Role of diagnostic laparoscopy in deciding primary treatment in advanced-stage ovarian cancer / 부인종양

Objective@#We evaluated the usefulness of preoperative diagnostic laparoscopy for treatment planning in patients with advanced-stage ovarian cancer. @*Methods@#We retrospectively analyzed 614 patients diagnosed with advanced-stage ovarian cancer between January 2010 and May 2018. Primary debulking surgery (PDS) or neoadjuvant chemotherapy (NAC) followed by interval debulking surgery were selected based on preoperative laparoscopic (Group 1, n=192) and computed tomography findings (Group 2, n=422). The primary outcomes in the PDS and NAC groups were suboptimal cytoreduction (residual disease >1 cm) rate and non-high-grade serous carcinoma (non-HGSC) rate, respectively. @*Results@#The patients who underwent PDS in group 1 and group 2 were 49 (25.5%) and 279 (66.1%), respectively. The suboptimal cytoreduction rate after PDS was lower in Group 1 than in Group 2 (2.0% vs 11.1%, p=0.023). Moreover, Group 1 showed a tendency toward a lower proportion of non-HGSC patients who underwent NAC than that in Group 2 (9.1% vs. 15.4%, p=0.069). Further, Group 1 showed lower rates of postoperative morbidity than Group 2 (5.2% vs. 10.4%, p=0.033). However, Kaplan–Meier analysis showed no significant differences in survival outcomes between the 2 groups. @*Conclusion@#Diagnostic laparoscopy reduced the suboptimal cytoreduction rate in the PDS group and the implementation rate of NAC in non-HGSC patients. Moreover, it reduced postoperative morbidity without affecting survival in both groups. Thus, diagnostic laparoscopy is a valuable diagnostic tool for determining the primary treatment.

Prognostic value of complete metabolic response on 18F-FDG-PET/CT after three cycles of neoadjuvant chemotherapy in advanced high-grade serous ovarian cancer / 부인종양

Objective@#We investigated the prognostic value of complete metabolic response (CMR) on 18F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG-PET/CT) after 3 cycles of neoadjuvant chemotherapy (NAC) in advanced high-grade serous ovarian cancer (HGSC). @*Methods@#PET/CT at baseline and after 3 cycles of NAC were performed; peak standardized uptakes were measured. PET parameters were compared with NAC parameter: cancer antigen-125 (CA-125) normalization before interval debulking surgery (IDS) and chemotherapy response score (CRS) to predict platinum-sensitivity. Kaplan-Meier analysis was used to determine correlations between PET parameters and survival. Prognostic factors were obtained by multivariate Cox regression analysis. @*Results@#Between 2007 and 2020, 102 patients were recruited: 19 (18.6%) were designated as CMR group and 83 (81.4%) as non-CMR group. CMR after 3 cycles of NAC showed the highest accuracy in predicting platinum-sensitivity (area under the curve [AUC]=0.729; 95% confidence interval [CI]=0.552–0.823; p=0.017), compared with CA-125 normalization before IDS (AUC=0.626; 95% CI=0.542–0.758; p=0.010) and CRS (AUC=0.613; 95% CI=0.490–0.735; p=0.080). CMR demonstrated better prognosis than non-CMR in progression-free survival (PFS) (median PFS, 23.9 months vs. 16.4 months; p=0.021) and overall survival (OS) (median OS, not reached vs. 69.7 months; p=0.025). In multivariate analysis, CMR was associated with a lower risk of recurrence (adjusted hazard ratio [aHR]=0.50; 95% CI=0.27–0.92; p=0.027) and death (aHR=0.23; 95% CI=0.05–0.99; p=0.048). @*Conclusion@#CMR after 3 cycles of NAC can be a prognostic factor for both recurrence and death in advanced HGSC.

Early Assessment of Response to Neoadjuvant Chemotherapy with 18F-FDG-PET/CT in Patients with Advanced-Stage Ovarian Cancer / Journal of the Korean Cancer Association, 대한암학회지

Purpose@#The aim of this study was to evaluate the ability of sequential 18F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG-PET/CT) after one cycle of neoadjuvant chemotherapy (NAC) to predict chemotherapy response before interval debulking surgery (IDS) in advanced-stage ovarian cancer patients. @*Materials and Methods@#Forty consecutive patients underwent 18F-FDG-PET/CT at baseline and after one cycle of NAC. Metabolic responses were assessed by quantitative decrease in the maximum standardized uptake value (SUVmax) with PET/CT. Decreases in SUVmax were compared with cancer antigen 125 (CA-125) level before IDS, response rate by Response Evaluation Criteria in Solid Tumors criteria before IDS, residual tumor at IDS, and I chemotherapy response score (CRS) at IDS. @*Results@#A 40% cut-off for the decrease in SUVmax provided the best performance to predict CRS 3 (compete or near-complete pathologic response), with sensitivity, specificity, and accuracy of 81.8%, 72.4%, and 72.4%, respectively. According to this 40% cut-off, there were 17 (42.5%) metabolic responders (≥ 40%) and 23 (57.5%) metabolic non-responders (< 40%). Metabolic responders had higher rate of CRS 3 (52.9% vs. 8.7%, p=0.003), CA-125 normalization (< 35 U/mL) before IDS (76.5% vs. 39.1%, p=0.019), and no residual tumor at IDS (70.6% vs. 31.8%, p=0.025) compared with metabolic non-responders. There were significant associations with progression-free survival (p=0.021) between metabolic responders and non-responders, but not overall survival (p=0.335). @*Conclusion@#Early assessment with 18F-FDG-PET/CT after one cycle of NAC can be useful to predic response to chemotherapy before IDS in patients with advanced-stage ovarian cancer.

Outcomes of Non-High Grade Serous Carcinoma after Neoadjuvant Chemotherapy for Advanced-Stage Ovarian Cancer: Single-Institution Experience

PURPOSE: Outcomes in patients with ovarian high-grade serous carcinoma (HGSC) treated with neoadjuvant chemotherapy (NAC) have been widely studied; however, there is limited information on responses to chemotherapy among patients with non-HGSC. The aim of this study was to compare the survival outcomes of patients with advanced-stage non-HGSC and HGSC treated with NAC. MATERIALS AND METHODS: This study was a retrospective analysis of patients with advanced-stage ovarian cancer treated at Yonsei Cancer Hospital between 2006 and 2017. The demographics, chemotherapy response, and survival rates were compared between patients with non-HGSC and those with HGSC. RESULTS: Among 220 patients who underwent NAC, 25 (11.4%) patients had non-HGSC histologic subtypes, and all received a taxane-platinum combination regimen for NAC. Patients with non-HGSC had lower baseline cancer antigen-125 levels (p < 0.001), poorer response rates (p < 0.001), lower rates of optimal cytoreduction (p=0.003), and poorer progression-free survival (PFS) (median PFS 10.3 months vs. 18.3 months; p=0.009) and overall survival (OS) (median OS 25.5 months vs. 60.6 months; p < 0.001), compared to those with HGSC. In multivariate analysis, non-HGSC was a negative prognostic factor for both PFS [hazard ratio (HR), 3.19; 95% confidence interval (CI), 1.73–5.88] and OS (HR, 4.22; 95% CI, 2.07–8.58). CONCLUSION: In this study, poorer survival outcomes were observed in patients who underwent NAC for treatment of non-HGSC versus those treated for HGSC. Different treatment strategies are urgently required to improve survival outcomes for patients with non-HGSC undergoing NAC.

Comparison of Clinical Features and Outcomes in Epithelial Ovarian Cancer according to Tumorigenicity in Patient-Derived Xenograft Models / Journal of the Korean Cancer Association, 대한암학회지

PURPOSE: Although the use of xenograft models is increasing, few studies have compared the clinical features or outcomes of epithelial ovarian cancer (EOC) patients according to the tumorigenicity of engrafted specimens. The purpose of this study was to evaluate whether tumorigenicity was associated with the clinical features and outcomes of EOC patients. MATERIALS AND METHODS: Eighty-eight EOC patients who underwent primary or interval debulking surgery from June 2014 to December 2015 were included. Fresh tumor specimens were implanted subcutaneously on each flank of immunodeficient mice. Patient characteristics, progression-free survival (PFS), and germline mutation spectra were compared according to tumorigenicity. RESULTS: Xenografts were established successfully from 49 of 88 specimens. Tumorigenicity was associated with lymphovascular invasion and there was a propensity to engraft successfully with high-grade tumors. Tumors from patientswho underwent non-optimal (residual disease ≥ 1 cm) primary orinterval debulking surgery had a significantly greater propensity to achieve tumorigenicity than those who received optimal surgery. In addition, patients whose tumors became engrafted seemed to have a shorter PFS and more frequent germline mutations than patients whose tumors failed to engraft. Tumorigenicity was a significant factor for predicting PFS with advanced International Federation of Gynecology and Obstetrics stage and high-grade cancers. CONCLUSION: sTumorigenicity in a xenograft model was a strong prognostic factor and was associated with more aggressive tumors in EOC patients. Xenograft models can be useful as a preclinical tool to predict prognosis and could be applied to further pharmacologic and genomic studies on personalized treatments.

Impact of increased utilization of neoadjuvant chemotherapy on survival in patients with advanced ovarian cancer: experience from a comprehensive cancer center / 부인종양

OBJECTIVE: The choice between primary debulking surgery (PDS) and neoadjuvant chemotherapy (NAC) in advanced ovarian cancer remains controversial. We evaluated NAC use in our center before and after results from a randomized trial were published, with the aim to determine the impact of changes in the neoadjuvant strategy on survival in advanced-stage ovarian cancer. METHODS: We retrospectively investigated the clinical course of 435 patients with ovarian, tubal, or peritoneal carcinoma (International Federation of Gynecology and Obstetrics [FIGO] stage III or IV). According to the period of treatment, we stratified patients into a control group (n=216; diagnosed between 2006 and 2010; 83.8% underwent PDS) and a study group (n=219; diagnosed between 2011 and 2014; 48.9% received NAC followed by interval debulking surgery [IDS]). RESULTS: There were no between-group differences in age, body mass index, histology findings, or tumor grade. Compared to patients in the control group, those in the study group were more likely to receive NAC followed by IDS as first-line treatment (48.9% vs. 16.2%; p < 0.001), cytoreductive surgery to no-residual disease (21.5% vs. 10.2%; p < 0.001), or radical surgery (57.5% vs. 35.6%; p < 0.001). However, there was no between-group difference in postoperative morbidity. Kaplan-Meier analysis showed no between-group differences in progression-free or overall survival (p=0.449 and 0.952, respectively). CONCLUSION: NAC incorporation resulted in increased optimal cytoreduction rates although no significant differences in survival outcomes were noted. NAC is advantageous for patients with high perioperative morbidity or unresectable disease.

In-bag power morcellation technique in single-port laparoscopic myomectomy

OBJECTIVE: This study introduces and evaluates the feasibility, safety, and surgical outcomes of the in-bag power morcellation technique during single-port assisted (SPA) laparoscopic myomectomy in comparison with manual scalpel morcellation. METHODS: This is a retrospective review of a total of 58 patients who underwent SPA laparoscopic myomectomy employing in-bag power morcellation (n=27) or manual scalpel morcellation (n=31), performed between December 2014 and December 2016. Surgical outcomes, including total operation time, estimated blood loss, postoperative hemoglobin changes, postoperative hospital stay, postoperative pain (visual analog scale), perioperative and postoperative complications were evaluated. RESULTS: The demographics and patient characteristics were similar between both groups. The median patient age was 34 years and median body mass index was 20.84 kg/m2. The median specimen weight was 110 g. The median operating time was 138 minutes. The median estimated blood loss was 50 mL and the median postoperative hemoglobin change was 2.2 g/dL. The median postoperative hospital stay was 2 days and the median postoperative pain scores were 5 after 6 hours, 3 after 24 hours, and 2 after 48 hours. Occult malignancy was not identified in any patients. There were no intraoperative complications such as LapBag ruptures or gross spillage. CONCLUSION: In-bag power morcellation for SPA laparoscopic myomectomy is feasible and safe, minimizing the risks of open power morcellation. There were also no statistically significant differences in surgical outcomes.

Pretreatment neutrophil-to-lymphocyte ratio and its dynamic change during neoadjuvant chemotherapy as poor prognostic factors in advanced ovarian cancer

OBJECTIVE: The purpose of this study was to determine the prognostic implications of the pretreatment neutrophil-to-lymphocyte ratio (NLR) and its dynamic change during chemotherapy in patients with advanced epithelial ovarian cancer undergoing neoadjuvant chemotherapy. METHODS: We performed a retrospective analysis of 203 patients who underwent neoadjuvant chemotherapy prior to interval debulking surgery for advanced-stage ovarian cancer at Yonsei Cancer Hospital between 2007 and 2015. Pretreatment NLR was evaluated before starting neoadjuvant chemotherapy. Change in NLR was defined as the post-neoadjuvant NLR value divided by the initial value. The correlation of NLR and its dynamic change with chemotherapy response score, response rate, and recurrence was analyzed. RESULTS: The NLR ranged from 0.64 to 22.8. In univariate analyses, a higher pretreatment NLR (> 3.81) was associated with poor overall survival (OS), but not progression-free survival (PFS). Through multivariate analysis, high pretreatment NLR was shown to be an independent parameter affecting OS, but not necessarily PFS. Changes in NLR during chemotherapy were better predictors of PFS than baseline NLR. Patients with increased NLR during chemotherapy showed significantly poor PFS, and this change was an independent predictor of PFS. CONCLUSION: Pretreatment NLR and its dynamic change during chemotherapy may be important prognostic factors in patients who undergo neoadjuvant chemotherapy.

Surgical technique for single-port laparoscopy in huge ovarian tumors: SW Kim's technique and comparison to laparotomy

OBJECTIVE: This study aimed to introduce a method to remove huge ovarian tumors (≥15 cm) intact with single-port laparoscopic surgery (SPLS) using SW Kim's technique and to compare the surgical outcomes with those of laparotomy. METHODS: Medical records were retrospectively reviewed for patients who underwent either SPLS (n=21) with SW Kim's technique using a specially designed 30×30-cm²-sized 3XL LapBag or laparotomy (n=22) for a huge ovarian tumor from December 2008 to May 2016. Perioperative surgical outcomes were compared. RESULTS: In 19/21 (90.5%) patients, SPLS was successfully performed without any tumor spillage or conversion to multi-port laparoscopy or laparotomy. There was no significant difference in patient characteristics, including tumor diameter and total operation time, between both groups. The postoperative hospital stay was significantly shorter for the SPLS group than for the laparotomy group (median, 2 [1 to 5] vs. 4 [3 to 17] days; P<0.001). The number of postoperative general diet build-up days was also significantly shorter for the SPLS group (median, 1 [1 to 4] vs. 3 [2 to 16] days; P<0.001). Immediate post-operative pain score was lower in the SPLS group (median, 2.0 [0 to 8] vs. 4.0 [0 to 8]; P=0.045). Patient-controlled anesthesia was used less in the SPLS group (61.9% vs. 100%). CONCLUSION: SPLS was successful in removing most large ovarian tumors without rupture and showed quicker recovery and less immediate post-operative pain in comparison to laparotomy. SPLS using SW Kim's technique could be a feasible solution to removing huge ovarian tumors.

External validation of chemotherapy response score system for histopathological assessment of tumor regression after neoadjuvant chemotherapy in tubo-ovarian high-grade serous carcinoma / 부인종양

OBJECTIVE: The chemotherapy response score (CRS) system based on histopathological examination has been recently proposed for tubo-ovarian high-grade serous carcinoma (HGSC) to assess response to neoadjuvant chemotherapy (NAC). This study was aimed at validating the CRS system in an external cohort of tubo-ovarian HGSC patients. METHODS: This study included 110 tubo-ovarian HGSC patients who underwent NAC followed by interval debulking surgery. The 3-tiered CRS of the omental and adnexal tissue sections was determined by 3 independent pathologists. Differences in patient outcomes according to CRS were analyzed. RESULTS: The CRS system was highly reproducible among the 3 pathologists. Fleiss' kappa value and Kendall's coefficient of concordance for the omental CRS were 0.656 and 0.669, respectively. The omental CRS significantly predicted progression-free survival (PFS). The median PFS of patients whose tumors exhibited the omental CRS 1–2 (15 months) was significantly shorter than that of patients with an omental CRS of 3 (19 months; p=0.016). In addition, after adjusting for age, stage, and debulking status, the omental CRS was an independent prognostic factor for PFS of tubo-ovarian HGSC patients who were treated with NAC (adjusted hazard ratio [HR]=1.74; 95% confidence interval [CI]=1.05–2.87). CONCLUSION: The CRS system for assessing NAC response was a reproducible prognostic tool in our cohort. The application of the CRS system after NAC can improve survival estimation in HGSC patients.

Role of surgical therapy in the management of gestational trophoblastic neoplasia

OBJECTIVE: To evaluate the role of adjuvant surgical procedures in the management of gestational trophoblastic neoplasia (GTN). METHODS: In a retrospective review of medical records at the Severance Hospital, we identified 174 patients diagnosed with GTN between 1986 and 2006. Of the 174 patients, 129 (74%) were assigned to the nonmetastatic group, and 45 (26%) to the metastatic group; of the metastatic group patients, 6 were in the low-risk group and 39 were in the high-risk group. Thirty-two patients underwent 35 surgical procedures as part of the GTN treatment. The procedures included hysterectomy, lung resection, craniotomy, uterine wedge resection, uterine suturing for bleeding, salpingo-oophorectomy, pretherapy dilatation and curettage, adrenalectomy, nephrectomy, and uterine artery embolization. RESULTS: Of the 32 patients who underwent surgical procedures, 28 (87%) survived. Eleven patients underwent surgery for chemoresistant disease after receiving one or more chemotherapy regimens. Twelve patients underwent procedures to control tumor hemorrhage. Nine (81%) of 11 patients with chemoresistant disease survived, and 8 patients who underwent salvage surgery for chemoresistant disease received further chemotherapy. Of 21 patients who underwent hysterectomy, 19 (90%) achieved remission. All of three patients who had resistant foci of choriocarcinoma in the lung achieved remission through pulmonary resection. CONCLUSION: Adjuvant surgical procedures, especially hysterectomy and pulmonary resection for chemoresistant disease, as well as procedures to control hemorrhage, are pivotal in the management of GTN.

Antioxidant activity and anti-inflammatory activity of ethanol extract and fractions of Doenjang in LPS-stimulated RAW 264.7 macrophages

BACKGROUND/OBJECTIVES: Fermentation can increase functional compounds in fermented soybean products, thereby improving antioxidant and/or anti-inflammatory activities. We investigated the changes in the contents of phenolics and isoflavones, antioxidant activity and anti-inflammatory activity of Doenjang during fermentation and aging. MATERIALS/METHODS: Doenjang was made by inoculating Aspergillus oryzae and Bacillus licheniformis in soybeans, fermenting and aging for 1, 3, 6, 8, and 12 months (D1, D3, D6, D8, and D12). Doenjang was extracted using ethanol, and sequentially fractioned by hexane, dichloromethane (DM), ethylacetate (EA), n-butanol, and water. The contents of total phenolics, flavonoids and isoflavones, 2,2-diphenyl-1 picryl hydrazyl (DPPH) radical scavenging activity, and ferric reducing antioxidant power (FRAP) were measured. Anti-inflammatory effects in terms of nitric oxide (NO), prostaglandin (PG) E2 and pro-inflammatory cytokine production and inducible nitric oxide synthase (iNOS) and cyclooxygenase (COX)-2 expressions were also measured using LPS-treated RAW 264.7 macrophages. RESULTS: Total phenolic and flavonoid contents showed a gradual increase during fermentation and 6 months of aging and were sustained thereafter. DPPH radical scavenging activity and FRAP were increased by fermentation. FRAP was further increased by aging, but DPPH radical scavenging activity was not. Total isoflavone and glycoside contents decreased during fermentation and the aging process, while aglycone content and its proportion increased up to 3 or 6 months of aging and then showed a slow decrease. DM and EA fractions of Doenjang showed much higher total phenolic and flavonoid contents, and DPPH radical scavenging activity than the others. At 100 microg/mL, DM and EA fractions of D12 showed strongly suppressed NO production to 55.6% and 52.5% of control, respectively, and PGE2 production to 25.0% and 28.3% of control with inhibition of iNOS or COX-2 protein expression in macrophages. CONCLUSIONS: Twelve month-aged Doenjang has potent antioxidant and anti-inflammatory activities with high levels of phenolics and isoflavone aglycones, and can be used as a beneficial food for human health.

Inhibitory effects of Doenjang, Korean traditional fermented soybean paste, on oxidative stress and inflammation in adipose tissue of mice fed a high-fat diet

BACKGROUND/OBJECTIVES: Doenjang, Korean traditional fermented soybean paste has been reported to have an anti-obesity effect. Because adipose tissue is considered a major source of inflammatory signals, we investigated the protective effects of Doenjang and steamed soybean on oxidative stress and inflammation in adipose tissue of diet-induced obese mice. MATERIALS/METHODS: Male C57BL/6J mice were fed a low fat diet (LF), a high-fat diet (HF), or a high-fat containing Doenjang diet (DJ) or a high-fat containing steamed soybean diet (SS) for 11 weeks. RESULTS: Mice fed a DJ diet showed significantly lower body and adipose tissue weights than those in the HF group. Although no significant differences in adipocyte size and number were observed among the HF diet-fed groups, consumption of Doenjang alleviated the incidence of crown-like structures in adipose tissue. Consistently, we observed significantly reduced mRNA levels of oxidative stress markers (heme oxygenase-1 and p40phox), pro-inflammatory adipokines (tumor necrosis factor alpha and macrophage chemoattractant protein-1), macrophage markers (CD68 and CD11c), and a fibrosis marker (transforming growth factor beta 1) by Doenjang consumption. Gene expression of anti-inflammatory adipokine, adiponectin was significantly induced in the DJ group and the SS group compared to the HF group. The anti-oxidative stress and anti-inflammatory effects observed in mice fed an SS diet were not as effective as those in mice fed a DJ diet, suggesting that the bioactive compounds produced during fermentation and aging may be involved in the observed health-beneficial effects of Doenjang. CONCLUSIONS: Doenjang alleviated oxidative stress and restored the dysregulated expression of adipokine genes caused by excess adiposity. Therefore, Doenjang may ameliorate systemic inflammation and oxidative stress in obesity via inhibition of inflammatory signals of adipose tissue.

Genotoxicity Assessment of Erythritol by Using Short-term Assay

Erythritol is a sugar alcohol that is widely used as a natural sugar substitute. Thus, the safety of its usage is very important. In the present study, short-term genotoxicity assays were conducted to evaluate the potential genotoxic effects of erythritol. According to the OECD test guidelines, the maximum test dose was 5,000 microg/plate in bacterial reverse mutation tests, 5,000 microg/ml in cell-based assays, and 5,000 mg/kg for in vivo testing. An Ames test did not reveal any positive results. No clastogenicity was observed in a chromosomal aberration test with CHL cells or an in vitro micronucleus test with L5178Y tk +/- cells. Erythritol induced a marginal increase of DNA damage at two high doses by 24 hr of exposure in a comet assay using L5178Y tk +/- cells. Additionally, in vivo micronucleus tests clearly demonstrated that oral administration of erythritol did not induce micronuclei formation of the bone marrow cells of male ICR mice. Taken together, our results indicate that erythritol is not mutagenic to bacterial cells and does not cause chromosomal damage in mammalian cells either in vitro or in vivo.

Inhibition of Arterial Myogenic Responses by a Mixed Aqueous Extract of Salvia Miltiorrhiza and Panax Notoginseng (PASEL) Showing Antihypertensive Effects

The dried roots of Danshen (Salvia miltiorrhiza) and Sanchi (Panax notoginseng) have been widely used in traditional Chinese medicine for promoting blood circulation as well as various other bodily functions. Here we investigated the effects of a mixture of aqueous extracts of Danshen and Sanchi, named PASEL, on blood pressure and vascular contractility in rats. Orally administered PASEL (62.5 mg/kg and 250 mg/kg, for 5 weeks) lowered the blood pressure of spontaneous hypertensive rats (SHR) but this was not observed in normal Wistar-Kyoto rats (WKR). We then investigated the effects of PASEL on the arterial contraction of the small branches of cerebral arteries (CAs) and large conduit femoral arteries (FAs) in rats. PASEL did not affect high-K (KCl 60 mM)- or phenyleprine (PhE)-induced contracture of FAs. The myogenic response, a reactive arterial constriction in response to increased luminal pressure, of small CA was dose-dependently suppressed by PASEL in SHR as well as control rats. Interestingly, the KCl-induced contraction of small CAs was slowly reversed by PASEL, and this effect was more prominent in SHR than control WKR. PASEL did not inhibit angiotensin-converting enzyme (ACE) activity. These results demonstrated that the antihypertensive effect of PASEL might be primarily mediated by altering the arterial MR, not by direct inhibition of L-type Ca2+ channels or by ACE inhibition.

Pharmacological Effects of Berberine and Palmatine on the Prostatic and Urethral Smooth Muscle of the Rabbit

PURPOSE: One of the major medical treatments for benign prostatic hyperplasia is targeted toward reducing bladder outlet obstruction by alpha-adrenoceptor blockade to relax the smooth muscle tone of the prostate. Berberine and palmatine, an isoquinoline alkaloids, have varied pharmacological actions and have been extensively used in folk medicine. A previous large scale screening test revealed that berberine derivatives have antagonistic effects at the alpha1-adrenoceptors, although they are less potent than prazosin. The aim of this study is to investigate the effect of the berberine and palmatine on the contractility of the isolated prostate, urethral and vascular smooth muscle tissues of the rabbit. MATERIALS AND METHODS: Muscle strips of the prostate, urethra and renal artery were obtained from 10-week-old male New Zealand White rabbits. In vitro isometric contraction was measured using organ bath study. Cumulative concentrations of phenylephrine as an agonist were added to produce concentration-response relationships. Breberin (1-500 microM) and palmatine (1-500 microM) were added to the bath before the repeated phenylephrine-induced concentration-response curve was made. Responses of developed tension to phenylephrine were plotted as percentage of the maximal increase for each concentration-response curve in the prostate, urethra and renal artery strips. RESULTS: Phenylephrine produced concentration-dependent contractions on the rabbit prostatic and urethral preparations. Berberine and palmatine induced a dose-dependent rightward shift of the dose-response curve of phenylephrine-induced contraction of both prostate and urethra with a reduction of maximal response, indicating the interactions of the two agents with phenylephrine in noncompetitive antagonism. The rank order of potency of the inhibitory effect was palmatine > berberine in the urethral tissue, while there was no significant difference between the two agents in the prostatic tissue. In the renal artery strips, both berberine and palmatine did not significantly inhibited the maximal contractile response to phenylephrine (1-50 microM). Higher concentration of berberine (500 microM) and palmatine (100-500 microM) decreased maximal contractile response induced by phenylephrine (0-10 microM), while they paradoxically increased maximal contraction induced by higher concentrations of phenylephrine (50-100 microM). CONCLUSIONS: Our results indicated that berberine or palmatine inhibited phenylephrine-induced contractions in urethral and prostatic smooth muscles, with no significant inhibition in the renal artery smooth muscle at lower concentration ranges of berberine and palmatine. A deeper understanding of the action mechanisms of berberine and palmatine would widen our therapeutic options for voiding disorders.

Antioxidant Assay of Extracted Fractions Xanthium Strumarium L Using Lens Protein Crosslink Activity

PURPOSE: To elucidate the anti-oxidant effect of extract fractions from Xanthium strumarium L. on lens protein by crosslinking assay. METHODS: [(1 4)C] N-formyl-lysine was synthesized and purified by ion exchange chromatography. The crosslinking activities of extract fractions(Xan Crude, Xan CHCl3, Xan EtAc and Xan H2O) to lens protein were determined by incorporation with [(14)C] N-formyl-lysine. RESULTS: It was observed that Xan Crude, Xan CHCl3, and Xan EtAc extracted from Xanthium strumarium L. showed approximately 10% of antioxidant effect whereas Xan H2O showed no effect by crosslinking assay. CONCLUSIONS: This study showed that the crosslinking assay described in this study can be developed as a potential tool to screen the anti-oxidant effect rapidly and accurately compared to MTT assay. The result was compared to MTT assay using Human Lens epithelial cell line.

Antioxidant Activity of Xanthium Strumarium L. Extracted F ractions in Lens Epithelial Cells

To elucidate the antioxidant effect of Xanthium strumarium L., a fruit of Dokomari or Daekori, which is a family of chrysanthemum on the H2O2-mediated cellualr damage, we examined the effect of Xanthium strumarium L. extraction fractions on survival of human lens epithelia, HLE B-3 cells by using cell culture system. H2O2-mediated cellualr death and its IC5 0, with approximately 100 micrometer H2O2 were determined by using MTT assay. The HLE B-3 cells pretreated with Xanthium strumarium L. extract fractions, were incubated with 100 micrometer H2O2, and in order to assess the cell viability the cultures were incubated with MTT solution. Among Xanthium strumarium L. extract fractions, Xan crude fraction, Xan CHCl3 fraction, and Xan EtAc fraction have antioxidant activity at the concentrations of 500 ng/ml, 1 microgram/ml and 100 ng/ml, respectively. These effects were statistically significant(p<0.05). Also, the fact that only the frations extracted with organic solvents have antioxidant activity suggests that the active components from the extract have hydrophobic property.

Effects of Antitumor Agents on the Spleen of Mouse Implanted with Ehrlich Carcinoma Cells: An Autoradiographic Study / 대한해부학회지

In this experiment, side effects of three anticancer drugs (5-fluorouracil, mitomycin C and AG60) on the structure of spleen were histologically studied. Each of ICR mice was inoculated with 1X10(7) Ehrlich carcinoma cells subcutaneously in the inguinal area. From next day, 0.2 ml of saline solution, 5-fluorouracil (30 mg/kg), mitomycin C (400 micorgram/kg), 5 mg/kg of AG60, or 30 mg/kg of AG60 (acriflavine (1) : guanosine (1) composition, Taerim Pharm. Co., Seoul, Korea) were injected subcutaneously every other day. The day following the 7th injection of anticancer drugs, each mouse was injected with a single dose of 0.7 microCi/gm of methyl-(3)H-thymidine (25 Ci/mmol, Amersham Lab., England) through tail vein. Seventy minutes after the thymidine injection, animals were sacrificed, and splenic tissues were collected and fixed in 10% neutral formalin. Tissue blocks were washed, dehydrated, embedded and cut into 6 micrometer-thick sections. Deparaffinized sections were coated with autoradiographic emulsion EM-1 (Amersham Lab., England) in the dark room and dried, and were kept in a light-tight box. The sections were exposured for 5 weeks in the dark room, and were deveoped in D-19 developer. The number of the labeled cells in the areas of the white pulp, the red pulp and the marginal zone (mean number of labeled cells per 0.21 mm2) were observed and calculated. The results were as follow: 1. On histological study, in the spleen of mitomycin C treated group, vacuoles containing pyknotic nuclei were observed more frequently than in those of 5-fluorouracil treated group. Whereas in the AG60 treated group, morphological changes of the spleen were not observed. 2. On autoradiographic study, most of the labeled cells were located near the marginal zone of the spleen. 3. On autoradiographic study, number of the labeled cells of normal control, experimental control, 5-fluorouracil-treated, mitomycin C-treated, AG60 (5 mg/kg)-, and AG60 (30 mg/kg)-treated groups were 214.0+/-56.87, 235.7+/-59.69, 331.0+/-67.20, 137.0+/-33.48, 124.6+/-34.28, and 64.9+/-16.26, respectively. 4. In the mitomycin C treated group and AG60 (5 mg/kg or 30 mg/kg) treated group, labeled cells containing a few silver grains of (3)H-thymidine were observed more frequently than in those of the normal and experimental control groups. But in the 5-fluorouracil treated group, number of the heavy labeled cells were observed more frequently than in those of the normal and experimental control groups. From the above results, DNA synthesis, in the cells of the marginal zone were more active than in the cells of the white pulp or the red pulp. And mitomycin C and AG60 may suppress the DNA synthesis of the splenic tissues. Especially, AG60 does not results any histological defect on the splenic tissues. These result suggest that AG60 is expected as one of most effective anticancer drugs.

Age Related Morphological Study on the Spleen of Mouse / 대한해부학회지

In this study, the structural components of mouse spleen were compared during their aging processes. Splenic tissues of 1 week-, 5 weeks-, 8 weeks-, 6 months-, 12 months-, 18 months-, 24 months-, and 30 months-old ICR mice were dissected out under anesthesia. Pieces of the tissues were taken from the spleen, fixed in 10% neutral formalin for light microscopy, and some splenic tissues, were prefixed with 2.5% glutaraldehyde-1.5% paraformaldehyde followed by post-fixation with 1% osmium tetroxide for electron microscopy. Paraffin sections stained with hematoxylin-eosin, Masson's trichrome, Bielschowsky's silver impregnation or aldehyde-fuchsin, were observed with light microscope. Ultrathin sections stained with uranyl acetate and lead citrate were observed with a JEM 100CX-II electron microscope. The observed results were as follow: 1. The thickness of the splenic capsule was prominently increased between 1 week-old and 5 weeks-old ones, whereas after 5 weeks-old, the thickness was very slightly increased during aging. 2. In the 1 week-old, 5 weeks-old and 8 weeks-old mice, blood forming cells were observed more frequently than those found in older ones. 3. The collagenous fibers and elastic fibers were increased in the spleens of 12 months-old mice, whereas after 18 months-old, fibers were not increased during aging. 4. The reticular fibers were increased by 8 weeks, whereas fibers were not increased afterwards. 5. In the 1-week old, mast cells were observed frequently, whereas from 5 weeks to 6 months they were observed rarely, and after 12 months, mast cells were observed frequently. 6. In the 5-weeks old, distended cisternae of granular endoplasmic reticula were first observed within the plasma cells. 7. After 12 months, the mast cell containing phagocytosed debris were observed frequently. 8. After 18 months, the plasma cell containing irregular distended cisternae of granular endoplasmic reticula were observed frequently. 9. In 30 months, the plasma cells containing myelin figures were observed frequently. From the above results, it was suggested that spleen of the mouse matures structurally in five weeks, but the function of the spleen is suppressed around 18 months, and thereafter the functional suppression is continued on aging.