republic

#### **References**

[9] Brodeur GM, Pritchard J, Berthold F, et al. Revisions of the international criteria for neuroblastoma diagnosis, staging, and response to treatment. J Clin Oncol 1993;11:1466–1477.

**Acknowledgements**

zation 00064203.

10 Neuroblastoma

**Author details**

Josef Malis\*

Czech Republic

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**Chapter 2**

**A Novel Diagnostic Tool for Therapy Stratification of**

**Using Circulating Tumor-Released DNA in Serum**

Shigeki Yagyu, Tomoko Iehara and Hajime Hosoi

Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/55793

**1. Introduction**

**Neuroblastoma: Preoperative Analysis of Tumor Biology**

Neuroblastoma (NB) patients fall into two clinically distinct subgroups; a low-risk subgroup and a high-risk subgroup. These subgroups are correlated with the age of onset [1], the extent of the disease (International Neuroblastoma Staging System) [2], pathological findings (International Neuroblastoma Pathological Criteria) [3], and genomic changes in NB tumors as represented by *MYCN* gene amplification (MNA) [4, 5]. Above all, the patterns of genetic changes can predict the subgroups of NB [6]. The low-risk, favorable NBs have mitotic disorders, and are characterized by near triploid karyotypes with whole chromosomal gains. On the other hand, the high-risk, unfavorable NBs exhibit genetic instability, and are charac‐ terized by chromosomal structural changes, including deletion of 1p or 11q, unbalanced gain of 17q, and/or MNA. MNA is the most powerful prognostic factor identified so far, and is useful regardless of the tumor stage. In the recent studies, the 5-year event free survival of patients who had NB tumors with MNA was 53% for localized NB [7] and 29% for all NBs [8], even with intensive, multimodal treatment. On the other hand, NB without *MYCN* amplifi‐ cation (non-MNA) falls into another two clinically distinct subgroups: a low-risk subgroup with overall survival rates of more than 95% without any intensive therapy, and a high-risk subgroup with overall survival rates of less than 40% despite the use of dose-intensive, multimodal therapy. In the high-risk non-MNA group, the development of NB depends on factors other than MNA, such as the expression profiles of other genes [9], aberrant hyperme‐ thylation of tumor suppressor genes [10], and chromosomal loss of heterozygosity (LOH) [11]. To determine the stratification of NB patients more precisely with regard to the treatment approach, a screen for these genetic aberrations should be performed before the initial treatment. Indeed, in the INRG staging system, routine assessments of MNA and 11q loss were

> © 2013 Yagyu et al.; licensee InTech. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use,

© 2013 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution,

distribution, and reproduction in any medium, provided the original work is properly cited.

and reproduction in any medium, provided the original work is properly cited.

[24] Bourdeaut F, de Carli E, Michon J: VIP Hypersecretion as Primary or Secondary Syn‐ drome in Neuroblastoma:Retrospective Study by the Socie´te´ Franc¸aise des Cancers de l'Enfant (SFCE)Pediatr Blood Cancer 2009;52:585–590