Clinicopathologic Differences Between Prostate Cancers Detected During Initial and Repeat Transrectal Ultrasound-Guided Biopsy in Korea

박동진,김기호,권태균,김천일,박철희,박재신,김덕윤,김재수,문기학,이경섭 대한비뇨의학회 2014 Investigative and Clinical Urology Vol.55 No.11

Purpose: The aim of this study was to investigate clinicopathologic differences betweenprostate cancer (PCa) detected at initial and repeat transrectal ultrasound-guidedprostate biopsy in a large Korean cohort. Materials and Methods: From 2000 through 2012, a total of 7,001 patients underwenttransrectal ultrasound-guided prostate biopsy at 6 centers in Daegu and Gyeongbukprovinces. Of these 7,001 patients, the initial biopsy was positive for PCa in 2,118patients. Repeat biopsy was performed in 374 of the 4,883 patients with an initial negativefinding and a persistently elevated prostate-specific antigen (PSA) level, nodulesor asymmetry by digital rectal examination (DRE), high-grade prostatic intraepithelialneoplasia, or atypical small acinar proliferation. Numbers of biopsy cores varied from6 to 12 according to center and biopsy date. Results: Cancer was diagnosed in 2,118 of the 7,001 patients (30.3%) at initial biopsyand in 86 of the 374 patients (23.0%) at repeat biopsy. The repeat biopsy rate was 5.3%. Mean PSA values were 68.7±289.5 ng/mL at initial biopsy and 18.0±55.4 ng/mL at repeatbiopsy (p<0.001). The mean number of cancer-positive cores per biopsy was5.5±3.5 for initial biopsy and 3.0±2.9 for repeat biopsy (p<0.001). Mean Gleason scorewas 7.5±1.4 at initial biopsy and 6.6±1.3 at repeat biopsy (p<0.001). For detected cancers,the low-stage rate was higher for repeat biopsy than for initial biopsy (p=0.001). Conclusions: Cancers detected at repeat biopsy tend to have lower Gleason scores andstages than cancers detected at initial biopsy. The present study shows that repeat biopsyis needed in patients with a persistently high PSA or abnormal DRE findings.

CT 유도하 폐병소의 생검 : 자동총생검과 미세바늘흡입생검의 진단정확도 및 합병증 발생빈도의 비교

김건우 대한영상의학회 1998 대한영상의학회지 Vol.38 No.4

Purpose: To compare the efficacy and safety of CT-guided automated gun biopsy with those of fine needle aspiration biopsy of pulmonary lesions. Materials and methods: Under CT guidance, we performed automated gun biopsies in 115 cases of 109 patients and fine needle aspiration biopsies in 119 cases of 108 patients with pulmonary lesions. Between the two methods, we compared the diagnostic rate, diagnostic accuracy and frequency of complications according to the depth and diameter of pulmonary lesions. Results: The overall diagnostic rates of automated gun biopsy and fine needle aspiration biopsy were 76.5%(88/115) and 64.7%(77/119) respectively. There was a significant statistical difference (p=0.048), especially in the case of malignant lesions less than 3 cm(p=0.027) and more than 6cm (p=0.008) in maximal diameter. The diagnostic accuracy of automated gun biopsy and fine needle aspiration biopsy showed significant statistical difference only in malignant lesions more than 6cm in maximal diameter(p=0.008), and in the lesions located from 1cm to less than 3cm from the pleura(p=0.030), as seen on CT. There was no significant statistical difference in the frequency of complications. Conclusion:Automated gun biopsy of pulmonary lesions under CT guidance is safe, with complications rate comparable to those of fine needle aspiration biopsy. A higher overall diagnostic rate can be achieved by automated gun biopsy than by fine needle aspiration biopsy. For the diagnosis of pulmonary lesions under CT guidance, automated gun biopsy is therefore a more useful procedure than fine needle aspiration biopsy.

A Prospective Study of Reducing Unnecessary Prostate Biopsy in Patients with High Serum Prostate-Specific Antigen with Consideration of Prostatic Inflammation

이안구,최용혁,조성용,조인래 대한비뇨의학회 2012 Investigative and Clinical Urology Vol.53 No.1

Purpose: We aimed to reduce unnecessary prostatic biopsy in patients with high prostate-specific antigen (PSA) by consideration of prostatic inflammation. Materials and Methods: The investigation was conducted prospectively in 413 patients with a PSA level of 4 to 10 ng/ml from January 2004 to December 2009. All patients underwent the expressed prostatic secretion (EPS) or voided bladder urine 3 (VB3) test to be classified into two groups: positive group and negative group. Patients with a positive result on the EPS or VB3 test were treated with antibiotics for 2 months, and in cases in which the PSA level remained high, we performed prostate biopsy. In patients with a negative result on the VB3 test, we performed prostate biopsy directly. Results: Of the 413 study patients, 215 (52%) patients had positive findings on the EPS or VB3 test. After 8 weeks of antibiotics therapy, 53 of the 215 men avoided prostate biopsy because their PSA level was normalized. The other patients (162 of 215) still had elevated PSA levels of more than 4 ng/ml, including 7 patients in whom the biopsy revealed cancer. Patients with negative findings (198 of 413) underwent prostate biopsy. Of the 198 patients, 41 were diagnosed with prostate cancer. The total prostate cancer detection rate was 11.6% in our subjects, where as it was 20.7% in the patients with negative findings on the EPS or VB3 and 3.3% in the patients with positive findings, respectively. Conclusions: In cases in which the PSA level is increasing, if we first exclude prostatitis and carry out a serial diagnostic procedure, it may help to reduce unnecessary prostatic biopsy. Purpose: We aimed to reduce unnecessary prostatic biopsy in patients with high prostate-specific antigen (PSA) by consideration of prostatic inflammation. Materials and Methods: The investigation was conducted prospectively in 413 patients with a PSA level of 4 to 10 ng/ml from January 2004 to December 2009. All patients underwent the expressed prostatic secretion (EPS) or voided bladder urine 3 (VB3) test to be classified into two groups: positive group and negative group. Patients with a positive result on the EPS or VB3 test were treated with antibiotics for 2 months, and in cases in which the PSA level remained high, we performed prostate biopsy. In patients with a negative result on the VB3 test, we performed prostate biopsy directly. Results: Of the 413 study patients, 215 (52%) patients had positive findings on the EPS or VB3 test. After 8 weeks of antibiotics therapy, 53 of the 215 men avoided prostate biopsy because their PSA level was normalized. The other patients (162 of 215) still had elevated PSA levels of more than 4 ng/ml, including 7 patients in whom the biopsy revealed cancer. Patients with negative findings (198 of 413) underwent prostate biopsy. Of the 198 patients, 41 were diagnosed with prostate cancer. The total prostate cancer detection rate was 11.6% in our subjects, where as it was 20.7% in the patients with negative findings on the EPS or VB3 and 3.3% in the patients with positive findings, respectively. Conclusions: In cases in which the PSA level is increasing, if we first exclude prostatitis and carry out a serial diagnostic procedure, it may help to reduce unnecessary prostatic biopsy.

Significance of Atypical Small Acinar Proliferation and High-Grade Prostatic Intraepithelial Neoplasia in Prostate Biopsy

Orhan Koca,Selahattin Çalışkan,Metin İshak Öztürk,Mustafa Güneş,Ihsan Karaman 대한비뇨의학회 2011 Investigative and Clinical Urology Vol.52 No.11

Purpose: In clinical practice, atypical small acinar proliferation (ASAP) and high-grade prostatic intraepithelial neoplasia (HGPIN) are two common findings on prostate biopsies. Knowing the frequency of a prostate cancer diagnosis on repeat biopsies would aid primary treating physicians regarding their decisions in suspicious cases. Materials and Methods: One hundred forty-three patients in whom biopsies revealed ASAP or HGPIN or both were enrolled in the present study; prostate cancer was not reported in the biopsy specimens and at least one repeat biopsy was performed. Age, digital rectal examination findings, prostate volumes, and free and total prostate-specific antigen (PSA) levels and the biopsy results of the patients were recorded. Results: Of the 97 patients with ASAP on the first set of biopsies, prostate cancer was diagnosed in the second and third biopsies of 32 and 6 patients, respectively. Prostate cancer was not detected in the second or third biopsies of the 40 patients with HGPIN in the first biopsy. Of the 6 patients with ASAP+HGPIN in the first biopsy, prostate cancer was detected in 3 patients in the second biopsy and in 1 patient in the third biopsy. Conclusions: The diagnosis of ASAP is a strong risk factor for prostate cancer. A repeat biopsy should be performed for the entire prostate subsequent to the diagnosis of ASAP. In patients with HGPIN according to the biopsy result, the clinical decision should be based on other parameters, such as PSA values and rectal examination, and a repeat biopsy should be avoided if the initial biopsy was performed with multiple sampling. Purpose: In clinical practice, atypical small acinar proliferation (ASAP) and high-grade prostatic intraepithelial neoplasia (HGPIN) are two common findings on prostate biopsies. Knowing the frequency of a prostate cancer diagnosis on repeat biopsies would aid primary treating physicians regarding their decisions in suspicious cases. Materials and Methods: One hundred forty-three patients in whom biopsies revealed ASAP or HGPIN or both were enrolled in the present study; prostate cancer was not reported in the biopsy specimens and at least one repeat biopsy was performed. Age, digital rectal examination findings, prostate volumes, and free and total prostate-specific antigen (PSA) levels and the biopsy results of the patients were recorded. Results: Of the 97 patients with ASAP on the first set of biopsies, prostate cancer was diagnosed in the second and third biopsies of 32 and 6 patients, respectively. Prostate cancer was not detected in the second or third biopsies of the 40 patients with HGPIN in the first biopsy. Of the 6 patients with ASAP+HGPIN in the first biopsy, prostate cancer was detected in 3 patients in the second biopsy and in 1 patient in the third biopsy. Conclusions: The diagnosis of ASAP is a strong risk factor for prostate cancer. A repeat biopsy should be performed for the entire prostate subsequent to the diagnosis of ASAP. In patients with HGPIN according to the biopsy result, the clinical decision should be based on other parameters, such as PSA values and rectal examination, and a repeat biopsy should be avoided if the initial biopsy was performed with multiple sampling.

Survival Outcomes of Patients With Breast Cancer Diagnosed Using Vacuum-Assisted Biopsy: A Nationwide Study From the Korean Breast Cancer Society

김봉균,안성귀,오세정,김하경,강은영,정용식,변경도,이지나,선우영 한국유방암학회 2022 Journal of breast cancer Vol.25 No.1

Purpose Breast cancer is mainly diagnosed using core needle biopsy (CNB), although other biopsy methods, including vacuum-assisted biopsy (VAB), may also be used. We compared differences in clinical characteristics and prognoses of patients with breast cancer according to biopsy methods used for diagnosis. Methods A total of 98,457 patients who underwent various biopsy methods (CNB, fine-needle aspiration [FNA], VAB, and excisional biopsy) for diagnosing breast cancer were recruited. Using CNB as a reference, related clinicopathological factors and prognostic differences between biopsy methods were analyzed retrospectively using large-scale data from the Korean Breast Cancer Society Registration System. The associations between biopsy methods and clinicopathological factors were compared using multinomial logistic regression analysis, and the prognoses of patients undergoing the different biopsy methods, as breast cancer-specific survival (BCSS) and overall survival (OS), were compared using the Kaplan-Meier method and Cox proportional hazard model. Results Univariate and multivariate analyses showed that unlike FNA, both VAB and excisional biopsy were significantly associated with tumor size, palpability, tumor stage, and histologic grade as relatively good prognostic factors compared to CNB. In particular, VAB showed lower odds ratios for these factors than excisional biopsy. In the univariate analysis, the prognosis of patients undergoing VAB was better than that of those undergoing CNB with respect to BCSS (hazard ratio [HR], 0.188, p < 0.001) and OS (HR, 0.359; p < 0.001). However, in the multivariate analysis, there were no significant prognostic differences from CNB in both BCSS and OS; differences were only evident for FNA. Conclusion In this study, we showed that the characteristics of breast cancer differed according to various biopsy methods. Although VAB is not a standard method for breast cancer diagnosis, it showed no prognostic differences to CNB.

Differences in Postoperative Pathological Outcomes between Prostate Cancers Diagnosed at Initial and Repeat Biopsy

강인호,김윤범,양승옥,이정기,정태영 대한비뇨의학회 2012 Investigative and Clinical Urology Vol.53 No.8

Purpose: We evaluated the differences in pathological outcomes between prostate cancers (PCas) diagnosed at initial and repeat biopsy. Materials and Methods: We retrospectively reviewed the medical records of 287 patients who underwent radical retropubic prostatectomy from 2005 to 2010. We investigated preoperative factors, such as age, serum prostate-specific antigen (PSA), prostate volume (PV), digital rectal examination (DRE) results, biopsy schema, clinical stage, and number of prior biopsies, and postoperative pathological outcomes, including specimen volume, percent tumor volume, Gleason score (GS), tumor bilaterality, pathological stage, positive surgical margin (PSM), lymphovascular invasion (LVI), and perineural invasion (PNI). Patients were then classified into two groups by the number of prior biopsies (initial biopsy vs. repeat biopsy). We compared preoperative factors and postoperative pathological outcomes between the two groups. Results: Of the 287 patients, 246 (85.7%) were diagnosed with cancer at the initial biopsy and 41 (14.3%) at the repeat biopsy. The repeat biopsy group was older (p=0.048), had a larger PV (p=0.009), had a significantly different biopsy schema (p<0.001), and had a lower (<10%) percentage tumor volume (p=0.016). In the multivariate analysis (after adjustment for biopsy schema, age, serum PSA, PV, and DRE), repeat biopsy was not an independent predictor of GS, tumor bilaterality, pathological stage, PSM, LVI, or PNI (p=0.212, 0.456, 0.459, 0.917, 0.991 and 0.827, respectively), but repeat biopsy could predict lower percentage tumor volume (p=0.037). Conclusions: The pathological outcomes of PCas detected at repeat biopsy were not significantly different from those of PCas detected at initial biopsy except for a lower (<10%) percentage tumor volume. Purpose: We evaluated the differences in pathological outcomes between prostate cancers (PCas) diagnosed at initial and repeat biopsy. Materials and Methods: We retrospectively reviewed the medical records of 287 patients who underwent radical retropubic prostatectomy from 2005 to 2010. We investigated preoperative factors, such as age, serum prostate-specific antigen (PSA), prostate volume (PV), digital rectal examination (DRE) results, biopsy schema, clinical stage, and number of prior biopsies, and postoperative pathological outcomes, including specimen volume, percent tumor volume, Gleason score (GS), tumor bilaterality, pathological stage, positive surgical margin (PSM), lymphovascular invasion (LVI), and perineural invasion (PNI). Patients were then classified into two groups by the number of prior biopsies (initial biopsy vs. repeat biopsy). We compared preoperative factors and postoperative pathological outcomes between the two groups. Results: Of the 287 patients, 246 (85.7%) were diagnosed with cancer at the initial biopsy and 41 (14.3%) at the repeat biopsy. The repeat biopsy group was older (p=0.048), had a larger PV (p=0.009), had a significantly different biopsy schema (p<0.001), and had a lower (<10%) percentage tumor volume (p=0.016). In the multivariate analysis (after adjustment for biopsy schema, age, serum PSA, PV, and DRE), repeat biopsy was not an independent predictor of GS, tumor bilaterality, pathological stage, PSM, LVI, or PNI (p=0.212, 0.456, 0.459, 0.917, 0.991 and 0.827, respectively), but repeat biopsy could predict lower percentage tumor volume (p=0.037). Conclusions: The pathological outcomes of PCas detected at repeat biopsy were not significantly different from those of PCas detected at initial biopsy except for a lower (<10%) percentage tumor volume.

The Prostate Cancer Detection Rate on the Second Prostate Biopsy according to Prostate-Specific Antigen Trend

김형상,이창용,임동훈,김철성,백승 대한비뇨의학회 2012 Investigative and Clinical Urology Vol.53 No.10

Purpose: To identify the prostate cancer detection rate on the patients who had second prostate biopsy out of the patients who were reported negative in their first biopsy. Materials and Methods: From July 2006 to February 2012, prostate biopsy was performed on 843 patients with over 4 ng/ml and on 618 biopsy negative patients PSA was performed from between 6 months and 9 months after biopsy. On 164 patients, second biopsy was performed, and 42 patients were selected. If there was less than 10% change between PSA before the prostate biopsy and PSA measured during 6 to 9 months after the first biopsy it was considered as no change. If above 10% increase, it was considered increase and if above 10% decrease it was considered as decrease. Results: The cancer detection rate in PSA increase group was 20%, the detection rate in no change in PSA level but still over the normal range group 8.3%, and that in the PSA decrease group was 0%. When comparing prostate cancer group and non-cancer group, it is more probable to have prostate cancer when they are older, prostate volume is smaller and PSA density is higher. Conclusions: The second biopsy is strongly recommended when PSA level shows no change or increase, age is older, prostate volume is smaller or PSA density is higher. Purpose: To identify the prostate cancer detection rate on the patients who had second prostate biopsy out of the patients who were reported negative in their first biopsy. Materials and Methods: From July 2006 to February 2012, prostate biopsy was performed on 843 patients with over 4 ng/ml and on 618 biopsy negative patients PSA was performed from between 6 months and 9 months after biopsy. On 164 patients, second biopsy was performed, and 42 patients were selected. If there was less than 10% change between PSA before the prostate biopsy and PSA measured during 6 to 9 months after the first biopsy it was considered as no change. If above 10% increase, it was considered increase and if above 10% decrease it was considered as decrease. Results: The cancer detection rate in PSA increase group was 20%, the detection rate in no change in PSA level but still over the normal range group 8.3%, and that in the PSA decrease group was 0%. When comparing prostate cancer group and non-cancer group, it is more probable to have prostate cancer when they are older, prostate volume is smaller and PSA density is higher. Conclusions: The second biopsy is strongly recommended when PSA level shows no change or increase, age is older, prostate volume is smaller or PSA density is higher.

Initial experience of magnetic resonance imaging/ultrasonography fusion transperineal biopsy: Biopsy techniques and results for 75 patients

태종현,심지성,진현정,윤성구,노태일,김재윤,강석호,천준,강성구 대한비뇨의학회 2018 Investigative and Clinical Urology Vol.59 No.6

Purpose: The aim of this study is to describe the technique and to report early results of transperineal magnetic resonance imaging and ultrasonography (MRI-US) fusion biopsy. Materials and Methods: A total of 75 patients underwent MRI-US fusion transperineal biopsy. Targeted biopsy via MRI-US fusion imaging was carried out for cancer-suspicious lesions with additional systematic biopsy. Detection rates for overall and clinically significant prostate cancer (csPCa) were evaluated and compared between systematic and targeted biopsy. In addition, further investigation into the detection rate according to prostate imaging reporting and data system (PI-RADS) score was done. Results of repeat biopsies were also evaluated. Results: Overall cancer detection rate was 61.3% (46 patients) and the detection rate for csPCa was 42.7% (32 patients). Overall detection rates for systematic and targeted biopsy were 41.3% and 57.3% (p<0.05), respectively. Detection rates for csPCa were 26.7% and 41.3%, respectively (p<0.05). The cancer detection rates via MRI fusion target biopsy were 30.8% in PI-RADS 3, 62.1% in PI-RADS 4 and 89.4% in PI-RADS 5. Rates of csPCa missed by targeted biopsy and systematic biopsy were 0.0% and 25.0%, respectively. The cancer detection rate in repeat biopsies was 61.1% (11 among 18 patients) in which 55.5% of cancer suspected lesions were located in the anterior portion. Conclusions: Transperineal MRI-US fusion biopsy is useful for improving overall cancer detection rate and especially detection of csPCa. Transperineal MRI-US targeted biopsy show potential benefits to improve cancer detection rate in patients with high PI-RADS score, tumor located at the anterior portion and in repeat biopsies.

Predictive Factors of Gleason Score Upgrading in Localized and Locally Advanced Prostate Cancer Diagnosed by Prostate Biopsy

문성진,박성열,이춘용 대한비뇨의학회 2010 Investigative and Clinical Urology Vol.51 No.10

Purpose: The Gleason score (GS) is an important factor that is considered when making decisions about prostate cancer and its prognosis. However, upgrading of the GS can occur between transrectal ultrasonography (TRUS) biopsy and radical prostatectomy. This study analyzed the clinical factors predictive of upgrading of the GS after radical prostatectomy compared with that at the time of TRUS biopsy. Materials and Methods: We analyzed the medical records of 107 patients who had undergone radical prostatectomy. Patients were divided into two groups. Group 1 consisted of patients in whom the GS was not upgraded, and group 2 consisted of patients in whom the GS was upgraded. Associations between preoperative clinical factors and upgrading of the GS were analyzed. Preoperative clinical factors included age, prostate-specific antigen (PSA), prostate volume, PSA density, GS of TRUS biopsy, maximum core percentage of cancer, percentage of positive cores, number of biopsies, location of positive core with maximum GS, high-grade prostatic intraepithelial neplasia (HGPIN), inflammation on biopsy, and clinical stage. Results: Among 85 patients, 42 (49%) patients had an upgraded GS after operation. TRUS biopsy core number of 12 or fewer (p=0.029) and prostate volume of 36.5 ml or less (p<0.001) were associated with upgrading of the GS. Preoperative clinical factors associated with nonupgrading of the GS were the detection of positive cores with a maximum GS at the apex (p=0.002) or in a hypoechoic lesion (p=0.002) in TRUS. Conclusions: If the positive cores with maximum GS are located at the apex or in a hypoechoic lesion in TRUS, we can expect that the GS will not be upgraded. In patients with the clinical predictive factors of a prostate volume of 36.5 ml or less and TRUS biopsy core number of less than 12, we can expect upgrading of the GS after radical prostatectomy, and more aggressive treatment may be needed. Purpose: The Gleason score (GS) is an important factor that is considered when making decisions about prostate cancer and its prognosis. However, upgrading of the GS can occur between transrectal ultrasonography (TRUS) biopsy and radical prostatectomy. This study analyzed the clinical factors predictive of upgrading of the GS after radical prostatectomy compared with that at the time of TRUS biopsy. Materials and Methods: We analyzed the medical records of 107 patients who had undergone radical prostatectomy. Patients were divided into two groups. Group 1 consisted of patients in whom the GS was not upgraded, and group 2 consisted of patients in whom the GS was upgraded. Associations between preoperative clinical factors and upgrading of the GS were analyzed. Preoperative clinical factors included age, prostate-specific antigen (PSA), prostate volume, PSA density, GS of TRUS biopsy, maximum core percentage of cancer, percentage of positive cores, number of biopsies, location of positive core with maximum GS, high-grade prostatic intraepithelial neplasia (HGPIN), inflammation on biopsy, and clinical stage. Results: Among 85 patients, 42 (49%) patients had an upgraded GS after operation. TRUS biopsy core number of 12 or fewer (p=0.029) and prostate volume of 36.5 ml or less (p<0.001) were associated with upgrading of the GS. Preoperative clinical factors associated with nonupgrading of the GS were the detection of positive cores with a maximum GS at the apex (p=0.002) or in a hypoechoic lesion (p=0.002) in TRUS. Conclusions: If the positive cores with maximum GS are located at the apex or in a hypoechoic lesion in TRUS, we can expect that the GS will not be upgraded. In patients with the clinical predictive factors of a prostate volume of 36.5 ml or less and TRUS biopsy core number of less than 12, we can expect upgrading of the GS after radical prostatectomy, and more aggressive treatment may be needed.

Quantitative Analysis of Applied Force on Biopsy Needle Insertions

Min Tae Kim,Jaebum Son,Chang Nho Cho,김광기,Chang Min Park 대한의용생체공학회 2012 Biomedical Engineering Letters (BMEL) Vol.2 No.4

Purpose The major drawback of conventional computed tomography (CT)-guided biopsy is the exposure of the operator to radiation during the procedure. One of the solutions to this problem is the biopsy utilizing modern robotic technology with the assistance of imaging technology. Methods In the design of a biopsy robot system, the structure and the size of the needle manipulator need to be optimized based on the quantitative analysis of the magnitude and pattern of the axial force applied during a biopsy. In this study, simulated biopsy experiments were conducted using the biopsy robot system previously developed at the National Cancer Center of Korea. The magnitude and the pattern of the axial forces applied to the needle insertion device located at the end of the slave arm were measured while varying the shape, diameter, and insertion angle of the biopsy needle and the specimen for biopsy. Results The results showed that the amount and the pattern of the axial force applied to the biopsy needle are affected by the physical properties of the biopsy specimen as well as the tip shape, diameter, and insertion angle of the needle. These results will facilitate the optimization of the required workspace, size, and weight of robot systems for robotic biopsy. Conclusions A quantitative analysis was performed to examine changes in the shape, diameter, and insertion angle affect the force on the biopsy needle. We found that the force applied on the needle might vary depending on the physical characteristics of the various internal organs and structures.