• Journal of Chest Surgery
• /
• v.39 no.7 s.264
• /
• pp.511-519
• /
• 2006

Background: Loss of cardiomyocytes in the myocardial infarction leads to regional contractile dysfunction, and necrotized cardiomyocytes in infracted ventricular tissues are progressively replaced by fibroblasts forming scar tissue. Although cardiomyoplasty, or implantation of ventricular assist device or artificial heart was tried in refractory heart failure, the cardiac transplantation was the only therapeutic modality because these other therapeutic strategies were not permanent. Cell transplantation is tried instead of cardiac transplantation, especially bone marrow is the most popular donated organ. But because bone marrow aspiration procedure is invasive and painful, and it had the fewer amounts of cellular population, the adipose tissue is recommended for harvesting of mesenchymal stem cells. Material and Method: After adipose tissues were extracted from abdominal subcutaneous adipose tissue and intra-abdominal adipose tissue individually, the cellular components were obtained by same method. These cellular components were tried to transformation with the various titers of 5-azacytidine to descript the appropriate concentration of 5-azacytidine and possibility of transformation ability of adipose tissue. Group 1 is abdominal subcutaneous adipose tissue and Group 2 is intra-abdominal adipose tissue-retroperitoneal adipose tissue and omentum. Cellular components were extracted by collagenase and $NH_4Cl$ et al, and these components were cultured by non-induction media - DMEM media containing 10% FBS and inducted by none, $3{\mu}mol/L,\;6{\mu}mol/L,\;and\;9{\mu}mol/L$ 5-azacytidine after the 1st and 2nd subculture. After 4 weeks incubation, tile cell blocks were made, immunostaining was done with the antibodies of CD34, heavy myosin chain, troponin T, and SMA. Result: Immunostaining of the transformed cells for troponin T was positive in the $6{\mu}mol/L\;&\;9{\mu}mol/L$ 5-azacytidine of Group 1 & 2, but CD34 and heavy myosin chain antibodies were negative and SMA antibody was positive in the $3{\mu}mol/L\;&\;6{\mu}mol/L$ 5-azacytidne of Group 2. Conclusion: These observations confirm that adult mesenchymal stem cells isolated from the abdominal subcutaneous adipose tissues and intra-abdominal adipose tissues can be chemically transformed into cardiomyocytes. This can potentially be a source of autologous cells for myocardial repair.

• Journal of Chest Surgery
• /
• v.40 no.4 s.273
• /
• pp.264-272
• /
• 2007

Background: Vascular endothelial growth factor (VEGF) plays an important role in angiogenesis, including stimulating the proliferation and migration of vascular smooth muscle cells (VSMCs). It has been known that diabetes is associated with accelerated cellular proliferation via VEGF, as compared to that under a normal glucose concentration. We investigated the effects of selective blockade of a VEGF receptor by using anti-Flt-1 peptide on the formation and hyperplasia of the neointima in balloon injured-carotid arteries of OLETF rats and also on the in vitro VSMCS' migration under high glucose conditions. Material and Method: The balloon-injury method was employed to induce neointima formation by VEGF. For f4 days beginning 2 days before the ballon injury, placebo or vascular endothelial growth factor receptor-1 (VEGFR-1) specific peptide (anti-Flt-1 peptide), was injected at a dose of 0.5mg/kg daily into the OLETF rats. At 14 days after balloon injury, the neointimal proliferation and vascular luminal stenosis were measured, and cellular proliferation was assessed by counting the proliferative cell nuclear antigen (PCNA) stained cells. To analyze the effect of VEGF and anti-Flt-1 peptide on the migration of VSMCs under a high glucose condition, transwell assay with a matrigel filter was performed. And finally, to determine the underlying mechanism of the effect of anti-Flt-1 peptide on the VEGF-induced VSMC migration in vitro, the expression of matrix metalloproteinase (MMP) was observed by performing reverse transcription-polymerase chain reaction (RT-PCR). Result: Both the neointimal area and luminal stenosis associated with neointimal proliferation were significantly decreased in the anti-Flt-1 peptide injected rats, ($0.15{\pm}0.04 mm^2$ and $ 36.03{\pm}3.78%$ compared to $0.24{\pm}0.03mm^2\;and\;61.85{\pm}5.11%$, respectively, in the placebo-injected rats (p<0.01, respectively). The ratio of PCNA(+) cells to the entire neointimal cells was also significantly decreased from $52.82{\pm}4.20%\;to\;38.11{\pm}6.89%$, by the injected anti-Flt-1 peptide (p<0.05). On the VSMC migration assay, anti-Flt-1 peptide significantly reduced the VEGF-induced VMSC migration by about 40% (p<0.01). Consistent with the effect of anti-Flt-1 peptide on VSMC migration, it also obviously attenuated the induction of the MMP-3 and MMP-9 mRNA expressions via VEGF in the VSMCS. Conclusion: Anti-Flt-1 peptide inhibits the formation and hyperplasia of the neointima in a balloon-injured carotid artery model of OLETF rats. Anti-Flt-1 peptide also inhibits the VSMCs' migration and the expressions of MMP-3 and MMP-9 mRNA induced by VEGF under a high glucose condition. Therefore, these results suggest that specific blockade of VEGFR-1 by anti-Flt-1 peptide may have therapeutic potential against the arterial stenosis of diabetes mellitus patients or that occurring under a high glucose condition.

• Journal of Food Hygiene and Safety
• /
• v.13 no.1
• /
• pp.53-61
• /
• 1998

This study was performed to investigate the antiulcer effects of Opuntia dillenii Haw. on the stomach ulcer induced by restraint and water-immersion stress in rats. For this experiment, 48 male Sprague-Dawley strain were used. The experimental groups were divided into four: a control (C) and 3 Opuntia dillenii Haw. treatment groups (E-1, E-2, E-3). Each dose of Opuntia dillenii Haw. was 30 mg/kg bw (E-1), 60 mgfKg bw (E-2) and 120 mg/kg bw (E-3). The rats were allocated to each group by 12 and observed for 4 weeks. The results were as following: 1. The stomach surface pH in each group showed no significant difference, but the values of Opuntia dillenii Haw. treatment groups were higher than the value of the control group. 2. The gastric wall mucus was increased in all Opuntia dillenii Haw. treatment groups compared with the control group. Especially in E-1 difference was higher (p<0.05) and in E-2 difference was significantly higher (p<0.01). 3. At shear rate 11.25, 45.0, 90.0, $225\;sec^{-1}$, whole blood viscosity and plasma viscosity were measured. Most of the values of Opuntia dillenii Haw. treatment groups were low compared with that of the control group. At shear rate 90.0, $225\;sec^{-1}$ the values of whole blood viscosity in E-1 were significantly low (p<0.05) and at shear rate 11.25, $45.0\;sec^{-1}$, more significant (p<0.01). At shear rate 11.25, 45.0, 90.0, $225\;sec^{-1}$ the values of whole blood viscosity in E-2 were significantly low (p<0.01). At shear rate $90.0\;sec^{-1}$ the value of plasma viscosity in E-1 was significantly low (p<0.05) and at shear rate 90.0, $225\;sec^{-1}$ the values of plasma viscosity in E-2 we resignificantly low (p<0.01). 4. Less severe ulcers were obsered in Opuntia dillenii Haw. treatment groups than in the control group. Especially E-1 groups tissues had only slight ulcers and necrosis of tissue was not observed in this group. From the results of this study, it can be concluded that the oral administratio-n of Opuntia dillenii Haw. results in protection of stomach ulcer by stimulating the secretion of gastric mucus and improving the gastric mucosal microcirculation.

• Sleep Medicine and Psychophysiology
• /
• v.24 no.2
• /
• pp.106-117
• /
• 2017

Objectives: Obstructive sleep apnea (OSA) is a sleep-related breathing disorder that is characterized by repetitive collapse or partial collapse of the upper airway during sleep in spite of ongoing effort to breathe. It is believed that OSA is usually worsened in REM sleep, because muscle tone is suppressed during REM sleep. However, many cases showed a higher apnea-hypopnea index (AHI) during NREM sleep than during REM sleep. We aimed here to determine the characteristics of REM sleep-dependent OSA (REM-OSA) and NREM sleep-dependent OSA (NREM-OSA). Methods: Five hundred sixty polysomnographically confirmed adult OSA subjects were studied retrospectively. All patients were classified into 3 groups based on the ratio between REM-AHI and NREM-AHI. REM-OSA was defined as REM-AHI/NREM-AHI > 2, NREM-OSA as NREM-AHI/REM-AHI > 2, and the rest as sleep stage-independent OSA (IND-OSA). In addition to polysomnography, questionnaires related to subjective sleep quality, daytime sleepiness, and emotion were completed. Chi-square test, ANOVA, and ANCOVA were performed. Results: There was no age difference among subgroups. The REM-OSA group was comprised of large proportions of mild OSA and female OSA patients. These patients experienced poor sleep and more negative emotions than other two groups. The AHI and oxygen desaturation index (ODI) were lowest in REM-OSA. Sleep efficiency and N3 percentage of REM-OSA were higher than in NREM-OSA. The percentage of patients who slept in a supine position was higher in REM-OSA than other subgroups. IND-OSA showed higher BMI and larger neck circumference and abdominal circumference than REM-OSA. The patients with IND-OSA experienced more sleepiness than the other groups. AHI and ODI were highest in IND-OSA. NREM-OSA presented the shortest total sleep time and the lowest sleep efficiency. NREM-OSA showed shorter sleep latency and REM latency and higher percentage of N1 than those of REM-OSA and the highest proportion of those who slept in a lateral position than other subgroups. NREM-OSA revealed the highest composite score on the Horne and ${\ddot{O}}stberg$ questionnaire. With increased AHI severity, the numbers of apnea and hypopnea events during REM sleep decreased, and the numbers of apnea and hypopnea events during NREM sleep increased. The results of ANCOVA after controlling age, sex, BMI, NC, AC, and AHI showed the lowest sleep efficiency, the highest AHI in the supine position, and the highest percentage of waking after sleep onset in NREM-OSA. Conclusion: REM-OSA was associated with the mild form of OSA, female sex, and negative emotions. IND-OSA was associated with the severe form of OSA. NREM-OSA was most closely related to position and showed the lowest sleep efficiency. Sleep stage-dependent characteristics could provide better understanding of OSA.

• Journal of the Korean Society of Food Science and Nutrition
• /
• v.43 no.5
• /
• pp.631-640
• /
• 2014

The inhibitory effects of Boswellia serrata (BW) extracts on degenerative osteoarthritis were investigated in primary-cultured rat cartilage cells and a monosodium-iodoacetate (MIA)-induced osteoarthritis rat model. To identify the protective effects of BW extract against $H_2O_2$ ($800{\mu}M$, 2 hr) in vitro, cell survival was measured by MTT assay. Cell survival after $H_2O_2$ treatment was elevated by BW extract at a concentration of $20{\mu}g/mL$. In addition, BW extract treatment significantly reduced and normalized the productions of pro-inflammatory factors, nuclear transcription factor ${\kappa}B$, cyclooxygenase-2, tumor necrosis factor-${\alpha}$, and interleukin-6 at a concentration of $20{\mu}g/mL$. Treatment of chondrocytes with BW extract significantly reduced 5-lipoxygenase activity and production of prostaglandin E2, especially at a concentration of $10{\sim}20{\mu}g/mL$. For the in vivo animal study, osteoarthritis was induced by intra-articular injection of MIA into knee joints of rats. Consumption of a diet containing BW extract (100 and 200 mg/kg) for 35 days significantly inhibited the development and severity of osteoarthritis in rats. To determine the genetic expression of arthritic factors in articular cartilage, real-time PCR was applied to measure matrix metalloproteinases (MMP-3, MMP-9, and MMP-13), collagen type I, collagen type II, and aggrecan, and BW extract had protective effects at a concentration of 200 mg/kg. In conclusion, BW extract was able to inhibit articular cartilage degeneration by preventing extracellular matrix degradation and chondrocyte injury. One can consider that BW extract may be a potential therapeutic treatment for degenerative osteoarthritis.

• Journal of Nutrition and Health
• /
• v.9 no.1
• /
• pp.92-98
• /
• 1976

The present studies were carried out to observe the nutritional effects of three kinds of locally produced dried infantile formula milk (DFM) and one fermented milk (FM). A feeding trial with 60 male growing albino rats weighing $60{\sim}70$ grams was conducted during 6 weeks to compare the nutritive values and protein qualities of three DFM and a FM. The diet treatments consisted of 100% control diet, 70% control diet plus 30% DFM-A, 70% control diet plus 30% DFM-B, 70% control diet plus 30% DFM-C, 100% control diet with FM and 70% control diet plus 30% DFM-B with FM. The items investigated were body weight gain, feed intake, feed efficiency ratio (FER), various organ weights, protein efficiency ratio (PER), digestibility of nutrients, biological value, utilizability of protein and intestinal microbial changes of albino rats. The results obtained are summarized as follows; 1. Although there was no statistical significance, rats fed diets containing DFMs and FM gained faster than the rats fed control diet. The best growth rate was obtained with the DFM-A and DFM-C groups. In spite of the lower protein contents of the three DFM diets than the control diet, the growth rate of albino rats fed the DFM diets was somewhat improved than rats fed control diet. 2. No statistical significance was found in feed consumption but the trend was that the feed intake of control group was higher than those of the DFM diet group. 3. Feed efficiency was inproved significantly (p<0.01) by feeding DFMs as compared with control diet. DFM-A group showed the best FER, although no statistical significance was found. 4. Rats fed the DFM diets showed significantly (p<0.01) higher PER as compared with those of the control group. But no difference was found anions DFM groups. The significant improvement (p<0.01) of PER due also to the feeding of FM was seemed to be brought about by the beneficial effect of FM. 5. The present data revealed that feeding DFM and FM didn't affect the weights of various organs of rats. 6. The protein digestibility of experimental diets was similar to each other. Although no statistical significance was found among treatments, the DFMs and FM surely tended to improve the biological value and utilizability of protein. 7. Microbial study indicated that among intestinal flora FM fed group, there were more Lactic acid bacteria than E. coli. From the experimental results described above, it may be concluded that the nutritive effects of three kinds of locally produced DFMs are much alike and the growth rate of growing albino rats can be improved by feeding either DFM or FM due to their beneficial effects on the feed efficiency and protein utilization.

• Journal of Nutrition and Health
• /
• v.9 no.1
• /
• pp.84-91
• /
• 1976

Chemical determination were made to analyze the concentration of nutrients including proximate composition, vitamins, minerals, amino acids and fatty acids in three kinds of locally produced infantile formula milk(DFM) and one fermented milk(FM). An attempt was also made to compare the analytical values of nutrients against guaranteed values. The results obtained are summarized as follows; 1. The analyzed value of protein and fat content in DFM-A.B.C was slightly lower than that of guaranteed values and a reverse trend was observed in the case of total carbohydrate. There were no differences in proximate composition among the three kinds of DFM. It was found that the FM contained less protein and fat than the fresh milk, but it seemed that a considerable amount of sugar was added to FM. 2. The analyzed values of vitamin $A(2{\sim}3\;times)$ and $E(4{\sim}6\;times)$ contents in DFMS were higher than those of the guaranteed values except niacin. There were a little differences in vitamin contents among DFMS analyzed. 3. In the case of minerals, the analyzed values were similar to the guaranteed values except the calcium concentration that analyzed value was much higher than guaranted value. When the DFMS were diluted to 15% by adding water to compare with the human and fresh cow milk, it was found that the diluted DFMS resembled the human milk rather than cow milk in the content of energy, carbohydrates, protein and ash. The higher contents of iron and most vitamins in the diluted DFMS than the human milk or cow milk would indicate that they were fortificated with these nutrients. When these diluted DFMS were compared with the Korean R.D.A. for infant, it was clear that they could supply sufficient amount of the nutrients required by R.D.A. except the niacin which failed to reach the recommended level. The fact that iron content of DFM-C was not sufficient while vitamin A supply was excessive by 6 fold would indicate that further studies for the improvement may be necessary. 4. There was a little difference among DFMS in amino acid composition. The similarity of the essential amino acids composition between DFMS and cow milk indicated that there was no modification of the essential amino acids. However, present data showed that the amino acid compositon of FM was similar to that of the cow milk. 5. There was no difference among DFMS in the degree of saturation of fatty acids. The similar or higher levels of essential fatty acids contents of DFMS as compared with human milk revealed that essential fatty acids were added to DFMS during the course of process. From the experimental results described above, it may be concluded that the nutritive effects of three kinds of locally produced DFMS were much alike. It was also found that macro and micro nutrient composition except amino acid composition of locally produced dried formula milk was very much similar to that of the human milk. Moreover, fortification of iron and vitamins resulted in improving their nutritive values as the single form of infantile food, but it seemed that more consideration should be given on the fortification of some nutrients.

• Journal of Nutrition and Health
• /
• v.9 no.2
• /
• pp.59-67
• /
• 1976

A series of experiment was carried out to study the effect of commonly used dietary fat or oils on the growth, feed efficiency, nutrient utilizability, nitrogen retention and serum cholesterol of rats and chicks fed various fat or oils at the level of 10% during 12 weeks of experimentation. Fat and oils used in this experiment were also analyzed for the composition of some fatty acids. The main observations made are as follows: 1. All groups received fat or oils gained more body weight than unsupplemented control group except chicks fed fish oil and rapeseed oil although no statistical significance was found between treatments. It was found that body weight gain achieved by the rats fed soybean oil, rapeseed oil, animal fat or corn oil was much greater than other group and that achieved by the chicks fed corn oil and animal fat was greater than other vegetable oil groups, although no statistical significance was found among treatments. 2. Feed intake data indicated that corn oil group of both rats and chicks consumed considerably more feed than other groups. Whereas feed intake of fish oil groups was the lowest among the experimental animals indicating that fish oil might contain unfavorable compound that depresses the palatability. In feed efficiency, soybean oil group of rats and corn oil group of chicks were significantly better than other experimental groups. In general, addition of fat or oils in the diet improved feed effeciency of diet. 3. Nutrient utiIizabiIity and nitrogen retention data showed that fat in the experimental diet containing 10% fat or oils was absorbed better than crude fat in control diet. It was also found that there was no significant difference in nitrogen retention among treatment. 4. Liver fat content of rapeseed oil group was much higher than that of control group and other group. It was also noticed that feeding more polyunsaturated fatty acids resulted in higher content of Iiver fat. 5. Present data indicated that serum cholesterol content of rapeseed oil and sesame oil group of rat was the higher than that of control group. Serum cholesterol content of animal fat group of chicks was higher than other group. It was interesting to note that serum cholesterol content of chicken was higher than that of rats?regardless of the kind of oils received. 6. Analytical data revealed that fatty acid composition of vegetable oil was composed mainly of oleic acid and linoleic acid, whereas animal fat and fish oil were composed of saturated fatty acid such as, myristic and palmitic acid. It should be mentionted that the perilla oil contained a very large amount of linolenic acid (58.4%) comparing with that in order vegetable oils. Little arachidonic acid was detected in vegetable oil, whereas none in animal fat and. fish oil.

• KOREAN JOURNAL OF CROP SCIENCE
• /
• v.17
• /
• pp.115-133
• /
• 1974

This study was done on the metabolism of chemical components during the seed development of ginseng. The changes of the chemical components were inspected in the following periods: from the early stage of flower organ formation to flowering time, from the early stage of fruiting to maturity, during the moisture stratification before sowing. From flower bud forming stage to meiosis stage, the changes in the fresh weight, dry weight, contents of carbohydrates, and contents of nitrogen compounds were slight while the content of TCA soluble phosphorus and especially the content of organic phosphorus increased markedly. From meiosis stage to microspore stage the fresh and dry weights increase greatly. Also, the total nitrogen content increases in this period. Insolub]e nitrogen was 62-70% of the total nitrogen content; the increase of insoluble nitrogen seems to have resulted form the synthesis of protein. The content of soluble sugar (reducing and non-reducing sugar) increases greatly but there was no observable increase in starch content. In this same period, TCA soluble phosphorus reached the maximum level of 85.4% of the total phosphorus. TCA insoluble phosphorus remained at the minimum content level of 14.6%. After the pollen maturation stage and during the flowering period the dry weight increased markedly and insolub]e nitrogen also increased to the level of 67% of the total nitrogen content. Also in this stage, the organic phosphorus content decreased and was found in lesser amounts than inorganic phosphorus. A rapid increase in the starch content was also observed at this stage. In the first three weeks after fruiting the ginseng fruit grows rapidly. Ninety percent of the fresh weight of ripened ginseng seed is obtained in this period. Also, total nitrogen content increased by seven times. As the fruits ripened, insoluble nitrogen increased from 65% of the total nitrogen to 80% while soluble nitrogen decreased from 35% to 20%. By the beginning of the red-ripening period, the total phosphoric acid content increased by eight times and was at its peak. In this same period, TCA soluble phosphorus was 90% of total phosphorus content and organic phosphorus had increased by 29 times. Lipid-phosphorus, nucleic acid-phosphorus and protein-phosphorus also increased during this stage. The rate of increase in carbohydrates was similar to the rate of increase in fresh weight and it was observed at its highest point three weeks after fruiting. Soluble sugar content was also highest at this time; it begins to decrease after the first three weeks. At the red-ripening stage, soluble sugar content increased again slightly, but never reached its previous level. The level of crude starch increased gradually reaching its height, 2.36% of total dry weight, a week before red-ripening, but compared with the content level of other soluble sugars crude starch content was always low. When the seeds ripened completely, more than 80% of the soluble sugar was non-reducing sugar, indicating that sucrose is the main reserve material of carbohydrates in ginseng seeds. Since endosperm of the ripened ginseng seeds contain more than 60% lipids, lipids can be said to be the most abundant reserve material in ginseng seeds; they are more abundant than carbohydrates, protein, or any other component. During the moisture stratification, ginseng seeds absorb quantities of water. Lipids, protein and starch stored in the seeds become soluble by hydrolysis and the contents of sugar, inorganic phosphorus, phospho-lipid, nucleic acid-phosphorus, protein phosphorus, and soluble nitrogen increase. By sowing time, the middle of November, embryo of the seeds grows to 4.2-4.7mm and the water content of the seeds amounts to 50-60% of the total seed weight. Also, by this time, much budding material has been accumulated. On the other hand, dry stored ginseng seeds undergo some changes. The water content of the seeds decreases to 5% and there is an observable change in the carbohydraes but the content of lipid and nitrogen compounds did not change as much as carbohydrates.

• Radiation Oncology Journal
• /
• v.18 no.1
• /
• pp.27-31
• /
• 2000

Purpose : The aim of this study was to investigate treatment results, toxicity and efficacy of hypefractionated radiation therapy combined with paclitaxel for paraaortic node recurrence in cervix cancer. Materials and Methods: Between September 1997 to March 1999, 12 patients with paraaortic node recurrence in cervix cancer who previously received radical or postoperative radiotherapy were treated with hypefractionated radiation therapy combined with paclitaxel. Of these, 2 patients who irradiated less than 30 Gy were excluded, 10 patients were eligible for this study. Median age was 51 years. Initial FIGO stage was 1 stage IBI, 2 stage IIA, 7 stage IIB. For initial treatment, 7 patients received radical radiotherapy and 3 received postoperative radiotherapy. The paraaortic field encompassed the gross recurrent disease with superior margin at T12, and inferior margin was between L5 and S1 with gap for previously pelvic radiation field. The radiation field was initially anterior and posterior opposed field followed by both lateral field. The daily dose was 1.2 Gy, twice daily fractions, and total radiotherapy dose was between 50.4 and 60 Gy(median, 58.8 Gy). Concurrent chemotherapy was done with paclitaxel as a radiosensitizer. Dose range was from 20 mg/m$^{3}$ to 30 mg/m$^{3}$ (median, 25 mg/m$^{3}$), and cycle of chemotherapy was from 3 to 6 (median, 4.5 cycle). Follow-up period ranged from 3 to 21 months. Results : Interval between initial diagnosis and paraaortic node recurrence was range from 2 to 63 months (median, 8 months). The 1 year overall survival rate and median survival were 75$\%$ and 9.5 months, respectively. The 1 year disease free survival rate and median disease free survival were 30$\%$ and 7 months, respectively. At 1 month after treatment, 4 (40$\%$) achieved a complete response and 6 (60$\%$) experienced a partial response and all patients showed response above the partial response. There was distant metastasis in 6 patients and pelvic node recurrence In 2 patients after paraaortic node irradiation. There was 2 patients with grade 3 to 4 leukopenla and 8 patients with grade 1 to 2 nausea/ vomiting which was usually tolerable with antlemetic drug. There was no chronic complication in abdomen and pelvis during follow up period. Conclusion : hypefractionated radiation therapy combined with paclitaxel chemotherapy diosensitizer showed high response rate and few complication rate in paraaortic node recurrence in cervix cancer Therefore, present results suggest that hypefractionated radiation therapy combined with paclitaxel chemotherapy can be used as optimal treatment modality in this patients.