Genetic mutations in smoking-associated prostate cancer.

OBJECTIVES: Tobacco smoking is known to cause cancers potentially predisposed by genetic risks. We compared the frequency of gene mutations using a next generation sequencing database of smokers and nonsmokers with prostate cancer (PCa) to identify subsets of patients with potential genetic risks. MATERIALS AND METHODS: Data from the American Association for Cancer Research Project Genomics Evidence Neoplasia Information Exchange (GENIE) registry was analyzed. The GENIE registry contains clinically annotated sequenced tumor samples. We included 1832 men with PCa in our cohort, categorized as smokers and nonsmokers, and compared the frequency of mutations (point mutations, copy number variations, and structural variants) of 47 genes with more than 5% mutation rate between the two categories and correlated with overall survival using logistic regression analysis. RESULTS: Overall, 1007 (55%) patients were nonsmokers, and 825 (45%) were smokers. The mutation frequency was significantly higher in smokers compared to nonsmokers, 47.6% and 41.3%, respectively (p = 0.02). The median tumor mutational burden was also significantly higher in the samples from smokers (3.59 mut/MB) compared to nonsmokers (1.87 mut/MB) (p < 0.001). Patients with a smoking history had a significantly higher frequency of PREX2, PTEN, AGO2, KMT2C, and a lower frequency of adenomatous polyposis coli (APC) and KMT2A mutations than compared to nonsmokers. The overall mortality rate (28.5% vs. 22.8%) was significantly higher among smokers (p = 0.006). On a multivariate logistic regression analysis, the presence of metastatic disease at the time of diagnosis (OR: 2.26, 95% CI: 1.78-2.89, p < 0.001), smoking history (OR: 1.32, 95% CI: 1.05-1.65, p = 0.02), and higher frequency of PTEN somatic gene mutation (OR: 1.89, 95% CI: 1.46-2.45, p < 0.001) were independent predictors of increased overall mortality among patients with PCa. Patients with PTEN mutation had poorer overall survival compared to men without PTEN mutations: 96.00 (95% CI: 65.36-113.98) and 120.00 (95% CI: 115.05-160.00) months, respectively (p < 0.001) irrespective of smoking history although the G129R PTEN mutation was characteristically detected in smokers. CONCLUSIONS: PCa patients with a tobacco smoking history demonstrated a significantly higher frequency of somatic genetic mutations. Whereas mutations of PREX2, KMT2C, AGO2, and PTEN genes were higher in smokers, the APC and KMT2A mutations were higher in nonsmokers. The PTEN somatic gene mutation was associated with increased overall mortality among patients with PCa irrespective of smoking history. We found that G129R PTEN mutation known to reduce the PTEN phosphatase activity and K267Rfs*9 a frameshift deletion mutation in the C2 domain of PTEN associated with membrane binding exclusively detected in smokers and nonsmokers, respectively. These findings may be used to further our understanding of PCa associated with smoking.

Emergency holmium laser enucleation of the prostate (HoLEP): a novel approach in the management of refractory hematuria for patients with benign prostatic hyperplasia (BPH): a single-institution experience.

INTRODUCTION: Refractory hematuria secondary to prostatic disease typically resolves with conservative management; however, this condition may require hospitalization with extensive measures to control life-threatening bleeding. The aim of this study was to report our experience using holmium laser enucleation of the prostate (HoLEP) as an emergency treatment in this clinical setting. METHODS: We conducted a retrospective review of all patients that presented to the emergency department with refractory hematuria of prostatic origin from October 2017 to September 2021, for whom hospitalization and conservative management failed to control bleeding. All emergency HoLEP procedures were performed by a single surgeon. Preoperative and intraoperative parameters, as well as perioperative outcomes, were collected and analyzed. Postoperative outcomes included duration of foley catheterization, length of postoperative hospital stay, and hospital readmissions. RESULTS: A total of 40 emergency HoLEP procedures were performed. Our cohort had a median prostate volume of 110.5 cc and a median resected weight of 81 g. Twenty-seven patients (67.5%) were on anticoagulant or antiplatelet medications on admission. The urethral catheter was removed within 1 day in 95% of patients with a successful trial of void (TOV). Moreover, 92.5% of patients were discharged home within 24 h of their procedure. Two patients (5%) experienced clot retention within one-week post-discharge with a 2.5% overall readmission rate. All postoperative parameters, including International Prostate Symptom Score (IPSS), quality of life (QoL), maximum flow rate (Qmax), and post-void residual volume (PVR), showed significant improvement at 1 year follow up. CONCLUSION: Our experience demonstrates that emergency HoLEP is an effective treatment option for patients with refractory hematuria of prostatic origin. Further studies are warranted to consolidate our results.

Diagnostic Significance of hsa-miR-21-5p, hsa-miR-192-5p, hsa-miR-155-5p, hsa-miR-199a-5p Panel and Ratios in Hepatocellular Carcinoma on Top of Liver Cirrhosis in HCV-Infected Patients.

Early hepatocellular carcinoma (HCC) diagnosis is challenging. Moreover, for patients with alpha-fetoprotein (AFP)-negative HCC, this challenge is augmented. MicroRNAs (miRs) profiles may serve as potential HCC molecular markers. We aimed to assess plasma homo sapiens-(hsa)-miR-21-5p, hsa-miR-155-5p, hsa-miR-192-5p, and hsa-miR-199a-5p-expression levels as a panel of biomarkers for HCC in chronic hepatitis C virus (CHCV) patients with liver cirrhosis (LC), especially AFP-negative HCC cases, as a step toward non-protein coding (nc) RNA precision medicine. SUBJECTS AND METHODS: 79 patients enrolled with CHCV infection with LC, subclassified into an LC group without HCC (n = 40) and LC with HCC (n = 39). Real-time quantitative PCR was used to measure plasma hsa-miR-21-5p, hsa-miR-155-5p, hsa-miR-192-5p, and hsa-miR-199a-5p. RESULTS: Plasma hsa-miR-21-5p and hsa-miR-155-5p demonstrated significant upregulation, while hsa-miR-199a-5p demonstrated significant downregulation in the HCC group (n = 39) when compared to the LC group (n = 40). hsa-miR-21-5p expression was positively correlated with serum AFP, insulin, and insulin resistance (r = 0.5, p < 0.001, r = 0.334, p = 0.01, and r = 0.303, p = 0.02, respectively). According to the ROC curves, for differentiating HCC from LC, combining AFP with each of hsa-miR-21-5p, hsa-miR-155-5p, and miR199a-5p improved the diagnostic sensitivity to 87%, 82%, and 84%, respectively, vs. 69% for AFP alone, with acceptable specificities of 77.5%, 77.5%, and 80%, respectively, and AUC = 0.89, 0.85, and 0.90, respectively vs. 0.85 for AFP alone. hsa-miR-21-5p/hsa-miR-199a-5p and hsa-miR-155-5p/hsa-miR-199a-5p ratios discriminated HCC from LC at AUC = 0.76 and 0.71, respectively, with sensitivities = 94% and 92% and specificities = 48% and 53%, respectively. Upregulation of plasma hsa-miR-21-5p was considered as an independent risk factor for HCC development [OR = 1.198(1.063-1.329), p = 0.002]. CONCLUSIONS: Combining each of hsa-miR-21-5p, hsa-miR-155-5p, and hsa-miR-199a-5p with AFP made it possible to identify HCC development in the LC patients' cohort with higher sensitivity than using AFP alone. hsa-miR-21-5p/hsa-miR-199a-5p and hsa-miR-155-5p/hsa-miR-199a-5p ratios are potential HCC molecular markers for AFP-negative HCC patients. hsa-miR-21-5p was linked, clinically and via in silico proof, to insulin metabolism, inflammation, dyslipidemia, and tumorigenesis in the HCC patients' group as well as for an upregulated independent risk factor for the emergence of HCC from LC in the CHCV patients.

A systematic review of multi-level stigma interventions: state of the science and future directions.

BACKGROUND: Researchers have long recognized that stigma is a global, multi-level phenomenon requiring intervention approaches that target multiple levels including individual, interpersonal, community, and structural levels. While existing interventions have produced modest reductions in stigma, their full reach and impact remain limited by a nearly exclusive focus targeting only one level of analysis. METHODS: We conducted the first systematic review of original research on multi-level stigma-reduction interventions. We used the following eligibility criteria for inclusion: (1) peer-reviewed, (2) contained original research, (3) published prior to initiation of search on November 30, 2017, (4) evaluated interventions that operated on more than one level, and (5) examined stigma as an outcome. We stratified and analyzed articles by several domains, including whether the research was conducted in a low-, middle-, or high-income country. RESULTS: Twenty-four articles met the inclusion criteria. The articles included a range of countries (low, middle, and high income), stigmatized conditions/populations (e.g., HIV, mental health, leprosy), intervention targets (e.g., people living with a stigmatized condition, health care workers, family, and community members), and stigma reduction strategies (e.g., contact, social marketing, counseling, faith, problem solving), with most using education-based approaches. A total of 12 (50%) articles examined community-level interventions alongside interpersonal and/or intrapersonal levels, but only 1 (4%) combined a structural-level intervention with another level. Of the 24 studies, only 6 (25%) were randomized controlled trials. While most studies (17 of 24) reported statistically significant declines in at least one measure of stigma, fewer than half reported measures of practical significance (i.e., effect size); those that were reported varied widely in magnitude and were typically in the small-to-moderate range. CONCLUSIONS: While there has been progress over the past decade in the development and evaluation of multi-level stigma interventions, much work remains to strengthen and expand this approach. We highlight several opportunities for new research and program development.

Impact of 5α-Reductase Inhibitors on Disease Reclassification among Men on Active Surveillance for Localized Prostate Cancer with Favorable Features.

PURPOSE: We determined the effect of 5α-reductase inhibitors on disease reclassification in men with prostate cancer optimally selected for active surveillance. MATERIALS AND METHODS: In this retrospective review we identified 635 patients on active surveillance between 2002 and 2015. Patients with favorable cancer features on repeat biopsy, defined as absent Gleason upgrading, were included in the cohort. Patients were stratified by those who did or did not receive finasteride or dutasteride within 1 year of diagnosis. The primary end point was grade reclassification, defined as any increase in Gleason score or predominant Gleason pattern on subsequent biopsy. This was assessed by multivariable Cox proportional hazards regression analysis. RESULTS: At diagnosis 371 patients met study inclusion criteria, of whom 70 (19%) were started on 5α-reductase inhibitors within 12 months. Median time on active surveillance was 53 vs 35 months in men on vs not on 5α-reductase inhibitors (p <0.01). Men on 5α-reductase inhibitors received them for a median of 23 months (IQR 6-37). On actuarial analysis there was no significant difference in grade reclassification for 5α-reductase inhibitor use in patients overall or in the very low/low risk subset. The overall percent of patients who experienced grade reclassification was similar at 13% vs 14% (p = 0.75). After adjusting for baseline clinicopathological features 5α-reductase inhibitors were not significantly associated with grade reclassification (HR 0.80, 95% CI 0.31-1.80, p = 0.62). Furthermore, no difference in adverse features on radical prostatectomy specimens was observed in treated patients (p = 0.36). CONCLUSIONS: Among our cohort of men on active surveillance 5α-reductase inhibitor use was not associated with a significant difference in grade reclassification with time.

Avoidance of androgen deprivation therapy in radiorecurrent prostate cancer as a clinically meaningful endpoint for salvage cryoablation.

BACKGROUND: To investigate the ability of salvage cryoablation of the prostate (SCAP) to delay the need for androgen deprivation therapy (ADT) in local recurrence after radiation therapy to the prostate using the Cryo-On-Line Database (COLD) registry. METHODS: The COLD registry is comprised of a combination of retrospectively and prospectively collected data on patients undergoing primary and SCAP. Patients with local recurrence after radiation therapy were identified. Kaplan-Meier analysis was used to calculate ADT-free survival. RESULTS: We identified 898 patients that have undergone SCAP in the COLD registry. Overall, the calculated 5-year ADT-free survival probability was 0.713. When stratified by D'Amico risk group, 264 high-risk patients (71.9%), 234 intermediate-risk (86.7%),and 228 low-risk (87.7%) were free of ADT post-SCAP. This correlates with a 5-year ADT-free survival of 60.7, 73.9, and 82.4%, respectively. Patients with post-SCAP PSA nadir of <0.2 ng/mL had a 5 year ADT-free survival of 87.1% compared to 48.7% with a PSA nadir ≥0.2 ng/mL. Pre-operative ADT use or full versus partial gland SCAP did not have an effect on ADT use post-operatively. In 118 (55.4%) of patients with post-operative biochemical recurrence, ADT was not used. CONCLUSION: For patients with local recurrence after radiation, SCAP is an option that provides a high chance of avoiding or delaying ADT. The potential to delay ADT and its associated side effects should be a part of counseling sessions with the patient when discussing treatment options for locally recurrent prostate cancer after radiation. Avoidance of ADT is more clinically relevant than PSA elevation.

Outcomes of Active Surveillance after Initial Surveillance Prostate Biopsy.

PURPOSE: We analyzed the rates of disease reclassification at initial and subsequent surveillance prostate biopsy as well as the treatment outcomes of deferred therapy among men on active surveillance for prostate cancer. MATERIALS AND METHODS: From a prospective database we identified 300 men on active surveillance who had undergone initial surveillance prostate biopsy, with or without confirmatory biopsy, within 1 year of diagnosis. Of these men 261 (87%) were classified as having NCCN very low or low risk disease at diagnosis. Disease reclassification on active surveillance was defined as the presence of 50% or more positive cores and/or surveillance prostate biopsy Gleason score upgrading. Patients with type I disease reclassification included those with any surveillance prostate biopsy Gleason score upgrading, while patients with type II reclassification had to have primary Gleason pattern 4-5 disease on surveillance prostate biopsy. Outcomes after initial surveillance prostate biopsy were evaluated using actuarial analyses. RESULTS: At the time of initial surveillance prostate biopsy 49 (16%) and 19 (6%) patients had type I and type II disease reclassification, respectively. Those who underwent confirmatory biopsy had significantly reduced rates of type I (9% vs 23%, p=0.001) and type II (3% vs 9%, p=0.01) reclassification at initial surveillance prostate biopsy. For the 251 patients without disease reclassification at initial surveillance prostate biopsy the 2-year rates of subsequent type I and II reclassification were 17% (95% CI 0-24) and 3% (95% CI 0.1-7), respectively. For the 93 patients who received deferred therapy the 5-year biochemical progression-free probability was 89% (95% CI 79-98), including 95%, 82% and 70% among those without, and those with type I and type II disease reclassification, respectively. CONCLUSIONS: Patients on active surveillance with stable disease at the time of initial surveillance prostate biopsy may be appropriate candidates for less intensive surveillance prostate biopsy schedules.

Intermediate-Term Outcomes for Men with Very Low/Low and Intermediate/High Risk Prostate Cancer Managed by Active Surveillance.

PURPOSE: We compare intermediate term clinical outcomes among men with favorable risk and intermediate/high risk prostate cancer managed by active surveillance. MATERIALS AND METHODS: A total of 635 men with localized prostate cancer have been on active surveillance since 2002 at a high volume academic hospital in the United States. Median followup is 50.5 months (IQR 31.1-80.3). Time to event analysis was performed for our clinical end points. RESULTS: Of the cohort 117 men (18.4%) had intermediate/high risk disease. Overall 5 and 10-year all cause survival was 98% and 94%, respectively. Cumulative metastasis-free survival at 5 and 10 years was 99% and 98%, respectively. To date no cancer specific deaths had been observed. Overall freedom from intervention was 61% and 49% at 5 and 10 years, respectively. Overall cumulative freedom from failure of active surveillance, defined as metastasis or biochemical failure after local therapy with curative intent, was 97% and 91% at 5 and 10 years, respectively. Of the men 21 (9.9%) experienced biochemical failure after deferred treatment and the 5-year progression-free probability was 92%. Compared to men with favorable risk disease those with intermediate/high risk cancer experienced no difference in metastases, surveillance failure or curative intervention. However, patients at higher risk were at significantly increased risk for all cause mortality, likely reflecting patient selection factors. These conclusions may be limited by the small number of events and the duration of our study. CONCLUSIONS: Patients with localized prostate cancer who are on active surveillance demonstrated a low rate of active surveillance failure, prostate cancer specific mortality and metastases regardless of baseline risk.

The expression profiling of serum miR-92a, miR-375, and miR-760 in colorectal cancer: An Egyptian study.

Dysregulation in microRNA expression is a common feature in colorectal cancer. Due to the inconsistent results regarding serum miR-92a expression pattern and the insufficient studies on serum miR-375 and miR-760, we aimed in this study to investigate their expression profile and diagnostic and prognostic power in Egyptian colorectal cancer patients. The expression profile of miR-92a, miR-375, and miR-760 was determined in the sera of 64 colorectal cancer patients using quantitative real-time reverse transcription polymerase chain reaction in comparison to 27 healthy control subjects. The expression fold change of the studied microRNAs was correlated with patients' clinicopathological features. Receiver operating characteristic curve analysis was done to determine the role of these microRNAs in colorectal cancer diagnosis and follow-up according to the yielded area under the curve. The expression pattern of miR-92a was significantly upregulated (3.38 ± 2.52, p < 0.0001), while both of miR-375 and 760 were significantly downregulated (-1.250 ± 1.80, p< 0.0001; -1.710 ± 1.88, p < 0.0001, respectively) in colorectal cancer than the control. MiR-92a was positively correlated ( r = 0.671, p = 0.0001), while miR-375 and miR-760 were inversely correlated ( r = -0.414, p = 0.001; r = -0.644, p = 0.0001) with advanced colorectal cancer stages. Receiver operating characteristic curve analysis disclosed the highest diagnostic potential for miR-760 to discriminate colorectal cancer patients and early-stage colorectal cancer from the control (area under the curve = 0.922 and 0.875, respectively), while the highest prognostic potential for discrimination between colorectal cancer stages was for miR-92a. In conclusion, serum level of miR-92a, miR-375, and miR-760 may serve as biomarkers of colorectal cancer in Egyptian patients with high diagnostic power for miR-760 and high prognostic power for miR-92a.

External validation of a PCA-3-based nomogram for predicting prostate cancer and high-grade cancer on initial prostate biopsy.

INTRODUCTION: The aim of this study was to externally validate a previously developed PCA3-based nomogram for the prediction of prostate cancer (PCa) and high-grade (intermediate and/or high-grade) prostate cancer (HGPCa) at the time of initial prostate biopsy. METHODS: A retrospective review was performed on a cohort of 336 men from a large urban academic medical center. All men had serum PSA <20 ng/ml and underwent initial transrectal ultrasound-guided prostate biopsy with at least 10 cores sampling for suspicious exam and/or elevated PSA. Covariates were collected for the nomogram and included age, ethnicity, family history (FH) of PCa, PSA at diagnosis, PCA3, total prostate volume (TPV), and abnormal finding on digital rectal exam (DRE). These variables were used to test the accuracy (concordance index) and calibration of a previously published PCA3 nomogram. RESULTS: Biopsy confirms PCa and HGPCa in 51.0% and 30.4% of validation patients, respectively. This differed from the original cohort in that it had significantly more PCa and HGPCA (51% vs. 44%, P = 0.019; and 30.4% vs. 19.1%, P < 0.001). Despite the differences in PCa detection the concordance index was 75% and 77% for overall PCa and HGPCa, respectively. Calibration for overall PCa was good. CONCLUSIONS: This represents the first external validation of a PCA3-based prostate cancer predictive nomogram in a North American population. Prostate 76:1019-1023, 2016. © 2016 Wiley Periodicals, Inc.

More Favorable Pathological Outcomes in Men with Low Risk Prostate Cancer Diagnosed on Repeat versus Initial Transrectal Ultrasound Guided Prostate Biopsy.

PURPOSE: We assessed the pathological outcomes after radical prostatectomy in men with favorable risk prostate cancer diagnosed on first/initial biopsy compared to those of men who were diagnosed on a subsequent/repeat prostate biopsy. MATERIALS AND METHODS: We identified 422 patients who met National Comprehensive Cancer Network® very low (199) and low risk (223) prostate cancer definitions who instead underwent radical prostatectomy. In each risk category we compared adverse pathological outcomes, defined as Gleason score upgrading, extraprostatic extension, seminal vesicle invasion and positive surgical margins, between men diagnosed on initial prostate biopsy vs repeat/subsequent prostate biopsy after a negative biopsy(-ies). RESULTS: There were no significant differences in the baseline clinical and demographic characteristics between the groups. However, men who were diagnosed on initial prostate biopsy demonstrated a higher median maximum cancer percent per single core (p <0.001) and higher median percent of positive cores (p <0.001). Compared to repeat/subsequent prostate biopsy, men diagnosed on initial prostate biopsy had a higher Gleason score upgrade (7 or greater) (57.7% vs 42.1%, p=0.005) and extraprostatic extension (14.1% vs 5.4%, p=0.01). On stratified analysis comparing initial prostate biopsy to repeat/subsequent prostate biopsy, very low risk disease was associated with Gleason score upgrade (49.3% vs 31.8%, p=0.02) and low risk disease demonstrated higher rates of extraprostatic extension (19.9% vs 6.0%, p=0.02). CONCLUSIONS: The likelihood of adverse pathological outcomes at radical prostatectomy is lower in men diagnosed with favorable risk prostate cancer on repeat/subsequent prostate biopsy than in men diagnosed on initial prostate biopsy, and may represent an important consideration in risk stratifying cases of favorable risk prostate cancer.

Salvage focal prostate cryoablation for locally recurrent prostate cancer after radiotherapy: initial results from the cryo on-line data registry.

BACKGROUND: Several investigators have tried to apply salvage focal prostate cryoablation to small numbers of patients with biopsy-proven unilateral recurrent prostate cancer (PCa) after radiotherapy with the aim of decreasing complications of salvage cryoablation. We report contemporary outcomes of salvage focal cryoablation for locally recurrent PCa after radiotherapy within the Cryo On-Line Data (COLD) Registry. METHODS: We queried the COLD Registry to identify patients diagnosed as locally recurrent PCa after radiotherapy and treated with salvage focal cryoablation. Patients with hormone ablation after cryotherapy were excluded. The biochemical disease-free survival and morbidities were analyzed. Biochemical failure was defined using the Phoenix definition. RESULTS: From 2002 to 2012, 91 patients with biopsy-proven radio-recurrent PCa underwent salvage focal cryoablation with curative intent. The biochemical disease-free survival rates were 95.3%, 72.4%, and 46.5% at 1, 3, and 5 years, respectively. Positive biopsies after salvage focal cryoablation were observed in four of 14 patients who underwent biopsy (28.6%). Rectourethral fistula was observed in three cases (3.3%). Urinary retention was observed in six cases (6.6%). Incontinence (requiring pad use) was reported in five cases (5.5%). Intercourse was reported in 10 of 20 patients (50%) who reported potency before salvage focal cryoablation. CONCLUSIONS: The outcomes from this observational study indicate that salvage focal cryoablation can be an effective treatment with encouraging potency preservation for patients with locally recurrent PCa after radiotherapy. However, other morbidity including rectourethral fistula and incontinence are not clearly lower than for patients treated with salvage whole gland cryoablation. Studies with longer follow-up, more patients, and direct comparison to salvage whole gland cryoablation are needed before recommending salvage focal cryoablation as a standard treatment option for these patients.

A pretreatment nomogram for prediction of biochemical failure after primary cryoablation of the prostate.

BACKGROUND: To create a predictive nomogram for biochemical failure following primary whole-gland cryoablation of the prostate for localized prostate cancer (LPCa). METHODS: We retrospectively analyzed 2,242 patients from the Cryo On-Line Database (COLD) who were treatment naive and had undergone primary whole gland cryoablation of the prostate for biopsy-confirmed LPCa. Kaplan-Meier (KM) curves estimating 5 year biochemical progression-free survival (bPFS) were generated. Multivariable Cox proportional hazards analysis (CoxPH) was performed in order to construct the nomogram. The nomogram was internally validated using the bootstrap technique. RESULTS: Overall, the KM estimated 5 year bPFS was 72.8%. Stratified by D'Amico risk, The KM estimated 5 year bPFS was 82.6%, 71.1%, and 57.8% for low-, intermediate-, and high-risk groups, respectively. Statistically significant predictors of biochemical outcomes from CoxPH analysis were pre-treatment prostate specific antigen (PTPSA) (P < 0.001), total prostate volume (P = 0.004), clinical stage (P = 0.034), and Gleason score (0.004). A nomogram for predicted 5 year biochemical progression free probability was constructed with a concordance index of 0.652. An online risk calculator was also generated. CONCLUSIONS: To the best of our knowledge, this is the first predictive nomogram for biochemical outcomes after primary whole gland cryoablation of the prostate using socio-demographic, pretreatment, clinical, and prostate biopsy data. Our nomogram and online risk calculator can guide both patients and urologists for shared decision making regarding definitive treatment options.

PCA3-based nomogram for predicting prostate cancer and high grade cancer on initial transrectal guided biopsy.

BACKGROUND: To develop a validated prostate cancer antigen 3 (PCA3) based nomogram that predicts likelihood of overall prostate cancer (PCa) and intermediate/high grade prostate cancer (HGPCa) in men pursuing initial transrectal prostate biopsy (TRUS-PBx). METHODS: Data were collected on 3,675 men with serum prostate specific antigen level (PSA) ≤ 20 ng/ml who underwent initial prostate biopsy with at least 10 cores sampling at time of the biopsy. Two logistic regression models were constructed to predict overall PCa and HGPCa incorporating age, race, family history (FH) of PCa, PSA at diagnosis, PCA3, total prostate volume (TPV), and digital rectal exam (DRE). RESULTS: One thousand six hundred twenty (44%) patients had biopsy confirmed PCa with 701 men (19.1%) showing HGPCa. Statistically significant predictors of overall PCa were age (P < 0.0001, OR. 1.51), PSA at diagnosis (P < 0.0001, OR.1.95), PCA3 (P < 0.0001, OR.3.06), TPV (P < 0.0001, OR.0.47), FH (P = 0.003, OR.1.32), and abnormal DRE (P = 0.001, OR. 1.32). While for HGPCa, predictors were age (P < 0.0001, OR.1.77), PSA (P < 0.0001, OR.2.73), PCA3 (P < 0.0001, OR.2.26), TPV (P < 0.0001, OR.0.4), and DRE (P < 0.0001, OR.1.53). Two nomograms were reconstructed for predicted overall PCa probability at time of initial biopsy with a concordance index of 0.742 (Fig. 1), and HGPCa with a concordance index of 0.768 (Fig. 2). CONCLUSIONS: Our internally validated initial biopsy PCA3 based nomogram is reconstructed based on a large dataset. The c-index indicates high predictive accuracy, especially for high grade PCa and improves the ability to predict biopsy outcomes.

Low risk patients benefit from extreme anterior apical sampling on initial biopsy for prostate cancer diagnosis.

BACKGROUND: To assess the effect of additional extreme apical sampling on prostate cancer (PCa) detection and aggressiveness in patients with standard risk versus high risk of a positive biopsy. METHODS: Three thousand fifty three men were reviewed from our institution review board approved prostate biopsy database. Two thousand five hundred and twenty one underwent biopsy with 12 cores while 532 underwent 14 core sampling (2 extra cores from the extreme anterior apex). Patients were stratified into one of two risk groups: (1) standard risk of PCa (elevated prostate specific antigen (PSA) < 10 ng/ml, normal digital rectal exam (DRE), and no lesions on transrectal ultrasound (TRUS)), and (2) higher risk of PCa (PSA > 10 ng/ml and/or abnormal DRE and/or lesion on TRUS). Prostate cancer detection and disease characteristics were compared between the biopsy schemes stratified by risk of a positive biopsy. RESULTS: PCa detection with 14 core sampling was more likely in all patients (OR 1.339, 95% CL 1.070-1.676) and in men with standard risk (OR 1.334, 95% CL 1.007-1.769). A greater median number of positive cores (3 vs. 2) and a higher maximum cancer % per core (40% vs. 25%) were seen in the 14 core cohort when stratified to standard risk. Gleason ≥7 was more likely detected with 14 cores in the standard risk group (55.6% vs. 45.2%). Differences in PCa detection and Gleason ≥7 between biopsy techniques were not noted in the higher risk group. CONCLUSION: Extreme apical sampling increases aggressive cancer detection on initial biopsy, especially in patients with standard risk of PCa.

Definition of biochemical success following primary whole gland prostate cryoablation.

PURPOSE: We identified an evidence-based definition of biochemical success following primary whole gland prostate cryoablation. MATERIALS AND METHODS: The COLD Registry was queried for a risk stratified cohort of otherwise treatment naïve patients who underwent primary whole gland prostate cryoablation, of whom none had received any type of adjuvant therapy. Minimum followup in all study patients was 5 years. Variables included patient age, prostate specific antigen at diagnosis, Gleason score, D'Amico risk category and followup prostate specific antigen. Biochemical progression-free survival was studied based on Kaplan-Meier results using the Phoenix definition. HRs were calculated using proc PHReg. RESULTS: Of 1,111 patients 891 achieved nadir prostate specific antigen less than 0.4 ng/ml, which correlated with a 5-year biochemical progression-free survival rate of 90.4% in those at low risk, 81.1% in those at intermediate risk and 73.6% in those at high risk. Nadir prostate specific antigen 0.4 ng/ml or greater was associated with 24-month biochemical failure of 29.2% in those at low risk, 46.4% in those at intermediate risk and 48.9% in those at high risk. Statistical analysis failed to reveal a superior prostate specific antigen end point compared to 0.4 ng/ml. HR findings supported the relevance of the end point of less than 0.4 ng/ml (p <0.0001). CONCLUSIONS: To our knowledge this study represents the first evidence-based definition of biochemical success after primary whole gland prostate cryoablation. Nadir prostate specific antigen less than 0.4 ng/ml was the best objective indicator of biochemical success. Nadir prostate specific antigen 0.4 ng/ml or greater was associated with less favorable biochemical progression, precluding the use of a higher nadir prostate specific antigen end point (HR 5.649, 95% CI 4.33-7.38, p <0.0001).

Urinary PCA3 as a predictor of prostate cancer in a cohort of 3,073 men undergoing initial prostate biopsy.

PURPOSE: PCA3 is a urinary marker that has shown promise in predicting the presence of prostate cancer in men undergoing repeat prostate biopsy. We studied PCA3 before initial prostate biopsy. MATERIALS AND METHODS: Records from a single organization were retrospectively reviewed. The predictive value of PCA3 was explored using nonparametric receiver operating characteristic curve analysis (ROC) and multivariable logistic regression analysis. RESULTS: A total of 3,073 men underwent PCA3 analysis before initial prostate biopsy sampling of 12 to 14 areas. Mean PCA3 was 27.2 and 52.5 for patients without and with cancer, respectively. Prostate cancer was identified in 1,341 (43.6%) men. Overall 54.5% had Gleason 6 disease and 45.5% had Gleason 7 or greater (high grade prostate cancer). Mean PCA3 was 47.5 and 58.5 for the patients with Gleason 6 and 7 or greater disease, respectively. On multivariable logistic analysis PCA3 was statistically significantly associated with prostate cancer and high grade prostate cancer after adjusting for prostate specific antigen (p<0.001 for both), free prostate specific antigen (p=0.04 and p=0.01, respectively), age (p<0.001 for both), family history (p<0.001 and p=0.59, respectively), abnormal digital rectal examination (p=0.31 and p<0.001, respectively), prostate volume (p<0.001 for both) and body mass index (p<0.001 for both). Using ROC analysis PCA3 outperformed prostate specific antigen in the prediction of prostate cancer (AUC 0.697 vs 0.599, p<0.01) but not for high grade prostate cancer (AUC 0.682 vs 0.679, p=0.702). CONCLUSIONS: PCA3 proved a useful tool in identifying patients at risk for prostate cancer before initial prostate biopsy. To our knowledge this is the largest PCA3 study in the initial biopsy population. These results suggest that further exploration of the value of PCA3 is warranted.

Gold weight implants for management of thyroid-related upper eyelid retraction.

PURPOSE: To evaluate the use of gold weight implantation in the upper eyelid in the treatment of upper eyelid retraction caused by thyroid ophthalmopathy as regards the cosmetic and functional results and the safety of the procedure. PATIENTS AND METHOD: This is a surgical intervention case series study. The study was carried out in Ophthalmology Department in El-Minya University Hospital between January 2013 and January 2014. The study was approved by the ethical committee board of El-Minya University. Test weights were applied to the skin of the upper eyelid using special adhesive tape in the sitting position to determine the suitable implantable weight. Three interrupted nonabsorbable sutures (5/0 Dacron) were used to secure the gold weight to the tarsus. The orbicularis was closed using interrupted 6/0 vicryl sutures. The skin was closed using interrupted 6/0 nylon sutures. RESULTS: As regards the postoperative results, by the end of the follow-up period, improvement of eyelid retraction was present in all cases. Normal upper eyelid margin position (covering 2 mm of the cornea) was attained in 10 eyelids (76.92%). Undercorrection was observed in 3 eyelids (23.07%). Two eyelids covered 1 mm of the cornea, and 1 eyelid rested at the upper limbus. All patients (100%) were satisfied as regards the cosmetic results, with the degree of satisfaction ranging between very good for 3 patients and excellent for 4 patients. One patient had bilateral brick-shaped appearance. CONCLUSIONS: Gold weight implantation for treatment of thyroid-related upper eyelid retraction markedly improves the cosmetic appearance of the patient and, to a lesser extent, improves the manifestations of exposure with high patient satisfaction, and it is a relatively easy and safe procedure.

Contribution of plasma MicroRNA-21, MicroRNA-155 and circulating monocytes plasticity to childhood neuroblastoma development and induction treatment outcome.

Neuroblastoma (NB) accounts for 15% of all pediatric cancer fatalities (NB). Biomarkers that facilitate early NB detection are needed because by the time of diagnosis, over half of NBs had spread. MicroRNA-21(miR-21) and miR-155 are involved in cancer biology due to their immune modulation functions. Altered monocyte subset distribution is thought to be involved in a number of solid tumors due to its immunological role. We aimed to investigate the expression levels of miR-21 and miR-155 and their association with circulating monocytes subsets in NB and to evaluate if they correlate to the disease pathogenesis and outcome. PATIENTS AND METHODS: This case control study involved 79 children classified into 39 newly diagnosed NB children and 40 age and sex matched healthy children. Real-time PCR was used to assess the expression of plasma miR-21 and miR-155. The frequency of circulating monocytes subsets was assessed by flow cytometry. RESULTS: NB group showed significant up-regulation in expression of miR-21(20.9 folds) and miR-155 (1.8 folds) when compared to the control group (p < 0.001) and (p = 0.02) respectively. Also, frequency of circulating intermediate monocytes revealed significant up regulation in children with NB. In NB patients, there was a positive correlation between miR-21 and frequency of total and intermediate monocytes (r = 0.5 p < 0.001 and r = 0.7, p < 0.001, respectively). We found no discernible differences when we compared study markers between the high risk and intermediate risk groups. In addition, no significant difference was seen in study markers when patients were sub-grouped according to their induction treatment response. ROC curve analysis revealed that miR-21 up-regulation distinguished NB in childhood at an AUC of 0.94 (82% sensitivity and 100% specificity) while miR-155 up-regulation had less capacity to distinguish NB in childhood at an AUC of 0.65 (38% sensitivity and 93% specificity). CONCLUSION: miR-21 can be utilized as a sensitive biomarker for childhood NB development. In pediatric NB, miR-21 was linked to intermediate monocyte plasticity. Both, miR-21 and miR-155 had no impact on NB outcome.

From diagnosis to resistance: a symphony of miRNAs in pheochromocytoma progression and treatment response.

Pheochromocytoma (PCC) is a neuroendocrine tumor that produces and secretes catecholamine from either the adrenal medulla or extra-adrenal locations. MicroRNAs (miRNAs, miR) can be used as biomarkers to detect cancer or the return of a previously treated disease. Blood-borne miRNAs might be envisioned as noninvasive markers of malignancy or prognosis, and new studies demonstrate that microRNAs are released in body fluids as well as tissues. MiRNAs have the potential to be therapeutic targets, which would greatly increase the restricted therapy options for adrenal tumors. This article aims to consolidate and synthesize the most recent studies on miRNAs in PCC, discussing their potential clinical utility as diagnostic and prognostic biomarkers while also addressing their limitations.