Extra-meningeal solitary fibrous tumor: an evolving entity with chameleonic morphological diversity, a hallmark molecular alteration and unresolved issues in risk stratification assessment.

Solitary fibrous tumor (SFT) is a rare type of mesenchymal lesion with variable clinical presentation in which specific clinicopathologic factors have been related to patient outcome. SFT shares an important morphologic and immunohistochemical overlap with other sarcomas, hence the differential diagnosis is challenging. Although molecular studies provide significant clues, especially in the differential diagnosis with other neoplasms, a thorough hematoxylin and eosin analysis and the integration of phenotypical, clinical, and radiological features remain an essential tool in SFT diagnosis. In this review, we discuss some emerging issues still under debate in SFT.

Cytotoxicity Assessment of a New Design for a Biodegradable Ureteral Mitomycin Drug-Eluting Stent in Urothelial Carcinoma Cell Culture.

Urothelial tumour of the upper urinary tract is a rare neoplasm, but unfortunately, it has a high recurrence rate. The reduction of these tumour recurrences could be achieved by the intracavitary instillation of adjuvant chemotherapy after nephron-sparing treatment in selected patients, but current instillation methods are ineffective. Therefore, the aim of this in vitro study is to evaluate the cytotoxic capacity of a new instillation technology through a biodegradable ureteral stent/scaffold coated with a silk fibroin matrix for the controlled release of mitomycin C as an anti-cancer drug. Through a comparative study, we assessed, in urothelial carcinoma cells in a human cancer T24 cell culture for 3 and 6 h, the cytotoxic capacity of mitomycin C by viability assay using the CCK-8 test (Cell counting Kit-8). Cell viability studies in the urothelial carcinoma cell line confirm that mitomycin C embedded in the polymeric matrix does not alter its cytotoxic properties and causes a significant decrease in cell viability at 6 h versus in the control groups. These findings have a clear biomedical application and could be of great use to decrease the recurrence rate in patients with upper tract urothelial carcinomas by increasing the dwell time of anti-cancer drugs.

Assessment of a Coated Mitomycin-Releasing Biodegradable Ureteral Stent as an Adjuvant Therapy in Upper Urothelial Carcinoma: A Comparative In Vitro Study.

A major limitation of the treatment of low-grade upper tract urothelial carcinoma is the difficulty of intracavitary instillation of adjuvant therapy. Therefore, the aim of this in vitro study was to develop and to assess a new design of biodegradable ureteral stent coated with a silk fibroin matrix for the controlled release of mitomycin C as a chemotherapeutic drug. For this purpose, we assessed the coating of a biodegradable ureteral stent, BraidStent®, with silk fibroin and subsequently loaded the polymeric matrix with two formulations of mitomycin to evaluate its degradation rate, the concentration of mitomycin released, and changes in the pH and the weight of the stent. Our results confirm that the silk fibroin matrix is able to coat the biodegradable stent and release mitomycin for between 6 and 12 h in the urinary environment. There was a significant delay in the degradation rate of silk fibroin and mitomycin-coated stents compared to bare biodegradable stents, from 6-7 weeks to 13-14 weeks. The present study has shown the feasibility of using mitomycin C-loaded silk fibroin for the coating of biodegradable urinary stents. The addition of mitomycin C to the coating of silk fibroin biodegradable stents could be an attractive approach for intracavitary instillation in the upper urinary tract.

Biodegradable ureteral stents: in vitro assessment of the degradation rates of braided synthetic polymers and copolymers.

OBJECTIVES: The control and predictability of degradation rates and the absence of obstructive phenomena are two main challenges for research regarding biodegradable ureteral stents. The objectives are to assess the degradation performance and safety of braided combinations of three synthetic biodegradable polymers and copolymers; and to evaluate the interference of a heparin dip coating on degradation and bacterial colonization. METHODS: The hydrolysis of polyglycolic acid (PGA), poly lactic-co-glycolic acid (PLGA) and Glycomer™ 631 is assessed in this in vitro study that comprises ten groups. Stent samples present a braided arrangement and are incubated in porcine urine that undergoes analysis and exchange every 48 h until degradation. Coating is carried out with sodium heparin via dip coating and determination of the heparin release is carried out by ELISA test. Variables of study are stent mass, mass fold change, degradation time, bacterial colonization and concentration of heparin released in artificial urine. RESULTS: There is statistical significance in degradation times between all materials except between the Glycomer™ 631 alone and combined with PGA. Mass fold change analysis of the Glycomer™ 631 evidences an increasing trend of its mass during degradation. The combination of Glycomer™ 631 and PGA presents a progressive and gradual degradation, where PGA degrades at week 3 while Glycomer™ 631 remains intact until its fragmentation at the late stage of degradation. Heparin coating has no significant impact on mean degradation times and trends in any group, nor on bacteriuria rates; heparin concentration decreases significantly after 72 h. Products of degradation are released steadily with minimum dimensions. CONCLUSIONS: The combination of synthetic biodegradable polymers and copolymers with different degradation rates provides a gradual staged degradation. Heparin dip coating is a safe and feasible technique to coat biodegradable ureteral stents without interfering in degradation rates although it does not have a significant effect on the onset of bacterial colonization.

Evaluation of Alternative Risk Stratification Systems in a Large Series of Solitary Fibrous Tumors with Molecular Findings and Ki-67 Index Data: Do They Improve Risk Assessment?

The clinical evolution of solitary fibrous tumors (SFTs) is often uncertain and several risk stratification systems (RSS) have been proposed. The Demicco et al. RSS is the most frequently implemented. In this study we aim to validate two alternative RSS (Sugita et al. and G-Score) using results for the Demicco RSS from a previous study of 97 SFTs. In addition, we aim to determine whether reclassified cases had any distinctive molecular features. As the Sugita et al. system substitutes mitotic count with Ki-67 index we also investigated whether Ki-67 results for tissue microarrays are comparable to those obtained using whole tissue sections. In the present study we detected that many cases classified by Demicco RSS as low-risk were reclassified as intermediate risk using the new system (G-score RSS). Kaplan-Meier survival plots for G-Score RSS showed that the low-risk and intermediate-risk SFTs had a similar evolution that contrasted with the more aggressive high-risk group. Moreover, the similar evolution in both low and intermediate-risk groups occurred despite the G-score system being stricter in classifying low-risk tumors. We observed that Sugita RSS does not provide any better risk stratification in comparison with the Demicco RSS, and testing both RSS in our series produced similar Kaplan-Meier survival data. We found some discordant results when comparing whole sections and the corresponding tissue microarrays samples, finding the hotspot areas easier to locate in whole sections. Forty-one SFTs with initial low-risk assigned by the Demicco RSS were reclassified as intermediate-risk by G-score finding both TP53 and HTER mutations in four cases, only HTER mutation in 11 cases, and only TP53 mutation in 2 cases. All six cases of SFT classified as high-risk by both the Demicco and G-score RSS suffered recurrence/metastasis, and half showed both TP53 and HTER mutations. Five SFTs were categorized as low-risk by both Demicco and G-score, of which 4 cases revealed HTER mutation. Regarding the outcome of these 5 patients, two were lost to follow-up, and one of the remaining three patients suffered recurrence. We believe that although the presence of both TP53 and HTER mutations may confer or be related to poor evolution, the isolated presence of HTER mutation alone would not necessarily be related to poor outcome. The G-score RSS more accurately identified low-risk patients than the other two risk models evaluated in the present series. Late recurrence/metastasis may occasionally be observed even in low-risk SFTs categorized by stricter classification systems such as the G-score RSS. These findings support the possibility that additional, as yet unknown factors may influence the clinical evolution of SFTs. In conclusion, given the possibility of late recurrence, long-term follow-up is recommended for all SFT patients, even in cases classified as low risk by the stricter G-score system. An integration of clinical, radiological, pathological, and molecular findings may improve SFT risk stratification and better predict patient outcome.

Ki-67 immunoexpression and radiological assessment of necrosis improves accuracy of conventional and modified core biopsy systems in predicting the final grade assigned to adult-soft tissue sarcomas. An international collaborative study.

Based on the French Federation Nationale des Centers de Lutte Contre le Cancer (FNCLCC) grading system, this study assesses the accuracy of conventional and modified core biopsy (CB) systems in predicting the final grade (low vs high) assigned to the resected specimen. Substituting Ki-67 immunoexpression for mitotic count, and radiological for histological assessment of necrosis, we used two modified FNCLCC CB grading systems: (1) Ki-67 immunoexpression alone, and (2) Ki-67 plus radiological assessment of necrosis. We graded 199 soft tissue sarcomas (STS) from nine centers, and compared the results for the conventional (obtained from local histopathology reports) and modified CB systems with the final FNCLCC grading of the corresponding resected specimens. Due to insufficient sample quality or lack of available radiologic data, five cases were not evaluated for Ki67 or radiological assessment of necrosis. The conventional FNCLCC CB grading system accurately identified 109 of the 130 high-grade cases (83.8%). The CB grading matched the final FNCLCC grading (low vs high) in 175 (87.9%) of the 199 resected tumors; overestimating the final grade in three cases and underestimating in 21 cases. Modified system 1 (Ki-67) accurately identified 117 of the 130 high-grade cases (90.0%). The CB grading matched the final FNCLCC grading (low vs high) in 175 (89.7%) of the 195 evaluated cases; overestimating seven and underestimating 13 cases. Modified system 2 (Ki-67 plus radiological necrosis) accurately identified 120 of the 130 high-grade cases (92.3%). This last matched the final FNCLCC grading (low vs high) in 177 (91.2%) of the 194 evaluated cases; overestimating seven and underestimating 10 cases. Modified system 2 obtained highest area under ROC curves, although not statistically significant. Underestimated CB grades did not correlate with histological subtypes, although many of the discrepant cases were myxoid tumors (myxofibrosarcomas or myxoid liposarcomas), leiomyosarcomas or undifferentiated pleomorphic/spindle cell sarcomas. Using modified FNCLCC CB grading systems to replace conventional mitotic count and histologic assessment of necrosis may improve the distinction between low and high-grade STS on CB. Our study confirms that classifying grade 1 as low grade and grades 2 and 3 as high grade improves correlation between CB and final grade by up to 21%, irrespective of CB system used. A higher than expected Ki-67 score in a low-grade sarcoma diagnosed on CB should raise concern that a higher-grade component may not have been sampled. Furthermore, correlation of all clinicopathological and radiological findings at multidisciplinary meetings is essential to assess the histological grade on CB as accurately as possible.

Heparin coating in biodegradable ureteral stents does not decrease bacterial colonization-assessment in ureteral stricture endourological treatment in animal model.

BACKGROUND: We assessed an antireflux biodegradable heparin-coated ureteral stent (BraidStent®-H) in an animal model comparative study after endoscopic treatment of ureteral strictures. METHODS: A total of 24 female pigs underwent initial endoscopic, nephrosonographic, and contrast fluoroscopy assessment of the urinary tract. Afterward, unilateral laparoscopic ureteral stricture model was performed. Three weeks later, the animals underwent laser endoureterotomy and were randomly assigned to Group-I, in which a double-pigtail stent was placed for 6 weeks, or Group-II, in which a BraidStent®-H was placed. Follow-up was carried out by ultrasonography, contrast fluoroscopy, ureteroscopy, urinalysis and bacteriuria assessment at 3, 6, 12 and 5 months. Finally, a pathological study of the urinary system was performed. RESULTS: There were no animals in Group-II with vesicoureteral reflux, with significance at 6 weeks with Group-I. Distal ureteral peristalsis was maintained in 50-75% in Group-II at 1-6 weeks. The 91.7% of stents in Group-II were degraded between 3-6 weeks, without obstructive fragments. Bacteriuria in Group II was 33.3-50% at 3 and 6 weeks. The global success rate by groups was 91.6% and 87.5% in groups I and II, respectively, with no statistical significance. CONCLUSIONS: BraidStent®-H has been shown to be as efficacious as current ureteral stents in the treatment of benign ureteral strictures following laser endoureterotomy. In addition, it reduces the morbidity associated with current stents and has a homogeneous and predictable degradation rate of about 6 weeks, with no obstructive fragments. Future studies are required to improve the antibacterial coating to reduce BraidStent®-H contamination in view of the results obtained with the heparin coating.

Assessment of the Grades of Vesicoureteral Reflux in Stented Ureters: An Experimental Study.

INTRODUCTION: The aim of this experimental study is to assess, in a porcine model, the onset and grades of vesicoureteral reflux associated with ureteral stents. METHODS: Twenty-four female porcine models were used. A 4.7-Fr ureteral stent was placed in all right ureters and kept in place for 6 weeks. Follow-ups were performed on weeks 1, 3, 6, and 12. Ultrasonography, cystoscopy, and fluoroscopy were used to analyze grade of hydronephrosis, presence and grade of vesicoureteral reflux, bacteriuria, and macroscopic changes of the ureteral orifices. Vesicoureteral reflux was classified using a modification of the International Reflux Study Committee grades. RESULTS: 91.7% animals present vesicoureteral reflux, 89.5% grade IA, 3.5% grade IB, and 7% grade II. There is a significant increase in reflux during follow-ups at 3 and 6 weeks, whereas 6 weeks after removal, 26.3% of the ureters still present vesicoureteral reflux. Hydronephrosis and macroscopic changes of the ureteral orifice increase significantly with stenting, but there is no significant association between them and vesicoureteral reflux; the relationship between bacteriuria and the presence of vesicoureteral reflux is not significant either. CONCLUSION: Vesicoureteral reflux caused by ureteral stents in an animal model is mostly low grade and mainly affects the distal ureter.

Comparative assessment of biodegradable-antireflux heparine coated ureteral stent: animal model study.

BACKGROUND: Double J ureteral stents are widely used on urological patients to provide drainage of the upper urinary tract. Unfourtunately, ureteral stents are not free from complications, as bacterial colonization and require a second procedure for removal. The purpose of the current comparative experimental study is to evaluate a new heparin-coated biodegradable antireflux ureteral stent (BraidStent®-H) to prevent urinary bacterial colonization. METHODS: A total of 24 female pigs were underwent determination of bacteriuria and nephrosonographic, endoscopic and contrast fluoroscopy assessment of the urinary tract. Afterward, were randomly assigned animals to Group-I, in which a 5Fr double-pigtail ureteral stent was placed for 6 weeks, or Group-II, in which a BraidStent®-H was placed. Follow-up assessments were performed at 1, 3, 6, 8, 12 weeks. The final follow-up includes the above methods and an exhaustive pathological study of the urinary tract was accomplished after 20 weeks. RESULTS: Bacteriuria findings in the first 48 h were significant between groups at 6 h and 12 h. Asymptomatic bacteriuria does not reach 100% of the animals in Group-II until 48 h versus Group-I where it appears at 6 h. The weekly bacteriuria mean rate was 27.7% and 44.4% in Group I and II respectively, without statistical significance. In Group II there were no animals with vesicoureteral reflux, with statistical significance at 3 and 6 weeks with Group-I. The 91.2% of stents in Group-II were degraded between 3 and 6 weeks, without obstructive fragments. Distal ureteral peristalsis was maintained in 66.6-75% in Group-II at 1-6 weeks. CONCLUSIONS: The heparin coating of BraidStent® allows an early decrease of bacterial colonization, but its effectiveness is low at the long term. Heparin coating did not affect scheduled degradation rate or size of stents fragments. BraidStent®-H avoids the side effects associated with current ureteral stents, thus should cause less discomfort to patients.

Experimental Assessment of New Generation of Ureteral Stents: Biodegradable and Antireflux Properties.

Objective: The aim was to assess a new biodegradable and antireflux intraureteral stent (BraidStent®) design in a swine model after ureteral laparoscopic operation. Materials and Methods: A total of 24 female pigs underwent initial endoscopic, nephrosonographic, and contrast fluoroscopy assessment of the urinary tract. Afterward, unilateral ureteropelvic junction obstruction was performed by laparoscopic approach. Six weeks later, the animals underwent laparoscopic Anderson-Hynes pyeloplasty, and were randomly assigned to Group-I, in which a double-pigtail ureteral stent was inserted for 6 weeks, or Group-II, in which a BraidStent®, a biodegradable intraureteral stent design, was placed. Follow-up assessments were performed at 3 and 6 weeks and 5 months. Results: In terms of therapeutic success, complete resolution was observed in 91.6% of Group-I animals and 88.8% in Group-II. No evidence of vesicoureteral reflux (VUR) was observed in Group-II animals and statistical significance in VUR and ureteral orifice damage were observed between groups. BraidStent® degradation occurred in a controlled manner between 3 and 6 weeks, without obstructive fragments. Distal ureteral peristalsis was maintained in 66.6% and 83.3% in Group-II at 3 and 6 weeks of follow-up, respectively. In Group-II, the positive bacteriuria rate was 41.6% and the migration rate 25%. Pathological assessment showed a significant improvement in ureteral healing in Group-II vs Group-I. Conclusions: The results of this comparative study in a porcine model indicate that the intraureteral BraidStent performed similarly to conventional ureteral stents. It avoids complete ureteral length intubation, the adverse effects associated with conventional ureteral stents, and maintains a high level of distal ureteral peristalsis. Moreover, the BraidStent® exhibited a predictable and controlled degradation rate and did not cause any obstructive fragments. However, further studies are needed to improve the anchoring system and reduce the risk of bacterial colonization.

Antireflux ureteral stent proof of concept assessment after minimally invasive treatment of obstructive uropathy in animal model.

OBJECTIVES: To assess the efficacy of a new anti-reflux intraureteral stent design in a swine model after minimally invasive treatment of ureteral stricture to reduce ureteral stent morbidity, previous to manufacture this design in a biodegradable fashion. METHODS: Twenty-eight female pigs were included. The study began with a cystoscopic, nephrosonographic and contrast fluoroscopic assessment. Afterwards, obstructive uropathy model in right ureter was created. Obstruction was confirmed 6 weeks later and animals were randomly distributed into 2 groups. Group I underwent laser endopyelotomy and Group-II laparoscopic pyeloplasty A 3Fr anti-reflux intraureteral stent was placed 6 weeks. Follow-up evaluations were performed at 3-6 weeks. The final follow-up was completed at 5 months and included the aforementioned diagnostic methods and pathological study. RESULTS: None of the study animals showed any vesicoureteral reflux signs or ureteral orifice injury. There were no urinomas or ureteric fistulas. The dislodgement rate was 10.7%. After 6 weeks of stenting, 71.4% of ureters showed ureteral peristalsis below the stent, and 100% at the final follow-up. After pathological assessment, no differences were shown at UPJ and healing in the incised area was correct in both groups. CONCLUSIONS: The new stent design avoids vesicoureteral reflux and bladder trigone irritation, consequently might reduce morbidity associated with double pigtail ureteral stents. This study also shows that it is only necessary temporary scaffolding the incised ureteral segment and not the entire length of the ureter after minimally invasive surgery. It is also necessary to manufacture this design in a biodegradable material, thus avoiding its removal.

Assessment of sensory thresholds and nociceptive fiber growth after sciatic nerve injury reveals the differential contribution of collateral reinnervation and nerve regeneration to neuropathic pain.

Following traumatic peripheral nerve injury reinnervation of denervated targets may be achieved by regeneration of injured axons and by collateral sprouting of neighbor undamaged axons. Experimental models commonly use sciatic nerve injuries to assess nerve regeneration and neuropathic pain, but behavioral tests for evaluating sensory recovery often disregard the pattern of hindpaw innervation. This may lead to confounding attribution of recovery of sensory responses to improvement in sciatic nerve regeneration instead of collateral reinnervation by the undamaged saphenous nerve. We used a standardized methodology to assess the separate contribution of collateral and regenerative skin reinnervation on sensory responses. Section and suture of the sciatic nerve induced loss of sensibility in the lateral and central areas of the injured paw, but nociceptive responses rapidly recovered by expansion of the intact saphenous innervation territory. We used electronic Von Frey and Plantar test devices to measure mechanical and thermal withdrawal thresholds in specific sites of the injured paw: lateral site innervated by the sciatic nerve, medial site that remained innervated by the saphenous nerve, and central site originally innervated by the sciatic nerve but affected by saphenous sprouting. After sciatic section, signs of early hyperalgesia developed in medial and central paw areas due to saphenous sprouting and expansion. The regenerating sciatic nerve fibers reached the paw at 3-4weeks and a late mechanical hyperalgesia was observed at the lateral site. Immunohistochemical staining of sensory fibers innervating the medial and lateral areas revealed a different pattern of skin reinnervation. Hypersensitivity in the intact saphenous nerve area was paralleled by early fiber sprout growth in the subepidermal plexus, but not entering the epidermis. On the other side, late sciatic hyperalgesia was accompanied by gradual skin reinnervation after 4weeks. The standardization of algesimetry testing in sciatic nerve injury models, as proposed in this study, provides a suitable model for studying in parallel neuropathic pain and sensory nerve regeneration processes. Our results also indicate that collateral sprouting and axonal regeneration contribute differently in the initiation and maintenance of neuropathic pain.

Assessment of antigenic fractions of varying hydrophobicity from Taenia solium metacestodes for the diagnosis of human neurocysticercosis.

OBJECTIVE: To evaluate the detergent and aqueous phases of crude saline extract (crude) of Taenia solium metacestodes extracted with Triton X-114, for the detection of immunoglobulin G (IgG) antibodies by enzyme-linked immunosorbent assay (ELISA) and immunoblot for the laboratory diagnosis of human neurocysticercosis. METHOD: Serum samples were collected from 138 individuals and tested; 40 were diagnosed with neurocysticercosis (NC; group 1), 58 presented other parasitic diseases (group 2) and 40 were apparently healthy (group 3). RESULTS: The detergent phase showed only one dominant component (70-50 kDa), while the aqueous phase showed four (116, 110, 97 and 77 kDa) by silver staining. ELISA sensitivity and specificity were 92.5% and 84.5% for crude phase, 92.5% and 93.3% for detergent phase and 72.5% and 72.6% for aqueous phase. CONCLUSIONS: The immunoblot of the antigens confirmed the results obtained by ELISA. Detergent phase purified from T. solium metacestodes was an important source of specific peptides and was efficient in detecting T. solium metacestodes antibodies in serum samples. This phase can be used for detecting IgG antibodies to T. solium metacestodes in seroepidemiological investigations and in the diagnostic screening of NC patients.