The optimal stent pusher position to achieve successful ureteral stent insertion under fluoroscopic guidance.

Objective: To examine factors to predict the optimal stent pusher position when inserting ureteral stents under fluoroscopy. Methods: We retrospectively reviewed 327 patients who underwent ureteral stent insertion. We considered the pubic bone as a useful anatomical landmark to insert ureteral stents under fluoroscopic guidance. Thus, we categorized patients into three groups (proximal, middle, and distal groups) according to the position of the radiopaque tip of the push catheter when inserting the ureteral stent. Success was defined as a completely curled ureteral stent tail. We compared stent insertion success rates among the three groups. A multivariate analysis was performed to identify the factors affecting stent insertion success. Results: In men, 36 (63.2%) cases were deemed successful in the proximal group compared with 40 (80.0%) cases in the middle group and 12 (20.7%) cases in the distal group (p<0.001). In women, 26 (45.6%) cases were deemed successful in the proximal group compared with 54 (98.2%) cases in the middle group and 38 (76.0%) cases in the distal group (p<0.001). With the multivariate analysis, the stent pusher position was the most significant factor influencing successful stent insertion (men: odds ratio 6.00, 95% confidence interval 2.66-13.51, p<0.001; women: odds ratio 37.80, 95% confidence interval 4.94-289.22, p<0.001). Conclusion: The position of the stent pusher affects stent insertion success. The middle of the pubic symphysis is the optimal position for the radiopaque tip of the pusher when inserting ureteral stents under fluoroscopic guidance.

Evaluation of ureteral injuries caused by ureteral access sheath insertion during ureteroscopic lithotripsy.

OBJECTIVE: To evaluate ureteral injuries caused by insertion of a 13-Fr ureteral access sheath and identify factors (other than pre-stenting) that are predictive of ureteral injury. METHODS: We enrolled 201 patients who underwent ureteroscopic lithotripsy (URSL). We excluded 80 patients who underwent ureteral stent insertion before URSL, 10 patients who did not use a ureteral access sheath, and 2 patients in whom a ureteral access sheath could not be inserted. In total, 109 patients were analyzed; all underwent insertion of a 13-Fr ureteral access sheath. We investigated ureteral injuries using the Traxer ureteral injury scale. RESULTS: There were 21 (19.3%) cases of ureteral access sheath-related ureteral injury, including 11 (10.1%) grade 2 cases and 10 (9.2%) grade 3 cases. The ureteral injury location was the proximal ureter in 20 cases (18.3%), middle ureter in one case (0.9%), and distal ureter in zero cases. Multiple logistic regression analysis showed that male sex and smaller stone diameter were significant predictive factors for ureteral injury (p = 0.037, odds ratio [OR]: 5.19, 95% confidence interval [CI]: 1.11-24.3 and p = 0.02, OR: 0.83, 95% CI: 0.71-0.97, respectively). Postoperative ureteral stricture did not occur in any cases. CONCLUSIONS: The rate of ureteral injury caused by a 13-Fr ureteral access sheath was considerable, and most ureteral injuries occurred in the proximal ureter. Male sex and smaller stone diameter were significant predictive factors for ureteral injury. The proximal ureter should be confirmed when using a 13-Fr ureteral access sheath, particularly in male patients and patients with small stones.

Prospective randomized controlled trial comparing a ureteral stent crossing versus not crossing the bladder midline.

PURPOSE: To evaluate the correlation between the position of a ureteral stent and stent-related symptoms in a single-center randomized study. METHODS: A total of 113 patients who required ureteral stent placement after lithotripsy were randomized at a 1:1 ratio into groups with stents crossing and not crossing the bladder midline. The ureteral stent remained in place until postoperative day 14, when we obtained each patient's International Prostate Symptom Score (IPSS), overactive bladder symptom score (OABSS), and visual analog scale (VAS) pain score. RESULTS: Comparing changes from baseline IPSS and OABSS scores between the two groups, the midline crossing group had a worse OABSS total score than the not crossing group (3.0 ± 2.8 vs. 2.0 ± 3.3; p = 0.032). There was no significant difference between the crossing and not crossing groups in IPSS total score (6.8 ± 7.6 vs. 5.1 ± 8.5; p = 0.14). The OABSS urgency mean score was significantly lower in the not crossing than in the crossing group (1.1 ± 1.8 vs. 1.6 ± 1.8; p = 0.042). However, there was no significant difference between groups for remaining items of the IPSS and OABSS and the mean VAS total pain score (1.9 ± 2.7 vs. 1.2 ± 1.9; p = 0.14). CONCLUSION: A ureteral stent that crossed the bladder midline led to worse urinary symptoms. Choosing the appropriate stent length for each patient is important to minimize stent-related symptoms. TRIAL REGISTRATION DATE: 1 October 2018; number: UMIN000034067.

Effectiveness and Safety of Ureteroscopic Lithotripsy in Young, Old-Old, and Oldest Old Patients.

Objectives: To investigate the efficacy and safety of ureteroscopic lithotripsy (URSL) in young, old-old, and oldest old patients. Materials and Methods: We enrolled 157 patients who underwent URSL. We divided the patients into young (<65 years), old-old (65-84 years), and oldest old (≥85 years) groups and compared the safety of surgery between young vs old-old and young vs oldest old, separately. Results: In the <65 group, 65 to 85 group, and ≥85 group, respectively, the mean stone diameters were 8.9 ± 4.9, 10.8 ± 7.7, and 11.4 ± 6.3 mm; mean operative time was 76.6 ± 33.1, 86.7 ± 44.7, and 84.0 ± 44.5 min; the stone-free rates were 95.9%, 94.4%, and 96.3%; and the complication rates were 8.2%, 9.8%, and 3.7%. Conclusions: In this study, we showed the feasibility and safety of URSL for elderly people. Although oldest old (≥85 years) people had multiple comorbidities with low performance status, URSL could be performed with acceptable complication rates. Clinical Trial Registration Number: 1809-1.

[EFFECTIVENESS AND SAFETY OF TRANSURETHRAL ENUCLEATION WITH BIPOLAR (TUEB) IN THE ELDERLY (OVER 80 YEARS OLD)].

(Objective) The number of elderly people is increasing in Japan, and there are many reports on the safety and effectiveness of treatment for the elderly. As the number of elderly men with benign prostatic hyperplasia is increasing, it is necessary to consider surgical treatment for the elderly. We analyzed the treatment outcome of transurethral enucleation with bipolar (TUEB), and investigated the effectiveness and safety of TUEB in the elderly (over 80 years old) at Saiseikai Izuo Hospital. (Methods) In total, 47 patients who underwent TUEB were enrolled. The patients were divided into two groups by age (< 80 years old group and ≥ 80 years old group). We investigated the factors related to the occurrence of complications by multivariate analysis. (Results) Mean duration of surgery was 107.8 min and 85.8 min (p=0.11) in the < 80 group and the ≥ 80 group, respectively. Mean resected prostate weight was 33.9 g and 31.0 g (p=0.61) and mean hemoglobin loss was 1.29 g/dL and 0.66 g/dL (p=0.01), respectively. Hemoglobin loss was significantly lower in the over 80 years old group. Complications were observed in six patients (24.0%) in the under 80 years old group and two patients (9.1%) in the over 80 years old group; however, there was no significant difference between the two groups (p=0.17). Fever was a complication in the over 80 years old group. In multivariate analysis, operative time was significant predictive factor for complications (odds ratio: 1.03, 95% confidence interval: 1.00-1.06, p=0.03) and, age was not significant predictive factor. (Conclusion) This study shows that TUEB for patients over 80 years old is effective and safe.

Laparoendoscopic single-site surgery for treatment of urachal remnants.

INTRODUCTION: To evaluate safety and excellent cosmetic outcome with laparoendoscopic single-site surgery (LESS). In this study, we compared the usefulness and efficacy of LESS versus conventional laparoscopic surgery for the treatment of urachal remnants. MATERIALS AND METHODS: We retrospectively reviewed the medical records of 20 consecutive patients who underwent either conventional laparoscopic surgery or LESS from January 2007 to February 2015 at Kansai Medical University Hospital. Ten patients underwent surgery using the standard laparoscopic 3-port technique, and 10 patients underwent LESS. The patients included 12 males and 8 females (mean age, 24.5 years; range, 10-68 years). The patients' characteristics, surgical data, and postoperative pain assessment results were retrospectively collected and analyzed. RESULTS: The median operative time, pneumoperitoneal surgery time, and estimated blood loss did not differ between the LESS and conventional laparoscopic groups. However, the total incision length was longer in the conventional laparoscopic group than in the LESS group. The degree of pain at 2 to 5 days postoperatively according to the Wong-Baker FACES Pain Rating Scale was lower in the LESS group than in the conventional laparoscopic group (p < 0.05). CONCLUSIONS: Less is a possible option in the surgical treatment for urachal remnants. In this very small cohort, there is no conversion to traditional laparoscopic surgery or open surgery. This technique is possibly feasible and may achieve less pain. Accumulation of surgical outcomes especially in safety and cosmesis is required to be an established method.

[Devices to Perform Laparo-Endoscopic Single Site Surgery for Urachal Remnants without Additional Ports].

The laparoscopic management of urachal remnants has gradually become a common practice. Recently, laparoscopic single-site surgery (LESS), a minimally invasive approach that provides excellent cosmetic results, has been adopted in several surgical procedures for treating urachal remnants. However, when suturing the bladder wall or peritoneal defect during LESS it may be difficult to conduct the procedure manually, and such cases require an additional port for suturing. Our strategy, however, employs a knot pusher to perform the suturing without the need for an additional port. We compared and examined the perioperative parameters of the patients with the additional port and one without it (knot-pusher group). For the additional-port and knot-pusher groups, the average operative time, was 146.8 and 161.7 minutes respectively, pneumoperitoneal surgery time was 90.8 and 88.0 minutes, respectively, suturing time for the bladder wall was 577 and 502 seconds, respectively suturing time for peritoneal defect was 758 vs 779 seconds, respectively, and estimated blood loss was 19 and 9.6 ml, respectively ; there being no significant difference between the two groups. We report our knot-pusher method because it can achieve comparable results without compromising the surgical outcome.

Preoperative sexual status of Japanese localized prostate cancer patients: comparison of sexual activity and EPIC scores.

OBJECTIVE: This study aimed to evaluate the relationship between sexual activity and sexual function using questionnaires distributed to middle-aged Japanese patients with localized prostate cancer. METHODS: A total of 145 patients who underwent radical prostatectomy were enrolled in the survey reported on herein. Sexual activity and sexual function were investigated via the Expanded Prostate Cancer Index Composite (EPIC) and an original self-reported questionnaire. RESULTS: Of participants, 24.1% and 20.7% had sexual activity within a month period as investigated via the EPIC and original questionnaire, respectively. However, 29.7% of all those who reported sexual activity rate reported "about once every 2 months to a year," as shown in the original questionnaire. Regarding sexual function as addressed through EPIC, no results within that questionnaire's measure of sexual function showed significant differences among patients with a rate of actual sexual activity. CONCLUSIONS: The present survey showed that more than quarter of preoperative middle-aged Japanese prostate cancer patients surveyed had actual sexual activity, though not within the preceding 4 weeks. To precisely evaluate sexual function of middle-aged Japanese patients, it is necessary to consider actual sexual activity.

Introduction of an Enhanced Recovery after Surgery Protocol for Robot-Assisted Laparoscopic Radical Prostatectomy.

INTRODUCTION: No studies have shown whether the enhanced recovery after surgery (ERAS) protocol is superior to the conventional protocol after robot-assisted laparoscopic radical prostatectomy (RALP). We compared intestinal function and perioperative parameters of patients with prostate cancer after the ERAS and conventional protocols to determine the superior protocol for recovery of intestinal function. MATERIAL AND METHODS: A retrospective analysis of 198 consecutive patients who underwent RALP between August 2013 and June 2015 was conducted. Our study design included 2 cohorts. Patients underwent conventional care in one group (n = 123) and the ERAS protocol in the other group (n = 75). The primary outcome was the time to first defecation. Secondary outcomes were perioperative parameters and the complication rate. RESULTS: The ERAS group showed a significantly shorter time to first defecation than did the conventional group (p = 0.006). Multivariate analysis showed that selection of the ERAS protocol was significantly associated with the number of days for first time to defecation. CONCLUSIONS: Successful application of an ERAS protocol was applied to our patients who underwent RALP and did not have major complications. The ERAS protocol included enhanced intestinal recovery. The ERAS group showed a significantly shorter time to first defecation than did the conventional group.

NDR1-Dependent Regulation of Kindlin-3 Controls High-Affinity LFA-1 Binding and Immune Synapse Organization.

Antigen-specific adhesion between T cells and antigen-presenting cells (APC) during the formation of the immunological synapse (IS) is mediated by LFA-1 and ICAM-1. Here, LFA-1-ICAM-1 interactions were measured at the single-molecule level on supported lipid bilayers. High-affinity binding was detected at low frequencies in the inner peripheral supramolecular activation cluster (SMAC) zone that contained high levels of activated Rap1 and kindlin-3. Rap1 was essential for T cell attachment, whereas deficiencies of ste20-like kinases, Mst1/Mst2, diminished high-affinity binding and abrogated central SMAC (cSMAC) formation with mislocalized kindlin-3 and vesicle transport regulators involved in T cell receptor recycling/releasing machineries, resulting in impaired T cell-APC interactions. We found that NDR1 kinase, activated by the Rap1 signaling cascade through RAPL and Mst1/Mst2, associated with and recruited kindlin-3 to the IS, which was required for high-affinity LFA-1/ICAM-1 binding and cSMAC formation. Our findings reveal crucial roles for Rap1 signaling via NDR1 for recruitment of kindlin-3 and IS organization.

Influence of scars on body image consciousness with respect to gender following laparoendoscopic single-site versus conventional laparoscopic surgery.

OBJECTIVE: The aim of this study was to evaluate and compare the cosmetic outcomes of laparoscopic single-site surgery (LESS) and conventional laparoscopy (CL) in the treatment of ureteropelvic junction obstruction (UPJO) and urachal remnant removal. LESS is thought to produce better cosmetic results than CL; however, patients' perception of their scars has not been assessed. This study compared the subjective body image and cosmesis ratings of patients who had undergone LESS or CL for UPJO and urachal remnant removal. MATERIALS AND METHODS: Fifty patients who underwent LESS or CL for UPJO or urachal remnant removal between June 2008 and June 2015 were included. Cosmetic outcomes were evaluated using the Body Image Questionnaire (BIQ) and Photo-Series Questionnaire (PSQ). RESULTS: The body image and cosmetic scores were significantly higher for patients who underwent LESS than for those who underwent CL, for both pyeloplasty and urachal remnant removal (p < .05 each). When performed for either a pyeloplasty or urachal remnant removal, significantly greater BIQ and PSQ scores were observed in females after LESS compared to CL, but not in males. CONCLUSION: LESS for UPJO and urachal remnant removal has better self-reported body image and cosmesis ratings than CL. This trend is particularly strong in female patients.

Urinary l-type fatty acid-binding protein is a predictor of early renal function after partial nephrectomy.

PURPOSE: Urinary biomarkers of renal injury urinary may identify loss of renal function following nephron-sparing surgery (NSS). This study was designed to evaluate whether urinary l-type fatty acid-binding protein (l-FABP) is an early biomarker of loss of renal function after NSS. Specifically, the kinetics of urinary l-FABP level after NSS and its correlation with factors related to ischemic renal injury were analyzed. METHODS: This study prospectively evaluated 18 patients who underwent NSS between July and December 2014, including 12 who underwent laparoscopic and six who underwent robot-assisted partial nephrectomy. Urinary l-FABP concentrations were measured preoperatively and 1, 2, 3, 6, 12, 24, 48, and 72 h after renal artery declamping. Loss of renal function loss was calculated by comparing the effective renal plasma flow, as determined by 99mTc-mercaptoacetyltriglycine (MAG3) clearance, on the operated and normal sides. The decrease in estimated glomerular filtration rate from before surgery to six months after surgery was also measured. RESULTS: Urinary l-FABP concentration peaked within 2 h of declamping, which may quantify nephron damage caused by ischemia. The decrease in MAG3 reduction ratio correlated with both the ischemia time and peak urinary l-FABP concentration. Peak urinary l-FABP concentration showed a significant correlation with MAG3 reduction ratio. CONCLUSIONS: l-FABP is a suitable urinary biomarker for predicting the extent of ischemic renal injury.

Sema3e/Plexin D1 Modulates Immunological Synapse and Migration of Thymocytes by Rap1 Inhibition.

Regulation of thymocyte trafficking plays an important role during thymic selection, but our understanding of the molecular mechanisms underlying these processes is limited. In this study, we demonstrated that class III semaphorin E (sema3e), a guidance molecule during neural and vascular development, directly inhibited Rap1 activation and LFA-1-dependent adhesion through the GTPase-activating protein activity of plexin D1. Sema3e inhibited Rap1 activation of thymocytes in response to chemokines and TCR stimulation, LFA-mediated adhesion, and T cell-APC interactions. Immunological synapse (IS) formation in mature thymocytes on supported lipid bilayers was also attenuated by sema3e. Impaired IS formation was associated with reduced Rap1 activation on the contact surface and cell periphery. Moreover, a significant increase of CD4(+) thymocytes was detected in the medulla of mice with T cell lineage-specific deletion of plexin D1. Two-photon live imaging of thymic explants and slices revealed enhanced Rap1 activation and migration of CD69(+) double-positive and single-positive cells with plexin D1 deficiency. Our results demonstrate that sema3e/plexin D1 modulates IS formation and Ag-scanning activities of thymocytes within thymic tissues.

Intravesical Prostatic Protrusion as a Predicting Factor for the Adverse Clinical Outcome in Patients With Symptomatic Benign Prostatic Enlargement Treated With Dutasteride.

OBJECTIVE: To evaluate the role of intravesical prostatic protrusion (IPP) as a predictive factor for adverse clinical outcomes in patients treated with dutasteride for lower urinary tract symptoms secondary to benign prostatic enlargement (BPE). METHODS: In total, 111 patients treated with dutasteride for symptomatic BPE were analyzed. Stepwise multivariate logistic regression was applied to evaluate predictors for acute urinary retention (AUR) or benign prostatic hyperplasia (BPH)-related surgery. We applied an IPP cutoff value of 10 mm. The clinical variables were assessed using univariate analysis. RESULTS: Of 111 patients, 27 (24.3%) developed AUR or required surgical intervention. On multivariate analysis, IPP remained as the independent predictor for AUR and need for BPH-related surgery (odds ratio, 1.27; P < .001). Both international prostate symptom score and maximum urinary flow rate significantly improved in patients with low IPP (P = .03 and P < .001, respectively), but not in those with high IPP. No significant reduction was found in the degree of IPP despite the significant reduction in prostate volume after dutasteride treatment (P = .84 and P < .001, respectively). The 3-year cumulative incidence of AUR or BPH-related surgery in the low IPP group vs the high IPP group was 9.9% vs 71.5%, respectively (P < .001). CONCLUSION: High IPP is associated with a higher risk of treatment resistance, AUR, or the need for prostatic surgery in patients receiving dutasteride treatment for symptomatic BPE. Dutasteride might not be effective for IPP reduction.

Enhanced cytotoxic T-cell function and inhibition of tumor progression by Mst1 deficiency.

Mammalian ste-20 like kinase Mst1 plays important roles during apoptosis, proliferation, cell polarity, and migration. Here, we report a novel role of Mst1 for cytotoxic T-cell responses and tumor suppression. The defect of Mst1 caused decreased levels of FoxO, and promoted cytotoxicity in vitro. Mst1(-/-) cytotoxic T cells also exhibited enhanced T-bet expression that was associated with elevated expression levels of IFNγ and granzyme B. Moreover, Mst1(-/-) cytotoxic T cells suppressed tumor growth in vivo. The data suggest that Mst1 inhibits cytotoxicity via T-bet suppression by FoxO1 and FoxO3a. Thus, Mst1 is a potential therapeutic target for tumor immunotherapy.

Short-term outcome and quality of life in kidney transplant recipient with monoclonal gammopathy.

Monoclonal gammopathy of undetermined significance (MGUS) is the common pre-malignant B cell disorders with a general prevalence of 3-5 % at age over 50. Because of the potential malignant transformation and immune insufficiency, pre-transplant MGUS recipient should be carefully followed after allograft transplantation. The post-transplant prognosis and quality of life (QOL) in patient with MGUS have not yet been fully determined. The aim of this study is to evaluate function and pathology of the renal allograft and self-assessment QOL changes during 2 years after transplantation in our case of MGUS-bearing recipient. We here studied the clinical course and QOL improvement before and 20 months after transplant in a 56-year-old woman, who had pre-existing MGUS and underwent living donor kidney transplantation. After the renal allograft transplant, the patients maintained normal GFR and had neither acute rejections nor histologic evidence of renal injuries related to the monoclonal gammopathy on the protocol biopsy of 1 year post-transplant. During further 20 months follow-up, the pre-transplant MGUS remained uneventful without any hematologic abnormalities and other medical complications, i.e., infection. Evaluation of QOL using a self-assessment questionnaire showed significant improvement for physical and mental items on both 6 and 18 months post-transplant. The renal transplant thus successfully provided a greater satisfaction for the recipient on both physical and mental health aspects. Our observations suggest that renal transplantation is beneficial even in those who had pre-existing MGUS if managed and followed carefully, which ultimately could significantly improve the patient QOL.

Hypermethylation of MST1 in IgG4-related autoimmune pancreatitis and rheumatoid arthritis.

The serine/threonine kinase Mst1 plays important roles in the control of immune cell trafficking, proliferation, and differentiation. Previously, we reported that Mst1 was required for thymocyte selection and regulatory T-cell functions, thereby the prevention of autoimmunity in mice. In humans, MST1 null mutations cause T-cell immunodeficiency and hypergammaglobulinemia with autoantibody production. RASSF5C(RAPL) is an activator of MST1 and it is frequently methylated in some tumors. Herein, we investigated methylation of the promoter regions of MST1 and RASSF5C(RAPL) in leukocytes from patients with IgG4-related autoimmune pancreatitis (AIP) and rheumatoid arthritis (RA). Increased number of CpG methylation in the 5' region of MST1 was detected in AIP patients with extrapancreatic lesions, whereas AIP patients without extrapancreatic lesions were similar to controls. In RA patients, we detected a slight increased CpG methylation in MST1, although the overall number of methylation sites was lower than that of AIP patients with extrapancreatic lesions. There were no significant changes of the methylation levels of the CpG islands in the 5' region of RASSF5C(RAPL) in leukocytes from AIP and RA patients. Consistently, we found a significantly down-regulated expression of MST1 in regulatory T cells of AIP patients. Our results suggest that the decreased expression of MST1 in regulatory T cells due to hypermethylation of the promoter contributes to the pathogenesis of IgG4-related AIP.

Mst1 regulates integrin-dependent thymocyte trafficking and antigen recognition in the thymus.

Thymocyte trafficking has an important role in thymic selection. Here we show that the Hippo homologue Mst1 is required for thymocyte migration and antigen recognition by LFA-1 and ICAM-1 within the medulla. Using two-photon imaging of thymic tissues, we found that highly motile mature thymocytes arrest and are activated in the vicinity of rare populations of Aire(+) ICAM-1(hi) medullary thymic epithelia in a negatively selecting environment. Notably, Mst1 deficiency or blocking the cell adhesion molecules LFA-1 and ICAM-1 results in inefficient migration and antigen recognition of CD4(+) thymocytes within the medulla. Consistent with these defects, thymocyte selection is impaired in Mst1(-/-) mice, which display T cell-dependent inflammatory infiltrates in multiple organs and develop autoantibodies. Our results suggest that Mst1 has a key role in regulating thymocyte self-antigen recognition in the medulla.

Deficiency of Rap1-binding protein RAPL causes lymphoproliferative disorders through mislocalization of p27kip1.

RAPL (an alternative spliced form of Rassf5) is a critical Ras-related protein1 (Rap1) effector that regulates lymphocyte adhesion. Here, we have shown that in addition to this previously described function, RAPL also negatively controls lymphocyte proliferation and prevents autoimmunity and lymphoma. RAPL-deficient mice experienced age-related lupus-like glomerulonephritis and developed B cell lymphomas. RAPL-deficient lymphocytes showed hyperproliferation by enhanced S phase entry after antigen receptor ligation. Compared to wild-type cells, RAPL-deficient naive lymphocytes had a 2- to 3-fold increase in Cdk2 kinase activity with a cytoplasmic mislocalization of the cyclin-dependent kinase inhibitor p27(kip1). RAPL was found to suppress the phosphorylation of p27(kip1) on serine 10 (S10) and promoted p27(kip1) nuclear translocation. An S10A mutation in p27(kip1) corrected its cytoplasmic accumulation, reduced hyperproliferation in RAPL-deficient lymphocytes, and suppressed glomerulonephritis and development of B cell lymphoma. Thus, RAPL serves as a checkpoint for S phase entry to prevent lymphoproliferative disorders through the spatial regulation of p27(kip1).