**5. Conclusions**

We considered the interaction of the optical waves with free electrons in metals. The theoretical analysis in such a case is based on Maxwell's equations and the equation of motion of a free electron in an external electric field. As a result, plasmonic excitations emerge. The dielectric function of a free electron gas with plasmonic oscillations is described by the dielectric function (22) known as the Drude model. The longitudinal plasma oscillations excited at the plasma frequency *ω* ¼ *ωp* are called the volume plasma oscillations, and the quasi-particles related to these oscillations are called the volume plasmons. SPPs may exist at the interface of the metal described by the Drude dielectric function and the dielectric medium. SPPs are the TM waves. They are characterized by the limited propagation length in the dielectric and the spatial confinement in the direction perpendicular to the propagation direction. The subwavelength confinement of the optical field is possible for SPPs. The nonlinear optical effects in plasmonic structures are significantly enhanced. The nonlinear optical phenomena such as modulation, switching, harmonic generation, FWM are possible in plasmonic nano-structures. Highly efficient all-optical switching and all-optical modulation can be realized in nonlinear plasmonic metamaterials based on nano-particles, split-ring resonators, and LCs.

Plasmonics plays an essential role in modern nonlinear optics. The nonlinear optical effects can be achieved at the reduced optical power due to enhanced effective nonlinearity in plasmonic nanostructures. The size of the nonlinear components can be scaled down which is important for the development of functional nanophotonic circuits. The ultrafast optical signal processing on the femtosecond scale can be realized due to the small response time of the plasmonic excitations.


*2.5. Endpoints*

The co-primary endpoints of this systematic review were the impact of investigational treatments on lung function and symptoms control.

The secondary endpoints were the impact of investigational treatments on blood eosinophil count, FENO, exacerbations and hospitalisations, the use of rescue medications, and QoL.

## *2.6. Strategy for Data Synthesis*

Data from original papers were extracted and reported via qualitative synthesis, and the statistical significance was set at *p* < 0.05.


**5.5.1 Antibody derivatives**

The use of mAbs has presented challenges in radionuclide imaging. Because of their large size (molecular weight of ~150 kDa), mAbs penetrate slowly and have long residence time in the blood circulation (days-weeks) due to active recycling by the neonatal Fc receptor, leading to limited tumor-to-normal organs ratio in biodistribution and low contrast images for the detection of biomarkers/tumors (Jonathan et al., 2000). Advances in protein

Breast Cancer: Radioimmunoscintigraphy and Radioimmunotherapy 175

cancer, it is essential that the antibody is well characterized with little cross-reactivity to other antigens. The antibodies show cross-reactivity with, e.g. leucocytes, potentially yielding false-positive images. The majority of breast cancer targeting antibody studies have

First described by Gold and Freedman in 1965, CEA was thought to be a specific marker for colon adenocarcinoma. However, subsequent studies demonstrated CEA expression in other human adenocarcinomas including the surface membrane of breast cancer cells (Jonathan et al., 2000). Expression of CEA has been reported in 10% to 95% of breast cancers (Hong et al., 2008, Denardo, 2005). Preliminary studies with 99mTc-labeled CEA antibody appeared to indicate a useful role for this agent in distinguishing between benign and malignant breast lesions in patients with indeterminate mammographic findings (Denardo, 2005). Therapy studies specifically in breast cancer have also been performed with T84.66 (Koppe et al., 2005). T84.66 is a well characterized murine IgG1 antibody with high specificity and affinity for a unique epitope of CEA molecules. A chimeric form of T84.66 (cT84.66) has been also used in clinical studies for the scintigraphic detection of breast cancer and in phase I/II therapy trials and scFv-based anti-CEA constructs are under study (Denardo, 2005). Another mAb that has been classified in this group is NP4. NP-4 belongs to the murine IgG1 subclass and is specific for CEA, reacting with a class III peptide epitope of

MUC-1 mucins are large, complex glycoproteins that have a polypeptide core with multiple oligosaccharide side chains (Mukhopadhyay et al., 2011). The mature molecule is anchored within the cell surface by a characteristic transmembrane domain, but most of the mucins are expressed extracellular. This polar distribution is lost with neoplastic transformation and increased heterogenous MUC-1 synthesis is a common feature of breast cancer. This glycoprotein is aberrantly over expressed in adenocarcinomas including 80% of breast cancers (Salouti et al., 2011). Targeting, using antibodies directed against the MUC-1 antigen has been tested in patients with breast cancer using various antibodies. BrE-3 is an IgG1 antibody directed against the peptide epitope of the MUC-1 antigen that have been evaluated for RIT (Mohammadnejad et al, 2010). The studies of the application of BrE-3 mAbs in patients with breast cancer showed minimal cross reactivity with normal breast tissues (Howell et al., 1995; Blank et al., 1992). Because the majority of the patients rapidly showed HAMA response against the murine BrE-3 mAb, a humanized version of BrE-3 (hBrE-3) was developed (Kramer et al., 1993). Kramer and colleagues investigated the pharmacokinetics and biodistribution of 111In-MX-DTPA-labeled hBrE-3 in seven patients with metastatic breast cancer (Kramer et al., 1993). hBrE-3 was proved to have a lower immunogenicity compared to murine BrE-3 (only one patient developed a HAMA response) while tumor-targeting properties were preserved (Denardo, 2005). Monoclonal antibody 170H.82 (m170) is a murine IgG1 prepared using a synthetic asialo GM1 terminal disaccharide immunogen related to the Thomsen–Friedenreich disaccharide and selected by reactivity with MUC-1 expressing cancer cell membranes (Jonathan et al., 2000). The results of experimens showed that labeled m170 was effective for imaging of primary and metastatic breast cancer and was able to detect lesions as small as 1 cm in size using SPECT with an overall clinical accuracy of 92%. In particular, mAb 170H.82 has been studied in

used antibodies against MUC1, CEA, TAG-72 and L6 antigens (Carlos et al., 2006).

**6.1 CEA**

**6.2 MUC-1**

CEA molecules (Richman & DeNardo, 2001).

engineering have led to a number of alternative constructs for imaging and therapy. These alternatives characterized by smaller size include:

When compared to intact IgGs, these antibody fragments have the advantages of faster biodistribution, rapid penetration into the tissues and improved tumor-to-normal organs ratio. These forms (e.g. F(ab')2, Fab or other molecular constructs) achieve maximum tumor accretion more quickly with improved tumor/blood ratio that make earlier visualization, possible (Colcher et al., 1998). The use of fragments of antibodies has also been advocated as a possible means to reduce the immunogenicity of rodent antibodies in human beings. Antibody fragments generated by proteolysis or by genetic engineering, have been tested both in vitro and in vivo. As monovalent binding entities, antibody fragments suffer from relatively low avidity binding. Hence, to increase their binding avidity, they have also been engineered into multivalent constructs include:


6.1.1. The Number of Targets: 3

The simulation considered the 2D surveillance region depicted in Figure 3. The targets maneuvered slightly to form curved trajectories within the surveillance region. To track maneuvering targets, the LM-IPDA-interacting multiple model (LM-IPDA-IMM) [32] was employed. The LM-IPDA-IMM algorithm used in this study utilized the NCV model and the CTR model introduced in Section 2. The targets were located apart at the beginning of the scenario, then they were located in the immediate vicinity at Scan 25, and then moved away from each other.

**Figure 3.** Simulation scenario with three targets.

The base clutter measurement density was 1 × 10−4 scans/m2, and it increased to 3 × 10−4 scans/m2 in the high clutter measurement density region; clutter measurements were spatially distributed with a uniform distribution inside each cluttered region for every scan. In Figure 3, the squares represent the measurements of each target. The gray symbols represent the clutter measurements generated during a single simulation run.

Figure 4 represents the CTTR for three targets in 500 Monte Carlo runs, and the position RMSE for Target 1 and the estimated clutter measurement density for Target 1 over time are listed in Figures 5 and 6, respectively. For fair comparisons, the number of confirmed false tracks of each case was made to be almost 40 for all 500 Monte Carlo simulation runs by adjusting the initial target existence probability while the confirmation threshold was equal for all the algorithms in comparison. Using the true clutter measurement density showed that the CTTR had the fastest build-up. Even if the same sparsity order was applied, the proposed clutter measurement density estimation method provided better tracking results than the SCMDE. The closer to the true clutter measurement density the estimated clutter measurement density was, the better the performance was. At around Scan 25, when the targets were located in the immediate vicinity, the SCMDE estimated the clutter measurement density of the target measurement, which appeared to be bigger than the actual. This resulted in a slow build-up of the CTTR. By comparing the CTTR results for the sparsity order of *n* = 1 and *n* = 5 for the same clutter measurement density estimation methods, one could find that higher sparsity order resulted in better tracking performance because the higher the sparsity order was, the more accurate the estimated clutter measurement density was, as shown in Figure 6. The position RMSEs shown in Figure 5 were calculated for only the confirmed true tracks, which satisfied (46) such that the RMSEs looked similar in the order of magnitudes for all the algorithms in comparison as the confirmed true tracks passed the condition of (46). However, the number of samples involved in the RMSE calculation was quite different for each algorithms, as shown by the CTTR of Figure 4, which implied high reliability in RMSE for the algorithms with high CTTR and low reliability in RMSE for the algorithms with low CTTR. Figure 7 shows the true states and the estimated states of Target 1 over time for the position, velocity, and acceleration elements of each coordinate axis. Only the averaged state estimates of the confirmed tracks are shown in Figure 7. The existing SCMDE with the sparsity order of *n* = 1 showed the worst estimation performance among the algorithms in comparison. The target tracking algorithm using the proposed MTT-SCMDE with the sparsity order of *n* = 5 showed similar estimation performance to the one using the true clutter measurement density, and its state estimates were close to the true target states. This implied that the proposed MTT-SCMDE produced more reliable and accurate estimates for multi-target tracking than the existing SCMDE.

**Figure 4.** Confirmed true track rate. CMD, clutter measurement density.

**Figure 5.** Position RMSE.

**Figure 6.** True clutter measurement density and estimated clutter measurement density.

**Figure 7.** *Cont.*

**Figure 7.** The true states and the estimated states of Target 1 over time.

Although the clutter measurement density was estimated close to the actual for the proposed method with sparsity order of *n* = 5, the tracking performance was slightly worse than using the true clutter measurement density. It produced the best tracking performance among the methods in comparison. Therefore, the proposed method with a high sparsity order was a viable solution for this environment.

Table 1 shows the statistics of the track retention test. The proposed clutter measurement density estimation method had a higher track maintenance performance in terms of true track confirmation and track losses including switch and merge than the SCMDE method with the same sparsity order.

**Table 1.** Track retention statistics for Monte Carlo simulation.


**4. Anesthetic challenges of MIE**

The anesthetic challenges of MIE include prolonged surgery, difficulties of lung isolation, and one lung ventilation (OLV) when patient is positioned right up and complications related to extraperitoneal CO2 . Pain relief has been described as a protective factor to avoid postoperative respiratory complications, so it is highly recommended to use regional techniques for reducing postoperative pain. Also, the amount of fluids administered perioperatively can lead to the development of pulmonary complications and should be adequately evaluated to avoid fluid overload.

#### **4.1. Prolonged surgery**

MIE is a long procedure and may extend at least 5–6 h, depending on the experience of the surgeon. Such prolonged surgery increases the risk of hypothermia which can lead to reduce oxygen delivery and increase myocardial work, stress response, and postoperative infection. Our main objective is to maintain normothermia. If at the end of the surgery the patient is normothermic, extubation will be possible and postoperative ventilation will not be necessary [27].

Balanced anesthesia, by an inhalation approach (sevoflurane and desflurane) or by propofol target-controlled infusion with remifentanil, may help promote early recovery after MIE. There is evidence that both sevoflurane and desflurane, when compared with propofol, produce a beneficial local immunomodulatory effect in patients undergoing OLV for thoracic surgery, significantly reducing inflammatory mediators, adverse postoperative events, and improving clinical outcomes [28, 29].

#### **4.2. One lung ventilation**

MIE with a patient in right up position requires a period of one lung ventilation during the mobilization of thoracic esophagus. Inadequately managed lung isolation contributes to mortality and morbidity [30].

When surgery is performed thoracoscopically, retraction of an inadequately collapsed lung or lobe results more difficult than in open surgery, and this is important when choosing the method used to achieve lung isolation. The options described to reach an adequate lung isolation are a left or right double lumen tube or a single lumen tracheal tube and a bronchial blocker. A retrospective study has not found differences in intraoperative hypoxemia, hypercapnia, and high airway pressures whether a left- or right-sided tube was placed for OLV [31]. As a consequence most MIE techniques involve access to the right thorax; a left double-lumen tube perhaps would be preferable, especially when the thoracic approach is done in lateral decubitus. If we used the prone position (PP), a single-lumen endotraqueal tube is a valid alternative. Whichever method of lung isolation is selected, a fiberoptic bronchoscope should be used to check correct positioning both after intubation and after moving the patient before surgery [32].

The combination of OLV and esophageal surgery results in an inflammatory response that will increase alveolar injury, leading to the development of acute lung injury (ALI) [33]. During and after OLV, the alveolar concentrations of IL-6 and IL-8 are increased. The lung protective ventilatory strategy can reduce airway pressure and airway resistance. It can decrease the release of IL-6 and IL-8 and inhibit lung inflammatory response during OLV and postoperatively [34]. Some of the consequences that may cause ventilator-induced lung injury are volutrauma (high tidal volume), barotrauma (excessive transpulmonary pressure), atelectrauma (repeated opening and closing of alveoli resulting), and biotrauma (caused by inflammatory mediators) [35].

Thus, it is essential for the implementation of protective ventilatory strategies to reduce the severity of lung injuries during mechanical ventilation. These strategies include restrict tidal volume to 5–6 ml/kg during OLV, optimizing positive expiratory end pressure (PEEP), and limiting plateau and peak inspiratory pressures to less than 25 cm H2 O and less than 35 cm H2 O, respectively [36]. In addition to reduce lung injury, these actions promote early extubation [37].

#### **4.3. Complications of extra-peritoneal carbon dioxide**

• Patients who have a Forced Expiratory Volume in one second (FEV 1) < 70% of the predicted normal in the pulmonary function tests with normal arterial gas blood measurements are considered of moderate risk and those with FEV 1 < 50% or if the arterial gas bold analysis show hypoxemia or carbon dioxide retention must be considered of high risk.

The anesthetic challenges of MIE include prolonged surgery, difficulties of lung isolation, and one lung ventilation (OLV) when patient is positioned right up and complications related

erative respiratory complications, so it is highly recommended to use regional techniques for reducing postoperative pain. Also, the amount of fluids administered perioperatively can lead to the development of pulmonary complications and should be adequately evaluated to

MIE is a long procedure and may extend at least 5–6 h, depending on the experience of the surgeon. Such prolonged surgery increases the risk of hypothermia which can lead to reduce oxygen delivery and increase myocardial work, stress response, and postoperative infection. Our main objective is to maintain normothermia. If at the end of the surgery the patient is normothermic, extubation will be possible and postoperative ventilation will not be necessary [27]. Balanced anesthesia, by an inhalation approach (sevoflurane and desflurane) or by propofol target-controlled infusion with remifentanil, may help promote early recovery after MIE. There is evidence that both sevoflurane and desflurane, when compared with propofol, produce a beneficial local immunomodulatory effect in patients undergoing OLV for thoracic surgery, significantly reducing inflammatory mediators, adverse postoperative events, and

MIE with a patient in right up position requires a period of one lung ventilation during the mobilization of thoracic esophagus. Inadequately managed lung isolation contributes to mor-

When surgery is performed thoracoscopically, retraction of an inadequately collapsed lung or lobe results more difficult than in open surgery, and this is important when choosing the method used to achieve lung isolation. The options described to reach an adequate lung isolation are a left or right double lumen tube or a single lumen tracheal tube and a bronchial blocker. A retrospective study has not found differences in intraoperative hypoxemia, hypercapnia, and high airway pressures whether a left- or right-sided tube was placed for OLV [31].

. Pain relief has been described as a protective factor to avoid postop-

• Patients with Child C stage cirrhosis must not be eligible for surgery.

**4. Anesthetic challenges of MIE**

to extraperitoneal CO2

38 Esophageal Abnormalities

avoid fluid overload.

**4.1. Prolonged surgery**

improving clinical outcomes [28, 29].

**4.2. One lung ventilation**

tality and morbidity [30].

MIE may require a large period of capnoperitoneum, while laparoscopic dissection and mobilization of the stomach are being performed. As a consequence of surgical communication between the chest and abdomen, carbon dioxide may pass into the right chest, where drain tube has been placed in thoracic step, and this gas can be vented by this drain. In this situation, laparoscopic abdominal dissection could be difficult. Moreover, carbon dioxide may diffuse into the mediastinum (capnomediastinum), into the left chest, and it can cause subcutaneous emphysema around the chest, axilla, and neck. We can realize that gas is spreading to these spaces if we object a rapid increase in end-tidal CO2 . If CO2 is accumulated inside thorax cavity, an increase of airway pressures and lung compression might occur, leading to oxygen desaturation. This fact could negatively affect cardiac output.

We can solve all these problems by reducing the pressure at which the capnoperitoneum is maintained, and this will reduce the diffusion of gas to thoracic cavity without impairing abdominal dissection. Anyway, if extra-abdominal CO2 compromises cardiac or respiratory function, the capnoperitoneum should be evacuated. We should not extubate patients with significant emphysema until we achieve normocarbia [27].

#### **4.4. Fluid management—goal directed therapy (GDT)**

Maintaining adequate fluid balance is essential in both open surgery and MIE. While excessive fluid administration may be associated with increased postoperative pulmonary complication, tissue edema, and compromised perfusion, an inadequate intravascular volume can predispose to ischemia, end-organ dysfunction, and risk of anastomotic failure and leak.

In esophagectomy patients, an accurate fluid balance is essential to achieve adequate perfusion pressure and oxygen delivery to vital organs. The form of fluid replacement therapy, which is currently recommended, seems to be based on the principles of goal-directed therapy (GDT) with the aim to increase cardiac output in high-risk surgical patients. Various studies have found that GDT-based fluid administration improves intraoperative hemodynamic stability and reduces intensive care unit admissions, the incidence of complications, and mortality [38].

Some authors have suggested that restrictive fluid therapy is preferable to fluid overload because it leads to improved gastrointestinal recovery time, reduced overall morbidity [39], improved respiratory parameters, decreased incidence of postoperative pulmonary complications and shorter recovery periods [40]. On the other hand, fluid overload causes lung injury and has negatively impact to intestinal anastomoses [41].

#### **4.5. Thoracic epidural analgesia (TEA) versus paravertebral analgesia**

Even with reduction in trauma access, MIE may still result in an important postoperative pain, and optimal multimodal analgesia is required. Effective analgesia accelerates extubation, recovery, and early mobilization. Despite the importance of regular postoperative simple analgesia, a regional technique is essential.

Thoracic epidural analgesia (TEA) offers many benefits in esophagectomy, reducing respiratory complications, such us pneumonia [42–44] and postoperative pain. TEA has also been associated with decreased incidence of anastomotic leakage [37], possibly as a consequence of improving microcirculation in the gastric conduit [45]. Moreover, epidural analgesia also decreases the risk of prolonged ventilation or reintubation and improves some lung function parameters and blood oxygenation [46]. However, TEA also has some disadvantages: the incidence of failure may reach 12%, there are risks in the application technique, and it does not only promote urinary retention but also cause hypotension which makes necessary additional fluid administration [47–49]. Contraindications to an epidural access include sepsis or bacteraemia, infection at the insertion site, hypovolemia or shock, coagulopathy or thrombocytopenia and increased intracranial pressure [50].

Paravertebral blockade has recently been shown to provide analgesia comparable with TEA after thoracic step of esophagectomy. It is associated with less incidence of failed block and reduces hypotension and urinary retention when it is compared with TEA. Several recent reviews and meta-analyses defend its benefits [51–53], and it is a standard practice in some UK hospitals for minimally invasive esophagectomy. Local data also show shorter stays in the intensive therapy unit comparing with TEA.

#### **4.6. Conclusion**

MIE supposes many anesthetic challenges, some of them unique for this type of procedure and requires an accurate knowledge of the different surgical steps performed. Moreover, it is essential to know and treat complications of one lung anesthesia and extra-peritoneal spread of CO2 . Paravertebral blockade might have more benefits than TEA to improve postoperative pain in patients undergoing for MIE.


**4. Conclusion**

*Geriatric Medicine and Gerontology*

on ARHL-related genetic factors.

*2.3.1 Consequences of suffering ARHL*

overcome obstacles caused by hearing loss.

**3. Hearing loss treatments**

aging or is not amenable to treatment.

caused by the atrophy of the stria vascularis resulting in a decrease in endolymphatic potential [74]. Also, there is a mixed type where the progressive degeneration of sensory cells is observed along loss of cochlear neurons [75–77]. Moreover, still controversial if the loss of neurons is a secondary consequence or a primary cause. The task to distinct between genetic and environmental factors in acquired hearing loss is very challenging. In this regard, to progress the understanding of the mechanisms that lead to the damage, physiopathology of age-related hearing loss had been assessed by *in vitro* (cell lines) and *in vivo* (rodents and zebrafish) models [70]. The studies provided evidences of specific inner damage such as inflammation, oxidative stress, reduced cochlear blood flow, disrupted ion hemostasis and death of sensory and neuronal cells [78]. **Table 3** summarizes all current knowledge

Age-related hearing loss affects communication and information reception reducing the quality of live and psychosocial well-being (e.g., anxiety or depression) of elder population. Limitation in communication has an impact on social and personal relationships triggering to loss of autonomy and dependency [122, 123]. Even though the World Health Organization estimates that by 2025 approximately 500 million will suffer from age-related hearing loss; there is a lack of awareness by health care professionals as well as no educational programs on how patients could

Few studies have investigated the psychological factor and how individuals develop their lives in the presence of hearing loss. The studies reveal that maladaptive behavior (e.g., escape, avoiding social interaction and/or pretending to understand) has a negative effect on well-being of elder patients comparing to adaptive strategies (e.g., training verbal skills or self-awareness) [124, 125]. Additionally, there is a significant increase of hearing aids use by cases who attend audiology clinic with a relative than others attending alone [126]. Therefore, elder population with acquired hearing loss requires social support from family and health care professionals. Educational programs on how to use hearing aids and communication strategies as well as counseling for follow-up and feedback are needed in order

Hearing loss is not a curable disease however science made some considerable progress. Current therapies based on cochlear implants (a device that provides direct electrical stimulation to the auditory nerve in the inner ear) and hearing aids (are non-surgically placed in the ear canal) which help patients to recover partly hearing. Hearing aids could be a stigma in the society as are negatively perceived as well as expensive making that only one out of five people who could benefit from a hearing aid actually wears it (WHO, [128]). Therefore, the major barriers to improve hearing in elder population include perception that hearing loss is a normal part of

Based on the animal research studies, several clinical trials are working to investigate the effects of a variety of drugs to prevent hearing loss including antioxidants, ROS scavengers, alpha lipoic acid, N-acetylcysteine or anti-inflammatory

New generation treatments based on microRNA, short interfering RNA as well as tissue regeneration using stem cells are promising tools [135, 136]. Due to

to increase adherence to treatment and improve life quality [127].

**124**

agents [129–134].

Of the senses that humans use to interact with their environment, hearing is considered as one of the dominant after vision. The loss of hearing can occur through genetic mutations, through environmental factors or through a combination of both. ARHL is an increasingly important public health problem which reduces life's quality, isolation, dependence and frustration. Besides basic research and more effective therapies for the optimal treatment, management of the condition is still a pending task. Social support by the family and health care professionals is critical to the life quality of the older adults with hearing loss. The quality of care and well-being could be improved by active education and counseling to provide appropriate support to facilitate everyday communication.