1.Follow-up analysis of sex hormone levels and prognosis in women after hematopoietic stem cell transplantation
Qianwen XU ; Yuanyuan DU ; Kangkang LYU ; Mimi XU ; Chengyuan GU ; Huizhu KANG ; Shanglong FENG ; Yuejun LIU ; Depei WU ; Yue HAN
Chinese Journal of Internal Medicine 2023;62(11):1303-1310
		                        		
		                        			
		                        			Objective:To investigate the levels of sex hormone and fertility in female patients after hematopoietic stem cell transplantation (HSCT), as well as their correlation with conditioning regimens, and analyse the effect of hormone replacement therapy (HRT) in young women after HSCT.Methods:Retrospective case series study. The clinical data of 147 women who underwent HSCT in the First Affiliated Hospital of Soochow University from January 2010 to January 2021 were retrospectively analyzed. The sex hormone levels were measured and followed-up, and the survival, menstrual fertility and the use of HRT of the patients were also followed-up. The sex hormone levels were measured after transplantation, and the ovarian function was evaluated. Independent sample t test and χ2 test were used for comparison between the two groups. Results:The median age of the 147 patients was 26 (range, 10-45) years. Of them, 135 patients received allogeneic HSCT and 12 patients received autologous HSCT. Furthermore, 129 patients received myeloablative conditioning, and 18 patients received reduced conditioning dose. The median follow-up time was 50 months (range, 18-134 months). Five patients died of disease recurrence during follow-up. Of the 54 patients with subcutaneous injection of zoladex, three recovered menstruation spontaneously after transplantation, and all of them were myeloablative conditioning patients, one patient gave birth to twins through assisted reproductive technology. Ninety-three patients did not use zoladex before conditioning, two patients with aplastic anemia with non-myeloablative transplantation resumed menstruation spontaneously, and conceived naturally. The level of follicle stimulating hormone after transplantation in patients receiving myeloablative conditioning regimen was significantly higher than that in patients receiving reduced-dose conditioning regimen [(95.28±3.94) U/L vs. (71.85±10.72) U/L, P=0.039]. Among 147 patients, 122 patients developed premature ovarian failure, 83 patients received sex hormone replacement therapy after transplantation, and 76 patients recovered menstruation and improved endocrine function. Conclusions:The incidence of premature ovarian failure is high in female patients after HSCT, and patients have a chance at natural conception. Reducing the dose of conditioning regimen and the application of zoladex before transplantation can reduce ovarian of conditioning drugs. HRT after transplantation can partially improve the endocrine function of patients.
		                        		
		                        		
		                        		
		                        	
2.Efficacy and safety of LY01005 versus goserelin implant in Chinese patients with prostate cancer: A multicenter, randomized, open-label, phase III, non-inferiority trial.
Chengyuan GU ; Zengjun WANG ; Tianxin LIN ; Zhiyu LIU ; Weiqing HAN ; Xuhui ZHANG ; Chao LIANG ; Hao LIU ; Yang YU ; Zhenzhou XU ; Shuang LIU ; Jingen WANG ; Linghua JIA ; Xin YAO ; Wenfeng LIAO ; Cheng FU ; Zhaohui TAN ; Guohua HE ; Guoxi ZHU ; Rui FAN ; Wenzeng YANG ; Xin CHEN ; Zhizhong LIU ; Liqiang ZHONG ; Benkang SHI ; Degang DING ; Shubo CHEN ; Junli WEI ; Xudong YAO ; Ming CHEN ; Zhanpeng LU ; Qun XIE ; Zhiquan HU ; Yinhuai WANG ; Hongqian GUO ; Tiwu FAN ; Zhaozhao LIANG ; Peng CHEN ; Wei WANG ; Tao XU ; Chunsheng LI ; Jinchun XING ; Hong LIAO ; Dalin HE ; Zhibin WU ; Jiandi YU ; Zhongwen FENG ; Mengxiang YANG ; Qifeng DOU ; Quan ZENG ; Yuanwei LI ; Xin GOU ; Guangchen ZHOU ; Xiaofeng WANG ; Rujian ZHU ; Zhonghua ZHANG ; Bo ZHANG ; Wanlong TAN ; Xueling QU ; Hongliang SUN ; Tianyi GAN ; Dingwei YE
Chinese Medical Journal 2023;136(10):1207-1215
		                        		
		                        			BACKGROUND:
		                        			LY01005 (Goserelin acetate sustained-release microsphere injection) is a modified gonadotropin-releasing hormone (GnRH) agonist injected monthly. This phase III trial study aimed to evaluated the efficacy and safety of LY01005 in Chinese patients with prostate cancer.
		                        		
		                        			METHODS:
		                        			We conducted a randomized controlled, open-label, non-inferiority trial across 49 sites in China. This study included 290 patients with prostate cancer who received either LY01005 or goserelin implants every 28 days for three injections. The primary efficacy endpoints were the percentage of patients with testosterone suppression ≤50 ng/dL at day 29 and the cumulative probability of testosterone ≤50 ng/dL from day 29 to 85. Non-inferiority was prespecified at a margin of -10%. Secondary endpoints included significant castration (≤20 ng/dL), testosterone surge within 72 h following repeated dosing, and changes in luteinizing hormone, follicle-stimulating hormone, and prostate specific antigen levels.
		                        		
		                        			RESULTS:
		                        			On day 29, in the LY01005 and goserelin implant groups, testosterone concentrations fell below medical-castration levels in 99.3% (142/143) and 100% (140/140) of patients, respectively, with a difference of -0.7% (95% confidence interval [CI], -3.9% to 2.0%) between the two groups. The cumulative probabilities of maintaining castration from days 29 to 85 were 99.3% and 97.8%, respectively, with a between-group difference of 1.5% (95% CI, -1.3% to 4.4%). Both results met the criterion for non-inferiority. Secondary endpoints were similar between groups. Both treatments were well-tolerated. LY01005 was associated with fewer injection-site reactions than the goserelin implant (0% vs . 1.4% [2/145]).
		                        		
		                        			CONCLUSION:
		                        			LY01005 is as effective as goserelin implants in reducing testosterone to castration levels, with a similar safety profile.
		                        		
		                        			TRIAL REGISTRATION
		                        			ClinicalTrials.gov, NCT04563936.
		                        		
		                        		
		                        		
		                        			Humans
		                        			;
		                        		
		                        			Male
		                        			;
		                        		
		                        			Antineoplastic Agents, Hormonal/therapeutic use*
		                        			;
		                        		
		                        			East Asian People
		                        			;
		                        		
		                        			Gonadotropin-Releasing Hormone/agonists*
		                        			;
		                        		
		                        			Goserelin/therapeutic use*
		                        			;
		                        		
		                        			Prostate-Specific Antigen
		                        			;
		                        		
		                        			Prostatic Neoplasms/drug therapy*
		                        			;
		                        		
		                        			Testosterone
		                        			
		                        		
		                        	
3.Observation of preliminary clinical effect and analysis of perioperative complications of radical prostatectomy for patients with oligometastatic prostate cancer
Gaoxiang LI ; Bo DAI ; Dingwei YE ; Yao ZHU ; Hualei GAN ; Guowen LIN ; Xiaojian QIN ; Wenjun XIAO ; Chengyuan GU
China Oncology 2017;27(1):20-25
		                        		
		                        			
		                        			Background and purpose:It has been demonstrated that radical prostatectomy for patients with oligometastatic prostate cancer may contribute to improving local control of prostate cancer and overall survival by several retrospective studies. Perioperative complications play an important role in determining whether radical prostatectomy is appropriate for patients with oligometastatic prostate cancer. This study aimed to discuss the recurrence rate and the sever-ity of perioperative complications, and the primary curative effect of radical prostatectomy on oligometastatic prostate can-cer patients.Methods:A total number of 247 patients who received radical prostatectomy were recruited in the study from Jul. 2015 to Jan. 2016, including 25 patients with oligometastatic prostate cancer and 222 patients with localized prostate cancer. Patients with perioperative complications in both groups were graded with the Clavien-Dindo grading system. The proportion of PSA decline and the rates and severity of perioperative complications were analyzed in both groups.Results:The cases of prostate specific antigen (PSA) decline in the oligometastatic group were 21 (84.0%), lower than the localized group with 212 cases (95.5%). There were 6 cases (24.0%) with postoperative complications in the oligometastatic group, including serious complications (Ⅲ or above) 1 case (4.0%), and 49 cases (22.1%) with postoperative complications in the localized group, including serious complications (Ⅲ or above) 7 cases (3.2%). The differences between the groups reached no statistical significance (P>0.05).Conclusion:Radical prostatectomy for patients with oligometastatic prostate cancer could be safe, effective, and appropriate, the risk of perioperative complications should not be one of the limiting factors.
		                        		
		                        		
		                        		
		                        	
4.Association between polymorphism in Vav3 genes and risk of primary prostatic cancer in Chinese Han population
Ming LIU ; Na MIAO ; Yao ZHU ; Chengyuan GU ; Xiaoli SHI ; Wenli CUI ; Wei ZHANG ; Qiaoxin LI
Chinese Journal of Pathology 2016;45(7):451-456
		                        		
		                        			
		                        			Objective To study the associations between genetic variations of Vav 3 gene and prostate cancer susceptibility.Methods Data were collected in a hospital-based and case-control study of 1 015 prostate cancer cases and 1 068 cancer-free controls collecting from a period of time between 2008 and 2012.Based on the online database , NCBI dbSNP ( http://www.ncbi.nlm.nih.gov/projects/SNP ) and SNPinfo ( http://snpinfo.niehs.nih.gov/snpfunc.htm ) . Functional single nucleotide polymorphisms (SNPs) of Vav3 were screened and genotyped , and assessed their associations with risk of prostate cancer by using logistic regression analysis.Furthermore, the associations between SNPs of Vav 3 and some clinicopathological parameters were evaluated.Results Among the two SNPs investigated , only Vav3 rs12410676 G>A was associated with decreased prostate cancer risk [additive model, OR=0.80 (0.69-0.93), P=0.003;dominant model, OR=0.81 (0.68-0.97), P=0.022;recessive model, OR=0.54 (0.36-0.82), P=0.004].The combined effect of Vav3 rs8676 G>A and rs12410676 G>A was found as a decreased prostate cancer risk along with the increased variant alleles ( P <0.05 ).Specifically , participants carrying Vav 3 rs12410676 AA/AG genotypes were more likely to be at lower prostate cancer risk, compared with participants carrying GG genotypes , in groups of BMI≤25 kg/m2 , smoking, Gleason>7(4+3), and higher invasive prostate cancer .Finally, some positive findings were evidently significant with false positive report probability values at different prior probability levels (0.25,0.1 and 0.01).Conclusion Vav3 SNPs may contribute to the risk of prostate cancer in Eastern Chinese men , but the effect is weak and needs further validation by larger , multicenter and ethnic-based studies.
		                        		
		                        		
		                        		
		                        	
5.Influence of clinical factors on Gleason score upgrade in patients undergoing radical prostatectomy.
Guiming ZHANG ; Xiaojian QIN ; Chengtao HAN ; Chengyuan GU ; Fangning WAN ; Yuanyuan QU ; Weijie GU ; Chunguang MA ; Yao ZHU ; Dingwei YE ; Email: DWYELI@163.COM.
Chinese Journal of Surgery 2015;53(7):543-546
OBJECTIVETo evaluate clinical factors affecting Gleason score upgrade in patients receiving radical prostatectomy (RP).
METHODSA total of 322 patients with prostate cancer who received RP from January 2012 to December 2013 at Department of Urology at Fudan University Shanghai Cancer Center were included, and their data of age, body mass index (BMI), prostate-specific antigen (PSA), prostate volume, percentage core, clinical staging, pathological characteristics, biopsy Gleason score and RP Gleason score were analyzed. Differences in categorical variables and continuous variables were compared using χ² tests and Student's t-test, respectively. Unconditional multiple logistic regression was used to estimate OR and 95% CI of the association of Gleason score upgrade with clinical factors.
RESULTSGleason score upgrade occurred in 107 of 322 (33.3%) patients. There was no difference in age, BMI and clinical staging between the two groups. Compared with patients without Gleason score upgrade, higher levels of PSA (χ² =6.740, P=0.034), smaller prostate volume (t=3.481, P=0.002) and elevated percentage core (t=-2.097, P=0.037) were observed in patients with Gleason score upgrade. In addition, lymph node metastasis (χ² =4.193, P=0.041) and extracapsular extension (χ² =4.747, P=0.029) were more common in patients with Gleason score upgrade. After adjusting for potential confounders, PSA levels (OR=2.451, 95% CI: 1.290-4.660), prostate volume (OR=0.982, 95% CI: 0.969-0.995) and percentage core (OR=2.756, 95% CI: 1.033-7.357) were independent predictors for Gleason score upgrade.
CONCLUSIONGleason score upgrade happens at a relatively high rate. PSA levels, prostate volume and percentage core are important factors affecting Gleason score upgrade.
Biopsy ; Body Mass Index ; China ; Humans ; Logistic Models ; Male ; Multivariate Analysis ; Neoplasm Grading ; Prostate-Specific Antigen ; blood ; Prostatectomy ; Prostatic Neoplasms ; diagnosis ; surgery
6.Comparison of the renal function after partial nephrectomy and radical nephrectomy for T1a renal cell carcinoma.
Chengyuan GU ; Hailiang ZHANG ; Bo DAI ; Yao ZHU ; Guohai SHI ; Yijun SHEN ; Yuanyuan QU ; Fangning WAN ; Guiming ZHANG ; Dingwei YE ; Email: DWYE@SHCA.ORG.CN.
Chinese Journal of Oncology 2015;37(6):441-444
OBJECTIVETo evaluate the alterations in renal function after radical nephrectomy (RN) and partial nephrectomy (PN) for renal cell carcinoma (RCC) and to determine the risk factors for the onset of postoperative renal function impairment.
METHODSWe assessed the renal function of 429 T1a RCC patients by investigating the time-dependent changes of the estimated glomerular filtration rate (eGFR) after surgery from August 2003 to August 2010. Univariate and multivariate regression models were used to determine the risk factors for the onset of an eGFR < 60 ml · min⁻¹ · 1.73 m⁻² function, and to evaluate the prognosis for the two groups.
RESULTSThe mean eGFR values (ml · min⁻¹ · 1.73 m⁻²) at postoperative 1, 7 days, 1, 3, 6, 12 and 24 months were 51.4 ± 12.6, 52.1 ± 17.8, 53.2 ± 19.5, 54.6 ± 20.2, 53.8 ± 16.6, 52.7 ± 22.3 and 51.5 ± 18.4 in the RN group and 69.6 ± 18.3, 70.3 ± 19.5, 71.5 ± 21.4, 76.2 ± 22.8, 75.4 ± 19.7, 74.3 ± 16.3 and 73.1 ± 23.2 in the PN group, respectively. The eGFR of the radical nephrectomy group was significantly lower than that of the partial nephrectomy group (P < 0.05). Multivariable analysis revealed that radical nephrectomy and age were risk factors for the onset of postoperative chronic renal dysfunction.
CONCLUSIONSRenal function recovered partially after partial and radical nephrectomy and is maintained constantly after 3 months. Surgical mode and age are risk factors for the onset of postoperative eGFR < 60 ml · min⁻¹ · 1.73 m⁻² impairment. Compared with radical nephrectomy, partial nephrectomy can preserve renal function and reduce the incidence of postoperative chronic renal dysfunction.
Age Factors ; Carcinoma, Renal Cell ; pathology ; physiopathology ; surgery ; Glomerular Filtration Rate ; Humans ; Kidney Neoplasms ; pathology ; physiopathology ; surgery ; Nephrectomy ; adverse effects ; methods ; Postoperative Complications ; physiopathology ; Postoperative Period ; Renal Insufficiency, Chronic ; etiology ; physiopathology ; Risk Factors
7.Laparoscopic retroperitoneal adrenalectomy for adrenal mass:report of 130 cases
Fangning WAN ; Hailiang ZHANG ; Dingwei YE ; Guiming ZHANG ; Chengyuan GU ; Bo DAI ; Shilin ZHANG ; Yijun SHEN ; Yao ZHU ; Guohai SHI ; Yiping ZHU
China Oncology 2015;(10):828-831
		                        		
		                        			
		                        			Background and purpose:Laparoscopic retroperitoneal adrenalectomy makes access to the adrenal glands easier and less invasive than open surgery. The aim of this study was to evaluate the clinical efifcacy of laparoscopic retroperitoneal adrenalectomy.Methods:A total of 130 patients who underwent retroperitoneal adrenalectomy for adrenal mass from Jan. 2007 to Dec. 2012 in Fudan University Shanghai Cancer Center were retrospectively assessed. Their clinicopathological factors, perioperative complications and short-term prognostic data were retrieved from the medical records.Results:One hundred and twenty-seven of 130 patients underwent retroperitoneal adrenalectomy successfully, and 3 patients were converted to open surgery due to severe bleeding. Among 130 patients, 63 were male and 67 were female, with the mean age 50.0 years. The pathological results of the 130 patients indicated adrenocortical adenoma in 68, pheochromocytoma in 15, medullary lipoma in 13, adrenal cysts in 10 , ganglioneuroma in 7, metastatic cancer in 5, adrenal hyperplasia in 4, schwannoma in 3, lymphangioma in 2, adrenal hematoma in 1, adrenal cortical carcinoma in 1, adrenal angiosarcoma in 1 and the deputy spleen in 1 (one patient suffering from both pheochromocytoma and ganglioneuroma). The maximum diameters were ranging from 0.5 to 9.0 cm, and mean diameter was 3.48 cm. The average blood loss in surgery was 62.73 mL. Mean length of stay in hospital was 7 d. GradeⅠ complications occurred in 5 patients, including 2 of fever, 1 of food allergy, 1 of drug allergy and 1 of hypokalemia.Conclusion: Retroperitoneal adrenalectomy should be considered as the procedure of choice for the resection of most adrenal tumors in skilled centers with the advantages of minimal invasion, increased safety and faster recovery.
		                        		
		                        		
		                        		
		                        	
8.Comparison of the renal function after partial nephrectomy and radical nephrectomy for T1a renal cell carcinoma
Chengyuan GU ; Hailiang ZHANG ; Bo DAI ; Yao ZHU ; Guohai SHI ; Yijun SHEN ; Yuanyuan QU ; Fangning WAN ; Guiming ZHANG ; Dingwei YE
Chinese Journal of Oncology 2015;(6):441-444
		                        		
		                        			
		                        			Objective To evaluate the alterations in renal function after radical nephrectomy ( RN) and partial nephrectomy ( PN) for renal cell carcinoma ( RCC) and to determine the risk factors for the onset of postoperative renal function impairment. Methods We assessed the renal function of 429 T1a RCC patients by investigating the time?dependent changes of the estimated glomerular filtration rate ( eGFR) after surgery from August 2003 to August 2010. Univariate and multivariate regression models were used to determine the risk factors for the onset of an eGFR<60 ml·min-1 ·1.73 m-2 function, and to evaluate the prognosis for the two groups. Results The mean eGFR values ( ml·min-1 ·1.73 m-2 ) at postoperative 1, 7 days, 1, 3, 6, 12 and 24 months were 51. 4 ± 12. 6, 52. 1 ± 17. 8, 53. 2 ± 19. 5, 54. 6 ± 20. 2, 53. 8 ± 16. 6, 52.7±22.3 and 51.5±18.4 in the RN group and 69.6±18.3, 70.3±19.5, 71.5±21.4, 76.2±22.8, 75.4± 19.7, 74.3±16.3 and 73.1±23.2 in the PN group, respectively. The eGFR of the radical nephrectomy group was significantly lower than that of the partial nephrectomy group ( P<0.05) . Multivariable analysis revealed that radical nephrectomy and age were risk factors for the onset of postoperative chronic renal dysfunction. Conclusions Renal function recovered partially after partial and radical nephrectomy and is maintained constantly after 3 months. Surgical mode and age are risk factors for the onset of postoperative eGFR<60 ml· min-1 ·1.73 m-2 impairment. Compared with radical nephrectomy, partial nephrectomy can preserve renal function and reduce the incidence of postoperative chronic renal dysfunction.
		                        		
		                        		
		                        		
		                        	
9.Comparison of the renal function after partial nephrectomy and radical nephrectomy for T1a renal cell carcinoma
Chengyuan GU ; Hailiang ZHANG ; Bo DAI ; Yao ZHU ; Guohai SHI ; Yijun SHEN ; Yuanyuan QU ; Fangning WAN ; Guiming ZHANG ; Dingwei YE
Chinese Journal of Oncology 2015;(6):441-444
		                        		
		                        			
		                        			Objective To evaluate the alterations in renal function after radical nephrectomy ( RN) and partial nephrectomy ( PN) for renal cell carcinoma ( RCC) and to determine the risk factors for the onset of postoperative renal function impairment. Methods We assessed the renal function of 429 T1a RCC patients by investigating the time?dependent changes of the estimated glomerular filtration rate ( eGFR) after surgery from August 2003 to August 2010. Univariate and multivariate regression models were used to determine the risk factors for the onset of an eGFR<60 ml·min-1 ·1.73 m-2 function, and to evaluate the prognosis for the two groups. Results The mean eGFR values ( ml·min-1 ·1.73 m-2 ) at postoperative 1, 7 days, 1, 3, 6, 12 and 24 months were 51. 4 ± 12. 6, 52. 1 ± 17. 8, 53. 2 ± 19. 5, 54. 6 ± 20. 2, 53. 8 ± 16. 6, 52.7±22.3 and 51.5±18.4 in the RN group and 69.6±18.3, 70.3±19.5, 71.5±21.4, 76.2±22.8, 75.4± 19.7, 74.3±16.3 and 73.1±23.2 in the PN group, respectively. The eGFR of the radical nephrectomy group was significantly lower than that of the partial nephrectomy group ( P<0.05) . Multivariable analysis revealed that radical nephrectomy and age were risk factors for the onset of postoperative chronic renal dysfunction. Conclusions Renal function recovered partially after partial and radical nephrectomy and is maintained constantly after 3 months. Surgical mode and age are risk factors for the onset of postoperative eGFR<60 ml· min-1 ·1.73 m-2 impairment. Compared with radical nephrectomy, partial nephrectomy can preserve renal function and reduce the incidence of postoperative chronic renal dysfunction.
		                        		
		                        		
		                        		
		                        	
10.Impact of AR-V7 expression on overall survival for patients with metastatic prostate cancer.
Yuanyuan QU ; Dingwei YE ; Bo DAI ; Yunyi KONG ; Kun CHANG ; Chengyuan GU ; Zijie SUN ; Hailiang ZHANG ; Yao ZHU ; Guohai SHI
Chinese Journal of Surgery 2014;52(8):622-626
OBJECTIVETo investigate the impact of androgen receptor splice variant 7 (AR-V7) expression on overall survival for patients with metastatic prostate cancer.
METHODSThe data of 113 diagnosed metastatic prostate cancer patients from January 2002 to June 2010 were collected retrospectively, including patient's age at diagnosis, prostate-specific antigen (PSA) level at diagnosis,Gleason score, clinical stage, PSA nadir during hormonal therapy, the time to PSA nadir, vital status, survival time and cause of death. The expression of AR-V7 in prostate cancer tissue was detected by using immunohistochemical staining. The correlation of AR-V7 expression and patient clinicopathological characteristics in all patients were analysed using Student t-test or Chi-square test. Cox proportional hazards regression models were used to evaluate the predictive role of AR-V7 expression and patient characteristics for overall survival.
RESULTSThe median PSA nadir was 0.7 µg/L (ranged from 0.0 to 143.0 µg/L). The median time to PSA nadir was 8.1 months (ranged from 0.9 to 71.0 months). The follow-up was performed until March 12, 2014. During the follow-up period, 67 of 113 metastatic prostate cancer patients (59.3%) died and the median overall survival was 96 months (ranged from 5 to 135 months). The AR-V7 detection rate was 20.4% (23/113). The serum PSA level in patients with positively expression of AR-V7 was significantly higher than that without AR-V7 expression (t = 2.521, P = 0.013). Multivariate Cox regression analysis indicated that the expression of AR-V7 (HR = 2.421, P = 0.002) and time to PSA nadir (HR = 1.019, P = 0.022) were independent prognostic factors of overall survival for metastatic prostate cancer patients.
CONCLUSIONSThe expression of AR-V7 in prostate cancer tissues and time to PSA nadir during hormonal therapy are independent prognostic factors of overall survival for metastatic prostate cancer patients. Therapy targeting AR-V7 may improve prognosis of metastatic prostate cancer patients.
Adult ; Aged ; Aged, 80 and over ; Humans ; Male ; Middle Aged ; Neoplasm Metastasis ; Prognosis ; Proportional Hazards Models ; Prostate-Specific Antigen ; blood ; Prostatic Neoplasms ; diagnosis ; metabolism ; pathology ; Protein Isoforms ; metabolism ; Receptors, Androgen ; metabolism ; Retrospective Studies
            
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