Giant Renal Cell Carcinoma (RCC): A Case Report of Delayed Diagnosis and Management.

Renal cell carcinoma (RCC) is the most common type of kidney cancer. It typically presents with macroscopic hematuria, weight loss, and or a palpable flank mass. Diagnosis of this disease involves imaging techniques such as abdominal ultrasound and CT scans. Care for RCC can consist of ablation, tumor removal, nephrectomy, and systemic treatment options. Herein, we present a case of a 50-year-old Hispanic male with complaints of rectal bleeding and hematuria. Prior to admission, the patient had been informed twice about high suspicion of renal malignancy. Due to low health literacy and barriers to communication, he failed to understand the magnitude of his diagnosis. Subsequently, he underwent a resection of a considerable 22 cm x 13 cm x 13 cm RCC of his left kidney. This case highlights the need for effective patient health education to prevent emotional distress in patients with low health literacy.

CD117⁺ cells in the circulation are predictive of advanced prostate cancer.

Circulating tumor cells (CTCs) are associated with cancer progression, aggressiveness and metastasis. However, the frequency and predictive value of CTCs in patients remains unknown. If circulating cells are involved in tumor aggressiveness and metastasis, then cell levels should decline upon tumor removal in localized cancer patients, but remain high in metastatic patients. Accordingly, proposed biomarkers CD117/c-kit, CD133, CXCR4/CD184, and CD34-positive cell percentages in the blood of patients undergoing radical prostatectomy for localized cancer were assessed by flow cytometry prior to intervention and 1-3 months postoperatively. Only circulating CD117⁺ cell percentages decreased after radical prostatectomy, increased with cancer progression and correlated with high PSA values. Notably, postoperative CD117⁺ levels did not decrease in patients experiencing biochemical recurrence. In a xenograft model, CD117-enriched tumors were more vascularized and aggressive. Thus, CD117 expression on CTCs promotes tumor progression and could be a biomarker for prostate cancer diagnosis, prognosis, and/or response to therapy.

Presurgical sunitinib reduces tumor size and may facilitate partial nephrectomy in patients with renal cell carcinoma.

OBJECTIVE: To determine whether presurgical sunitinib reduces primary renal cell carcinoma (RCC) size and facilitates partial nephrectomy (PN). METHODS: Data from potential candidates for PN treated with sunitinib with primary RCC in situ were reviewed retrospectively. Primary outcome was reduction in tumor bidirectional area. RESULTS: Included were 72 potential candidates for PN who received sunitinib before definitive renal surgery on 78 kidneys. Median primary tumor size was 7.2 cm (interquartile range [IQR]: 5.3-8.7 cm) before and 5.3 cm (IQR: 4.1-7.5 cm) after sunitinib treatment (P<0.0001), resulting in 32% reduction in tumor bidirectional area (IQR: 14%-46%). Downsizing occurred in 65 tumors (83%), with 15 partial responses (19%). Tumor complexity per R.E.N.A.L. score was reduced in 59%, with median posttreatment score of 9 (IQR: 8-10). Predictors of lesser tumor downsizing included clinical evidence of lymph node metastases (P<0.0001), non-clear cell histology (P = 0.0017), and higher nuclear grade (P = 0.023). Surgery was performed for 68 tumors (87%) and was not delayed in any patient owing to sunitinib toxicity. Grade ≥ 3 surgical complications occurred in 5 patients (7%). PN was performed for 49 kidneys (63%) after sunitinib, including 76% of patients without and 41% with metastatic disease (P = 0.0026). PN was completed in 100%, 86%, 65%, and 60% of localized cT1a, cT1b, cT2, and cT3 tumors, respectively. CONCLUSION: Presurgical sunitinib leads to modest tumor reduction in most primary RCC, and many patients can be subsequently treated with PN with acceptable morbidity and preserved renal function. A randomized trial is required to definitively determine whether presurgical therapy enhances feasibility of PN.

Surgical outcomes after cytoreductive nephrectomy with inferior vena cava thrombectomy.

OBJECTIVE: To determine postoperative outcomes in patients with metastatic renal cell carcinoma (mRCC) and level II through IV inferior vena cava (IVC) thrombus (IVCT), and their ability to receive systemic therapy. MATERIALS AND METHODS: We reviewed medical records of all patients with mRCC and level II through IV IVCT who underwent surgery between January 1990 and December 2012 at our institution. Complications within 30 days of surgery were recorded according to the Clavien-Dindo system. Survival was calculated according to the Kaplan-Meier method, and intergroup comparisons were performed with the log-rank statistics. RESULTS: Seventy-six patients were identified, of which 30 (40%), 31 (41%), and 15 (20%) patients had a level II, III, and IV IVCT, respectively. Perioperative mortality was 6.6%. The overall postoperative complication rate was 37%, of which 7.8% (n = 6) were classified as major postoperative complications (Clavien grade 3-5). Follow-up information was available in 60 patients, of whom 90% received a postoperative systemic therapy. Four patients chose expectant management, and 2 patients died of progressive disease before receiving systemic therapy. Overall median survival was 14 months and was significantly related to postoperative treatment with targeted molecular therapies and number of prognostic risk factors, but was not influenced by the level of IVC tumor thrombus. CONCLUSION: Cytoreductive nephrectomy and IVC thrombectomy can be performed with acceptable complication rates and should be considered as an integral part of the treatment approach for patients with mRCC and IVC tumor thrombi.

Optimal definition of biochemical recurrence after radical prostatectomy depends on pathologic risk factors: identifying candidates for early salvage therapy.

BACKGROUND: The use of prostate-specific antigen (PSA) thresholds (<0.2 ng/ml) below currently accepted biochemical recurrence (BCR) definitions for patients treated with radical prostatectomy may be useful in the identification of candidates for early salvage therapy with improved outcome; however, the practice risks overtreatment, as the risk of subsequent PSA progression may be low. OBJECTIVE: To analyze 14 BCR definitions for their association with subsequent PSA and treatment progression among subgroups of patients at varying risk of prostate cancer-specific mortality. DESIGN, SETTING, AND PARTICIPANTS: The subsequent risk of PSA and treatment progression after BCR based on 14 BCR definitions (six standard definitions and eight definitions requiring one or more successive PSA rises ≤0.1 ng/ml) was analyzed according to various clinicopathologic risk criteria among 2348 patients with a detectable PSA ≥0.03 ng/ml at least 6 wk after radical prostatectomy. INTERVENTION: Radical prostatectomy. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Probability of subsequent PSA progression after BCR, defined as a PSA rise >0.1 ng/ml above BCR PSA, initiation of secondary treatment, or clinical progression. RESULTS AND LIMITATIONS: Using standard BCR definitions, the risk of PSA progression was >70%, regardless of clinicopathologic features. A single PSA ≤0.1 ng/ml was associated with PSA progression in only 30-55% of patients but ranged from 18-25% to 73-88% for patients without and with adverse pathologic features, respectively. Based on discrimination and calibration analysis, the optimal BCR definition for patients with 5-yr progression-free probability of <50%, 50-75%, 76-90%, and >90% was a single PSA ≥0.05 ng/ml, two or more rising PSAs ≥0.05 ng/ml, PSA ≥0.2 ng/ml and rising, and PSA ≥0.4 ng/ml and rising. CONCLUSIONS: BCR definitions below currently accepted PSA thresholds appear to be valid for selecting patients with adverse clinicopathologic risk factors for secondary therapy. This information may be useful in selecting for early salvage radiotherapy to improve clinical outcome.

Robot-assisted laparoscopic retroperitoneal lymph node dissection for left clinical stage I non-seminomatous germ cell testicular cancer: focus on port placement and surgical technique.

The aim of our report was to describe the feasibility of robotic retroperitoneal lymph node dissection in the contemporary era. We suggest the linear port location and 90° robotic docking as the main key to minimizing instrument clashing and improving the range of surgical accessibility.

Development of a clinical prediction model for assessment of malignancy risk in Bosniak III renal lesions.

OBJECTIVE: To identify independent predictors of malignancy in Bosniak III (BIII) renal lesions and to build a prediction model based on readily identifiable clinical variables. METHODS: In this institutional review board-approved, Health Insurance Portability and Accountability Act (HIPAA)-compliant retrospective study, radiology, and hospital information systems containing data from January 1, 1994, to August 31, 2009, were queried for adult patients (age >18 years) with surgically excised BIII lesions. Clinical variables and results of histopathology were noted. Univariate and multiple-variable logistic regression analyses were performed to identify potential predictors and to build a prediction model. Cross-validation was used to assess generalizability of the model's performance, as characterized by concordance (c) index. RESULTS: Of the 107 lesions in 101 patients, 59 were malignant and 48 benign. On univariate analyses, the strongest potential predictors of malignancy were African American race (P = .043), history of renal cell carcinoma (RCC; P = .026), coexisting BIII lesions (P = .032), coexisting Bosniak IV (BIV) lesions (P = .104), body mass index (BMI; P = .078), and lesion size (P <.001). A model with lesion size (odds ratio [OR] = 0.69; 95% confidence interval [CI] 0.58-0.82), history of RCC (9.02; CI 0.99-82.15), and BMI (OR 1.1; 95% CI 0.99-1.19) offered the best performance with a c-index after cross-validation of 0.719. Using an estimated probability of malignancy of >80%, the positive predictive value of the model is 92% (CI 78%-100%). CONCLUSION: Clinical risk factors offer modest but definite predictive ability for malignancy in BIII lesions. In particular, a prediction model encompassing lesion size, BMI, and history of RCC seems promising. Further refinements with possible inclusion of imaging biomarkers and validation on an independent dataset are desirable.

Intratumoral inflammation is associated with more aggressive prostate cancer.

PURPOSE: Inflammation may play a role in the development and progression of many cancers, including prostate cancer. We sought to test whether histological inflammation within prostate cancer was associated with more aggressive disease. METHODS: The slides of prostatectomy specimens were reviewed by a board-certified pathologist on 287 men from a Veterans Affairs Medical Center treated with radical prostatectomy from 1992 to 2004. The area with the greatest tumor burden was scored in a blinded manner for the degree of inflammation: absent, mild, or marked. We used logistic and Cox proportional hazards regression analysis to examine whether categorically coded inflammation score was associated with adverse pathology and biochemical progression, respectively. RESULTS: No inflammation was found in 49 men (17%), while 153 (53%) and 85 (30%) had mild and marked inflammation. During a median follow-up of 77 months, biochemical recurrence occurred among 126 (44%) men. On multivariate analysis, more inflammation was associated with greater risk of positive margins, capsular penetration, and seminal vesicle invasion (all p < 0.05). Marked inflammation was associated with increased PSA recurrence risk when adjusting for preoperative features only (HR 2.08, 95% CI 1.02-4.24), but not after adjusting for pathologic features. CONCLUSIONS: Inflammation within prostate cancer was associated with more advanced disease, although it is unclear whether aggressive disease caused increased inflammation or inflammation caused aggressive disease.

Robot-assisted partial nephrectomy for hilar tumors: perioperative outcomes.

OBJECTIVE: To compare perioperative outcomes of robot-assisted partial nephrectomy (RAPN) for hilar vs nonhilar tumors. MATERIALS AND METHODS: The study retrospectively reviewed 364 patients with available computed tomography scans undergoing RAPN. Demographic data and perioperative outcomes results were compared between the hilar (group 1, n = 70) and nonhilar tumors (group 2, n = 294). Multivariate analysis was used to identify predictors of warm ischemia time (WIT), estimated blood loss (EBL), major perioperative complications, and postoperative renal function. RESULTS: There were no differences with respect to demographic variables. Hilar tumors had higher RENAL (radius, exophytic/endophytic properties of the tumor, nearness of tumor deepest portion to the collecting system or sinus, anterior/posterior descriptor and the location relative to polar lines) scores (P <.001) and were larger (3.9 vs 2.6 cm, P <.001). Surgeries for hilar tumors were associated with greater operative time (210 vs 180 minutes, P <.001), longer WIT (27 vs 17 minutes, P <.001), and increased EBL (250 vs 200 mL, P = .04). No differences were noted in transfusion rate, length of stay, complications (overall and major) and positive margins. Postoperative estimated glomerular filtration rate showed no significant difference between hilar vs nonhilar patients on postoperative day 3 (70.12 vs 74.71 mL/min/1.73 m(2), P = .31) or at last follow-up (72.62 vs 75.78 mL/min/1.73 m(2), P = .40), respectively. Multivariate analysis found hilar location was independently associated with increased WIT without significant changes in EBL, major complications, or postoperative renal function. CONCLUSION: RAPN represents a safe and effective procedure for hilar tumors. Hilar location for patients undergoing RAPN in a high-volume institution seems not be associated with an increased risk of transfusions, major complications, or decline of early postoperative renal function.

Resveratrol worsens survival in SCID mice with prostate cancer xenografts in a cell-line specific manner, through paradoxical effects on oncogenic pathways.

BACKGROUND: Resveratrol increases lifespan and decreases the risk of many cancers. We hypothesized resveratrol will slow the growth of human prostate cancer xenografts. METHODS: SCID mice were fed Western diet (40% fat, 44% carbohydrate, 16% protein by kcal). One week later, human prostate cancer cells, either LAPC-4 (151 mice) or LNCaP (94 mice) were injected subcutaneously. Three weeks after injection, LAPC-4 mice were randomized to Western diet (control group), Western diet plus resveratrol 50 mg/kg/day, or Western diet plus resveratrol 100 mg/kg/day. The LNCaP mice were randomized to Western diet or Western diet plus resveratrol 50 mg/kg/day. Mice were sacrificed when tumors reached 1,000 mm(3). Survival differences among groups were assessed using Cox proportional hazards. Serum insulin and IGF axis were assessed using ELISAs. Gene expression was analyzed using Affymetrix gene arrays. RESULTS: Compared to control in the LAPC-4 study, resveratrol was associated with decreased survival (50 mg/kg/day--HR 1.53, P = 0.04; 100 mg/kg/day--HR 1.22, P = 0.32). In the LNCaP study, resveratrol did not change survival (HR 0.77, P = 0.22). In combined analysis of both resveratrol 50 mg/kg/day groups, IGF-1 was decreased (P = 0.05) and IGFBP-2 was increased (P = 0.01). Resveratrol induced different patterns of gene expression changes in each xenograft model, with upregulation of oncogenic pathways E2F3 and beta-catenin in LAPC-4 tumors. CONCLUSION: Resveratrol was associated with significantly worse survival with LAPC-4 tumors, but unchanged survival with LNCaP. Based on these preliminary data that resveratrol may be harmful, caution should be advised in using resveratrol for patients until further studies can be conducted.

Comparative outcomes of laparoscopic and open adrenalectomy for adrenocortical carcinoma: single, high-volume center experience.

PURPOSE: Adrenocortical carcinoma (ACC) is a rare and clinically aggressive cancer. Previous studies reported increased recurrence rates associated with laparoscopic adrenalectomy (LA). We evaluated a single-center experience of LA versus open adrenalectomy (OA) for the management of ACC. METHODS: Between 1993 and 2011, 44 consecutive patients with primary ACC were treated at our institution. Baseline patient characteristics and surgical and pathological outcomes were compared between OA and LA groups. Multivariable Cox proportional hazards analysis was used to estimate the association between OA versus LA with recurrence-free and overall survival. RESULTS: Eighteen and 26 patients underwent LA and OA, respectively. Patients who underwent OA had larger tumors and more advanced clinical stage compared with LA group. During a median follow-up of 22 months, 22 recurrences and 26 deaths were observed. The 2-year, recurrence-free and overall survivals for OA and LA were 60 vs. 39 % (P = 0.7) and 54 vs. 58 % (P = 0.6), respectively. After adjusting for clinical stage, OA was associated with lower risk of recurrence (hazard ratio (HR) 0.4; 95 % confidence interval (CI) 0.2-1.2; P = 0.099) and improved overall survival (HR 0.5; 95 % CI 0.2-1.2; P = 0.122) compared with LA, although differences were not statistically significant. CONCLUSIONS: A nonstatistically significant increase in recurrence and death was observed among patients undergoing LA versus OA after adjusting for clinical stage. The rarity of this disease limits the ability to assess for significant differences in a single-institution series. Patients with suspected ACC should be considered for OA.

Robotic partial nephrectomy for small renal masses in patients with pre-existing chronic kidney disease.

OBJECTIVE: To assess the outcomes of robotic partial nephrectomy in patients with pre-existing chronic kidney disease (CKD). MATERIALS AND METHODS: Patients who underwent robotic partial nephrectomy for renal tumors between 2007 and 2011 were identified from our prospectively maintained institutional database. Perioperative as well as short-term oncological and functional outcomes were assessed. A comparative analysis was performed between patients with pre-existing CKD (estimated glomerular filtration rate [eGFR] 15-60 mL/min, group 1, n = 52) and patients with eGFR >60 mL/min (group 2, n = 303). RESULTS: Group 1 patients were older (median 68 vs 57 years, P < .001), with higher American Society of Anesthesiology (ASA) score (3 vs 2, P < .001) and a higher Charlson comorbidity index (7 vs 4, P < .001). Warm ischemia time (WIT) was similar in both groups (18 vs 18 minutes, P = .52). Group 1 had a higher postoperative complication rate (40.4% vs 21.1%, P = .003). Pathologic and oncological data were similar. After a median follow-up of 3 months (interquartile: 1-10), deterioration of eGFR was lower in group 1 patients (-5% vs -12%, P = .004). No endstage renal disease was noted in either group. There was significantly less CKD upstaging in group 1 than in group 2 (11.5% vs 33.9%, P = .001). After multivariate analysis, preoperative eGFR and WIT were independent predictors of latest eGFR. Less than 15% of patients with normal baseline renal function developed CKD stage III or higher. CONCLUSION: Despite a high risk of surgical complications, robotic partial nephrectomy only marginally affects renal function in patients with pre-existing CKD.

High-grade prostatic intraepithelial neoplasia.

High-grade prostatic intraepithelial neoplasia (HGPIN) has been established as a precursor to prostatic adenocarcinoma. HGPIN shares many morphological, genetic, and molecular signatures with prostate cancer. Its predictive value for the development of future adenocarcinoma during the prostate-specific antigen screening era has decreased, mostly owing to the increase in prostate biopsy cores. Nevertheless, a literature review supports that large-volume HGPIN and multiple cores of involvement at the initial biopsy should prompt a repeat biopsy of the prostate within 1 year. No treatment is recommended for HGPIN to slow its progression to cancer.

Association between statins and prostate tumor inflammatory infiltrate in men undergoing radical prostatectomy.

BACKGROUND: Cholesterol-lowering drugs known as statins have been reported to have significant anti-inflammatory properties. Given that inflammation may contribute to prostate cancer progression and that statins may reduce the risk for advanced prostate cancer, we investigated whether statin use was associated with reduced intratumoral inflammation in radical prostatectomy (RP) specimens. METHODS: Inflammation within index tumors of 236 men undergoing RP from 1996 to 2004 was graded by a single pathologist as grade 0 (absent), 1 (mild: < or =10%), and 2 (marked: >10%). Preoperative statin use was analyzed by grouping subjects as statin users or nonusers. Type and dosage of statin was accounted for using dose equivalents with 20 mg simvastatin as reference. Logistic regression was used to determine the association between statin use and intratumoral inflammation controlling for age, race, body mass index, prostate-specific antigen, year of surgery, clinical stage, pathologic Gleason sum, surgical margin status, extracapsular extension, seminal vesicle invasion, prostate weight, time from prostate biopsy to RP, and nonsteroidal anti-inflammatory drug use. RESULTS: Preoperative statin use was significantly associated with lower risk for any (grade > or =1) intratumoral inflammation (odds ratio, 0.31; 95% confidence interval, 0.10-0.98; P = 0.047) on multivariable analysis, with doses > or =20 mg simvastatin equivalents being more strongly associated (relative to nonuse; odds ratio, 0.22; 95% confidence interval, 0.06-0.79; P = 0.02). CONCLUSION: In a cohort of men undergoing RP, statin use was associated with significantly lower risk of any inflammation within prostate tumors. IMPACT: Given previous reports that inflammation is associated with advanced prostate cancer, and statin use is associated with decreased prostate cancer progression risk, our findings suggest that inhibition of inflammation within tumors may be a potential mechanism for purported anti-prostate cancer properties of statins.

Effect of intermittent fasting with or without caloric restriction on prostate cancer growth and survival in SCID mice.

INTRODUCTION: Caloric restriction (CR) delays cancer growth in animals, though translation to humans is difficult. We hypothesized intermittent fasting (i.e., intermittent extreme CR), may be better tolerated and prolong survival of prostate cancer (CaP) bearing mice. METHODS: We conducted a pilot study by injecting 105 male individually-housed SCID mice with LAPC-4 cells. When tumors reached 200 mm(3), 15 mice/group were randomized to one of seven diets and sacrificed when tumors reached 1,500 mm(3): Group 1: ad libitum 7 days/week; Group 2: fasted 1 day/week and ad libitum 6 days/week; Group 3: fasted 1 day/week and fed 6 days/week via paired feeding to maintain isocaloric conditions to Group 1; Group 4: 14% CR 7 days/week; Group 5: fasted 2 days/week and ad libitum 5 days/week; Group 6: fasted 2 day/week and fed 5 days/week via paired feeding to maintain isocaloric conditions to Group 1; Group 7: 28% CR 7 days/week. Sera from mice at sacrifice were analyzed for IGF-axis hormones. RESULTS: There were no significant differences in survival among any groups. However, relative to Group 1, there were non-significant trends for improved survival for Groups 3 (HR 0.65, P = 0.26), 5 (0.60, P = 0.18), 6 (HR 0.59, P = 0.16), and 7 (P = 0.59, P = 0.17). Relative to Group 1, body weights and IGF-1 levels were significantly lower in Groups 6 and 7. CONCLUSIONS: This exploratory study found non-significant trends toward improved survival with some intermittent fasting regimens, in the absence of weight loss. Larger appropriately powered studies to detect modest, but clinically important differences are necessary to confirm these findings.

Levels of evidence ratings in the urological literature: an assessment of interobserver agreement.

OBJECTIVE: To determine to what extent urologists with no specific training agree upon level of evidence (LoE) ratings of studies published in the urological literature, as LoE are commonly referenced as a measure of evidence quality. MATERIALS AND METHODS: In all, 86 clinical research studies published in four major urology journals were reviewed. Each article was independently reviewed by eight reviewers using a standardized data abstraction form. Articles were assessed for type of study (therapy, prognosis, diagnosis or economic) and LoE (I, II, III or IV). Reviewers received only written instructions and no formal training in the application of this classification system. RESULTS: Of the 86 articles, 69% related to therapy, 16% to prognosis, and 15% to diagnosis. Eight studies (9%) provided Level I evidence, 18 studies (21%) Level II, 14 studies (16%) Level III and 46 studies (54%) Level IV evidence. The intraclass correlation coefficient (95% confidence interval) based on all reviewers (eight reviewers) was 0.67 (0.59-0.74; P= 0.001) for the type of study and 0.55 (0.48-0.64; P= 0.001) for the LoE. In an analysis limited to a subset of studies in which all reviewers agreed upon the type of study question (n= 40) the intraclass correlation coefficient was 0.79 (0.70-0.86; P= 0.001). CONCLUSION: In the present study there was a low interobserver agreement for LoE ratings by urologists with no specific training. These findings suggest caution in the interpretation of LoE ratings and emphasize the importance of specific training for individuals that are charged with quality of evidence determinations.

Primary carcinoid tumor in an ileal conduit.

Carcinoid tumors are neuroendocrine tumors that typically arise in the gastrointestinal tract. We present the case of a 74-year-old woman with a primary carcinoid tumor in an ileal conduit urinary diversion who presented with gross hematuria. We also provide a brief review of relevant reports. The patient subsequently underwent resection and replacement of her ileal conduit.

Smooth muscle-specific expression of SV40 large TAg induces SMC proliferation causing adaptive arterial remodeling.

To study the effects of enhanced smooth muscle cell (SMC) proliferation on arterial vessel geometry in the absence of vessel trauma, we developed a transgenic mouse model expressing SV40 large T antigen under control of the 2.3-kb smooth muscle-myosin heavy chain promoter. Transgenic mice studied at ages from 3 to 13 wk showed a 3.2-fold increase in arterial wall SMC density, with 28% of SMC exhibiting proliferative cell nuclear antigen staining, confirming enhanced SMC proliferation, which was accompanied by two- to threefold increases in arterial wall areas (P < 0.05). Remarkably, despite increased vessel wall mass, the lumen area was not compromised, but rather was increased. A tightly conserved linear relationship was found between arterial circumference and wall thickness with slopes of 0.036 for both transgenics (r = 0.93, P < 0.01) and controls (r = 0.77, P < 0.01), suggesting the hypothesis that the conservation of wall stress functions as a primary determinant of adaptive arterial remodeling. This establishes a new model of adaptive vessel remodeling occurring in response to a proliferative input in the absence of mechanical injury or primary flow perturbation.