Development of a North American coordinated registry network for surgical treatment of benign prostatic hyperplasia.

PURPOSE: To create a prospective, multicenter coordinated registry network (CRN) of robust "real world" data for benign prostatic hyperplasia (BPH) that links surgical practices to objective and subjective outcomes of patients who undergo surgery for the improvement in lower urinary tract symptoms (LUTS) secondary to BPH. METHODS: We gathered a group of BPH experts from various institutions to identify the minimum core data elements needed to assess BPH procedures. To achieve consensus on the data elements, we used a Delphi method adaptation, in which a series of surveys were answered by the expert panel individually and anonymously. Survey results were collected and analyzed. Questions for the following round were based on response analysis from the prior survey. This process was repeated until consensus was achieved. RESULTS: Participation rates in the first and second rounds were 100% and 90%, respectively. The expert panel reached consensus on 148 data elements out of the 182 proposed, capturing patient medical and surgical history, procedure, discharge, short- and long-term follow-up, device factors, surgery, and surgeon factors. CONCLUSION: We have successfully developed a set of core data elements to support the study of BPH surgical therapies by gathering an expert panel on BPH and using the Delphi method. These data elements influence provider decisions about treatment and include important outcomes related to efficacy and safety.

Overactive Bladder Prescribing Considerations: The Role of Polypharmacy, Anticholinergic Burden, and CYP2D6 Drug‒Drug Interactions.

Overactive bladder (OAB) is a common disorder in the general population, and the prevalence increases with age. Adults with OAB typically have a greater number of comorbid conditions, such as hypertension, depression, and dementia, compared with adults without OAB. Subsequent to an increased number of comorbidities, adults with OAB take a greater number of concomitant medications, which may increase the risk of potentially harmful drug‒drug interactions. There are two important considerations for many of the medications approved for the treatment of OAB in the USA: anticholinergic burden and potential for drug‒drug interactions, notably related to cytochrome P450 (CYP) 2D6, which is responsible for the metabolism of approximately 25% of all drugs. A substantial number of drugs used for the treatment of OAB and comorbid conditions (e.g., cardiovascular and neurologic disorders) are CYP2D6 substrates or inhibitors. Furthermore, a substantial number of drugs with CYP2D6 properties also have strong anticholinergic properties. Here, we review polypharmacy associated with OAB and its common comorbidities, identify drugs with reported anticholinergic properties, and provide an overview of clinically relevant drug‒drug interactions in the treatment of OAB as they relate to CYP2D6 metabolism. This review aims to provide clinicians with essential information necessary for making treatment decisions when managing OAB.

Evaluating the Quality of Overactive Bladder Patient Education Material on YouTube: A Pilot Study Using the Patient Education Materials Assessment Tool.

OBJECTIVES: To assess the characteristics and quality of patient education content for overactive bladder (OAB) on YouTube. METHODS: We searched YouTube on September 10, 2019 and reviewed the top 25 search results for "overactive bladder." For comparison, we reviewed 3 Urology Care Foundation (UCF) OAB education videos on YouTube. Videos were scored using the Agency for Healthcare Research and Quality's Patient Education Materials Assessment Tool (PEMAT) for Audiovisual materials, which is subdivided into understandability and actionability domains, each with a maximum score of 100%. RESULTS: The mean length was 9.5 (0.9-34) minutes and the mean number of views was 151,382 (127-2,032,441). Of the top 25 search results, the mean PEMAT understandability score was 74% ± 16% (range 41%-100%). The mean PEMAT actionability score was 57% ± 39% (range 0%-100%). Seventy-two percent of the reviewed videos featured a physician. In comparison, the 3 UCF videos had an average of 5840 views, 3 minutes length, and PEMAT understandability and actionability scores of 93% and 100%. All UCF OAB videos featured urologists. CONCLUSION: The quality of OAB patient education materials on YouTube varies significantly in understandability and actionability. Although the UCF videos scored much higher on the PEMAT than our reviewed videos, they did not appear within the top 25 search results for OAB. There is great opportunity for the American Urological Association (AUA)/UCF and Society of Urodynamics, Female Pelvic Medicine & Urogenital Reconstruction (SUFU) to increase its outreach to patients on platforms like YouTube.

Increased Time between Scheduling Date and Appointment Date Results in Increased No-Show Rates in the Academic Urology Practice.

INTRODUCTION: No-show appointments can weigh heavily on a urology practice's finances and productivity. Our objective was to investigate if a relationship existed between lag time and no-show appointments at the Columbia University Medical Center department of urology. METHODS: We queried adult new patient appointments from July 2017 to July 2018 and excluded rescheduled or cancelled visits. We organized appointments by subspecialty training/practice of the urologist (general urology, voiding dysfunction/female urology, male sexual dysfunction/infertility, urological oncology, endourology and reconstructive urology). We performed logistic regression analysis to determine the relationship between lag time and no-show rate. We did the same for age and gender. We also organized lag time into 4 categories (less than 3 days, 3 to 7 days, 8 to 14 days, more than 14 days) and performed a goodness of fit test for no-show rates. RESULTS: A total of 6,060 new patient appointments were scheduled from July 2017 to July 2018. The no-show rate was 14.3% (865 patients). Each daily increase in lag time resulted in a 2% rise in the odds of no-shows for the overall practice (OR 1.02). There were similar results for sexual dysfunction (OR 1.03), general urology (OR 1.02), oncology (OR 1.02) and voiding dysfunction (OR 1.01). There was a positive correlation with increasing lag time category and no-show rates for all subspecialties (R2 >0.80) except reconstructive urology (R2=0.68). Each increase in age resulted in a 2% rise in the odds of no-shows (OR 0.98). CONCLUSIONS: Lag time for new patient visits is highly correlated with no-show rates, with a 2% rise in the odds of a no-show with each daily increase in lag time. Increasing age also demonstrated a correlation with no-show rates. Practice interventions to reduce lag time will hopefully reduce no-show rates.

The Prevalence of Bladder Cancer During Cystoscopy for Asymptomatic Microscopic Hematuria.

OBJECTIVE: To investigate the rate of bladder cancer in patients undergoing cystoscopic evaluation for asymptomatic microscopic hematuria (AMH) in order to identify groups at sufficiently low-risk for bladder cancer in whom invasive testing may be avoided. METHODS: We performed a retrospective review of patients who underwent cystoscopic evaluation for AMH between 2010 and 2018. Age, gender, smoking status, history of pelvic radiation, and number of red blood cells per high-power field on urine microscopy were recorded. We used logistic regression to explore the association between specific risk factors and a diagnosis of bladder cancer on cystoscopy. RESULTS: Among the 2118 patients who underwent cystoscopy for AMH, 25 patients (1.2%) were diagnosed with a bladder cancer, all of which were nonmuscle invasive urothelial carcinoma. There were no bladder cancers detected in patients under the age of 50. Older age and positive smoking history were significantly associated with bladder cancer. CONCLUSION: Bladder cancer was an uncommon finding on cystoscopy among patients being evaluated for AMH, especially in younger patients. We confirmed several known risk factors for bladder cancer, including older age and smoking history. Further studies are required to evaluate the utility of cystoscopy for identifying latent bladder cancers in low-risk patients.

Alpha Blocker and 5-Alpha Reductase Inhibitor Prescribing Habits among Urologists and Primary Care Physicians.

INTRODUCTION: While primary care physicians often prescribe medical therapy for voiding symptoms attributed to benign prostate enlargement, it is not clear to what extent they use novel or varied agents. We describe alpha blocker and 5-alpha reductase inhibitor prescribing habits of primary care physicians and compare them with those of urologists. METHODS: Within Medicare Part D we identified providers who prescribed alpha blockers and 5-alpha reductase inhibitors in 2015. We determined the proportions that prescribed 1 versus multiple agents, different types of agents and both types of medications, and compared them between providers. RESULTS: Overall 94% (9,327) of urologists, 50% (54,253) of internal medicine physicians and 61% (60,063) of family medicine physicians prescribed an alpha blocker in 2015. Urologists were more likely to prescribe multiple alpha blockers. However, they were also more likely to predominantly use a single agent. A higher percentage of urologists prescribed newer agents (alfuzosin, silodosin) while a higher percentage of primary care physicians prescribed older agents (terazosin, doxazosin). For 5-alpha reductase inhibitors 87.5% (8,692) of urologists, 32.0% (34,598) of internal medicine physicians and 34.4% (33,720) of family medicine physicians issued prescriptions. Urologists were more likely to prescribe a single 5-alpha reductase inhibitor predominantly and prescribe multiple 5-alpha reductase inhibitors. More primary care physicians prescribed alpha blockers without also prescribing 5-alpha reductase inhibitors. CONCLUSIONS: Most primary care physicians prescribed alpha blockers to Medicare beneficiaries. Urologists were more likely to use diverse as well as newer agents, signaling greater awareness of medical options, although also more complex cases. Urologists were more likely to habitually prescribe single medications. As primary care physicians are involved in the initial treatment of these patients, further education regarding medical options and appropriate indications should be considered.

Utility of catheterized specimens in reducing overdiagnosis of urinary tract infections in women.

AIMS: To evaluate the utility of catheterized samples in reducing overdiagnosis of UTI based on voided specimens among patients presenting with a range of urinary symptoms. We also aimed to determine variables that may modify the predictive value of the voided midstream urine culture. METHODS: Patient charts were reviewed to identify female patients referred to our voiding dysfunction clinic with a range of complaints warranting urine studies (5/2014-8/2016). Patients with a positive voided urine culture who also had a catheterized urine culture in our system were included. Multiple logistic regression analysis was performed to identify patient characteristics associated with a negative catheterized specimen despite a positive voided specimen. RESULTS: One hundred and seven women were included in the study. Eighty percent of the cohort was post-menopausal. Although all patients had positive voided specimens, only 53 (49.5%) had positive catheterized specimens. On multivariate analysis negative nitrites on clean catch UA was a significant predictor of a negative catheterized sample (adjusted OR 8.9, 95%CI 2.2-43.7, P = 0.003). WBC/HPF <10 on clean catch UA trended towards significance (adjusted OR 4.72, 95%CI 1.1-26.1, P = 0.05). CONCLUSIONS: Relying on clean catch urine samples may lead to significant over-diagnosis of UTIs. Our study suggests that in female patients who have vague symptoms of UTI, obtaining catheterized specimens may be beneficial in avoiding the overdiagnosis of UTIs and the overuse of antibiotics. Larger, prospective studies testing our hypothesis are necessary, and would greatly assist in establishing clinical practices that reduce the amount of antibiotics inappropriately prescribed.

Analysis of Transurethral Resection of the Prostate Costs across New York State Hospitals Using Severity of Illness Score.

INTRODUCTION: Using data on surgical treatment for benign prostatic hyperplasia we evaluated the effect of beneficiary health status on hospital reported costs. METHODS: We examined the records of 9,895 patients in the New York State Hospital Inpatient Cost Transparency database who underwent surgical treatment for benign prostatic hyperplasia, including laser prostatectomy and traditional transurethral resection of the prostate, in New York State from 2009 to 2011. RESULTS: Using the 3M™ APR-DRG (All Patient Refined Diagnosis Related Group) severity of illness index as a measure of patient preoperative health we found a significant increase in the cost of transurethral resection of the prostate for patients with higher severity of illness scores. We confirmed an increase in the cost and the cost variability of transurethral resection of the prostate for patients with higher severity of illness scores. CONCLUSIONS: Our findings illustrate the inherent unpredictability of cost forecasting and budgeting for these patients.

Management of urethral stricture in women.

PURPOSE: We describe the diagnosis and treatment of urethral strictures in women. MATERIALS AND METHODS: We retrospectively identified female urethral strictures from 1998 to 2010. Study inclusion criteria were 1) clinical diagnosis of stricture, 2) stricture seen on cystoscopy, 3) urethral obstruction on videourodynamics according to the Blaivas-Groutz nomogram and/or 4) urethral caliber less than 17Fr. Postoperative recurrence was defined by the preoperative criteria. RESULTS: We identified 17 women with a mean age of 62 years (range 32 to 91) with stricture. Stricture was idiopathic in 8 patients, iatrogenic in 6, traumatic in 2 and associated with a urethral diverticulum in 1. Videourodynamics could not be done in 3 women due to complete obliteration of the urethra. Ten of 14 patients satisfied videourodynamic criteria for obstruction and 4 had impaired detrusor contractility. Nine women underwent vaginal flap urethroplasty, including 5 who also had a pubovaginal sling and 1 who had a Martius flap. One patient received a buccal mucosal graft as primary treatment after initial dilation. There was no recurrence at a minimum 1-year followup but 2 strictures recurred 5½ and 6 years postoperatively, respectively. These 2 women received a buccal mucosal graft and were stricture free 12 to 15 months postoperatively. Of 17 patients initially treated with urethral dilation recurrence developed in 16, requiring repeat dilations until urethroplasty was performed. CONCLUSIONS: In select women vaginal flap urethroplasty and buccal mucosal graft have high success rates, including 100% at 1 year and 78% at 5 years. Urethral dilation has a 6% success rate. Long-term followup is mandatory. Treatment should be individualized.

How do urodynamics findings influence the treatment of the typical patient with overactive bladder?

Overactive bladder (OAB) is a clinical symptom complex whose hallmark is the symptom of urinary urgency, usually accompanied by frequency and nocturia, with or without urgency incontinence. Historically, urodynamics (UDS) evaluation has not been recommended in the initial evaluation of OAB, since it is defined primarily by clinical symptoms. As the pathophysiology of the OAB complex has become more clearly elucidated from recent studies, the role of UDS has again become a topic of discussion as a tool that can provide objective data to reflect these new findings. The utility of UDS in the diagnosis and treatment of OAB is still evolving, but in certain clinical scenarios, especially when empiric treatment has failed, it can provide definitive information that can identify associated pathologies and/or alter the treatment course. Herein, we will discuss the current literature regarding use of UDS in OAB patients and offer our own opinions as to its use.

Reliability and validity of the Overactive Bladder Symptom Score in Spanish (OABSS-S).

PURPOSE: To validate the Spanish translation of the Overactive Bladder Symptom Score (OABSS) questionnaire. MATERIALS AND METHODS: The OABSS was translated into Spanish (OABSS-S) and back translated. The OABSS-S was self-administered to subjects, following internal IRB and ISPOR Good Practices guidelines. Spanish speaking patients >18 years of age were recruited from primary care clinics. Content validity was achieved by having the first 25 subjects complete the questionnaire in privacy; afterwards they were interviewed and the clarity of each question was discussed with the patient. All subjects recruited, including the first 25, were divided into two groups by the presence of OAB as determined by a previously validated intake question. Subjects completed the OABSS-S in privacy on two occasions within 10 days. Patients were excluded if their symptoms changed between the first and second administration of the questionnaire. Internal consistency was determined with Cronbach's alpha. Test-retest was determined by Spearman's rho. Discriminant validity was assessed between each group using one-way ANOVA and the Tukey post hoc test. RESULTS: One hundred and seventeen of 128 enrolled subjects completed this study (mean age 55; SD 18). Of 117, 74 (63%) were women 29 with OAB and 45 without OAB. There were 43 men (37%), 18 with OAB and 25 without OAB. A high level of consistency was observed among the seven items answered at visit 1 and 2, with a Cronbach's raw alpha statistic of 0.92. No differences in OABSS-S with age or gender were noted. However, subgroup analysis showed patients in the OAB group were significantly older and post-test analysis showed they had higher scores both for each individual question as well as overall symptom severity scores. Spearman's rank order correlation coefficients showed that there was significant difference between the seven items of the OABSS-S; a strong association (Spearman's rho) was also observed between the total seven-item score at visits 1 and 2 for the total score of all subjects r = 0.84, with OAB: r = 0.81, and without OAB: r = 0.83. Comparison of average total scores obtained for all patients at visits 1 and 2 was not significant (10.47 ± 6.53 vs. 11.02 ± 0.66). Discriminant validity testing revealed that there were significant differences in the responses between all diagnostic groups at visits 1 and 2: with OAB versus without OAB; total versus with OAB; total versus without OAB. CONCLUSION: The Spanish version of the OABSS is valid and reliable and will allow health care providers to easily and quickly assess a Spanish-speaking patient's symptoms.

Can we predict if overactive bladder symptoms will resolve after sling surgery in women with mixed urinary incontinence?

Persistent overactive bladder and urgency urinary incontinence after sling surgery (pubovaginal sling or midurethral sling) in women with mixed urinary incontinence (MUI) is devastating to patients and frustrating to surgeons who perform anti-incontinence surgery. To better predict the outcomes of sling surgery in women with MUI, preoperative parameters need to be examined to accurately predict postsurgical outcomes. In this review article, we will explore recent literature exploring possible preoperative predictors of persistent overactive bladder and urgency urinary incontinence after sling surgery in women with MUI.

KTP/LBO laser vaporization of the prostate.

Laser-based treatments have emerged in the past 15 years as an alternative to transurethral resection of the prostate (TURP) for treatment of symptomatic benign prostatic hyperplasia. Increasing demand for a minimally invasive procedure to alleviate lower urinary tract symptoms with greater efficacy and fewer side effects has led to the introduction of various lasers. The excellent clinical outcomes, low morbidity, technical simplicity, and cost-effectiveness of GreenLight laser photoselective vaporization have made this technology a valid and efficacious clinical alternative to TURP.

The use of sacral neuromodulation for the treatment of non-obstructive urinary retention secondary to Guillain-Barré syndrome.

Guillain-Barré syndrome, an acute autoimmune polyneuropathy and demyelinating disease, is characterized by weakness, sensory loss, areflexia, pain, autonomic dysfunction, and occasionally, micturition disturbances including voiding difficulty, urinary retention, nocturnal urinary frequency, and urge incontinence. Typically, urinary dysfunction resolves simultaneously with other neurologic deficits. We report the case of a 20-year-old woman with Guillain-Barré syndrome and persistent urinary retention 18 months following initial diagnosis. This patient is the first described in the literature to undergo successful treatment with sacral neuromodulation. Immediately following neuromodulator placement, the patient voided spontaneously and has had no voiding dysfunction or postvoid residual after 5 months of follow-up.

Urodynamics: what to do and when is it clinically necessary?

The role of urodynamics in the evaluation and treatment of men with lower urinary tract symptoms is not well defined. Symptoms do not correlate very well with urodynamic findings, but patients with prostatic obstruction fare better after ablative prostatic surgery than those with impaired detrusor contractility. The only proven method for distinguishing between the two is urodynamics, ie, the detrusor pressure/uroflow study. This article reviews urodynamic techniques and the literature pertaining to urodynamics, along with their clinical utility in benign prostatic hyperplasia. The role of urodynamics in clinical practice is discussed as well.

Female sexual dysfunction, voiding symptoms and depression: common findings in partners of men with erectile dysfunction.

The aim of this study was to investigate the prevalence of female sexual dysfunction (FSD), urinary symptoms, and depressive symptoms in female partners of men presenting with erectile dysfunction (ED). A multi-component questionnaire was administered to female partners of men with erectile dysfunction presenting to a urology center. It contained a standardized sexual function component (the Brief Index of Sexual Function for Women), a depression scale (Centers for Epidemiologic Studies-Depression, CES-D), a demographics questionnaire and a general medical questionnaire. A total of 73 consecutive female partners of male patients presenting with ED, were surveyed using the questionnaire at their counterpart's visit. Fifty-two women responded, of whom 50 filled out the questionnaire adequately for proper evaluation. This indicated a response rate of 68% (50/73). The mean age was 44.8 years (range 20.0-83.0). Thirty-eight of the 50 women (76%) reported being sexually active. A variety of sexual behaviors were reported including 40% (20/50) of women engaging in vaginal intercourse. Sexual dysfunction symptoms included: anxiety/inhibition (26%), hypoactive desire (20%), arousal/lubrication difficulty (30%), orgasmic difficulty (24%), dyspareunia (18%), incontinence during intercourse (8%), and sexual dissatisfaction (34%). Eight women (16%) reported difficulty communicating sexual issues with their partners. Forty-one women (82%) rated sexual activity as an important part of their lives. Urinary symptoms of frequency and urgency were reported by 18/50 (36%). Depressive symptoms were present in 22/50 (44%). FSD disorders, urinary symptoms and depressive symptoms are common in partners of men with erectile dysfunction.

Spiral sling salvage anti-incontinence surgery in female patients with a nonfunctional urethra: technique and initial results.

PURPOSE: Female patients with severe urethral incompetence are a unique surgical challenge. Urethral closure and continent diversion are often the next step in the treatment of these patients. We present a technique that provides circumferential coaptation of the urethra as a salvage procedure in this severe subset of patients. MATERIALS AND METHODS: We prospectively evaluated 47 patients who had a spiral sling. A 1 x 15 cm piece of soft polypropylene mesh was prepared with a zero polyglactin suture applied at each end. A clamp was used to pass the mesh between the urethra and pubis. The ends of the mesh were crossed at the ventral aspect of the urethra, creating a complete circle around the urethra. The sutures were transferred to the suprapubic area and tied without tension. The surgical outcome was determined by patient self-assessment, including symptom, bother and quality of life questionnaires. RESULTS: Mean patient age was 59 years. At presentation patients had undergone a mean of 2.6 incontinence procedures and wore a mean of 6 pads daily. Mean daily pad use decreased to 0.9 (p <0.005). Preoperatively mean SUI symptom severity and bother scores were 2.8 and 2.9, respectively, on a scale of 0--none to 3--severe. Postoperatively these values decreased to 0.6 and 0.4, respectively (each p <0.005). There was a mean 87% overall improvement in symptoms. CONCLUSIONS: The spiral sling is an effective salvage transvaginal procedure that may be considered in a small subset of female patients with a nonfunctional urethra as a last resort before urethral closure procedures.

Repair of vaginal vault prolapse and pelvic floor relaxation using polypropylene mesh.

AIMS: The sacrouterine ligament/cardinal (SULC) complex and prerectal fascia attach at the perineal body, forming a single support unit preventing levator descent. Many patients with vault prolapse have levator descent and widening of the hiatus. Existing transvaginal procedures do not address pelvic floor descent. We describe a technique utilizing polypropylene mesh to repair pelvic floor relaxation and prevent levator descent, along with restoration of the SULC complex in vaginal vault repair. MATERIALS AND METHODS: We prospectively evaluated 50 patients who had a transvaginal mesh vault/posterior wall reconstruction. A T-shaped soft prolene mesh is prepared fixing the two arms of the mesh and recreating the SULC complex in support of the cuff. The vertical segment of the mesh is transferred over the prerectal fascia and secured to the pelvic floor musculature. The rectocele is repaired incorporating the mesh distally preventing pelvic floor descent. Surgical outcome was determined by patient self-assessment including quality of life (QoL) measure as well as pelvic examination using POP-Q staging. RESULTS: Mean age was 67 years. Mean follow-up was 6 months (range 3-12). There were no intraoperative complications. There have been two apical (4%) recurrences. Mean QoL score postoperatively on a 0-6 scale was 0.74 (0 = delighted, 1 = pleased). Pelvic floor descent has been repaired on all patients. Postoperative POP-Q reveals restoration of normal anatomy. CONCLUSIONS: We report a new technique that recreates the SULC complex in support of the vaginal vault with the aid of prolene mesh. It is the first transvaginal procedure described to reconstruct the pelvic floor in attempt to prevent pelvic floor descent.

Clinical and pathologic tumor size in renal cell carcinoma; difference, correlation, and analysis of the influencing factors.

OBJECTIVES: To investigate the relation between the clinical and pathologic size and to identify the factors that affect this relationship. The clinical size of the tumor is essential for choosing the appropriate treatment in renal cell carcinoma. The pathologic size, on the other hand, is an important prognostic indicator. METHODS: We reviewed the charts of 291 open nephrectomy patients treated for nonmetastatic renal cell carcinoma. Clinical size was defined as the largest diameter on contrast-enhanced computed tomography. Pathologic size was defined as the largest diameter on pathologic examination. The clinical and pathologic sizes were compared, and their correlation was analyzed. The effect of various clinical and pathologic factors on the percentage of the size difference (%Delta(size)) was analyzed. RESULTS: The mean clinical and pathologic size was 5.4 +/- 3.2 and 5.3 +/- 3.3 cm, respectively. The difference was not significant (P = 0.1679). The clinical and pathologic size also correlated highly (r = 0.9540; P <0.0001). The estimated blood loss, local tumor extension, and cell type had significant influence on the %Delta(size) (P = 0.0018, 0.0415, and 0.0079, respectively). Additionally, in approximately one half of the patients with the greatest size difference, features such as cystic masses, hemorrhage, pyelonephritis, localization near or invasion of the collecting system, cysts or dilated calices adjacent to the tumor, and multiple cysts within the kidney were present, which were identified as factors that might have influenced the accuracy of the clinical size. CONCLUSIONS: The overall accuracy of the clinical size and its correlation with the pathologic size was acceptable. However, the presence of the above-mentioned factors should be taken into consideration during the interpretation of clinical tumor size.