Detrusor Overactivity After Partial Bladder Outlet Obstruction Is Associated With High Urinary Adenosine Triphosphate Levels in Female Wistar Rats.

PURPOSE: Bladder outlet obstruction (BOO) commonly causes detrusor overactivity (DO). In this study, a post hoc analysis of previous obtained data, we investigate if DO occurring in initial phases of BOO is associated with changes in urinary adenosine triphosphate (ATP) levels. METHODS: Adult female Wistar rats were submitted to partial BOO (pBOO) or to sham obstruction. Cystometry was performed at 3 or 15 days after pBOO and saline voided was collected for ATP determination. Normality was tested using Shapiro-Wilk test. The mean frequency of voiding contractions (VCs) of the sham-operated animals at 15 days after surgery, plus or minus 3 standard deviations, was used to represent the normal range. Statistical analyses were performed using the chi-square and Mann-Whitney tests. RESULTS: DO was indicated by a VC frequency greater than or equal to 0.9 VCs/min. DO was observed in 63% of animals at 3 days and in 33% at 15 days following pBOO. ATP levels were significantly higher in rats with DO compared to those without DO. CONCLUSION: The DO phenotype, occurring in the initial phases of BOO, is associated with comparatively high urinary ATP levels.

A Peculiar Cause of Shock: Analysing Two Clinical Cases.

Introduction: Pheochromocytoma is a rare neoplasia arising from the adrenal medulla that secretes catecholamines. Those afflicted by this condition can present a wide range of symptoms. One of the most common is paroxysmic hypertension. Interestingly, although rare, some patients present with shock. We describe two cases of pheochromocytoma in which the initial presentation was shock. Case 1. 49 year-old woman, with a history of resistant hypertension, presented to the emergency department with thoracic pain and fever. EKG, echocardiogram (ECC), and myocardial necrosis markers were compatible with Takotsubo syndrome (TS). CT demonstrated a staghorn calculus, hydronephrosis, and signs compatible with xanthogranulomatous pyelonephritis in the right kidney. Additionally, and incidentally, it revealed a 60 mm nodule on the right adrenal gland. Piperacillin/tazobactam was started immediately, and the patient was submitted to urgent upper urinary tract drainage. This procedure was complicated by a cardiorespiratory arrest that was treated with adrenaline administration. The patient was admitted to the ICU due to multifactorial shock and started alpha and, posteriorly, beta blockage. Biochemical adrenal incidentaloma endocrinologic study was negative (under hemodialysis). Multiorgan failure progressively improved. After 2 weeks, the patient was submitted to a laparoscopic transperitoneal right adrenalectomy. No complications were reported. Histological analysis revealed a pheochromocytoma. Case 2. 28-year-old woman presented to the emergency department with headaches and nausea. Vitals were compatible with shock. CT revealed an incidental 72 mm mass on the right adrenal. EKG, ECC, and myocardial necrosis markers were compatible with TS. The patient was started on alpha and, posteriorly, beta blockage. Adrenal incidentaloma endocrinological study demonstrated high urinary catecholamines. Right transperitoneal adrenalectomy was performed. No complications were noted. Histological analysis revealed a pheochromocytoma. Conclusion: Pheochromocytoma can present with complex, enigmatic, and rare clinical pictures. Clinicians should be wary of the possibility of this diagnosis when managing adrenal masses.

Incidence of urological cancers in neurological patients: a review of the literature from the EAU Young Academic Urologist Functional Group.

INTRODUCTION: Urological cancers can be challenging in the diagnosis and treatment of patients with neurological diseases. As a result, there are still uncertainties regarding the incidence and risk factors favouring the development of urological cancers in these patients. The aim of this study was to review the available evidence regarding the incidence for the development of urological cancers in neurological patients to provide a basis for future recommendations and research. EVIDENCE ACQUISITION: A narrative review of the literature in Medline and Scopus up to June 2019 was performed. EVIDENCE SYNTHESIS: After screening 1729 records, 30 retrospective studies were retained. For bladder cancer (BC), 21 articles were identified, including a total of 673,663 patients. Among these patients, 4744 had a diagnosis of BC (1265 females, 3214 males, gender not reported in 265). In this group, 2514 were diagnosed with BC associated with a neurological disease. For prostate cancer (PC), 14 articles were identified, including a total of 831,889 men. Among these patients, 67,543 had a diagnosis of PC and 1457 had PC and a neurological disease. Two articles reported kidney cancer (KC), one reported testicular cancer (TC) and none described penile cancer or urothelial carcinomas of the upper urinary tract in neurological patients. CONCLUSIONS: The incidence of urological cancers, especially BC and PC, in patients with neurological diseases appears comparable to the general population. However due to the paucity of studies, specific recommendations for the management are lacking in neurologically disabled patients. In this report we investigated the frequency of urinary tract cancers in patients with neurological diseases. We conclude that urological cancers, especially bladder and prostate cancer, in patients with neurological diseases occur with similar frequency as in the general population.

The value of surgeon's perception during transurethral resection of bladder tumors: can we trust in our eyes and experience to predict grade and staging?

Transurethral resection of newly diagnosed bladder tumors (TURBT) is a hallmark ¡n the treatment of bladder cancer. We evaluated the surgeon capacity to predict bladder tumor stage (T), grade, and presence of muscular layer based upon cystoscopic characteristics during primary TURBT. Methods: Prospective study enrolling 100 consecutive patients undergoing primary TURBT for newly diagnosed bladder cancers. Cystoscop¡c tumor characteristics at the time of TURBT was evaluated by an urology senior and a resident regarding histological grade, invasion (T stage), and presence of muscular layer in the specimen. We analyzed the surgeon's accuracy in predicting these parameters using the final histology as gold standard. In addition, the predictive capacity between seniors and residents was compared. Results: The resident's arm correctly predicted tumor invasiveness in 76% of cases, while seniors correctly predicted 87% of cases. Regarding tumor grade, high grade cancer was reported in 78% of the specimens and 75% and 77% of them were correctly predicted by residents and seniors, respectively. Finally, 80% of the TURBT specimens had muscle representativeness. In nearly 75% of the cases, both resident and senior correctly predicted the TURBT resection depth (presence of detrusor muscle in the specimen). The positive predictive value for this parameter was 79% for the resident, and 81% for the senior, and the negative predictive value was 25% and 40%, respectively. Conclusion: The surgeon's naked eye analysis showed a good, but limited predictive ability to detect non-muscle invasive and high-grade bladder tumors in TURBT specimens. Positive predictive value for muscle representativeness is around 80%, which reinforces the need of carrying out a careful and extensive TURBT, irrespective of the surgeon experience.

Systematic Review of the Incidence of and Risk Factors for Urothelial Cancers and Renal Cell Carcinoma Among Patients with Haematuria.

CONTEXT: The current impact of haematuria investigations on health care organisations is significant. There is currently no consensus on how to investigate patients with haematuria. OBJECTIVE: To evaluate the incidence of bladder cancer, upper tract urothelial carcinoma (UTUC), and renal cell carcinoma (RCC) among patients undergoing investigation for haematuria and identify any risk factors for bladder cancer, UTUC, and RCC (BUR). EVIDENCE ACQUISITION: Medline, Embase, and Cochrane controlled trials databases and ClinicalTrials.gov were searched for all relevant publications from January 1, 2000 to June 2021 according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement. Prospective, retrospective, and cross-sectional studies with a minimum population of 50 patients with haematuria were considered for the review. EVIDENCE SYNTHESIS: A total of 44 studies were included. The total number of participants was 229701. The pooled incidence rate for urothelial bladder cancer was 17% (95% confidence interval [CI] 14-20%) for visible haematuria (VH) and 3.3% (95% CI 2.45-4.3%) for nonvisible haematuria (NVH). The pooled incidence rate for RCC was 2% (95% CI 1-2%) for VH and 0.58% (95% CI 0.42-0.77%) for NVH. The pooled incidence rate for UTUC was 0.75% (95% CI 0.4-1.2%) for VH and 0.17% (95% CI 0.081-0.299%) for NVH. On sensitivity analysis, the proportions of males (risk ratio [RR] 1.14, 95% CI 1.10-1.17 for VH; 1.54, 95% CI 1.34-1.78 for NVH; p < 0.00001; moderate certainty evidence) and individuals with a smoking history (RR 1.41, 95% CI 1.24-1.61 for VH; 1.53, 95% CI 1.36-1.72 for NVH; p < 0.00001; moderate certainty evidence) appeared to be higher in BUR than in non-BUR groups. CONCLUSIONS: Male gender and smoking history are risk factors for BUR cancer in haematuria, with bladder cancer being the commonest cancer. The incidence of RCC and UTUC in NVH is low. The review serves as a reference standard for future policy-making on investigation of haematuria by global organisations. PATIENT SUMMARY: Our review shows that male gender and smoking history are risk factors for cancers of the bladder, kidney, and ureter. The review also provides information on the proportion of patients who have cancer when they have blood in their urine (haematuria) and will allow policy-makers to decide on the most appropriate method for investigating haematuria in patients.

DU Is Induced by Low Levels of Urinary ATP in a Rat Model of Partial Bladder Outlet Obstruction: The Incidence of Both Events Decreases after Deobstruction.

Objectives: To investigate, in initial phases of bladder outlet obstruction (BOO), the urinary ATP levels, the incidence of detrusor underactivity (DU), and if they change after deobstruction. Methods: Adult female Wistar rats submitted to partial BOO (pBOO) and sham-obstruction were used. Cystometry was performed 3 or 15 days after pBOO and fluid was collected from the urethra for ATP determination. Bladders were harvested for morphological evaluation of the urothelium. DU was defined as the average of voiding contractions (VC) of sham-operated animals, with 3 SD at 15 days after the sham surgery. In another group of animals in which pBOO was relieved at 15 days and bladders were let to recover for 15 days, the incidence of DU and ATP levels were also accessed. The Kruskal-Wallis test was followed by Dunn's multiple comparisons test, and Spearman's correlation test was used. Results: DU was present in 13% and 67% of the bladders at 3 and 15 days after pBOO, respectively, and in 20% of the bladders at 15 days after deobstruction. ATP levels were significantly lower in DU/pBOO versus sham and non-DU/pBOO rats. A strong positive correlation between ATP levels and VC/min was obtained (r = 0.63). DU bladders had extensive areas in which umbrella cells appeared stretched, the width exceeding that presented by sham animals. Conclusions: Low urothelial ATP parallels with a high incidence of DU early after pBOO.

Treatment of idiopathic overactive bladder with botulinum toxin: real-life results and patients' expectations.

Background: Overactive bladder (OAB) is a prevalent syndrome affecting 11% to 16% of the adult population. When first-line pharmacological therapy is not effective, intradetrusorial injections of onabotulinumtoxinA (BTX-A) might have an important role in controlling symptoms. The main aim of this study was to access both the efficacy and safety of intradetrusor injections of 100U BTX-A in real clinical practice, among women with idiopathic OAB (iOAB). Methods: Retrospective study, based on clinical diaries in 136 iOAB female patients, with or without urinary incontinence, submitted to BTX-A injections, between 2005 and 2018 in a tertiary university hospital. Positive response was considered only when the patient mentioned she had great improvement after the injection, otherwise, it was considered negative. Results: A positive response was obtained in 90 patients (66%) after the first injection. Women with a positive response after the first treatment had 7.5 times more chances to improve with the second (P = .01). Discontinuation of the therapy after the first injection was neither dependent on the presence of incontinence at baseline (P = .73) nor it was related to age (P = .6). On univariate analyses, none of the parameters evaluated was useful of predicting successful response, although there was a trend in women who had had a previous midurethral sling surgery for stress urinary incontinence, to have a lower chance of having a positive response after the first injection (P = .06).Thirty-nine women (29%) had at least 1 adverse event, urinary tract infection, and straining to void were the most frequent. Women above 65 years old had less risk of developing a urinary tract infection (P = .04). Conclusion: In real clinical practice, BTX-A injection is an effective (66%) and safe treatment, capable of improving quality of life. Moreover, responding to the first injection seems to predict good clinical outcomes in the second treatment. This procedure can be done with minimal restrictions.

Prognostic Factors in Penile Cancer: Should We Avoid Inguinal Lymph Node Staging?

INTRODUCTION: Penile cancer (PC) is a rare neoplasm, mostly in developed countries. Herewith, we evaluate the main prognostic factors of patients with PC undergoing surgery. METHODS: This is a retrospective analysis of prognostic factors of overall survival in 65 patients with PC treated at a tertiary referral center over the last 15 years (2004-2018). RESULTS: Almost half (48%) of the patients were diagnosed at an advanced local stage pT3/4. Thirty-eight (58%) patients underwent inguinal lymphadenectomy, and 25 (66%) were negative for lymph node (LN) invasion. Overall survival was 80% at a median follow-up of 31 months. In the multivariate analysis, the main factors of poor prognosis were nodal staging (pN) (p = 0.008) and perineural invasion (p = 0.023). The presence of LN metastasis and perineural invasion in the primary tumor increased the risk of death by 29 (hazard ratio 29.0, 95% confidence interval 2.4-354.2) and 13 (hazard ratio 12.7, 95% confidence interval 1.4-112.0) times, respectively. DISCUSSION/CONCLUSION: Late diagnosis of PC has a negative impact on overall survival, as nodal invasion correlates with survival. Despite the high number of negative inguinal lymphadenectomy, we continue to advocate aggressive surgical treatment of this disease due to the poor prognosis associated with LN metastasis.

Improving Intraoperative Communication in Trauma: The Educational Effect of the Joint DSTC™-DATC™ Courses.

BACKGROUND: Operative management of severe trauma requires excellent communication among team members. The surgeon and anesthesiologist need to interact efficiently, exchanging vital information. The Definitive Surgical Trauma Care (DSTC) and Definitive Anesthesia Trauma Care (DATC) courses provide an excellent opportunity for teamwork training. Our goal was to study the impact of the joint DSTC-DATC courses in candidates' self-reported assessment in communication skills and techniques in a simulated intraoperative trauma scenario. METHODS: Study population consists of 93 candidates (67 surgeons and 26 anesthesiologists) participating in four consecutive joint DSTC-DATC courses in May and June 2019 in Brazil (3) and in Portugal (1). Median age was 30 years; 53 (60%) of subjects were male (46 senior residents and 47 specialists). All participants attended joint lectures, case discussions and surgical skills session, emphasizing intraoperative communication. Post-course survey on several aspects of perioperative communication (responses on a Likert scale) was conducted with participants being asked which aspects of intraoperative communication they valued the most. RESULTS: All participants responded to the survey. Results displayed an increase in the self-assessed importance of team briefing and intraoperative communication, particularly routine periodic communication, rather than only at critical moments. Postoperative team debriefing was also valued as highly relevant. Closed-loop and direct, by-name communication were highly rated. Self-reported communication skills improved significantly during the course. CONCLUSIONS: Joint training in the DSTC-DATC courses improved candidates' perception and skills on proficient intraoperative communication. Further studies should address both the durability of these changes and the potential impact on patient care.

In the Beginning ... It was Already the End.

Sometimes, the presentation of some diseases can be fulminating. The authors present the case of a 51-year- old male brought to the emergency department visibly drunk and complaining of abdominal pain. Immediately, the diagnosis of hemorrhagic shock due to an accentuated drop of the hemoglobin level was made. After stabilization, he underwent a computed tomography of the abdomen, revealing a hepatocellular carcinoma with rupture of the Glisson capsule and massive intraperitoneal hemorrhage. With this case, the authors want to bring attention to a rare first presentation of hepatocellular carcinoma with a catastrophic result.

Por vezes a apresentação de algumas patologias pode ser fulminante. Os autores apresentam o caso de um doente de 51 anos que foi trazido ao Serviço de Urgência em etilismo agudo com dor abdominal mas rapidamente foi constatado choque com queda acentuada da hemoglobina confirmando-se choque hemorrágico. Após estabilização realizou Tomografia Computadorizada abdominal constatando-se carcinoma hepatocelular com rotura da cápsula de gleason e hemorragia intra-peritoneal maciça. Com este caso os autores pretendem chamar a atenção para uma apresentação inicial rara de carcinoma hepatocelular mas cujo resultado é catastrófico.

Endoscopic transvesical adenomectomy of the prostate, a new minimally invasive approach for large benign prostatic hyperplasia. What has our experience taught us?

INTRODUCTION: Recent technical advances have made new minimally invasive techniques possible to treat large volume (>80 ml) benign prostatic hyperplasia (BPH). The endoscopic transperitoneal adenomectomy of the prostate (ETAP) is a new minimally invasive technique developed in our centre. The aim of this study was to describe the safety, efficacy and to evaluate our learning curve in ETAP. MATERIAL AND METHODS: This was a single-centre study that enrolled eighty-eight consecutive patients with large BPH who underwent ETAP. Pre-, per- and postoperative data were prospectively collected. Statistical analysis compared the first 40 patients submitted to ETAP (Group A) with the subsequent 48 patients (Group B). RESULTS: There were no significant differences in the surgical procedure between groups. The median operating time was 94 (80-110) minutes and the estimated blood loss 150 (100-300) ml. There were no perioperative blood transfusions nor any conversions to open approach needed. Median hospital stay was 3 (3-5) days and catheter was removed mainly at day 9 (5-11). The median Qmax improved from 8.0 (6.2-9.9) ml/s to 15.0 (11.5-23.0) ml/s postoperatively and the median International Prostate Symptom Score (IPSS) score decreased from 20 (15-24) to 6 (4-11) after the procedure. CONCLUSIONS: ETAP is a secure and feasible minimally invasive technique for treatment of large BPH. The functional outcomes of this technique are consistent and promising.

The Role of Urinary Microbiota in Lower Urinary Tract Dysfunction: A Systematic Review.

CONTEXT: Until 2012, the urinary tract of healthy individuals was considered to be sterile. The advent of metagenomic sequencing revealed a unique urinary microbiota (UM). This paradigm shift appears to have prolific implications in the etiology of several functional lower urinary tract (LUT) disorders. OBJECTIVE: To systematically summarize recent data on the role of UM in LUT dysfunction. EVIDENCE ACQUISITION: We performed a critical review according to the Preferred Reporting Items for Systematic Review and Meta-analysis (PRISMA) statement. We conducted a search on PubMed/MEDLINE and SCOPUS with the following MESH terms/keywords: "Microbiome OR Microbiota AND (urinary disorder OR urinary tract symptom OR overactive bladder OR urinary incontinence OR interstitial cystitis OR chronic prostatitis)." The range of search was placed between January 2010 and April 2018, and articles with no full text available or those not written in English were excluded. All retrieved papers were first reviewed by title and abstract, yielding a total of 303 papers. Additional manuscripts, such as those referenced by reviews, were further included. Thirty-six publications were included. EVIDENCE SYNTHESIS: Analysis by 16S rRNA sequence and expanded quantitative urine culture provided evidence for the presence of live bacteria in urine, nondetectable by standard culture protocols. Moreover, differences in the UM between healthy individuals and patients with LUT dysfunction were demonstrated. CONCLUSIONS: In the near future, urologists must consider urinary dysbiosis as a possible cause of different functional LUT disorders, with potential clinical implications in their diagnosis and treatment. PATIENT SUMMARY: Development of metagenomic sequencing revealed a unique urinary microbiota nondetectable by standard culture protocols. This systematic review summarizing recent data on the role of urinary microbiota in lower urinary tract (LUT) dysfunction supports urinary dysbiosis as a possible cause of different functional LUT disorders.

Datasets generated by shotgun sequencing of metagenomic libraries of the guajataca water reservoir.

The Guajataca Water Reservoir (GWR) was constructed for irrigation and to bring potable water to the northwestern region of Puerto Rico. The generation of DNA sequencing data from aquatic bodies (AB) using culture-independent approaches allows the investigation of the total microbial diversity as well as the potential anthropogenic impact. Metagenomic libraries were constructed for two GWR sampling sites and genomic information access through shotgun sequencing. After removing the bacterial host cell genome and the library fosmid sequences, the environmental genome was processed through Rapid Annotation using Subsystems Technology for Metagenomes (MG-RAST). The sequences consisted primarily of bacteria (95.70%), followed by viruses (2.94%), other sequences (0.28%) and eukaryote (0.09%). The most abundant species were Enterobacter cloacae (31%), Enterobacter sp. 638 (20%), Enterobacter cancerogenus (10%) and Escherichia coli (11%). Furthermore, the subsystem data showed that 13% of the genes belong to carbohydrates functionality, 12% to clustering-based-subsystems and another 9% related to virulence-disease-and-defense (out of which 8% pertain to genes of antibiotic resistance and toxic compounds). This unique data input will serve as a baseline to a better understanding not only the microbial communities present in the AB, but also the microbial activities with potential application in biotechnological and biomedical fields.

Top-down characterization of endogenous protein complexes with native proteomics.

Protein complexes exhibit great diversity in protein membership, post-translational modifications and noncovalent cofactors, enabling them to function as the actuators of many important biological processes. The exposition of these molecular features using current methods lacks either throughput or molecular specificity, ultimately limiting the use of protein complexes as direct analytical targets in a wide range of applications. Here, we apply native proteomics, enabled by a multistage tandem MS approach, to characterize 125 intact endogenous complexes and 217 distinct proteoforms derived from mouse heart and human cancer cell lines in discovery mode. The native conditions preserved soluble protein-protein interactions, high-stoichiometry noncovalent cofactors, covalent modifications to cysteines, and, remarkably, superoxide ligands bound to the metal cofactor of superoxide dismutase 2. These data enable precise compositional analysis of protein complexes as they exist in the cell and demonstrate a new approach that uses MS as a bridge to structural biology.

Characterizing the Structure and Oligomerization of Major Royal Jelly Protein 1 (MRJP1) by Mass Spectrometry and Complementary Biophysical Tools.

Royal jelly (RJ) triggers the development of female honeybee larvae into queens. This effect has been attributed to the presence of major royal jelly protein 1 (MRJP1) in RJ. MRJP1 isolated from royal jelly is tightly associated with apisimin, a 54-residue α-helical peptide that promotes the noncovalent assembly of MRJP1 into multimers. No high-resolution structural data are available for these complexes, and their binding stoichiometry remains uncertain. We examined MRJP1/apisimin using a range of biophysical techniques. We also investigated the behavior of deglycosylated samples, as well as samples with reduced apisimin content. Our mass spectrometry (MS) data demonstrate that the native complexes predominantly exist in a (MRJP14 apisimin4) stoichiometry. Hydrogen/deuterium exchange MS reveals that MRJP1 within these complexes is extensively disordered in the range of residues 20-265. Marginally stable secondary structure (likely antiparallel ß-sheet) exists around residues 266-432. These weakly structured regions interchange with conformers that are extensively unfolded, giving rise to bimodal (EX1) isotope distributions. We propose that the native complexes have a "dimer of dimers" quaternary structure in which MRJP1 chains are bridged by apisimin. Specifically, our data suggest that apisimin acts as a linker that forms hydrophobic contacts involving the MRJP1 segment 316VLFFGLV322. Deglycosylation produces large soluble aggregates, highlighting the role of glycans as aggregation inhibitors. Samples with reduced apisimin content form dimeric complexes with a (MRJP12 apisimin1) stoichiometry. The information uncovered in this work will help pave the way toward a better understanding of the unique physiological role played by MRJP1 during queen differentiation.

Insulin receptor substrate-1 is an important mediator of ovarian cancer cell growth suppression by all-trans retinoic acid.

There is a need to identify more effective drugs for the treatment of ovarian cancer as it is the leading cause of death among gynecologic tumors. All-trans retinoic acid (ATRA), a natural retinoid, arrests the growth of CA-OV3 ovarian carcinoma cells in G(0)-G(1). Because the insulin-like growth factor-I receptor has been implicated in the proliferation of various tumors, we investigated its potential role in the suppression of ovarian cancer cell growth by ATRA. Our studies revealed that insulin receptor substrate-1 (IRS-1) protein levels decrease in CA-OV3 cells on ATRA treatment, whereas no differences in IRS-1 levels were seen in the ATRA-resistant SK-OV3 cells. Moreover, CA-OV3 clones overexpressing IRS-1 were growth inhibited less by ATRA, whereas SK-OV3 clones in which levels of IRS-1 were reduced by expression of antisense IRS-1 became sensitive to growth inhibition by ATRA treatment. Studies to determine the mechanism by which ATRA reduced IRS-1 expression showed that ATRA altered steady-state levels of IRS-1 mRNA and the stability of IRS-1 protein. Finally, the role of IRS-1 as a potential molecular target of ATRA in ovarian tumors was assessed by immunohistochemistry in an ovarian cancer tissue array. Compared with normal ovary, the majority of malignant epithelial ovarian tumors overexpressed IRS-1. Thus, there seems to be a correlation between IRS-1 expression and malignancy in ovarian tumors. Our results suggest that IRS-1 is in fact an important growth-regulatory molecule that can be a potential effective target for chemotherapeutic intervention with growth-suppressive agents, including retinoids.