Progression of Pentosan-Polysulfate Sodium-Associated Retinopathy: Intermediate Follow-Up.

BACKGROUND AND OBJECTIVE: To compare the risk factors for the development and progression of pigmentary retinopathy in patients exposed to pentosan polysulfate sodium (PPS). MATERIALS AND METHODS: Retrospective cohort study of patients exposed to PPS with at least two follow-up visits with multimodal imaging. RESULTS: A total of 97 patients were included (33 with PPS-associated retinopathy and 64 without). The average follow-up was 29.4 months, overall cumulative dose was 1,220 ± 910 g (1,730 ± 870 vs 959 ± 910; P < 0.0001), and total PPS duration was 12.1 ± 7.1 years (16.0.2 ± 6.1 vs 10.1 ± 6.9; P < 0.0001). The best-corrected visual acuity remained stable during follow-up. At presentation, the average area of the retinopathy in the worse eye was 54.1 ± 50 mm2 in the PPS-retinopathy group, worsening at a rate of 6.10 ± 10 mm2/year. Patients who developed choroidal neovascular membranes (CNVMs) had faster rates of retinopathy progression (11.6 ± 12 vs 3.53 ± 7.6 mm2/year, P = 0.036). No patient had the exact same gene mutation. CONCLUSION: PPS-associated pigmentary retinopathy can continue to progress over time, even after discontinuing the medication. CNVM development may be associated with faster rates of retinopathy progression. [Ophthalmic Surg Lasers Imaging Retina 2023;54:388-394.].

Initial Real-World Experience with Faricimab in Treatment-Resistant Neovascular Age-Related Macular Degeneration.

Purpose: To evaluate the initial efficacy and safety of intravitreal faricimab in eyes previously treated for neovascular age-related macular degeneration (nARMD). Patients and methods: A retrospective review of all patients with nARMD previously treated with anti-vascular endothelial growth factor (anti-VEGF) injections who received at least 3 intravitreal faricimab injections with at least 3 months of follow-up. Results: A total of 190 eyes were included. Patients received a mean of 34.2±23 anti-VEGF injections over 182.41±128 weeks prior to switching to faricimab. Patients then received a mean of 6.99±2.3 faricimab injections with an average 34.88±8.2 weeks of follow-up. The mean best corrected visual acuities improved from 0.33±0.32 logMAR ≈20/43 to 0.27±0.32 logMAR ≈20/37 (P=0.0022). The central subfield thickness (CST) improved from 312±87µm to 287±71µm (P<0.0001). At the last clinical visit, 24% had no subretinal fluid or intraretinal fluid on optical coherence tomography. The mean dosing interval between the last two consecutive faricimab injections (7.64±6.2 weeks) was significantly longer than that for ranibizumab (5.16±2.0 weeks, P<0.001) or aflibercept (5.57±3.6 weeks, P<0.001). No patients developed idiopathic intraocular inflammation. Conclusion: Intravitreal faricimab was associated with improved vision and CSTs, even in treatment-resistant nARMD eyes. The mean last dosing interval for faricimab was longer than for ranibizumab or aflibercept. No significant adverse events were directly attributed to faricimab during the study.

Probing the Role of Melanocortin Type 1 Receptor Agonists in Diverse Immunological Diseases.

Background: The melanocortin α-melanocyte stimulating hormone (α-MSH), an endogenous peptide with high affinity for the melanocortin 1 receptor (MC1r), has demonstrated prevention and reversal of intestinal and ocular inflammation in animal models. Preclinical studies were performed to determine whether two MC1r receptor agonists, PL-8177 and PL-8331, exhibit actions and efficacy similar to α-MSH in preventing and reversing intestinal and ocular inflammation. Methods: Both PL-8177 and PL-8331 were assessed in a Eurofins LeadProfilingScreen selectivity panel including 72 in vitro assays. PL-8177 and PL-8331 were evaluated in an in vitro assay using human whole blood stimulated by lipopolysaccharide to determine inhibition of tumor necrosis factor alpha (TNF-α); for comparison, adrenocorticotropic hormone (ACTH) and α-MSH were used as positive controls. PL-8177, dosed at 0.5, 1.5, and 5.0 µg, was assessed in a cannulated rat model of dinitrobenzene sulfonic acid (DNBS)-induced bowel inflammation versus vehicle and oral sulfasalazine. PL-8177 was also dosed at 0.3 mg/kg/mouse injected intraperitoneally versus untreated controls and α-MSH treatment in mice with experimental autoimmune uveitis (EAU). PL-8331 at 3 doses, 3 times daily, was evaluated in a murine model of scopolamine-induced dry eye disease (SiccaSystemTM model), versus twice-daily Restasis® and Xiidra®. Results: Both PL-8177 and PL-8331 demonstrated no significant activity at the 1 µm concentration in any of the 72 in vitro assays. PL-8177 and PL-8331 inhibited lipopolysaccharide-induced TNF-α to a similar degree as ACTH and α-MSH. In the DNBS rat model of bowel inflammation, PL-8177 was significantly superior to untreated controls at all 3 doses (P < 0.05) in reducing bowel inflammation parameters, with effects similar to sulfasalazine. In the murine EAU model, PL-8177 significantly reduced retinal inflammation scores versus untreated controls (P = 0.0001) over 3-5 weeks, and to a similar degree as α-MSH. In the murine scopolamine-induced model of dry eye disease, PL-8331 reduced corneal fluorescein staining scores at all doses, significantly (P = 0.02) for the highest dose (1 × 10-5 mg⋅mL-1), and similarly to Restasis®; Xiidra® demonstrated no effect. Conclusion: The MC1r receptor agonists PL-8177 and PL-8331 exhibited actions similar to those of α-MSH in preventing and reversing intestinal and ocular inflammation in preclinical disease models.

A systematic review of as needed versus treat and extend ranibizumab or bevacizumab treatment regimens for neovascular age-related macular degeneration.

PURPOSE: To evaluate the relative efficacy of as needed versus treat and extend regimen for the treatment of neovascular age-related macular degeneration (AMD). METHODS: We conducted a systematic review of studies that evaluated the efficacy of as needed or treat and extend regimen for neovascular AMD by searching multiple databases up to December 2013. Included studies were selected based on study duration of no less than 12 months, availability of outcome data, treatment protocol for as needed groups or pro re nata (PRN) receiving bevacizumab or ranibizumab, and all studies with treat extend protocols following the 'inject and extend' regimen. The outcome data were pooled and analysed. RESULTS: 1046 peer reviewed articles meeting our initial search criteria were returned. After further review by two independent reviewers, 8 studies meeting treat and extend protocol and 62 studies meeting PRN protocol were included. The mean improvement in visual acuity in the PRN group was 5.4 ETDRS letters compared with 10.4 ETDRS letters in the treat and extend group. The PRN group received an average of 5.60 injections at 1 year compared with 8.09 in the treat and extend group. Central retinal thickness improved on average by 100.32 µ in the PRN group compared with 87.7 µ in the treat and extend group. CONCLUSIONS: Though our study suggests superiority of the treat and extend regimen to PRN treatment in a 12-month period, this review demonstrates the need for randomised clinical trials to confirm our findings and to evaluate long-term efficacy outcomes with these regimens compared with monthly therapy.

Seeing through VEGF: innate and adaptive immunity in pathological angiogenesis in the eye.

The central role of vascular endothelial growth factor (VEGF) signaling in regulating normal vascular development and pathological angiogenesis has been documented in multiple studies. Ocular anti-VEGF therapy is highly effective for treating a subset of patients with blinding eye disorders such as diabetic retinopathy and neovascular age-related macular degeneration (AMD). However, chronic VEGF suppression can lead to adverse effects associated with poor visual outcomes due to the loss of prosurvival and neurotrophic capacities of VEGF. In this review, we discuss emerging evidence for immune-related mechanisms that regulate ocular angiogenesis in a VEGF-independent manner. These novel molecular and cellular pathways may provide potential therapeutic avenues for a multitarget strategy, preserving the neuroprotective functions of VEGF in those patients whose disease is unresponsive to VEGF neutralization.

Presumed ocular histoplasmosis.

PURPOSE OF REVIEW: To update the knowledge on the risk factors and treatment options for choroidal neovascular membrane due to ocular histoplasmosis and to provide a treatment algorithm. RECENT FINDINGS: Smoking has been shown to be a strong risk factor in the development of choroidal neovascularization. Alleles that have been identified as a risk factor for the development of choroidal neovascularization in age-related macular degeneration have not shown to be associated with Presumed Ocular Histoplasmosis Syndrome-related choroidal neovascularization. Treatment has largely moved away from submacular surgery and macular photocoagulation to antivascular endothelial growth factor therapy. SUMMARY: This review highlights the devastating vision loss that may occur in ocular histoplasmosis from the development of an atrophic scar at the fovea or following choroidal neovascularization. Many therapies have been tried with varied amounts of success. Antivascular endothelial growth factor therapy appears to be the gold-standard treatment with the possibility of combined photodynamic therapy in refractory cases.

Intraocular penetration of systemic antibiotics in eyes with penetrating ocular injury.

PURPOSE: To determine whether penetrating scleral or corneal injury can enhance intraocular penetration of systemic moxifloxacin, vancomycin, and ceftazidime. METHODS: Thirty rabbits were divided into 3 groups for each antibiotic and then further subdivided to receive either scleral or corneal injury to the right eye. The left eye served as a control. Intravenous antibiotics were given following injury, and eyes were subsequently enucleated. Vitreous antibiotic concentration was determined by high-performance liquid chromatography analysis. Plasma concentration was measured for comparison. RESULTS: Intravitreal moxifloxacin concentration was unchanged by injury. Minimum inhibitory concentration (MIC90) was achieved in the vitreous against the most common gram-positive endophthalmitis-causing organisms. Intravitreal vancomycin levels were not enhanced by injury and did not reach the MIC90 for gram-positive organisms commonly causing intraocular infection. Intravitreal ceftazidime was increased in the injured eyes, 67% and 73% higher in scleral and corneal injury eyes. It reached MIC90 of many gram-negative bacteria. CONCLUSIONS: Intravitreal antibiotic penetration of systemic antibiotics with or without penetrating ocular injury varies depending on the antibiotic. For prevention or treatment of gram-positive-bacteria-causing endophthalmitis, intravitreal vancomycin is necessary and provides the most reliable coverage. Systemic ceftazidime can be used for many gram-negative bacteria, but intravitreal injection is recommended for better coverage, especially for more-potent organisms. Systemic moxifloxacin can be considered for most gram-positive and -negative infections due to its excellent intraocular penetration and broad coverage, but the patient's previous history of its topical use and increasing resistance patterns must be considered.

Observation of improved adherence with frequent urine drug testing in patients with pain.

OBJECTIVE: To determine the relationship between urine drug testing (UDT) frequency and patient adherence for prescribed buprenorphine, carisoprodol, fentanyl, hydrocodone, methadone, morphine, and oxycodone. SETTING: Patients with pain routinely seen by private practitioners. DESIGN: A retrospective analysis was conducted on urinary excretion data analyzed by Millennium Laboratories between March 2008 and May 2011. PATIENT PARTICIPANTS: Patients in the United States with chronic pain who underwent routine UDT to confirm adherence for prescribed medications. INTERVENTIONS: Adherence for the urine drug test was defined as the presence of parent drug and/or metabolite(s) greater than or equal to the lower limit of quantitation. The percent of adherence for prescribed medications was compared to the average percent of the same in subjects with five or more visits. MAIN OUTCOMES: Correlation analyses were used to determine the relationship between adherence for prescribed medications and number of visits. RESULTS: There were 255,168 specimens submitted for testing from 166,755 individuals. When monitoring with more frequent visits (≥5 visits) adherence was higher by 1 percent for buprenorphine (89 percent vs 88 percent); 8 percent for carisoprodol (77 percent vs 69 percent); 5 percent for fentanyl (95 percent vs 90 percent); 7 percent for hydrocodone (83 percent vs 76 percent); 3 percent for methadone (96 percent vs 93 percent); 5 percent for morphine (92 percent vs 87 percent); and 8 percent for oxycodone (90 percent vs 82 percent). CONCLUSIONS: Adherence for prescribed medications is higher with frequent urine monitoring. UDT can be used as tool that may help improve this in patients with chronic pain.

Observations on the urine metabolic profile of codeine in pain patients.

This retrospective data analysis explored the relationship between codeine and its metabolites morphine, hydrocodone and hydromorphone. The objectives were: (i) to determine urine concentrations and mole fractions of codeine and metabolites and (ii) to examine the effect of cytochrome P450 (CYP) 2D6 inhibition on metabolite mole fractions. De-identified urine specimens were collected between September 2010 and July 2011 and analyzed using LC-MS-MS to determine codeine, morphine, hydrocodone and hydromorphone concentrations. Geometric mean urine concentrations were 0.833, 0.085 and 0.055 for morphine, hydrocodone and hydromorphone, respectively. Mole fractions were 0.23, 0.025 and 0.014 for morphine, hydrocodone and hydromorphone, respectively. The fraction of excreted codeine in the urine increased (slope = 0.06 ± .01, R² = 0.02) with total moles. As the total amount of codeine and metabolites increased, the fraction of codeine increased, while the fraction of active metabolites decreased. CYP2D6 inhibition with paroxetine, fluoxetine, bupropion and methadone significantly decreased the fraction of morphine excreted. The prevalence of codeine metabolism to morphine was considerably higher than codeine to hydrocodone. The urine concentration of codeine excreted was the greatest, followed by morphine and hydrocodone. Subjects should be monitored during concomitant use of codeine and CYP2D6 inhibitors as this affects the amount of morphine metabolite formation.

Observations on the urine metabolic ratio of oxymorphone to oxycodone in pain patients.

The object of this study was to evaluate the metabolism of oxycodone to oxymorphone in a pain patient population using a quantitative liquid chromatography-tandem mass spectrometry analysis of 32,656 urine specimens obtained from pain patients between March 2008 and Feb 2010. The observed excretion was modeled using logarithmic transformation and approximated a Gaussian distribution. Oxycodone excretion into urine had a geometric mean of 1.93 mg/g of creatinine and oxymorphone had a value of 0.41 mg/g of creatinine. Increasing concentrations of oxycodone correlated with a smaller proportion of oxymorphone excretion suggesting saturation of oxycodone metabolism. Urine samples containing oxycodone without oxymorphone allowed an estimation of the proportion of poor metabolizers (2.4 ± 2.1%) in the population. A similar analysis of samples containing oxymorphone without oxycodone gave an estimate of the proportion of ultra-rapid metabolizers (1.8 ± 1.1%) in the population. Samples with concentrations of oxycodone above 10 mg/g of creatinine showed a sub-population of subjects with metabolic ratios roughly 100-fold less than the linear predictive model in this study. This study describes typical ranges for oxycodone and oxymorphone in urine, and showed that it is possible to identify fast or slow metabolizers who may be at risk for adverse events.

Locally advanced prostate cancer: a population-based study of treatment patterns.

UNLABELLED: Study Type--Therapy (practice patterns). Level of Evidence 2b. What's known on the subject? And what does the study add? The treatment of locally advanced prostate cancer varies widely even though there is level one evidence supporting the use of multimodality therapy as compared with monotherapy. This study defines treatment patterns of locally advanced prostate cancer within the United States and identifies predicators of who receives multimodality therapy rather than monotherapy. OBJECTIVE: • To identify treatment patterns and predictors of receiving multimodality therapy in patients with locally advanced prostate cancer (LAPC). PATIENTS AND METHODS: • The cohort comprised patients ≥66 years with clinical stage T3 or T4 non-metastatic prostate cancer diagnosed between 1998 and 2005 identified from the Surveillance, Epidemiology and End Results (SEER) cancer registry records linked with Medicare claims. • Treatments were classified as radical prostatectomy (RP), radiation therapy (RT) and androgen deprivation therapy (ADT) received within 6 and 24 months of diagnosis. • We assessed trends over time and used multivariable logistic regression to identify predictors of multimodality treatment. RESULTS: • Within the first 6 months of diagnosis, 1060 of 3095 patients (34%) were treated with a combination of RT and ADT, 1486 (48%) received monotherapy (RT alone, ADT alone or RP alone), and 461 (15%) received no active treatment. • The proportion of patients who received RP increased, exceeding 10% in 2005. • Use of combined RT and ADT and use of ADT alone fluctuated throughout the study period. • In all 6% of patients received RT alone in 2005. • Multimodality therapy was less common in patients who were older, African American, unmarried, who lived in the south, and who had co-morbidities or stage T4 disease. CONCLUSIONS: • Treatment of LAPC varies widely, and treatment patterns shifted during the study period. • The slightly increased use of multimodality therapy since 2003 is encouraging, but further work is needed to increase combination therapy in appropriate patients and to define the role of RP.

Costs of medical care after open or minimally invasive prostate cancer surgery: a population-based analysis.

BACKGROUND: Evidence suggests that minimally invasive radical prostatectomy (MRP) and open radical prostatectomy (ORP) have similar short-term clinical and functional outcomes. MRP with robotic assistance is generally more expensive than ORP, but it is not clear whether subsequent costs of care vary by approach. METHODS: In the Surveillance, Epidemiology, and End Results (SEER) cancer registry linked with Medicare claims, men aged 66 years or older who received MRP or ORP in 2003 through 2006 for prostate cancer were identified. Total cost of care was estimated as the sum of Medicare payments from all claims for hospital care, outpatient care, physician services, home health and hospice care, and durable medical equipment in the first year from the date of surgical admission. The impact of surgical approach on costs was estimated, controlling for patient and disease characteristics. RESULTS: Of 5445 surgically treated prostate cancer patients, 4454 (82%) had ORP and 991 (18%) had MRP. Mean total first-year costs were more than $1200 greater for MRP compared with ORP ($16,919 vs $15,692; P = .08). Controlling for patient and disease characteristics, MRP was associated with 2% greater mean total payments, but this difference was not statistically significant. First-year costs were greater for men who were older, black, lived in the Northeast, had lymph node involvement, more advanced tumor stage, or greater comorbidity. CONCLUSIONS: In this population-based cohort of older men, MRP and ORP had similar economic outcomes. From a payer's perspective, any benefits associated with MRP may not translate to net savings compared with ORP in the first year after surgery.

Receptor kinase inhibitors target NSCLC: two antibodies and a small-molecule MET inhibitor.

Joining cetuximab, sorafenib, afatinib, intedanib, and crizotinib in phase III development for non-small cell lung cancer (NSCLC) are ramucirumab (developed by ImClone, a subsidiary of Lilly), necitumumab (developed by ImClone and Bristol-Myers Squibb), and tivantinib (ARQ 197, developed by ArQule and Daiichi Sankyo). Necitumumab is a second-generation anti-EGFR monoclonal antibody (mAb) similar to cetuximab. Enrollment has been stopped in one of two necitumumab phase III trials because of safety concerns. Ramucirumab is an anti-VEGFR2 mAb targeting the same pathway as bevacizumab. Although the phase II safety data for ramucirumab appear better than the data for necitumumab, fewer phase III data are available. Tivantinib is a highly selective, orally available MET tyrosine kinase inhibitor. MET is overexpressed in 61% of NSCLC cases. Although tivantinib is the last of the three agents discussed here to enter phase III, its phase II results are the most robust.

Ethnic differences in bladder cancer survival.

OBJECTIVE: To examine trends in bladder cancer survival among whites, blacks, Hispanics, and Asian/Pacific Islanders in the United States over a 30-year period. Racial disparities in bladder cancer outcomes have been documented with poorer survival observed among blacks. Bladder cancer outcomes in other ethnic minority groups are less well described. METHODS: From the Surveillance, Epidemiology and End Results cancer registry data, we identified patients diagnosed with transitional cell carcinoma of the bladder between 1975 and 2005. This cohort included 163,973 white, 7731 black, 7364 Hispanic, and 5934 Asian/Pacific Islander patients. We assessed the relationship between ethnicity and patient characteristics. Disease-specific 5-year survival was estimated for each ethnic group and for subgroups of stage and grade. RESULTS: Blacks presented with higher-stage disease than whites, Hispanics, and Asian/Pacific Islanders, although a trend toward earlier-stage presentation was observed in all groups over time. Five-year disease-specific survival was consistently worse for blacks than for other ethnic groups, even when stratified by stage and grade. Five-year disease-specific survival was 82.8% in whites compared with 70.2% in blacks, 80.7% in Hispanics, and 81.9% in Asian/Pacific Islanders. There was a persistent disease-specific survival disadvantage in black patients over time that was not seen in the other ethnic groups. CONCLUSION: Ethnic disparities in bladder cancer survival persist between whites and blacks, whereas survival in other ethnic minority groups appears similar to that of whites. Further study of access to care, quality of care, and treatment decision making among black patients is needed to better understand these disparities.

Temporal trends and predictors of pelvic lymph node dissection in open or minimally invasive radical prostatectomy.

BACKGROUND: Pelvic lymph node dissection (PLND) is an important component of prostate cancer staging and treatment, especially for surgical patients who have high-risk tumor features. It is not clear how the shift from open radical prostatectomy (ORP) to minimally invasive radical prostatectomy (MIRP) has affected the use of PLND. The objectives of this study were to identify predictors of PLND and to assess the impact of surgical technique in a contemporary, population-based cohort. METHODS: In Surveillance, Epidemiology, and End Results (SEER) cancer registry data linked with Medicare claims, the authors identified men who underwent ORP or MIRP for prostate cancer during 2003 to 2007. The impact of surgical approach on PLND was evaluated, and interactions were examined between surgical procedure, prostate-specific antigen (PSA), and Gleason score with the analysis controlled for patient and tumor characteristics. RESULTS: Of 6608 men who underwent ORP or MIRP, 70% (n = 4600) underwent PLND. The use of PLND declined over time both overall and within subgroups defined by procedure type. PLND was 5 times more likely in men who underwent ORP than in men who underwent MIRP when the analysis was controlled for patient and tumor characteristics. Elevated PSA and biopsy Gleason score, but not clinical stage, were associated with a greater odds of PLND in both the ORP group and the MIRP group. However, the magnitude of the association between these factors and PLND was significantly greater for patients in the ORP group. CONCLUSIONS: PLND was less common among men who underwent MIRP, independent of tumor risk factors. A decline in PLND rates was not fully explained by an increase in MIRP. The authors concluded that these trends may signal a surgical approach-dependent disparity in prostate cancer staging and therapy.

Renal oncocytosis: management and clinical outcomes.

PURPOSE: Renal oncocytosis is a rare pathological condition in which renal parenchyma is diffusely involved by numerous oncocytic nodules in addition to showing a spectrum of other oncocytic changes. We describe our experience with renal oncocytosis, focusing on management and outcomes. MATERIALS AND METHODS: A total of 20 patients with a final pathological diagnosis of renal oncocytosis from July 1995 through June 2009 were included in the analysis. Patient demographics, intraoperative variables and postoperative outcomes are reported. RESULTS: Median age at nephrectomy was 71 years (IQR 59-75). Of the patients 15 (75%) had bilateral disease. There were 23 operations (9 right side, 14 left side) performed on 20 patients, and of these procedures 13 (57%) were partial nephrectomies and 10 (43%) were radical nephrectomies. Median dominant tumor mass diameter was 4.1 cm (IQR 3-6.4, range 1 to 14.6). The most common dominant tumor histology was hybrid tumor between oncocytoma and chromophobe renal cell carcinoma in 13 of 23 specimens (57%), followed by chromophobe renal cell carcinoma in 6 (26%), oncocytoma in 3 (13%) and conventional renal cell carcinoma in 1 (4%). Ten patients (50%) had preexisting chronic kidney disease before nephrectomy and chronic kidney disease developed in 5 more after surgery. After a median followup of 35 months no patients had metastatic disease. CONCLUSIONS: Patients with renal oncocytosis usually present with multiple and bilateral renal nodules. Half of the patients had chronic kidney disease at diagnosis and 25% had new onset of chronic kidney disease. No patient had distant metastatic disease during followup. Our management approach is to perform partial nephrectomy when possible and then use careful surveillance of the remaining renal masses.

Role of prostate specific antigen and immediate confirmatory biopsy in predicting progression during active surveillance for low risk prostate cancer.

PURPOSE: We evaluated predictors of progression after starting active surveillance, especially the role of prostate specific antigen and immediate confirmatory prostate biopsy. MATERIALS AND METHODS: A total of 238 men with prostate cancer met active surveillance eligibility criteria and were analyzed for progression with time. Cox proportional hazards regression was used to evaluate predictors of progression. Progression was evaluated using 2 definitions, including no longer meeting 1) full and 2) modified criteria, excluding prostate specific antigen greater than 10 ng/ml as a criterion. RESULTS: Using full criteria 61 patients progressed during followup. The 2 and 5-year progression-free probability was 80% and 60%, respectively. With prostate specific antigen included in progression criteria prostate specific antigen at confirmatory biopsy (HR 1.29, 95% CI 1.14-1.46, p <0.0005) and positive confirmatory biopsy (HR 1.75, 95% CI 1.01-3.04, p = 0.047) were independent predictors of progression. Of the 61 cases 34 failed due to increased prostate specific antigen, including only 5 with subsequent progression by biopsy criteria. When prostate specific antigen was excluded from progression criteria, only 32 cases progressed, and 2 and 5-year progression-free probability was 91% and 76%, respectively. Using modified criteria as an end point positive confirmatory biopsy was the only independent predictor of progression (HR 3.16, 95% CI 1.41-7.09, p = 0.005). CONCLUSIONS: Active surveillance is feasible in patients with low risk prostate cancer and most patients show little evidence of progression within 5 years. There is no clear justification for treating patients in whom prostate specific antigen increases above 10 ng/ml in the absence of other indications of tumor progression. Patients considering active surveillance should undergo confirmatory biopsy to better assess the risk of progression.

Prognostic significance of lymphovascular invasion in radical prostatectomy specimens.

UNLABELLED: Study Type - Prognosis (case series). LEVEL OF EVIDENCE: 4. What's known on the subject? and What does the study add? The reported incidence of lymphovascular invasion (LVI) in radical prostatectomy specimens ranges from 5% to 53%. Although LVI has a strong and significant association with adverse clinicopathologic features, it has almost uniformly not been found to be a predictor of biochemical recurrence (BR) on multivariate analysis. This study confirms that LVI is associated with features of aggressive disease and is an independent predictor of BCR. Given that LVI may play a role in the metastatic process, it may be useful in clinical decision-making regarding adjuvant therapy for patients treated with RP. OBJECTIVES: To determine whether lymphovascular invasion (LVI) in radical prostatectomy (RP) specimens has prognostic significance. The study examined whether LVI is associated with clinicopathological characteristics and biochemical recurrence (BCR). PATIENTS AND METHODS: LVI was evaluated based on routine pathology reports on 1298 patients treated with RP for clinically localized prostate cancer between 2004 and 2007. LVI was defined as the unequivocal presence of tumour cells within an endothelium-lined space. The association between LVI and clinicopathological features was assessed with univariate logistic regression. Cox regression was used to test the association between LVI and BCR. RESULTS: LVI was identified in 10% (129/1298) of patients. The presence of LVI increased with advancing pathological stage: 2% (20/820) in pT2N0 patients, 16% (58/363) in pT3N0 patients and 17% (2/12) in pT4N0 patients; and was highest in patients with pN1 disease (52%; 49/94). Univariate analysis showed an association between LVI and higher preoperative prostate-specific antigen levels and Gleason scores, and a greater likelihood of extraprostatic extension, seminal vesicle invasion, lymph node metastasis and positive surgical margins (all P < 0.001). With a median follow-up of 27 months, LVI was significantly associated with an increased risk of BCR after RP on univariate (P < 0.001) and multivariate analysis (hazard ratio, 1.77; 95% confidence interval, 1.11-2.82; P = 0.017). As a result of the relatively short follow-up, the predictive accuracy of the standard clinicopathological features was high (concordance index, 0.880), and inclusion of LVI only marginally improved the predictive accuracy (0.884). CONCLUSIONS: Although associated with features of aggressive disease and BCR, LVI added minimally to established predictors on short follow-up. Further study of cohorts with longer follow-up is warranted to help determine its prognostic significance.

The Wnt inhibitory factor 1 restoration in prostate cancer cells was associated with reduced tumor growth, decreased capacity of cell migration and invasion and a reversal of epithelial to mesenchymal transition.

BACKGROUND: Aberrations in the Wnt pathway have been reported to be involved in the metastasis of prostate cancer (PCa) to bone. We investigated the effect and underlying mechanism of a naturally-occurring Wnt inhibitor, WIF1, on the growth and cellular invasiveness of a bone metastatic PCa cell line, PC3. RESULTS: The WIF1 gene promoter was hypermethylated and its expression down-regulated in the majority (7 of 8) of PCa cell lines. Restoration of WIF1 expression in PC-3 cells resulted in a decreased cell motility and invasiveness via up-regulation of epithelial markers (E-cadherin, Keratin-8 and-18), down-regulation of mesenchymal markers (N-cadherin, Fibronectin and Vimentin) and decreased activity of MMP-2 and -9. PC3 cells transfected with WIF1 consistently demonstrated reduced expression of Epithelial-to-Mesenchymal Transition (EMT) transcription factors, Slug and Twist, and a change in morphology from mesenchymal to epithelial. Moreover, WIF1 expression significantly reduced tumor growth by approximately 63% in a xenograft mouse model. This was accompanied by an increased expression of E-cadherin and Keratin-18 and a decreased expression of vimentin in tumor tissues. CONCLUSION: These data suggest that WIF1 regulates tumor invasion through EMT process and thus, may play an important role in controlling metastatic disease in PCa patients. Blocking Wnt signaling in PCa by WIF1 may represent a novel strategy in the future to reduce metastatic disease burden in PCa patients.