*4.10. NADPH Assay*

The rate of NADPH (ε = 6.2 108 mM−1·cm−1 at A340nm) consumption by each CYP2C8 variant (0.2 μM) incubated with CPR (0.6 μM) and PAC (70 μM) in 0.1 M potassium phosphate buffer and 200 μM NADPH was determined via UV–vis spectroscopy using a Cary 300 UV–vis spectrometer in kinetics mode (Agilent Technologies), as previously described [41,44].

#### *4.11. Stopped-flow Kinetics of Electron Transfer*

An Applied Photophysics SX-17 MV Spectrophotometer (Leatherhead UK) was used to monitor the reduction of CYP2C8\*1/\*2/\*3/R139K/K399R, as previously described with the following modifications [41]. Reaction cell 1 containing CYP2C8 (2 μM) in 0.1% cholate, CPR (2 or 6 μM), paclitaxel (70 μM), glucose oxidase (1 U/mL), and glucose (10 mM) dissolved in 100 mM potassium phosphate buffer was kept anaerobic and CO-saturated. Reaction cell 2 containing excess NADPH (1 mM), paclitaxel (70 μM), glucose oxidase (1 U/mL), and glucose (10 mM) dissolved in 100 mM potassium phosphate buffer was also kept anaerobic. The reaction cells were kept at 4 ◦C until rapid mixing followed by absorbance readings at 37 ◦C.

#### *4.12. Data Analysis of Stopped-Flow Experiments*

The reduction of ferric CYP2C8 to a ferrous–CO complex was monitored near A450nm upon mixing the two separate reaction cells in logarithmic mode and analyzed as described previously, with the following changes [41]. All data indicate the average of 3–6 individual reactions fitted using either a monophasic or biphasic exponential equation using OriginPro 2017. The initial decrease in absorbance at 450 nm (A450nm) corresponding to the rapid reduction of CPR were not included in these analyses due to spectroscopic noise. *R2* values for fits exceeded 0.99 in most cases. The errors reported are SEM.


**4. Clinical parameters affecting prediction accuracy of postoperative lung function**

Prediction accuracy of postoperative lung function is affected not only by the calculation technique, but also the clinical factors associated with the actual postoperative lung function. The actual lung function closely relates to the physiology of lung volume reduction, reversibility of airway obstruction, pharmacotherapy, and postoperative respiratory rehabilitation.

#### **4.1 Chronic obstructive pulmonary sisease**

Pulmonary function is affected by lung resection and the decline in lung function varies with the extent of the resection. The degree of functional loss appears to be less in individuals with poor baseline lung function uniformly across the studies (Bobbio, et al. 2005; Boushy, et al. 1971; Edwards, et al. 2001). In patients with severe emphysema, surgery performed to remove the most emphysematous portion of the lung may lead to improvements in lung function (Fishman, et al. 2003). A case-matched study demonstrated that the patients with COPD had a three-fold higher rate of cardiopulmonary morbidity (28% versus 10%, p=0.04), but lower reduction in FEV1 (6% versus 13%, p=0.0002) compared with non-COPD patients after lobectomy for lung cancer (Pompili, et al. 2010). Importantly, although the postoperative quality of life in both groups was reduced, there were no significant differences in quality of life between the groups. This suggests that the patients with lung cancer and COPD may be unexpectedly tolerable with the curative lung resection if the candidates are carefully selected. This is attributed to lung volume reduction effect which takes place very early. The risk-benefit should be balanced based on the negative physiologic effects of thoracotomy versus positive effects of lung volume reduction in the

Prediction of Postoperative Lung Function 257

resected, apoFEV1 tended to be larger than ppoFEV1. It is noteworthy that the corresponding means of apoFEV1/ppoFEV1 for each number of resected lung segments gathered on a straight line of a constant slope. The apoFEV1 was closest to ppoFEV1 when four segments were resected. Contrary to the previous report, resected lung portion (upper or lower portion resection) was not related to the prediction accuracy (p = 0.10). However, more number of segments was resected in lower portion resection compared with upper portion resection (5.6 ± 1.1 vs. 3.7 ± 1.0, p = 0.001), which might be a confounding factor. Lung functions of 46/82 patients were followed at 106 ± 30 days after surgery, which was reflecting plateau lung function of the patients undergoing lung resection. As expected, plateau apoFEV1 was increased by 13% compared with apoFEV1 measured at 24 days after surgery. In predicting plateau lung function, split radionuclide perfusion scanning method was also superior to anatomic calculation (plateau apoFEV1/ppoFEV1 = 1.11 ± 0.24 vs. 1.18 ± 0.30, p < 0.001). These data also indicate that the prediction methods are fitter for short-term postoperative value rather than long-term value. In general, postoperative lung function gradually improves with time (Brunelli, et al. 2007). However, the plateau apoFEV1 was lower than the apoFEV1 measured at 24 days in 9/46 (19%) patients. Their preoperative bronchodilator response values were higher than those of the others although it did not reach statistical significance (11.2 ± 8.4% vs. 7.0 ± 6.8%, p = 0.11). The study did not investigate prescription status of bronchodilator or the patients' adherence to the drugs. However, this finding suggests that adequate perioperative bronchodilator therapy is necessary for the patients with high bronchodilator response, especially for the patients with poor lung function. Bronchodilator response is a well known predictor of pulmonary function improvement after long term treatment with long acting beta-2 agonist. A study demonstrated that bronchodilator response, wheezing history positively correlated with improvement in FEV1 after three months inhalation treatment with salmeterol/fluticasone combination, conversely negative correlation with emphysema extent (Lee, et al. 2011). COPD is a complex and heterogeneous disorder of mixed chronic bronchitis and emphysema. Another study showed that three months inhalation treatment with long-acting beta-agonist and corticosteroid significantly improved the FEV1 of obstruction-dominant patients compared with the emphysema-dominant subgroup. Again, baseline bronchodilator response and DLco were the meaningful predictors associated with improvement of FEV1 after the treatment (Lee, et al. 2010). If the patients with high bronchodilator response do not receive regular bronchodilator treatment after surgery, the FEV1 should decrease and the prediction accuracy

of postoperative lung function would be affected as a matter of course.

**5. Physiologic changes in the lung volume reduction surgery**

that of the non-COPD group.

Preoperative FEV1 was significantly lower in the COPD group than in the non-COPD group (67.1 ± 8.3% vs. 101.6 ± 15.2%, p < 0.001). The apoFEV1 was about 14% larger than ppoFEV1 in the COPD group while apoFEV1 was very similar to ppoFEV1 in the non-COPD group (apoFEV1/ppoFEV1 = 1.1 ± 0.2 in COPD group and 1.0 ± 0.1 in non-COPD group, p < 0.001). These are the same results with the previous studies indicating that the prediction of postoperative lung function is more accurate in the non-COPD group than in the COPD group, and postoperative lung function of the COPD group may be less deteriorated than

Actual postoperative FEV1 is better than the predicted value in the patients with COPD, which is universally observed in many clinical studies. This phenomenon is explained by the physiology of lung volume reduction. In patients with COPD, inhaled air is trapped in

surgical decision for the patients with lung cancer and COPD. As most lung cancer patients have more or less emphysematous changes, adequate volume reduction may open small airways, expand or overinflate functional alveoli, improve diaphragmatic movement and consequently increase postoperative FEV1 than the expected. This is consistent with the basic principle of volume reduction surgery for severe emphysema that postoperative lung function can be improved by resection of relatively functionless emphysematous lung.

#### **4.2 Resected lung portion**

Besides preoperative lung function, a study has suggested that the prediction accuracy of postoperative lung function could be influenced by other clinical factor such as resected lung portion (Sekine, et al. 2003). Sekine et al. reported that the presence of COPD and resection of the lower lung portion (lower lobectomy or middle-lower bilobectomy) were significantly associated with minimal deterioration of pulmonary function after lobectomy. The authors retrospectively analyzed 521 patients who had undergone lobectomy for lung cancer. The ppoFEV1 was calculated by modified anatomic calculation by multiplying a specific coefficient according to the baseline FEV1 categories. The apoFEV1 was measured at 1 month after operation. Minimal alteration of postoperative lung function, defined as apoFEV1 ≥ 1.15 ppoFEV1, was confirmed to be associated with COPD (vs. non-COPD) and resection of the lower lung portion (vs. upper lung portion) in multivariate analysis. Lung volume reduction theory can explain minimal alteration of apoFEV1 in the patients with COPD. The authors speculated that occasional anatomic repositioning after upper lobectomy, which causes narrowing of the orifice of lower or middle lobe bronchus, and different movement and elevation of diaphragm between upper lobectomy and lower lobectomy might be the potential causes the minimal alteration in the cases of resection of the lower lung portion (Nonaka, et al. 2000; Van Leuven, et al. 1999).

#### **4.3 Number of resected lung segment and bronchodilator response**

The writer of this chapter and his colleagues (Kim, et al. 2008) investigated another clinical factors affecting prediction accuracy. Some of the findings would like to be introduced in detail, because those may help for the selection of candidates for surgery and perioperative management of the patients.

A total of 82 patients with non-small-cell lung cancer undergoing pulmonary resection were retrospectively analyzed in this study. Forty eight patients underwent lobectomy, 11 patients underwent bilobectomy, and the remaining 23 patients underwent pneumonectomy. The ppoFEV1 was dually estimated by anatomical calculation and split radionuclide perfusion scanning method. The mean time interval between surgery and apoFEV1 was 24 ± 7 days. The ppoFEV1 calculated by split radionuclide perfusion scanning method was more accurate than that by anatomic calculation method (apoFEV1/ppoFEV1 = 1.00 ± 0.19 vs. 1.07 ± 0.23, p < 0.001). Multivariate linear regression analysis was performed to identify clinical parameters affecting the prediction accuracy with the covariates of age, gender, preoperative FEV1, time interval between surgery and the day of measuring apoFEV1, preoperative bronchodilator response (% increase in FEV1 after inhalation of short acting beta-2 agonist), resected lung portion, and the number of resected lung segments. Among these clinical factors, the number of resected lung segments and preoperative FEV1 were significant clinical factors affecting the prediction accuracy (p = 0.026 and 0.002, respectively). As the preoperative FEV1 became smaller and the more lung segments were

surgical decision for the patients with lung cancer and COPD. As most lung cancer patients have more or less emphysematous changes, adequate volume reduction may open small airways, expand or overinflate functional alveoli, improve diaphragmatic movement and consequently increase postoperative FEV1 than the expected. This is consistent with the basic principle of volume reduction surgery for severe emphysema that postoperative lung function can be improved by resection of relatively functionless emphysematous lung.

Besides preoperative lung function, a study has suggested that the prediction accuracy of postoperative lung function could be influenced by other clinical factor such as resected lung portion (Sekine, et al. 2003). Sekine et al. reported that the presence of COPD and resection of the lower lung portion (lower lobectomy or middle-lower bilobectomy) were significantly associated with minimal deterioration of pulmonary function after lobectomy. The authors retrospectively analyzed 521 patients who had undergone lobectomy for lung cancer. The ppoFEV1 was calculated by modified anatomic calculation by multiplying a specific coefficient according to the baseline FEV1 categories. The apoFEV1 was measured at 1 month after operation. Minimal alteration of postoperative lung function, defined as apoFEV1 ≥ 1.15 ppoFEV1, was confirmed to be associated with COPD (vs. non-COPD) and resection of the lower lung portion (vs. upper lung portion) in multivariate analysis. Lung volume reduction theory can explain minimal alteration of apoFEV1 in the patients with COPD. The authors speculated that occasional anatomic repositioning after upper lobectomy, which causes narrowing of the orifice of lower or middle lobe bronchus, and different movement and elevation of diaphragm between upper lobectomy and lower lobectomy might be the potential causes the minimal alteration in the cases of resection of

the lower lung portion (Nonaka, et al. 2000; Van Leuven, et al. 1999).

**4.3 Number of resected lung segment and bronchodilator response**

The writer of this chapter and his colleagues (Kim, et al. 2008) investigated another clinical factors affecting prediction accuracy. Some of the findings would like to be introduced in detail, because those may help for the selection of candidates for surgery and perioperative

A total of 82 patients with non-small-cell lung cancer undergoing pulmonary resection were retrospectively analyzed in this study. Forty eight patients underwent lobectomy, 11 patients underwent bilobectomy, and the remaining 23 patients underwent pneumonectomy. The ppoFEV1 was dually estimated by anatomical calculation and split radionuclide perfusion scanning method. The mean time interval between surgery and apoFEV1 was 24 ± 7 days. The ppoFEV1 calculated by split radionuclide perfusion scanning method was more accurate than that by anatomic calculation method (apoFEV1/ppoFEV1 = 1.00 ± 0.19 vs. 1.07 ± 0.23, p < 0.001). Multivariate linear regression analysis was performed to identify clinical parameters affecting the prediction accuracy with the covariates of age, gender, preoperative FEV1, time interval between surgery and the day of measuring apoFEV1, preoperative bronchodilator response (% increase in FEV1 after inhalation of short acting beta-2 agonist), resected lung portion, and the number of resected lung segments. Among these clinical factors, the number of resected lung segments and preoperative FEV1 were significant clinical factors affecting the prediction accuracy (p = 0.026 and 0.002, respectively). As the preoperative FEV1 became smaller and the more lung segments were

**4.2 Resected lung portion**

management of the patients.

resected, apoFEV1 tended to be larger than ppoFEV1. It is noteworthy that the corresponding means of apoFEV1/ppoFEV1 for each number of resected lung segments gathered on a straight line of a constant slope. The apoFEV1 was closest to ppoFEV1 when four segments were resected. Contrary to the previous report, resected lung portion (upper or lower portion resection) was not related to the prediction accuracy (p = 0.10). However, more number of segments was resected in lower portion resection compared with upper portion resection (5.6 ± 1.1 vs. 3.7 ± 1.0, p = 0.001), which might be a confounding factor. Lung functions of 46/82 patients were followed at 106 ± 30 days after surgery, which was reflecting plateau lung function of the patients undergoing lung resection. As expected, plateau apoFEV1 was increased by 13% compared with apoFEV1 measured at 24 days after surgery. In predicting plateau lung function, split radionuclide perfusion scanning method was also superior to anatomic calculation (plateau apoFEV1/ppoFEV1 = 1.11 ± 0.24 vs. 1.18 ± 0.30, p < 0.001). These data also indicate that the prediction methods are fitter for short-term postoperative value rather than long-term value. In general, postoperative lung function gradually improves with time (Brunelli, et al. 2007). However, the plateau apoFEV1 was lower than the apoFEV1 measured at 24 days in 9/46 (19%) patients. Their preoperative bronchodilator response values were higher than those of the others although it did not reach statistical significance (11.2 ± 8.4% vs. 7.0 ± 6.8%, p = 0.11). The study did not investigate prescription status of bronchodilator or the patients' adherence to the drugs. However, this finding suggests that adequate perioperative bronchodilator therapy is necessary for the patients with high bronchodilator response, especially for the patients with poor lung function. Bronchodilator response is a well known predictor of pulmonary function improvement after long term treatment with long acting beta-2 agonist. A study demonstrated that bronchodilator response, wheezing history positively correlated with improvement in FEV1 after three months inhalation treatment with salmeterol/fluticasone combination, conversely negative correlation with emphysema extent (Lee, et al. 2011). COPD is a complex and heterogeneous disorder of mixed chronic bronchitis and emphysema. Another study showed that three months inhalation treatment with long-acting beta-agonist and corticosteroid significantly improved the FEV1 of obstruction-dominant patients compared with the emphysema-dominant subgroup. Again, baseline bronchodilator response and DLco were the meaningful predictors associated with improvement of FEV1 after the treatment (Lee, et al. 2010). If the patients with high bronchodilator response do not receive regular bronchodilator treatment after surgery, the FEV1 should decrease and the prediction accuracy of postoperative lung function would be affected as a matter of course. Preoperative FEV1 was significantly lower in the COPD group than in the non-COPD group

(67.1 ± 8.3% vs. 101.6 ± 15.2%, p < 0.001). The apoFEV1 was about 14% larger than ppoFEV1 in the COPD group while apoFEV1 was very similar to ppoFEV1 in the non-COPD group (apoFEV1/ppoFEV1 = 1.1 ± 0.2 in COPD group and 1.0 ± 0.1 in non-COPD group, p < 0.001). These are the same results with the previous studies indicating that the prediction of postoperative lung function is more accurate in the non-COPD group than in the COPD group, and postoperative lung function of the COPD group may be less deteriorated than that of the non-COPD group.

#### **5. Physiologic changes in the lung volume reduction surgery**

Actual postoperative FEV1 is better than the predicted value in the patients with COPD, which is universally observed in many clinical studies. This phenomenon is explained by the physiology of lung volume reduction. In patients with COPD, inhaled air is trapped in

Prediction of Postoperative Lung Function 259

with emphysema or chronic bronchitis, though these two disease entities are frequently mixed up to a varying ratio. It is accompanied with some significant extrapulmonary effects and comorbidities (Agusti 2005). COPD has been defined in several ways, and the differences in definitions and diagnosis affect the estimates of the burden of the disease. The Global Initiative for Chronic Obstructive Lung Disease (GOLD) defines the disease in stages of clinical severity based on FEV1 and FEV1/FVC (forced vital capacity) from postbronchodilator spirometry (Rabe, et al. 2007). The statement recommends to use the fixed ratio post-bronchodilator FEV1/FVC < 0.7 for definition of airflow limitation despite a

COPD are at risk for lung cancer due to common risk factors like aging, smoking, reactive oxygen species (Azad, et al. 2008; Soriano, et al. 2005; Young, et al. 2009). Tobacco smoking is considered to be the leading cause both of lung cancer and COPD. Smokers have a higher prevalence of respiratory symptoms and lung function abnormalities, a greater annual decline rate in FEV1 and a greater COPD mortality rate than nonsmokers. Smoking accounts for more than 85-90% of all lung cancer related deaths (Doll & Peto 1976). Cancer cells proliferate in reactive oxygen species rich inflammatory environment which is promoting DNA damage, inactivation of apoptosis, upregulation of growth factors, cytokines, and activating growth supporting genes (Cook, et al. 2004). Reactive oxygen species and chronic inflammation are also important pathologic mechanisms of COPD. A meta-analysis demonstrated that overall relative risk of lung cancer for subjects with COPD was 2.22 (95% confidence interval, 1.66-2.97%). Besides COPD, previous history of pneumonia or tuberculosis also increased the lung cancer risk even in never-smoker population (Brenner, et al. 2011). Chronic inflammation has been proposed as a cause of cancer development. An effective COPD management includes severity assessment, regular monitoring, risk factor elimination, pharmacotherapy, and rehabilitation. This multidimensional approach includes patient education, health advice, counseling about smoking cessation, instruction in exercise and nutrition. Almost all the same therapeutic approach and monitoring should be also applied to the patients with the patients undergoing lung resection. Pharmacotherapy is helpful to prevent and control respiratory symptoms, reduce the frequency and severity of exacerbation, and improve exercise capacity and quality of life. The existing medications for COPD do not modify the long-term decline in lung function, but regular treatment with long-acting anticholinergic bronchodilator (Tiotropium bromide), long-acting beta-2 agonists, inhaled glucocorticoid, and its combination can decrease the rate of decline of lung function (Celli, et al. 2008; Tashkin, et al. 2008). Bronchodilators acting on peripheral airways reduce air trapping, thereby reducing residual lung volume and improving respiratory symptoms and exercise capacity. Patient education is essential in COPD like any other chronic diseases. The component of education should include smoking cessation, disease information about pathophysiology and natural course, general approach to the therapy, and self management skill. The poor adherence of the patients with COPD to the inhaler medication has been pointed out (Bender, et al. 2006). However, it is essential to remind the patients of regular using inhaler medication, because adherence to inhaled medication has been shown to be significantly associated with reduced risk of death and admission to hospital due to exacerbation in COPD (Vestbo, et al. 2009). COPD doubles the risk of postoperative pulmonary complications (Kroenke, et al. 1993). Strategies for reducing pulmonary complications are needed. Preoperatively, inhaled bronchodilators such as long-acting anticholinergics or beta-2 agonists are indicated for the patients with COPD. Adequate drug therapies can maximize the potential to tolerate lung

problematic issue of overdiagnosis.

the thorax as a result of decreased elastic recoil of the lung and early closure of the small airways during exhalation. This is manifested as hyperinflation of the chest, flattening of the diaphragm, increased intra-thoracic pressure, and reduced inspiratory capacity. These worsen during exercise and result in dyspnea and limitation of exercise capacity. After surgical volume reduction, there is expansion of the remaining lung in addition to reduction of the overall thoracic volume and pressure, and it is probable that some areas of relative compression have been reexpanded. Lung volume reduction surgery is associated with improvement in exercise capacity, lung function, quality of life, and dyspnea, but the changes after surgery are variable according to the individuals (Gelb, et al. 2001). The improvement of FEV1 and reduction in hyperinflation has been explained by the increase of lung parenchymal elastic recoil (Sciurba, et al. 1996). It is accompanied with subsequent repositioning of the diaphragm, recruitment of inspiratory muscles, and improvement of respiratory mechanics (Benditt, et al. 1997; Criner, et al. 1998).

Surgical treatment of emphysema had been tried with multiple wedge resections and plications technique which is no longer used (Brantigan & Mueller 1957), and then Cooper et al. reintroduced lung volume reduction surgery as a possible surgical therapy for selected patients with a heterogeneous form of emphysema (Cooper, et al. 1995). The most affected portions are excised about 20% to 35% of the volume of each lung for lung volume reduction. The surgical mortality rate ranges 4-15% and one-year mortality rates are as high as 17% (Argenziano, et al. 1996; Flaherty, et al. 2001; Gelb, et al. 2001). A large randomized controlled trial was conducted to compare lung volume reduction surgery with medical therapy for severe emphysema (Fishman, et al. 2003). The FEV1 of surgery arm was significantly better than that of medical treatment group after 6, 12, and 24 months followup. The rates of improvement versus deterioration of FEV1 compared with the baseline were 65% : 35% at 6 months follow-up, 56% : 44% at 12 months, and 43% : 57% at 24 months in the lung volume reduction surgery group. It is also observed in the bullectomy case series that FEV1 is initially improved after lung volume reduction surgery and then returns to the baseline lung function with time. The 90-day mortality was 7.9% (95% confidence interval, 5.9-10.3%) in surgery group, and 1.3% (95% confidence interval, 0.6-2.6%) in medical treatment group. The functional benefits of lung volume reduction surgery came at the price of increased short-term mortality. Overall mortality was similar in both treatment groups, but subgroup analysis showed that the survival benefit was observed in the patients with predominantly upper lobe emphysema and a low baseline exercise capacity. Patients with non–upper lobe emphysema and high baseline exercise capacity are poor candidates for lung volume reduction surgery, because of increased mortality and negligible functional gain.

The similar physiologic changes can be also expected in the giant bullae. If a giant bulla compresses the adjacent normal lung parenchyma and it is causing incapacitating dyspnea, it should be resected for the reexpansion of the normal lung. Bullectomy can produce immediate lung function improvement, but the benefit usually decline with time (Laros, et al. 1986; Schipper, et al. 2004). Giant bullae are frequently combined with emphysema.

#### **6. COPD and lung cancer**

COPD is characterized by chronic airflow limitation that is not fully reversible and usually progressive with time. The airflow limitation is usually associated with an abnormal inflammatory response of the lung to noxious particles or gases. COPD refers to patients

the thorax as a result of decreased elastic recoil of the lung and early closure of the small airways during exhalation. This is manifested as hyperinflation of the chest, flattening of the diaphragm, increased intra-thoracic pressure, and reduced inspiratory capacity. These worsen during exercise and result in dyspnea and limitation of exercise capacity. After surgical volume reduction, there is expansion of the remaining lung in addition to reduction of the overall thoracic volume and pressure, and it is probable that some areas of relative compression have been reexpanded. Lung volume reduction surgery is associated with improvement in exercise capacity, lung function, quality of life, and dyspnea, but the changes after surgery are variable according to the individuals (Gelb, et al. 2001). The improvement of FEV1 and reduction in hyperinflation has been explained by the increase of lung parenchymal elastic recoil (Sciurba, et al. 1996). It is accompanied with subsequent repositioning of the diaphragm, recruitment of inspiratory muscles, and improvement of

Surgical treatment of emphysema had been tried with multiple wedge resections and plications technique which is no longer used (Brantigan & Mueller 1957), and then Cooper et al. reintroduced lung volume reduction surgery as a possible surgical therapy for selected patients with a heterogeneous form of emphysema (Cooper, et al. 1995). The most affected portions are excised about 20% to 35% of the volume of each lung for lung volume reduction. The surgical mortality rate ranges 4-15% and one-year mortality rates are as high as 17% (Argenziano, et al. 1996; Flaherty, et al. 2001; Gelb, et al. 2001). A large randomized controlled trial was conducted to compare lung volume reduction surgery with medical therapy for severe emphysema (Fishman, et al. 2003). The FEV1 of surgery arm was significantly better than that of medical treatment group after 6, 12, and 24 months followup. The rates of improvement versus deterioration of FEV1 compared with the baseline were 65% : 35% at 6 months follow-up, 56% : 44% at 12 months, and 43% : 57% at 24 months in the lung volume reduction surgery group. It is also observed in the bullectomy case series that FEV1 is initially improved after lung volume reduction surgery and then returns to the baseline lung function with time. The 90-day mortality was 7.9% (95% confidence interval, 5.9-10.3%) in surgery group, and 1.3% (95% confidence interval, 0.6-2.6%) in medical treatment group. The functional benefits of lung volume reduction surgery came at the price of increased short-term mortality. Overall mortality was similar in both treatment groups, but subgroup analysis showed that the survival benefit was observed in the patients with predominantly upper lobe emphysema and a low baseline exercise capacity. Patients with non–upper lobe emphysema and high baseline exercise capacity are poor candidates for lung volume reduction surgery, because of increased mortality and negligible functional

The similar physiologic changes can be also expected in the giant bullae. If a giant bulla compresses the adjacent normal lung parenchyma and it is causing incapacitating dyspnea, it should be resected for the reexpansion of the normal lung. Bullectomy can produce immediate lung function improvement, but the benefit usually decline with time (Laros, et al. 1986; Schipper, et al. 2004). Giant bullae are frequently combined with emphysema.

COPD is characterized by chronic airflow limitation that is not fully reversible and usually progressive with time. The airflow limitation is usually associated with an abnormal inflammatory response of the lung to noxious particles or gases. COPD refers to patients

respiratory mechanics (Benditt, et al. 1997; Criner, et al. 1998).

gain.

**6. COPD and lung cancer**

with emphysema or chronic bronchitis, though these two disease entities are frequently mixed up to a varying ratio. It is accompanied with some significant extrapulmonary effects and comorbidities (Agusti 2005). COPD has been defined in several ways, and the differences in definitions and diagnosis affect the estimates of the burden of the disease. The Global Initiative for Chronic Obstructive Lung Disease (GOLD) defines the disease in stages of clinical severity based on FEV1 and FEV1/FVC (forced vital capacity) from postbronchodilator spirometry (Rabe, et al. 2007). The statement recommends to use the fixed ratio post-bronchodilator FEV1/FVC < 0.7 for definition of airflow limitation despite a problematic issue of overdiagnosis.

COPD are at risk for lung cancer due to common risk factors like aging, smoking, reactive oxygen species (Azad, et al. 2008; Soriano, et al. 2005; Young, et al. 2009). Tobacco smoking is considered to be the leading cause both of lung cancer and COPD. Smokers have a higher prevalence of respiratory symptoms and lung function abnormalities, a greater annual decline rate in FEV1 and a greater COPD mortality rate than nonsmokers. Smoking accounts for more than 85-90% of all lung cancer related deaths (Doll & Peto 1976). Cancer cells proliferate in reactive oxygen species rich inflammatory environment which is promoting DNA damage, inactivation of apoptosis, upregulation of growth factors, cytokines, and activating growth supporting genes (Cook, et al. 2004). Reactive oxygen species and chronic inflammation are also important pathologic mechanisms of COPD. A meta-analysis demonstrated that overall relative risk of lung cancer for subjects with COPD was 2.22 (95% confidence interval, 1.66-2.97%). Besides COPD, previous history of pneumonia or tuberculosis also increased the lung cancer risk even in never-smoker population (Brenner, et al. 2011). Chronic inflammation has been proposed as a cause of cancer development.

An effective COPD management includes severity assessment, regular monitoring, risk factor elimination, pharmacotherapy, and rehabilitation. This multidimensional approach includes patient education, health advice, counseling about smoking cessation, instruction in exercise and nutrition. Almost all the same therapeutic approach and monitoring should be also applied to the patients with the patients undergoing lung resection. Pharmacotherapy is helpful to prevent and control respiratory symptoms, reduce the frequency and severity of exacerbation, and improve exercise capacity and quality of life. The existing medications for COPD do not modify the long-term decline in lung function, but regular treatment with long-acting anticholinergic bronchodilator (Tiotropium bromide), long-acting beta-2 agonists, inhaled glucocorticoid, and its combination can decrease the rate of decline of lung function (Celli, et al. 2008; Tashkin, et al. 2008). Bronchodilators acting on peripheral airways reduce air trapping, thereby reducing residual lung volume and improving respiratory symptoms and exercise capacity. Patient education is essential in COPD like any other chronic diseases. The component of education should include smoking cessation, disease information about pathophysiology and natural course, general approach to the therapy, and self management skill. The poor adherence of the patients with COPD to the inhaler medication has been pointed out (Bender, et al. 2006). However, it is essential to remind the patients of regular using inhaler medication, because adherence to inhaled medication has been shown to be significantly associated with reduced risk of death and admission to hospital due to exacerbation in COPD (Vestbo, et al. 2009).

COPD doubles the risk of postoperative pulmonary complications (Kroenke, et al. 1993). Strategies for reducing pulmonary complications are needed. Preoperatively, inhaled bronchodilators such as long-acting anticholinergics or beta-2 agonists are indicated for the patients with COPD. Adequate drug therapies can maximize the potential to tolerate lung

Prediction of Postoperative Lung Function 261

Agusti, A.G. (2005). Systemic effects of chronic obstructive pulmonary disease. *Proc Am*

Argenziano, M., Moazami, N., Thomashow, B., Jellen P.A., Gorenstein L.A., Rose E.A., et al.

Azad, N., Rojanasakul, Y., Vallyathan, V. (2008). Inflammation and lung cancer: roles of

Ballantyne, J.C., Carr, D.B., deFerranti, S., Suarez, T., Lau, J., Chalmers, T.C., et al. (1998).

Baser, S., Shannon, V.R., Eapen, G.A., Jimenez, C.A., Onn, A., Keus, L., et al. (2006).

Beckles, M.A., Spiro, S.G., Colice, G.L., Rudd, R.M. (2003). The physiologic evaluation of

Bender, B.G., Pedan, A., Varasteh, L.T. (2006). Adherence and persistence with fluticasone

Benditt, J.O., Wood, D.E., McCool, F.D., Lewis, S., Albert, R.K. (1997). Changes in breathing

Berthezène, Y., Croisille, P., Wiart, M., Howarth, N., Houzard, C., Faure, O., et al. (1999).

Bobbio, A., Chetta, A., Carbognani, P., Internullo, E., Verduri, A., Sansebastiano, G., et al.

Bolliger, C.T., Jordan, P., Solèr, M., Stulz, P., Grädel, E., Skarvan, K., et al. (1995). Exercise

Bolliger, C.T., Jordan, P., Solèr, M., Stulz, P., Tamm, M., Wyser, C., et al. (1996). Pulmonary

Bolliger, C.T., Solèr, M., Stulz, P., Grädel, E., Müller-Brand, J., Elsasser, S., et al. (1994).

Bolliger, C.T., Wyser, C., Roser, H., Solèr, M., Perruchoud, A.P. (1995). Lung scanning and

small-cell lung cancer. *Clin Lung Cancer,* Vol.7, No.5, pp. 344-349

surgery. *Am J Respir Crit Care Med,* Vol.155, No.1, pp. 279-284

*Am J Respir Crit Care Med,* Vol.151, No.5, pp. 1472-1480

(1996). Extended indications for lung volume reduction surgery in advanced

reactive oxygen/nitrogen species. *J Toxicol Environ Health B Crit Rev,* Vol.11, No.1,

The comparative effects of postoperative analgesic therapies on pulmonary outcome: cumulative meta-analyses of randomized, controlled trials. *Anesth Analg,*

Pulmonary dysfunction as a major cause of inoperability among patients with non-

patients with lung cancer being considered for resectional surgery. *Chest,* Vol.123,

propionate/salmeterol combination therapy. *J Allergy Clin Immunol,* Vol.118, No.4,

and ventilatory muscle recruitment patterns induced by lung volume reduction

Prospective comparison of MR lung perfusion and lung scintigraphy. *J Magn Reson*

(2005). Changes in pulmonary function test and cardio-pulmonary exercise capacity in COPD patients after lobar pulmonary resection. *Eur J Cardiothorac Surg,* Vol.28,

capacity as a predictor of postoperative complications in lung resection candidates.

function and exercise capacity after lung resection. *Eur Respir J,* Vol.9, No.3, pp.

Evaluation of high-risk lung resection candidates: pulmonary haemodynamics versus exercise testing. A series of five patients. *Respiration,* Vol.61, No.4, pp. 181-

exercise testing for the prediction of postoperative performance in lung resection candidates at increased risk for complications. *Chest,* Vol.108, No.2, pp. 341-348

*Thorac Soc,* Vol.2, No.4, pp. 367-370; discussion 371-372

emphysema. *Ann Thorac Surg,* Vol.62, No.6, pp. 1588-1597

**8. References**

pp. 1-15

Vol.86, No.3, pp. 598-612

No.1 Suppl, pp. 105S-114S

*Imaging,* Vol.9, No.1, pp. 61-68

pp. 899-904

No.5, pp. 754-758

415-421

186

resection, help us to offer potentially curative treatment to the patients as many as possible. Postoperatively, lung expansion maneuvers and pain control are the two most important methods for reducing the risk of pulmonary complications. Both the incentive spirometry and deep breathing exercise are proved to be effective for lung expansion and reducing pulmonary complications (Thomas & McIntosh 1994). A meta-analysis of randomized controlled trials of postoperative pain control and pulmonary complications demonstrated that epidural local anesthetics significantly reduce the risk of pneumonia and all postoperative pulmonary complications (Ballantyne, et al. 1998). Pulmonary function recovers up to 6 months after a lobectomy, and up to 3 months after a pneumonectomy (Bolliger, et al. 1996; Nezu, et al. 1998). There has been little research on long term postoperative optimized outcome in terms of lung function and quality of life. There is no direct evidence supporting an additional role of bronchodilators in the lung resection candidate beyond what would be standard use for COPD or asthma. A study showed that post-operative respiratory rehabilitation after lung resection for lung cancer was beneficial for the Borg dyspnea scale, exercise capacity represented by 6-minute walk distance, and maintenance of lung function (Cesario, et al. 2007). The inpatient rehabilitation program included supervised incremental exercise and educational sessions covering such topics as pulmonary physiopathology, pharmacology of patients' medications, dietary counseling, relaxation and stress management techniques, energy conservation principles, and breathing retraining. The individuals joining the rehabilitation program had the significantly improved exercise capacity and maintained FEV1, whereas the control group had the significantly decreased exercise capacity and decreased FEV1 compared with baseline values. Although the rehabilitation is not confined to pharmacotherapy, it should be kept in mind that multidimensional efforts to maintain exercise capacity and lung function should be required because they could be labile after lung resection.


*Review* **Resonance in Chirogenesis and Photochirogenesis: Colloidal Polymers Meet Chiral Optofluidics**

**Michiya Fujiki**

**Citation:** Fujiki, M. Resonance in Chirogenesis and Photochirogenesis: Colloidal Polymers Meet Chiral Optofluidics. *Symmetry* **2021**, *13*, 199. https://doi.org/10.3390/ sym13020199

Academic Editors: Rui Tamura and Ivan Fernandez-Corbaton Received: 15 November 2020 Accepted: 18 January 2021 Published: 26 January 2021

**Publisher's Note:** MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.

**Copyright:** © 2021 by the author. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/).

Division of Materials Science, Graduate School of Science and Technology, Nara Institute of Science and Technology, 8916-5 Takayama, Ikoma, Nara 630-0192, Japan<EMAIL_ADDRESS>
**Abstract:** Metastable colloids made of crystalline and/or non-crystalline matters render abilities of photonic resonators susceptible to chiral chemical and circularly polarized light sources. By assuming that μm-size colloids and co-colloids consisting of π- and/or σ-conjugated polymers dispersed into an optofluidic medium are artificial models of open-flow, non-equilibrium coacervates, we showcase experimentally resonance effects in chirogenesis and photochirogenesis, revealed by gigantic boosted chiroptical signals as circular dichroism (CD), optical rotation dispersion, circularly polarized luminescence (CPL), and CPL excitation (CPLE) spectral datasets. The resonance in chirogenesis occurs at very specific refractive indices (RIs) of the surrounding medium. The chirogenesis is susceptible to the nature of the optically active optofluidic medium. Moreover, upon an excitation-wavelengthdependent circularly polarized (CP) light source, a fully controlled absolute photochirogenesis, which includes all chiroptical generation, inversion, erase, switching, and short-/long-lived memories, is possible when the colloidal non-photochromic and photochromic polymers are dispersed in an achiral optofluidic medium with a tuned RI. The hand of the CP light source is not a determining factor for the product chirality. These results are associated with my experience concerning amphiphilic polymerizable colloids, in which, four decades ago, allowed proposing a perspective that colloids are connectable to light, polymers, helix, coacervates, and panspermia hypotheses, nuclear physics, biology, radioisotopes, homochirality question, first life, and cosmology.

**Keywords:** symmetry breaking; biomolecular handedness; circular dichroism; circularly polarized luminescence; non-equilibrium; colloid; absolute asymmetric synthesis; conjugated polymer; dissipative structure


**11. Summary**

Simultaneous mastopexy and augmentation is challenging, but also highly rewarding and well accepted by informed patients. A clear understanding of not only the individual procedures, but the added variables involved when combining these techniques will greatly aid the surgeon in obtaining safe and predictable results while keeping the vast majority of complications relatively minor.