GPNMB promotes tumor growth and is a biomarker for lymphangioleiomyomatosis.

Lymphangioleiomyomatosis (LAM) is a rare, progressive cystic lung disease affecting almost exclusively female-sexed individuals. The cysts represent regions of lung destruction caused by smooth muscle tumors containing mutations in one of the two tuberous sclerosis (TSC) genes. mTORC1 inhibition slows but does not stop LAM advancement. Furthermore, monitoring disease progression is hindered by insufficient biomarkers. Therefore, new treatment options and biomarkers are needed. LAM cells express melanocytic markers, including glycoprotein non-metastatic melanoma protein B (GPNMB). The function of GPNMB in LAM is currently unknown; however, GPNMB's unique cell surface expression on tumor versus benign cells makes GPNMB a potential therapeutic target, and persistent release of its extracellular ectodomain suggests potential as a serum biomarker. Here we establish that GPNMB expression is dependent on mTORC1 signaling, and that GPNMB regulates TSC2-null tumor cell invasion in-vitro. Further, we demonstrate that GPNMB enhances TSC2-null xenograft tumor growth in-vivo, and that ectodomain release is required for this xenograft growth. We also show that GPNMB's ectodomain is released from the cell surface of TSC2-null cells by proteases ADAM10 and 17, and we identify the protease target sequence on GPNMB. Finally, we demonstrate that GPNMB's ectodomain is present at higher levels in LAM patient serum compared to healthy controls, and that ectodomain levels decrease with mTORC1 inhibition, making it a potential LAM biomarker.

Prevalence and Predictors of Barrett's Esophagus After Negative Initial Endoscopy: Analysis From Two National Databases.

BACKGROUND & AIMS: Guidelines suggest a single screening esophagogastroduodenoscopy (EGD) in patients with multiple risk factors for Barrett's esophagus (BE). We aimed to determine BE prevalence and predictors on repeat EGD after a negative initial EGD, using 2 large national databases (GI Quality Improvement Consortium [GIQuIC] and TriNetX). METHODS: Patients who underwent at least 2 EGDs were included and those with BE or esophageal adenocarcinoma detected at initial EGD were excluded. Patient demographics and prevalence of BE on repeat EGD were collected. Multivariate logistic regression was performed to assess for independent risk factors for BE detected on the repeat EGD. RESULTS: In 214,318 and 153,445 patients undergoing at least 2 EGDs over a median follow-up of 28-35 months, the prevalence of BE on repeat EGD was 1.7% in GIQuIC and 3.4% in TriNetX, respectively (26%-45% of baseline BE prevalence). Most (89%) patients had nondysplastic BE. The prevalence of BE remained stable over time (from 1 to >5 years from negative initial EGD) but increased with increasing number of risk factors. BE prevalence in a high-risk population (gastroesophageal reflux disease plus ≥1 risk factor for BE) was 3%-4%. CONCLUSIONS: In this study of >350,000 patients, rates of BE on repeat EGD ranged from 1.7%-3.4%, and were higher in those with multiple risk factors. Most were likely missed at initial evaluation, underscoring the importance of a high-quality initial endoscopic examination. Although routine repeat endoscopic BE screening after a negative initial examination is not recommended, repeat screening may be considered in carefully selected patients with gastroesophageal reflux disease and ≥2 risk factors for BE, potentially using nonendoscopic tools.

Population Based Time Trends in the Epidemiology and Mortality of Gastroesophageal Junction and Esophageal Adenocarcinoma.

BACKGROUND: Limited data are available on the epidemiology of gastroesophageal junction adenocarcinoma (GEJAC), particularly in comparison to esophageal adenocarcinoma (EAC). With the advent of molecular non-endoscopic Barrett's esophagus (BE) detection tests which sample the esophagus and gastroesophageal junction, early detection of EAC and GEJAC has become a possibility and their epidemiology has gained importance. AIMS: We sought to evaluate time trends in the epidemiology and survival of patients with EAC and GEJAC in a population-based cohort. METHODS: EAC and GEJAC patients from 1976 to 2019 were identified using ICD 9 and 10 diagnostic codes from the Rochester Epidemiology Project (REP). Clinical data and survival status were abstracted. Poisson regression was used to calculate incidence rate ratios (IRR). Survival analysis and Cox proportional models were used to assess predictors of survival. RESULTS: We included 443 patients (287 EAC,156 GEJAC). The incidence of EAC and GEJAC during 1976-2019 was 1.40 (CI 1.1-1.74) and 0.83 (CI 0.61-1.11) per 100,000 people, respectively. There was an increase in the incidence of EAC (IRR = 2.45, p = 0.011) and GEJAC (IRR = 3.17, p = 0.08) from 2000 to 2004 compared to 1995-1999, plateauing in later time periods. Most patients had associated BE and presented at advanced stages, leading to high 5-year mortality rates (66% in EAC and 59% in GEJAC). Age and stage at diagnosis were predictors of mortality. CONCLUSION: The rising incidence of EAC/GEJAC appears to have plateaued somewhat in the last decade. However, both cancers present at advanced stages with persistently poor survival, underscoring the need for early detection.

Lymphangioleiomyomatosis: where endocrinology, immunology and tumor biology meet.

Abstract: Lymphangioleiomyomatosis (LAM) is a cystic lung disease found almost exclusively in genetic females and caused by small clusters of smooth muscle cell tumors containing mutations in one of the two tuberous sclerosis genes (TSC1 or TSC2). Significant advances over the past 2-3 decades have allowed researchers and clinicians to more clearly understand the pathophysiology of LAM, and therefore better diagnose and treat patients with this disease. Despite substantial progress, only one proven treatment for LAM is used in practice: mechanistic target of rapamycin complex 1 (mTORC1) inhibition with medications such as sirolimus. While mTORC1 inhibition effectively slows LAM progression in many patients, it is not curative, is not effective in all patients, and can be associated with significant side effects. Furthermore, the presence of established and accurate biomarkers to follow LAM progression is limited. That said, discovering additional diagnostic and treatment options for LAM is paramount. This review will describe recent advances in LAM research, centering on the origin and nature of the LAM cell, the role of estrogen in LAM progression, the significance of melanocytic marker expression in LAM cells, and the potential roles of the microenvironment in promoting LAM tumor growth. By appreciating these processes in more detail, researchers and caregivers may be afforded novel approaches to aid in the treatment of patients with LAM.

Estradiol Augments Tumor-Induced Neutrophil Production to Promote Tumor Cell Actions in Lymphangioleiomyomatosis Models.

Lymphangioleiomyomatosis (LAM) is a rare cystic lung disease caused by smooth muscle cell-like tumors containing tuberous sclerosis (TSC) gene mutations and found almost exclusively in females. Patient studies suggest LAM progression is estrogen dependent, an observation supported by in vivo mouse models. However, in vitro data using TSC-null cell lines demonstrate modest estradiol (E2) responses, suggesting E2 effects in vivo may involve pathways independent of direct tumor stimulation. We previously reported tumor-dependent neutrophil expansion and promotion of TSC2-null tumor growth in an E2-sensitive LAM mouse model. We therefore hypothesized that E2 stimulates tumor growth in part by promoting neutrophil production. Here we report that E2-enhanced lung colonization of TSC2-null cells is indeed dependent on neutrophils. We demonstrate that E2 induces granulopoiesis via estrogen receptor α in male and female bone marrow cultures. With our novel TSC2-null mouse myometrial cell line, we show that factors released from these cells drive E2-sensitive neutrophil production. Last, we analyzed single-cell RNA sequencing data from LAM patients and demonstrate the presence of tumor-activated neutrophils. Our data suggest a powerful positive feedback loop whereby E2 and tumor factors induce neutrophil expansion, which in turn intensifies tumor growth and production of neutrophil-stimulating factors, resulting in continued TSC2-null tumor growth.

Neutrophil elastase from myeloid cells promotes TSC2-null tumor growth.

Chronic inflammation promotes progression of many cancers, with circulating myeloid-derived suppressor cell (MDSC) levels correlating with poor prognosis. Here we examine effects of MDSCs on lymphangioleiomyomatosis (LAM), a rare disease occurring almost exclusively in women whereby estrogen-sensitive metastatic TSC2-null tumors grow throughout the lungs, markedly reducing pulmonary function. The LAM cell origin remains unknown; however, previous work demonstrated that Tsc2 inactivation in the mouse uterus induced estrogen-dependent myometrial tumors with nearly all features of LAM. Half of these animals developed metastatic myometrial tumors in the lungs, suggesting that LAM cells might originate from the myometrium, possibly explaining its overwhelming female prevalence and estrogen-sensitivity. Here we report that MDSC levels, and in particular granulocytic myeloid cell levels, are elevated in the periphery and in tumors of uterine-specific Tsc2-null mice. Importantly, MDSC depletion or inhibition of their recruitment impairs myometrial tumor growth. RNA and protein analysis of Tsc2-null myometrial tumors and xenografts demonstrate high expression and activity of the serine protease neutrophil elastase (NE), with selective qPCR studies indicating a stromal origin of the NE. Notably, treatment with sivelestat, a known NE inhibitor already approved for human use in some countries, reduces tumor growth similar to MDSC depletion. Furthermore, NE promotes Tsc2-null tumor cell growth, migration, and invasion in vitro. Finally, NE-expressing myeloid cells are present throughout the lungs of LAM patients but not controls. These data suggest that NE derived from granulocytic myeloid cells might directly promote LAM tumor cell progression and could be a novel therapeutic target for LAM.

Acute bowel morbidity after prostate brachytherapy with cesium-131.

PURPOSE: The present study evaluates the severity and time to resolution of bowel symptoms in men undergoing prostate brachytherapy (PB) with cesium-131 ((131)Cs). METHODS AND MATERIALS: A longitudinal, prospective study of patients who had undergone PB with (131)Cs at a single institution was performed. All patients were asked to complete the Expanded Prostate Cancer Index Composite preoperatively and at 2 weeks and 1, 3, and 6 months postoperatively. Outcomes were analyzed using descriptive statistics and Student's t test. RESULTS: The first 142 patients to have undergone PB with (131)Cs at our institution were included in the study. The mean Expanded Prostate Cancer Index Composite bowel summary score at baseline was 90.1±11.0 compared with 71.5±22.8 (p=0.000), 70.1±20.7, 87.1±13.8 (p=0.01), and 90.7±9.2 (p=0.70) at 2 weeks and 1, 3, and 6 months postoperatively, respectively. CONCLUSIONS: In men undergoing PB as monotherapy with (131)Cs, bowel symptoms returned to baseline by 3 months after the procedure. For patients undergoing PB with (131)Cs as part of combination therapy, bowel symptoms return to their post-external beam radiotherapy, pre-PB baseline by 3 months after the procedure.

Resection of a staggering 36-cm angiomyolipoma.

Angiomyolipomas (AMLs) are benign tumours characterized by fat, smooth muscle and vascular components. Epithelioid AML is a recognized variant of AML that is comprised of epithelioid smooth muscle cells. We present a case of a 41-year-old male who presented with light-headedness, dizziness, right-sided abdominal pain and, on subsequent computed tomography, was found to have an enormous right kidney mass characteristic of an AML. The patient underwent preoperative selective arterial embolization followed by a right radical nephrectomy. The pathology revealed a 36-cm AML with focal epithelioid features. Although uncommon, AMLs can present as enormous retroperitoneal masses.

Partial nephrectomy without hilar control or cooling: longitudinal data over 5 years.

INTRODUCTION: Partial nephrectomy for the management of small renal masses has become a well accepted technique. Contemporary series have shown its safety and efficacy in well selected patients. We present our experience of partial nephrectomies exclusively without hilar control or parenchymal cooling stratified into imperative and elective patients. METHODS: We retrospectively reviewed our experience in 124 patients who underwent partial nephrectomy between December 1995 and September 2003. Patients were followed with regular radiographic and laboratory studies at 6 months postsurgery and then annually. Renal function was followed by serum creatinine. RESULTS: Of the 124 patients, 105 were performed without hilar control or renal cooling and met our criteria for analysis. The operation was elective in 78 patients (74%) and imperative in 27 patients (26%). Mean specimen size was 2.8 cm for elective cases and 3.3 cm for imperative cases. The mean estimated blood loss was 606 533 cc and 950 656 cc in elective and imperative cases respectively. Surgical margins were positive in 6.6% with an overall recurrence rate of 3.8%. At a mean follow up time of 31 months and 23 months in the elective and imperative groups respectively, there were no statistically significant differences between baseline and follow up serum creatinine levels in either elective or imperative cases at time intervals of 0-12, 13-24, 25-48 and > 48 months. The intraoperative complication rate was 5.7% and the postoperative complication rate was 4.7% including three patients requiring blood transfusions. CONCLUSION: Partial nephrectomy without hilar control or renal cooling is a safe and reliable method of removing small renal tumors. In this cohort, intraoperative blood loss is slightly higher than historical series. However, blood transfusion rates, complications, renal function and oncologic outcomes are comparable to historical series of patients in whom vascular control and renal cooling are used.

Dosimetric outcomes in prostate brachytherapy: is downsizing the prostate with androgen deprivation necessary?

OBJECTIVES: A large prostate volume has historically been a relative contraindication to prostate brachytherapy (PB) because of concerns of toxicity and potential pubic arch interference. Common practice has been to downsize large prostates with androgen deprivation therapy (ADT) before proceeding with brachytherapy. The present study compares postimplant dosimetry in patients with prostate volumes >50 cc with those with prostate volumes 50 cc (mean 58.1 cc, range 50.2-86.0 cc); the mean D(90), V(100), V(150), and V(200) was 125.1%, 95.2%, 68.2%, and 41.7%, respectively. The rectal V(100) was 1.0 cc for both cohorts. There was no statistically significant difference between the cohorts with respect to postimplant dosimetry for D(90), V(100), and V(150). The V(200) for prostate volumes >50 cc was significantly lower (p<0.05). CONCLUSIONS: In the present study, patients with prostate volumes >50 cc have postimplant dosimetry parameters similar to patients with prostate volumes

Management of bilateral synchronous renal cell carcinoma in a single versus staged procedure.

OBJECTIVES: The presentation of synchronous bilateral renal lesions is rare. We report our experience with the surgical management of these lesions in both a single and staged procedure. METHODS: We retrospectively reviewed the records of all patients with bilateral synchronous renal lesions who underwent surgical management by one surgeon between 2000-2007. We compared characteristics including pre and postoperative renal function, complication rates, and oncological outcomes between the single and staged cohorts. Data were analyzed using descriptive statistics, Student's t-test, and Fisher's exact test. RESULTS: A total of 26 patients (73% male, mean age 65.5 +/- 12.2 years) with bilateral synchronous lesions were identified with a mean follow-up of 25.9 +/- 19.7 months. Of these, 18 (69%) were performed as a single procedure, 5 (19%) were done as a staged procedure, and 3 (12%) had only the first part of the staged procedure performed. The single and staged cohorts were comparable in regards to preoperative creatinine (Cr) (1.1 +/- 0.4 mg/dl versus 1.1 +/- 0.2 mg/dl, p = 0.70), postoperative Cr (1.5 +/- 1.0 mg/dl versus 1.4 +/- 0.5 mg/dl, p = 0.73), and median hospital length of stay (HLOS) (5 days versus 4 days). The complication rate was 22% and 20% for the single and staged cohorts, respectively. One patient had a local recurrence and one patient developed metastatic disease in the single cohort versus no local recurrence or metastatic disease in the staged cohort. CONCLUSION: In the appropriate setting, surgical management of synchronous bilateral renal lesions can be done safely in a single procedure with comparable outcomes to those done in a staged manner.

Overcoming pubic arch interference with free-hand needle placement in men undergoing prostate brachytherapy.

PURPOSE: The present study evaluates the postimplant dosimetry when free-hand needles were placed to overcome interference from the pubic arch. METHODS AND MATERIALS: A review of all patients who underwent prostate brachytherapy at our institution from 2001 to 2006 was performed. Postimplant dosimetry in men requiring free-hand needle placement was compared with postimplant dosimetry in men not requiring free-hand needle placement. RESULTS: Of the 145 patients who underwent prostate brachytherapy, 8 patients required free-hand needle placement. The mean prostate volume in the free-hand needle cohort was 46.0cc with a mean of 3.4 free-hand needles placed. In the 137 patients not requiring free-hand needle placement, the mean volume was 39.7cc. The mean D(90), V(100), V(150), and rectal V(100) for the free-hand cohort was 129.5%, 96.3%, 81.6%, and 1.45cc, respectively. The mean D(90), V(100), V(150), and rectal V(100) in men not requiring free-hand needle placement was 126.8%, 97.1%, 78.7%, and 1.03cc, respectively. CONCLUSION: The present study finds that adequate postimplant dosimetry can be obtained if free-hand needles are required due to pubic arch interference.

Prostate brachytherapy after ileal pouch-anal anastomosis reconstruction.

OBJECTIVE: To determine the safety of prostate brachytherapy in patients with clinically localized prostate cancer who have undergone proctocolectomy with ileal pouch-anal anastomosis (IPAA). METHODS: We performed a retrospective chart review of patients with a prior history of IPAA reconstruction who underwent prostate brachytherapy at our institution. Clinical records were reviewed for demographic characteristics, postoperative dosimetry, changes in bowel function, and oncologic outcomes. Data were analyzed using descriptive statistics. RESULTS: Five patients with an IPAA underwent prostate brachytherapy for clinically localized prostate cancer. Mean time from colorectal reconstruction to prostate brachytherapy was 6.3 years. Adequate dosimetry (mean D90 114.9%, mean V100 91.1%, mean R100 0.76 mL) was achieved in each patient. Bowel frequency worsened in the immediate postoperative period in all patients, but all patients returned to their baseline bowel pattern by 4 months after their procedure. Serious complications, such as J-pouch ulcers, fistulas, or fecal incontinence, did not occur in these patients. CONCLUSIONS: Prostate brachytherapy is a safe treatment option in patients with clinically localized prostate cancer and a history of proctocolectomy and IPAA reconstruction.

Planning based on postneedle volume with early dosimetric assessment is beneficial for Cesium-131 permanent prostate seed implantation.

PURPOSE: This study reports on prostate edema after prostate brachytherapy using Cesium-131 ((131)Cs) and describes our method to compensate. METHODS AND MATERIALS: Thirty-one patients underwent brachytherapy using an afterloading technique. Volume measurements of the prostate were taken at various time intervals relative to the date of implant. Real-time operating room dosimetry was used for seed placement on the postneedle prostate volume. The prostate volumes at the various time points were used to determine the effect of prostate edema on dosimetry. RESULTS: Increase in prostate volume occurred immediately after needle placement, as measured by both ultrasound (mean increase of 17.7% (0-75.0%) from 36.8 to 46.9 cc) and Day 0 CT (mean increase of 15.3% (0-54.8%) to 45.9 cc). Day 0 assessment of dosimetry revealed a median D(90) of 102.7% (86.7-133.4%), median V(100) of 91.8% (75.9-98.4%), median V(150) of 44.4% (23.8-81.3%), and median V(200) of 16.3% (7.8-36.9%). This edema dissipated over the next 4 weeks, with resultant changes in dosimetric parameters. By 4 weeks, prostate volume had returned to the preimplant volume (37.7 cc) with increased D(90) (118.2%), V(100) (95.6%), V(150) (63.9%), and V(200) (28.4%). CONCLUSIONS: There is significant immediate edema with prostate brachytherapy. This affects the dosimetry of the implant substantially. Because of this edema, our planning for brachytherapy is done on the postneedle implant volume. Quality assurance studies should be done on the same day as the implant to avoid substantial overestimation of dosimetric parameters.

Laparoscopic nephrectomy using the EnSeal Tissue Sealing and Hemostasis System: successful therapeutic application of nanotechnology.

The potential impact of nanotechnology in the field of urology is broad with diagnostic and therapeutic benefits that have only recently begun to be explored. Application of nanotechnology principles to tissue and vessel sealing during laparoscopic procedures may reduce associated thermal injury and inflammatory response. We report our initial experience using the EnSeal Tissue Sealing and Hemostasis System during laparoscopic nephrectomy and discuss its potential advantages and disadvantages compared with those of contemporary technologies.

Complete ureteral stent encrustation managed with serial nephroscopy and laser lithotripsy.

Encrustation is a well-established complication of retained biomaterials in the urinary tract. Severe stent encrustation is a potentially serious complication of prolonged indwelling ureteral stenting often managed with open surgery when endoscopic techniques are unsuccessful. We present a case of a 2800-mm2 stent encrustation managed with serial nephroscopy and laser lithotripsy.

Feasibility and outcome of retrograde endoscopy in a post-prostatectomy population.

PURPOSE: To determine the feasibility of retrograde endoscopy after radical retropubic prostatectomy (RRP) and its effects on post-prostatectomy continence. PATIENTS AND METHODS: We retrospectively reviewed all patients who underwent RRP at our institution between 1999 and 2005, identifying those who subsequently required endoscopic instrumentation. Patient records were examined for the interval between procedures, method of endoscopy, and continence after endoscopy compared with baseline post-prostatectomy continence. RESULTS: Twenty-one patients were identified who required endoscopic instrumentation from 4 to 49 months after RRP. Of these, 13 patients underwent ureteroscopy for stones (N = 8) or stricture disease (N = 5). In 3 cases, a ureteral access sheath was used, and in 12 cases, a ureteral stent placed postoperatively. Review of the operative reports revealed no complications or difficulty with cannulation of the ureteral orifice(s) or sheath placement. Eight patients underwent rigid cystoscopy for hematuria, removal of a foreign body, or treatment of bladder stones (N = 2 each) or for stent placement and frequency (N = 1 each). The ureter could not be identified in one case of attempted stent placement for hydronephrosis because of a distal-ureteral stone. A follow-up intravenous urogram confirmed passage of the stone and resolution of the hydronephrosis. There were no other reported difficulties with rigid cystoscopy. There was no documented change or adverse outcome regarding continence after endoscopy. CONCLUSIONS: Post-prostatectomy retrograde endoscopy is feasible for the management of common urologic pathologies. Endoscopic instrumentation across the urethrovesical anastomosis did not have an adverse effect on urinary continence.