Ki-67 labeling index as a prognostic marker in advanced stomach cancer

Sang Hyuk Seo,Kwang Hee Kim,Sang Hoon Oh,Yunseon Choi,Ki Jung Ahn,Ji Young Lee,Sang Min Lee,박지선,Woo Gyeong Kim 대한외과학회 2019 Annals of Surgical Treatment and Research(ASRT) Vol.96 No.1

Purpose: Proliferation marker Ki-67 is widely used in cancer prognosis prediction. We tried to investigate the role of Ki-67 as a prognostic factor in stomach cancer after surgery in this study. Methods: We retrospectively evaluated 251 patients who underwent curative resection for gastric cancer from 2010 to 2015. In pathologic examination, Ki-67 labeling index was defined as the percentage of Ki-67 antigen positive cells. Prognostic significance of Ki-67 for gastric cancer was evaluated. Disease-free survival (DFS) was assessed as a primary end-point. Results: The median follow-up period was 28.0 months. Thirty-one patients (12.4%) showed Ki-67 labeling index (LI) lower than 25%. Sixty-eight patients (26.6%) showed recurrence during follow-up period. Recurrence was associated with Ki- 67 LI level (≤25%, P = 0.016), and lymph node metastasis status (P = 0.002). High Ki-67 LI level (>25%) was also related to p53 positivity (P < 0.001) and poorly cohesive type (P = 0.002). The 3-year DFS was 69.4%. Low Ki-67 LI level (≤25%) was related with low DFS (47.6% vs. 72.6%, P = 0.016). T stage (P < 0.001), N stage (P = 0.006), lymphovascular invasion (P = 0.010), and neuronal invasion (P = 0.001) also affected the DFS. In addition, T stage (P = 0.03) and Ki-67 LI (P = 0.035) were independent prognostic factors for DFS. In patients treated with adjuvant chemotherapy (n = 239, 93.4%), low Ki-67 (≤25%) was a poor prognostic factor for DFS (P = 0.013). Conclusion: Low Ki-67 LI predicts high rate of progression and low DFS of stomach cancer. Ki-67 LI can be a predictive marker in resected stomach cancer treated with surgery and adjuvant chemotherapy.

위 아전절제술 후 십이지장 위 역류성 위염에서 p53 및 Ki-67 단백 발현 양상

최석채 ( Suck Chei Choi ),김용성 ( Yong Sung Kim ),김기훈 ( Ki Hoon Kim ),김헌수 ( Hun Soo Kim ),윤기중 ( Ki Jung Yun ) 대한소화기기능성질환·운동학회 2007 Journal of Neurogastroenterology and Motility (JNM Vol.13 No.2

목적 : 십이지장 위 역류성 위염은 위절제 등에 의해서 발생하는 것으로 후에 암종이 발생할 가능성이 높은 것으로 알려져 왔다. 그러나 사람에서 십이지장 내용물의 역류와 암종 발생 사이의 병인론적 연구가 흔하지 않다. 이에 십이지장 위 역류성 위염을 보이는 환자의 조직과 대조군 환자의 조직을 대상으로 Ki-67 및 p53 단백 발현 정도를 측정하여 상피 세포증식 유도 및 암억제 유전자의 발현 정도를 비교 연구하였다. 대상 및 방법 : 위암종으로 위아전절제술을 받은 총 57예 중 내시경 및 조직학적으로 십이지장 위 역류성 위염으로 진단된 16예의 내시경 조직과 대조군 16예의 내시경 조직을 대상으로 하여 Ki-67 및 p53 단백 발현을 면역조직화학적 염색을 하였고 그 강도를 점수화하였다. 결과 : 십이지장 위 역류성 위염 소견을 보인 환자의 내시경적 추적 기간은 평균 607일, 대조군 556일 그리고 57예의 평균은 471일로 유의한 차이는 없었다. 십이지장 위 역류성 위염 환자의 Ki-67 발현 강도의 중간값은 3.0로 대조군 중간값 2.0보다 의미있게 높았으며, p53 단백의 발현 강도 중간값도 2.0으로 대조군 중간값 1.0 보다 의미있게 높았다. 결론 : 십이지장 위 역류성 위염은 담즙 등이 점막의 상피세포 증식을 유도하고 유전자 이상을 초래할 가능성이 높아 시간 경과 후 암종이 발생할 가능성이 대조군에 비해서 높을 수 있음을 알 수 있었다. Background/Aims: Duodenogastric reflux of bile and other contents of duodenum is one of the main etiologic fators in chronic gastritis, and chronic inflammation has been recognized as a risk factor of human cancer. The aim of this study was therefore to evaluate the expression of p53 and Ki-67 protein in duodenogastric reflux gastritis. Methods: To evaluate the proliferation activity and tumor suppressor gene expression, 16 cases of duodenogastric reflux gastritis and 16 cases of control gastric tissue after subtotal gastrectomy were examined immunohistochemically using the monoclonal antibodies to Ki-67 and p53 protein. Results: The mean duration of follow-up endoscopic biopsy after subtotal gastrectomy was 607 days in duodenogastric reflux gastritis and 556 days in control groups. The mean intensity of Ki-67 in duodenogastric reflux gastritis was significantly higher than that of control tissues (3.0 vs 2.0). The mean intensity of p53 protein in duodenogastric reflux gastritis was significantly higher than that of control tissues (2.0 vs 1.0). Conclusions: The high expressions of Ki-67 and p53 protein in duodenogastric reflux gastritis may be one of the main mechanisms in the development of gastric stump carcinoma. (Kor J Neurogastroenterol Motil 2007;13:118-122)

정신분열병에 대한 리스페리돈의 효과 및 안정성

이민수,김용구,김영훈,연병길,오병훈,윤도준,윤진상,이철,정희연,강병조,김광수,김동언,김명정,김상훈,김희철,나철,노승호,민경준,박기창,박두병,백기청,백인호,손봉기,손진욱,양병환,양창국,우행원,이정호,이종범,이홍식,임기영,전태연,정영조,정영철,정인과,정인원,지익성,채정호,한상익,한선호,한진희,서광윤 大韓神經精神醫學會 1998 신경정신의학 Vol.37 No.1

연구목적 : 본 시험의 목적은 임상시험 시작전에 연구자들을 대상으로 PANSS Workshop을 통하여 PANSS, ESRS에 대한 국내에서의 표준화 작업을 구축하고 새로운 정신병 치료제인 리스페리돈의 효과와 안정성을 재확인하여 리스페리돈 사용에 대한 적정화를 이루는데 있다. 연구방법 : 1996년 4월부터 1996년 9월까지 국내 39개 대학병원 정신과에 입원중인 혹은 증상이 악화되어 입원하는 정신분열병 환자 377명을 대상으로 다시설 개방 연구를 시행하였다. 1주일간의 약물 배설기간을 가진후, 리스페리돈을 8주간 투여하였고, 기준점, 1주, 2주, 4주, 그리고 8주후에 평가되었다. 용량은 제1일에는 리스페리돈 1mg씩 1일 2회, 제2일에는 2mg씩 1일 2회, 제3∼7일에는 3mg씩 1일 2회 투여하였다. 이후 환자의 임상상태에 따라 임의로 증량할 수 있으며, 최대 일일 16mg을 초과하지 않도록 하였다. 추체외로 증상을 조절하기 위한 투약을 허용하였다. 임상증상 및 부작용의 평가는 PANSS(Positive and Negative Syndrome Scale), CGI(Clinical Global Impression) 그리고 ESRS(Extrapyramidal Symptom Rating Scale)을 사용하였다. 연구결과 : 377명중 343명(91%)이 8주간의 연구를 완결하였다. 치료 종결시점인 8주후 PANSS 총점수가 20% 이상 호전된 경우를 약물 반응군으로 정의할때, 약물반응군은 81.3%였다. 리스페리돈에 반응하는 예측인자로는 발병연령, 이전의 입원 횟수, 유병기간이 관련 있었다. 리스페리돈은 1주후부터 PANSS양성, 음성, 및 일반정신병리 점수상에 유의한 호전을 보여 효과가 빨랐다. CGI의 경우도 기준점에 비해 1주후부터 유의한 감소를 나타내었다. ESRS의 경우, 파킨슨 평가점수는 기준점과 비교해 투여 1주, 2주, 4주후 유의하게 증가되었다가 8주후 기준점과 차이가 없었다. Dystonia 평가점수는 1주후만 유의한 증가를 보였으며, dyskinesia 평가점수는 유의한 차이가 없었다. 혈압, 맥박수의 생명징후 및 일반 혈액학 검사, 생화학적 검사, 심전도 검사에서 유의한 변화는 없었다. 결 론 : 이상의 다시설 개방 임상 연구를 통해 리스페리돈은 정신분열병 환자에서 양성증상뿐만 아니라 음성증상 및 전반적인 증상에도 효과적인 것으로 사료된다. 보다 명확한 평가를 위해서는 다른 항정신병약물과의 이중맹검 연구가 필요할 것으로 생각되며, 또한 장기적 치료에 대한 평가도 함께 이루어져야 하겠다. Objective : The purpose of this study was to investigate the efficacy and safety of risperidone in the treatment of Korean schizophrenic patients. Method : This multicenter open study included 377 schizophrenic patients drawn from 39 university hospitals. After a wash-out period of 1 week, the schizophrenic patients were treated with risperidone for 8 weeks and evaluated at 5 points ; at baseline, and 1, 2, 4 and 8 weeks of treatment. The dose was increased from 2mg/day(1mg twice daily) to 6mg/day(3mg twice daily) during the first week and adjusted to a maximum of 16mg/day over the next 7 weeks according to the patient's clinical response. Medication to control extrapyramidal symptoms was permitted. The psychiatric and neurological status of the patients was assessed by PANSS, CGI, and ESRS scales. Results : 343(91%) of 377 patients completed the 8-week trial period. Clinical improvement, as defined by a 20% or more reduction in total PANSS score at end point, was shown by 81.3% of patients. The predictors of response to risperidone were associated older age, shorter duration of illness, fewer previous hospitalization. Risperidone had rapid onset of action ; a significant decrease of the total PANSS and three PANSS factor(positive, negative, general), and CGI was already noticed at the end of first week. For the ESRS, parkinsonism rating scores were significantly increased until week 4 comparing with baseline. Dystonia rating scores were significantly increased until week 1, and dyskinesia rating scores were not significantly changed during the study. Laboratory parameters including vital sign, EKG, hematological, and biochemical values showed no significant changes during the trial. Conclusions : This study suggests that risperidone is generally safe and effective against both the positive and negative symptoms in our group of patients.

식도의 원주상피 피복 점막에서 점액유전자 발현 및 세포증식능에 대한 연구

최석채 ( Suck Chei Choi ),김용성 ( Yong Sung Kim ),김기훈 ( Ki Hoon Kim ),김헌수 ( Hun Soo Kim ),조향정 ( Hyang Jeong Jo ),윤기중 ( Ki Jung Yun ) 대한소화기기능성질환·운동학회 2007 Journal of Neurogastroenterology and Motility (JNM Vol.13 No.1

목적 : 바렛식도는 지속적인 위식도역류 등으로 원위부 식도에 정상적으로 존재하는 편평상피세포 대신에 배상세포를 포함하는 장형 원주세포로 식도 점막이 피복되는 것을 말한다. 그리고 이형성을 거쳐 선암종으로 진행할 수 있기 때문에 이형성 이전 단계인 바렛식도의 발암과정에 대한 연구가 필요하다. 이에 바렛식도와 배상세포를 포함하지 않은 원주세포만 있는 식도를 대조군으로 하여 점액유전자 및 세포증식능에 대해 비교 연구하였다. 대상 및 방법 : 임상 및 내시경적으로 바렛식도가 의심되어 원위부 식도에서 생검한 환자들 중에서 배상세포가 있어 조직학적으로 바렛식도로 증명된 25명의 환자와 배상세포가 없었던 환자들 중에서 무작위로 선택한 30예를 대조군으로 하였다. 생검 당시의 나이와 성별 그리고 MUC1, MUC2, Ki-67에 대한 면역조직화학적 염색을 시행하였다. 결과 : 바렛식도의 평균 나이 및 남자 비율은 각각 65.3±10.1세, 76.0%이였고, 대조군의 평균 나이 및 남자 비율은 각각 53.0±14.8세, 60.0%로 바렛식도의 나이가 대조군식도보다 의의있게 높았다. MUC1은 바렛식도 및 대조군 모두에서 100% 발현되었고, MUC2 발현율은 바렛식도 및 대조군에서 각각 92%, 20%이었다. Ki-67 발현율은 바렛식도 및 대조군에서 각각 80.0%, 70.0%이였고, Ki-67 발현 강도의 평균은 바렛식도 1.20±0.76, 대조군 0.77±0.57로 발현 강도에서 바렛식도가 의의있게 높았다. 결론 : 바렛식도는 원주세포만 있는 식도에서 보다 좀더 지속적인 위식도역류 등의 자극으로 생긴다. 그리고 MUC2는 주로 바렛식도에서 발현되고 세포증식능은 바렛식도에서 좀더 높으며 이는 MUC2 발현과 관련될 수 있다고 생각된다. Background/Aims: Barrett`s esophagus is characterized by the presence of metaplastic columnar epithelium with goblet cells in the distal esophagus. Barrett`s esophagus progresses through low grade dysplasia and high grade dysplasia to adenocarcinoma. We studied the patient age, the mucin gene and the proliferation activity of biopsy-proven Barrett`s esophagus and simple columnar epithelium-lined esophagus. Methods: To evaluate the mucin gene expression and proliferation activity, twenty five cases of Barrett`s esophagus and thirty cases of control esophagus were examined immunohistochemically with using the monoclonal antibodies to MUC1, MUC2 and Ki-67. Results: The Barrett`s esophagus patients were older (mean: 65.3±10.1 years) than the control patients (mean: 53.0±14.8 years). The MUC1 expression was 100% in both Barrett`s esophagus and the control esophagus. An MUC2 expression was observed in 92.0% of the Barrett`s esophagus and 20.0% of the control esophagus. The rate and intensity of the Ki-67 expression was higher in the Barrett`s esophagus (80.0%, 1.20±0.76) than that in the control esophagus (70.0%, 0.77±0.57). Conclusions: Barrett`s esophagus is a metaplastic lesion due to the more long-standing gastroesophageal reflux than that in a simple columnar epithelium-lined esophagus. The cause of increased proliferation activity in Barrett`s esophagus may be related to the MUC2 expression. (Kor J Neurogastroenterol Motil 2007;13:21-25)

P196 : Effects of different electrical parameter settings on hair growth: the changes of dermal papilla cell in vitro and at microscopic level in animal tissue

( Ki Min Sohn ),( Kwan Ho Jeong ),( Joo Hyun Lee ),( Jung Eun Kim ),( Hoon Kang ) 대한피부과학회 2014 대한피부과학회 학술발표대회집 Vol.66 No.2

Background: Frequency electrical stimulation is clinically being used in variable skin therapeutic conditions such as skin rejuvenation and hair disorder. There have been several clinical studies demonstrating the positive effect of electrical stimuli on hair regrowth. However, its exact mechanism is yet to be clarified. Objectives: The objective of this study is to investigate effects of different electrical parameter settings on hair growth by revealing the changes of dermal papilla cell in vitro and at microscopic level in animal tissue. Methods: Cultured dermal papilla cells (DPCs) and dorsal skin of rabbit were electrically stimulated with different parameter settings at alternating-current to find the optimal condition for hair growth. Cell viability and proliferation were measured by MTT. In addition, Ki67, proliferation marker, expression was measured by immunofluorescence. Hair growth-related gene expression in DPCs and the skin of rabbit were measured by RT-PCR. Results: At certain electrical settings, DPCs responded well and their proliferation was successfully induced. Wnt/β -catenin, Ki67, p-ERK and p-AKT expressions in DPCs increased at certain frequency settings. Dermal thickness and hair related genes (PDGF, VEGF, SOX9 and KGF) expressions in the skin of rabbit also significantly increased. Conclusion: These data suggest that electrical stimulations at certain electrical settings, may give more effective therapeutic outcomes for hair growth.

Hair growth promoting effects of different alternating- current parameter settings are mediated by the activation of Wnt/β-catenin and MAPK pathway

( Ki Min Sohn ),( Kwan Ho Jeong ),( Jung Eun Kim ),( Young Min Park ),( Hoon Kang ) 대한피부과학회 2015 대한피부과학회 학술발표대회집 Vol.67 No.2

Background: There are clinical studies demonstrating the positive effect of electrical stimuli on hair regrowth. However, the underlying mechanism and optimal parameter settings are not clarified. Objectives: To investigate the effects of different parameter settings of electrical stimuli on hair growth by examining changes in human dermal papilla cells (hDPCs) in vitro and by observing molecular changes in animal tissue. Methods: In vitro, cultured hDPCs were electrically stimulated with different parameter settings. Cell proliferation was measured by MTT assay. The Ki67 expression was measured by immunofluorescence. Hair growth-related gene expressions were measured by RT-PCR. In animal model, different parameter settings were applied to the shaved dorsal skin of rabbit for 8 weeks. Expression of hair-related genes in the skin of rabbit was examined by RT-PCR.Results: At low voltage power (3.5V) and low frequency (1MHz or 2MHz) alterating current, in vitro proliferation of hDPCs was successfully induced. A significant increase in Wnt/モ-catenin, Ki67, p-ERK and p-AKT expression was observed. In animal model, hair regrowth was observed in the entire stimulated areas and expression of hair-related genes in the skin significantly increased. Conclusion: There are optimal conditions for electric stimulated hair growth and they might be different in the cells, animal, and human tissue. Electric stimuli induces mechanisms such as activation of Wnt/モ-catenin and MAPK pathway in hair follicles.

Effects of Streptozotocin-Induced Type 1 Diabetes on Cell Proliferation and Neuronal Differentiation in the Dentate Gyrus : Correlation with Memory Impairment

Jung Hoon Choi,In Koo Hwang,Sun Shin Yi,Ki-Yeon Yoo,Choong Hyun Lee,Hyung-Cheul Shin,Yeo Sung Yoon,Moo-Ho Won 대한해부학회 2009 Anatomy & Cell Biology Vol.42 No.1

We examined the effects of steptozotocin (STZ)-induced type 1 diabetes on cell proliferation and neuroblasts in the subgranular zone of the hippocampal dentate gyrus (SZDG) of male Wistar rats. Change in memory function was also investigated using the passive avoidance test. In the SZDG, Ki67 (a marker for cell proliferation) positive nuclei were significantly decreased at 2 and 3 weeks and slightly decreased at 4 weeks after STZ treatment. Doublecortin (DCX, a marker for neuronal differentiation)-immunoreactive (+) neuroblasts with tertiary dendrites were significantly decreased in the STZ-treated group compared to those in the vehicle-treated group. However, DCX+ neuroblasts without tertiary dendrites were abundant at 4 weeks after STZ treatment. In addition, retention latency time in STZ-treated group was similar to that of vehicle-treated group at 2 and 3 weeks after STZ treatment. However, the retention latency time was significantly decreased at 4 weeks after STZ treatment. These results suggest that STZ significantly reduced cell proliferation and neuroblasts at 2~3 weeks after STZ treatment, but not at 4 weeks after STZ treatment although memory impairment was detected at 4 weeks after STZ treatment. The gradual reduction of DCX+ neuroblasts with tertiary dendrites may be associated with the impairment of hippocampus-related memory function.

Cell proliferation and neuroblast differentiation in the rat dentate gyrus after intrathecal treatment with adipose-derived mesenchymal stem cells.

Choi, Jung Hoon,Chung, Jin Young,Yoo, Dae Young,Hwang, In Koo,Yoo, Ki-Yeon,Lee, Choong Hyun,Yan, Bing Chun,Ahn, Jin Ok,Youn, Hwa Young,Won, Moo-Ho Kluwer Academic/Plenum Publishers 2011 Cellular and molecular neurobiology Vol.31 No.8

<P>Mesenchymal stem cells (MSC) have emerged as a new therapeutic tool for a number of clinical applications, because they have multipotency and paracrine effects via various factors. In the present study, we investigated the effects of adipose-derived MSC (Ad-MSC) transplantation via intrathecal injection through the cisterna magna on cell proliferation and differentiation of endogenous stem cells in the hippocampal dentate gyrus (DG) using Ki-67 (a marker for proliferating cells), and doublecortin (DCX, a marker for neuroblasts). The transplanted Ad-MSC were detected in the meninges, not in the hippocampal parenchyma. However, the number of Ki-67-immunoreactive cells was significantly increased by 83% in the DG 2 days after single Ad-MSC injection, and by 67% at 23 days after repeated Ad-MSC treatment compared with that in the vehicle-treated group after Ad-MSC transplantation. On the other hand, the number of DCX-immunoreactive cells in the DG was not changed at 2 days after single Ad-MSC injection; however, it was significantly increased by 62% 9 days after single Ad-MSC injection. At 23 days after repeated Ad-MSC application, the number of DCX-immunoreactive cells was much more increased (223% of the vehicle-treated group). At this time point, DCX protein levels were also significantly increased compared with those in the vehicle-treated group. These results suggest that the intrathecal injection of Ad-MSC could enhance endogenous cell proliferation, and the repeated Ad-MSC injection could be more efficient for an enhancement of endogenous cell proliferation and differentiation in the brain.</P>

The high dosage of earthworm (Eisenia andrei) extract decreases cell proliferation and neuroblast differentiation in the mouse hippocampal dentate gyrus.

Yan, Bing Chun,Yoo, Ki-Yeon,Park, Joon Ha,Lee, Choong Hyun,Choi, Jung Hoon,Won, Moo-Ho Korean Association of Anatomists 2011 Anatomy & Cell Biology Vol.44 No.3

<P>Earthworm extract has shown anticancer characteristics. In the present study, we examined the effect of chronic treatment with a high dose of earthworm (Eisenia andrei) extract (EE) on cell proliferation and neuroblast differentiation in the hippocampal dentate gyrus (DG) of 3-week-old mice using 5-bromo-2'-deoxyuridine (BrdU) and Ki-67 immunohistochemistry for cell proliferation and doublecortin (DCX) immunohistochemistry for neuroblast differentiation, respectively. BrdU-, Ki-67-, and DCX-immunoreactive cells were easily detected in the subgranular zone of the DG in vehicle (saline)-treated mice. However, BrdU-, Ki-67-, and DCX-immunoreactive cells in the 500 mg/kg EE-treated mice decreased distinctively compared to those in the vehicle-treated mice. In addition, brain-derived neurotrophic factor (BDNF) immunoreactivity and its protein level decreased markedly in the DG of the EE-treated group compared to those in the vehicle-treated group. These results indicate that chronic treatment with high dose EE decreased cell proliferation and neuroblast differentiation, and that BDNF immunoreactivity decreased in the DG of EE-treated mice.</P>

The high dosage of earthworm (Eisenia andrei) extract decreases cell proliferation and neuroblast differentiation in the mouse hippocampal dentate gyrus

Bing Chun Yan,Ki-Yeon Yoo,Joon Ha Park,Choong Hyun Lee,Jung Hoon Choi,Moo-Ho Won 대한해부학회 2011 Anatomy & Cell Biology Vol.44 No.3

Earthworm extract has shown anticancer characteristics. In the present study, we examined the effect of chronic treatment with a high dose of earthworm (Eisenia andrei) extract (EE) on cell proliferation and neuroblast differentiation in the hippocampal dentate gyrus (DG) of 3-week-old mice using 5-bromo-2’-deoxyuridine (BrdU) and Ki-67 immunohistochemistry for cell proliferation and doublecortin (DCX) immunohistochemistry for neuroblast differentiation, respectively. BrdU-, Ki-67-, and DCX-immunoreactive cells were easily detected in the subgranular zone of the DG in vehicle (saline)-treated mice. However, BrdU-, Ki-67-, and DCX-immunoreactive cells in the 500 ㎎/㎏ EE-treated mice decreased distinctively compared to those in the vehicle-treated mice. In addition, brain-derived neurotrophic factor (BDNF) immunoreactivity and its protein level decreased markedly in the DG of the EE-treated group compared to those in the vehicle-treated group. These results indicate that chronic treatment with high dose EE decreased cell proliferation and neuroblast differentiation, and that BDNF immunoreactivity decreased in the DG of EE-treated mice.