Evaluation of the optimal strategy in men with a single unilateral suspicious lesion on MRI undergoing transperineal MRI/ultrasound fusion prostate biopsy.

BACKGROUND: Targeting biopsy (TBx) of suspicious lesions combined with random systematic biopsy (SBx) improves detection rates of prostate cancer (PCa) during magnetic resonance imaging (MRI)/ultrasound (US) fusion prostate biopsy. However, this combination increases the number of biopsy cores, prolongs the procedure time, and increases complications and costs, leading to the overdiagnosis of clinically insignificant PCa (ciPCa). This study aims to evaluate the optimal sampling design to achieve a detection rate of clinically significant PCa (csPCa) equal to standard TBx with SBx with fewer biopsy cores. MATERIALS AND METHODS: Of 508 consecutive men who underwent transperineal MRI/US fusion prostate biopsy at our center between January 2020 and December 2022, 364 patients with a single unilateral suspicious lesion on MRI were included in the study. Three biopsy strategies were randomly selected to evaluate the diagnostic accuracy of PCa detection: (1) TBx with ipsilateral SBx, (2) TBx with contralateral SBx, and (3) TBx only. The PCa detection sensitivity for selected biopsy strategies was compared with the reference standards. The significance of differences in cancer detection between sampling schemes was determined using McNemar's test. RESULTS: PCa was diagnosed in 182 of 364 men using TBx with bilateral SBx. International Society of Urological Pathology grade group (ISUP GG) ≥ 2 and ISUP GG ≥ 3 PCa was detected in 84/364 (23.1%) and 42/364 (11.5%), respectively, while ISUP GG 1 PCa was diagnosed in 98/364 (26.9%). Combining TBx with ipsilateral SBx detected 94.5% of all, 98.8% of ISUP GG ≥ 2, 100% of ISUP GG ≥ 3, and 89.8% of ISUP GG 1 PCa. TBx with contralateral SBx detected fewer csPCa (91.7% vs. 98.8%, p = 0.03), as did TBx alone (90.5 vs. 98.8, p = 0.008). CONCLUSIONS: Our study demonstrates that TBx with ipsilateral SBx performed around the multiparametric MRI-suspected lesion in transperineal MRI/US biopsy of the prostate achieves a very high detection rate for csPCa (ISUP ≥ 2) without compromising the detection of increased risk PCa (ISUP ≥ 3). In addition, this strategy reduces the number of biopsy cores by 8-10 per patient, procedure time, and pathology processing costs and decreases ciPCa detection.

ß-TrCP upregulates HIF-1 in prostate cancer cells.

The substantial availability of hypoxia-inducible factor 1 (HIF-1) for pathophysiological states, such as malignancies and ischemia, is primarily regulated post-translationally through the ubiquitin proteolytic system. The balance between degradation and stabilization of HIF-1α protein is determined by specific E3 ligases. In our search for new E3 ligases that might affect HIF-1α protein expression, we studied the effects of beta-transducin repeat-containing protein (ß-TrCP) on the hypoxic pathway in cancer cells. ß-TrCP is overexpressed in many tumors and regulates various cellular processes through mediating the degradation of important targets. Unexpectedly, we found that ß-TrCP overexpression increases HIF-1α protein expression level as well as HIF-1 transcriptional activity by stabilizing HIF-1α protein and preventing its ubiquitination and proteasomal degradation in prostate cancer cells. By using a proteomic approach, we succeeded in demonstrating that ß-TrCP interferes with the association between HIF-1α and HSP70/CHIP, a HIF-1α established E3 ligase complex. Whereas the E3 ligase activity of ß-TrCP is well known, antagonizing another E3 ligase is a new mechanism of action of this important E3. We suggest that destroying or suppressing ß-TrCP and thereby interrupting the HIF-1 pathway, could be valuable antitumor therapy.

Ga-PSMA PET/CT Staging of Newly Diagnosed Intermediate- and High-Risk Prostate Cancer.

BACKGROUND: Ga-prostate-specific membrane antigen positron emission tomography/computerized tomography (Ga-PSMA PET/CT) is part of the initial workup of patients with intermediate and high-risk prostate cancer provided by the Israeli national health services. OBJECTIVES: To assess the incidence of metastatic spread in consecutive patients with newly diagnosed cancer, and the potential added value of Ga-PSMA PET/CT to the staging imaging algorithm. METHODS: Patients with newly diagnosed intermediate- and high-risk prostate cancer were referred for initial staging by Ga-PSMA PET/CT between May 2016 and April 2017. Blood prostate-specific antigen (PSA) levels, clinical history, imaging reports and histopathological reports (including Gleason scores) were obtained. Maximal standardized uptake values (SUVmax) were determined for the primary lesions detected within the prostate. RESULTS: The study included 137 consecutive patients with intermediate- and high-risk disease who underwent Ga-PSMA PET/CT staging. Of these, 75 had Ga-PSMA uptake in both prostate lobes, 57 had unilateral uptake, and 5 patients had no uptake. SUVmax in the primary tumor correlated significantly with PSA levels. Thirty-five patients had increased uptake compatible with metastatic disease involving lymph nodes, bone, and viscera. Twenty-seven patients had available bone scintigraphy results: 18 (69%) of their 26 bone metastases detected by Ga-PSMA PET/CT were missed on bone scintigraphy. CONCLUSIONS: Ga-PSMA PET/CT shows promise as a sole whole-body imaging modality for assessing the presence of soft tissue and bone metastases in the setting of prostate cancer.

High cancer detection rate using cognitive fusion - targeted transperineal prostate biopsies.

OBJECTIVE: MRI of the prostate improves diagnostic accuracy of prostate cancer. Different fusion approaches with transrectal ultrasound images are employed. To determine detection rate of prostate cancer in men undergoing transperineal MRIbased cognitive fusion biopsy. MATERIALS AND METHODS: One hundred and sixty-four consecutive men underwent a multiple-core prostate transperineal biopsy. Univariable and multivariable logistic regression analyses were used to address the relationship between clinical parameters and prostate cancer detection rate. RESULTS: One hundred and fourteen patients underwent mpMRI prior to the transperineal biopsy, 52 (45%) were diagnosed with prostate cancer, of them, 36 had Gleason score ≥7 (69%). Among these 114 patients, 82 had suspicious lesions on MRI, and 43 of them were diagnosed with cancer (52%). On multivariate analysis, the most significant independent predictive factors were PSA density (P<0.001) and suspicious MRI lesion (P=0.006). Men with a PSA density of more than 0.22 and a suspicious lesion on MRI had a detection rate of 78%. Detection rate among 50 patients with no MRI study prior to this biopsy was 26%. CONCLUSIONS: This study showed that among a group of mostly multi-biopsied patients, the presence of mpMRI lesions and high PSA density values helped to detect clinically significant prostate cancer using cognitive MRI/TRUS fusion biopsies.

Is diagnostic cystoscopy painful? Analysis of 1,320 consecutive procedures.

OBJECTIVE: To prospectively evaluate self-reported pain levels associated with diagnostic cystoscopy. MATERIALS AND METHODS: Patients who underwent diagnostic cystoscopy and subsequently graded their pain level during the procedure were enrolled. Pain was graded on a Likert visual analog scale (VAS) of 1-10 where 0 = no pain and 10 = excruciating unbearable pain. Local lidocaine gel 2% was used as intraurethral lubricant. RESULTS: Data from 1320 consecutive cystoscopies (929 males, 391 females, age range 15-93 years) between 6/2009-1/2010 were analyzed. This was the first cystoscopy for 814 patients. The overall mean VAS was 2.74 ± 1.51 (range 0-9) for rigid cystoscopy and 2.48 ± 1.53 (range 0-10) for flexible cystoscopy (P = 0.004). The reported mean pain level for first-time cystoscopy was significantly higher than that for repeat cystoscopy (2.8 ± 1.6 vs. 2.2 ± 1.4, P < 0.001), regardless of gender or type of cystoscope. Men reported significantly higher pain levels than women 2.6 ± 1.5 vs. 2.4 ± 1.4 (P < 0.04). The highest mean pain level was reported by men (3.4 ± 1.6) and women (2.5 ± 1.6) for rigid cystoscopy compared to flexible cystoscopy (2.5 ± 1.4 and 1.1 ± 1.9, respectively, P < 0.001). Pain levels > 5 were reported in 75 (5.7%) cystoscopies. CONCLUSIONS: Cystoscopy was not associated with distressing levels of pain. Pain levels during first cystoscopies were higher than those for repeated ones. Using a flexible cystoscope is associated with a lower pain level in both men and women and it should be used for both genders.

Identifying patients at risk for depression after radical cystectomy.

INTRODUCTION: We aimed to assess rates of depression in patients with bladder cancer undergoing radical cystectomy and identify its predictors. METHODS: Depressive symptoms in 42 consecutive patients were evaluated using the Beck's Depression Inventory (BDI) on the day prior to surgery, postoperative day (POD) 6, six weeks after surgery, and 12-18 months postoperatively. RESULTS: Fifteen patients (36%) presented with BDI scores ≥10 before the operation; this rate increased to 64% on POD 6 and 69% at six weeks post-surgery. Depression score rose from a preoperative median of 7 to 11 on POD 6 (p=0.003) and to 15 at six weeks after surgery (p=0.001). Patients who arrived with BDI score of <10 had a higher increase in the BDI at six weeks compared to patients with depressive symptoms prior to surgery (average increase 9.8 vs. 0.8, p<0.01). Age, gender, type of diversion, and complications were not associated with depression at presentation or progression of depression. Patients who did not receive neoadjuvant chemotherapy tended to be at increased risk for depression progression (57.1% vs. 14.3%, p=0.093). Twenty-four patients completed a fourth questionnaire 12-18 months postoperatively. Median BDI score was 8; three patients with disease recurrence had a higher increase in the BDI score (average 12.7 vs. -5.2, p<0.01). CONCLUSIONS: Depression among patients facing cystectomy is high and postoperative progression is substantial. Patients without depressive symptoms preoperatively are at increased risk of developing postoperative depression. After 12-18 months, the most influential risk factor for depression is recurrence. These findings highlight the need to consider interventions in selected patients.

Management of Upper Tract Urothelial Carcinoma in a Double Collecting System Kidney.

Upper tract urothelial carcinoma (UTUC) in a duplex collecting system (DCS) is a relatively uncommon presentation with unclear management guidelines. Herein, we retrospectively reviewed all published cases of DCS with UTUC aiming to suggest personalized clinical care options for future cases. We conducted a systematic search for all cases of UTUC in DCS from published literature using the following keywords: UTUC, urothelial carcinoma (UC), collecting duct carcinoma, and DCS. The cases were summarized based on demographics, clinical presentation, predisposing risk factors, tumor location, management, and follow-up. We present an additional case based on our experience with a 69-year-old female with high-grade (HG) UTUC of the upper moiety in complete DCS. The patient underwent a robotic upper pole hemi-nephroureterectomy (hemi-NU) with a common sheath distal ureterectomy and a bladder cuff, followed by lower pole ureteral reimplantation. Overall, 34 patients with 35 renal units of UTUC in DCS were included and analyzed. To conclude, UTUC of DCS is rare and underreported. Hence, it is difficult to define a standard treatment. Although hemi-NU has been previously described, to the best of our knowledge, this is the first case report of robot-assisted hemi-NU for complete DCS with single-moiety UC.

Targeting HIF-1 for prostate cancer: a synthesis of preclinical evidence.

INTRODUCTION: Hypoxia-inducible factor (HIF) mediates multiple intracellular processes that drive cellular metabolism and induce proliferation. Dysregulated HIF expression is associated with oncogenic cellular transformation. Moreover, high HIF levels correlate with tumor aggressiveness and chemoresistance, indicating the vital effect of HIF-1α on tumorigenicity. Currently, widespread in-vitro and in-vivo research is focusing on targeting HIF with drugs that have already been approved for use by the FDA, such as belzutifan, in renal cell carcinoma. HIF inhibition is mostly associated with tumor size reduction; however, drug toxicity remains a challenge. AREA COVERED: In this review, we focus on the potential of targeting HIF in prostate cancer (PC) and summarize the scientific background of HIF activity in PC. This finding emphasizes the rationale for using HIF as a therapeutic target in this malignancy. We have listed known HIF inhibitors that are being investigated in preclinical studies and their potential as anticancer drugs for PC. EXPERT OPINION: Although HIF-targeting agents have been investigated for over a decade, their use in therapy-resistant cancers remains relevant and should be explored further. In addition, the use of naturally occurring HIF inhibitors should be considered as an add-on therapy for the currently used regimens.

High detection rate of significant prostate tumours in anterior zones using transperineal ultrasound-guided template saturation biopsy.

UNLABELLED: Study Type - Diagnostic (exploratory cohort) Level of Evidence 2b. What's known on the subject? and What does the study add? Men with persistent suspicion for prostate cancer after previous negative standard transrectal biopsy series are offered saturation biopsy either transrectally or transperineally to increase cancer detection rate. A high-risk group of men with at least two previous negative transrectal biopsies underwent transperineal template-guided saturation biopsy. Prostate cancer was detected in 26%, predominantly in the anterior zones. PSA velocity or doubling time were the most powerful factors to predict cancer. OBJECTIVE: To evaluate the detection rate and the regional location of prostate cancer in men undergoing transperineal template-guided saturation biopsy (TTSB). PATIENTS AND METHODS: In all, 92 consecutive men with at least two previous negative transrectal biopsy series who underwent a multiple-core prostate TTSB at our centre were included in the study. • Univariable and multivariable logistic regression analyses were used to address the relationship between parameters before TTSB and prostate cancer-detection rate. • Covariates consisted of age at biopsy, free and total prostate-specific antigen (PSA), prostate volume, digital rectal examination findings, histological findings on previous biopsy, PSA velocity (PSAV), PSA-doubling time (PSADT) and the number of previous negative biopsy sets. RESULTS: Prostate cancer was diagnosed in 26% of the men. • A median of 30 cores was taken by TTSB. • Adenocarcinoma in >2 cores was detected in 58.5% and Gleason score ≥7 was detected in 46% of the diagnosed men. • Most of the tumours (83.3%) were found in the anterior zones of the gland, with a significantly higher number of positive cores vs the posterior zones (mean 4.9 vs 1.5, P= 0.015). • PSADT and PSAV were the only independent predictors of prostate cancer detection at multivariate analyses with odds ratios of 0.71 (P= 0.014) and 1.58 (P= 0.025), respectively. CONCLUSIONS: TTSB has a high prostate cancer-detection rate, especially in the anterior zones. • Men after at least two previous negative transrectal biopsy series and persistent suspicion of prostate cancer, as evidenced by rapid PSA dynamics, should be offered TTSB.

Validation and comparison of the two Kattan nomograms in patients with prostate cancer treated with (125) iodine brachytherapy.

UNLABELLED: Study Type - Prognostic (cohort) Level of Evidence 2b What's known on the subject? and What does the study add? Nomograms are based on large patient population. Their applicability should be externally validated. Among 747 brachytherapy patients we evaluated two Kattan nonograms and conclude that they have limited value to predict PSA-free survival. OBJECTIVE: To validate and compare the preoperative and postoperative Kattan prediction nonograms for prostate cancer recurrence after brachytherapy. PATIENTS AND METHODS: Patients (n= 747) treated with (125) I-brachytherapy were evaluated. Both nomograms were used to calculate the prediction of 5-year biochemical-freedom from failure (BFFF) based on clinical stage, Gleason score, prostate-specific antigen (PSA) level, receipt of androgen deprivation therapy and the post-implant dosimetry variable D90 (values of the minimal dose received by 90% of the prostate volume). The predicted values using the Kattan nomograms and the observed values were compared. Predictive accuracy was determined using the concordance index. RESULTS: The 5-year BFFF probability was 94% (95% confidence interval [CI], 92-96%) for the modified American Society for Radiation Oncology (ASTRO) definition and 97% (95% CI, 95-98%) for the Phoenix definition using Kaplan-Meier analysis. The predicted values of BFFF using both Kattan nomograms were lower than the observed rates in our cohort. The concordance index values were 0.51 and 0.52 for preoperative and postoperative nomograms, respectively. Concordance correlation coefficient between the two nomograms was 0.15. CONCLUSIONS: In our population, the 5-year BFFF outcomes rates were superior to nomogram predictions. Neither nomogram predicted outcomes after (125) I-brachytherapy in this non-US cohort. The postoperative nomogram was also a poor predictor, although it included D90 dosimetry values, as a variable of treatment quality. Strict inclusion criteria, perhaps more favourable than the ones on which the Kattan nomograms were based, could be the explanation for these discrepancies.

2ME2 inhibits tumor growth and angiogenesis by disrupting microtubules and dysregulating HIF.

Inhibition of angiogenesis is an important new modality for cancer treatment. 2-methoxyestradiol (2ME2) is a novel antitumor and antiangiogenic agent, currently in clinical trials, whose molecular mechanism of action remains unclear. Herein, we report that 2ME2 inhibits tumor growth and angiogenesis at concentrations that efficiently disrupt tumor microtubules (MTs) in vivo. Mechanistically, we found that 2ME2 downregulates hypoxia-inducible factor-1 (HIF) at the posttranscriptional level and inhibits HIF-1-induced transcriptional activation of VEGF expression. Inhibition of HIF-1 occurs downstream of the 2ME2/tubulin interaction, as disruption of interphase MTs is required for HIF-alpha downregulation. These data establish 2ME2 as a small molecule inhibitor of HIF-1 and provide a mechanistic link between the disruption of the MT cytoskeleton and inhibition of angiogenesis.

Can We Predict a Higher Risk of Urothelial Bladder Cancer With a Simple Blood Test?

BACKGROUND/AIM: The COVID-19 pandemic highlighted the need to develop tools prioritizing high risk patients for urgent evaluation. Our objective was to determine whether Glasgow Prognostic Score (GPS), an inflammation-based score, can predict higher grade and stage urothelial bladder cancer in patients with gross hematuria who need urgent evaluation. PATIENTS AND METHODS: We analyzed a database of 129 consecutive patients presenting with gross hematuria. GPS was calculated using pretreatment C-reactive protein (CRP) and albumin levels. Patients with bacteriuria or other known malignancies were excluded. The relationship between GPS and final diagnosis was analyzed with multivariate logistic regression. RESULTS: A total of 101 patients were included in the study and 24 patients were identified without any pathology and 77 with a bladder tumor. Pathology demonstrated 21 with muscle invasive, 18 with high grade non-muscle invasive, and 38 with low grade superficial bladder cancer. Twenty-six of 39 (67%) patients with high grade tumors had a GPS of 1 or 2 compared to only 8 out of 62 (13%) patients with either low grade or negative findings (p<0.0001). Ten of 21 (48%) patients with muscle invasive disease had a GPS of 2 compared to 1 out of 18 (6%) with high grade non muscle invasive tumors (p=0.04). On multivariate analysis, GPS was a strong independent predictor of high grade and stage bladder cancer. CONCLUSION: GPS may serve as a highly accessible predictor of high grade, high stage, and large urothelial bladder tumors at the time of initial evaluation and can help identify patients who need urgent evaluation.

Neutrophil to lymphocyte ratio as an early indicator for ureteral catheterization in patients with renal colic due to upper urinary tract lithiasis.

PURPOSE: To evaluate whether the neutrophil-to-lymphocyte ratio (NLR) can predict the need for ureteral catheterization in patients with renal colic. MATERIALS AND METHODS: We retrospectively studied 15,887 patients with renal colic between 2005 and 2019. Patients with prior antibiotics treatment (156), with hematological diseases (15), with negative computerized tomography scan (CTS) for stone disease (473) or with no available laboratory findings (1750) were excluded. A ureteral double J stent (DJS) was inserted in case of ongoing pain, fever, sepsis, single kidney and elevated blood creatinine levels concomitant with hydronephrosis. A cut-off value of 2.1 NLR was determined to stratify and to compare patients using multivariable logistic regression models. A locally weighted scatterplot smoothing (LOWESS) plot was also applied to show the relationship between NLR and predicted probability for DJS insertion. RESULTS: Thirteen-thousand and 493 patients with a mean age of 42.7 years (30% females and 70% males) were included in the study. Five-hundred and 57 patients (4.1%) underwent early DJS insertion: 5.3% vs. 1.5% of patients with high vs. low NLR, respectively, (p<0.001). High NLR was significantly associated with longer hospitalization time, admission to the intensive care unit and overall mortality within a month from admission (p<0.05). LOWESS plot showed that NLR value >2.1 escalates progressively the probability for DJS insertion. CONCLUSIONS: A high NLR is associated with the need for early internal DJS insertion due to urolithiasis. The NLR is easily calculated from simple blood tests and based on our results can be used for clinical decision making in patients with renal colic needing renal decompression.

The effect of delaying transperineal fusion biopsy of the prostate for patients with suspicious MRI findings-Implications for the COVID-19 era.

OBJECTIVE: Image guided biopsies are an integral part of prostate cancer evaluation. The effect of delaying biopsies of suspicious prostate mpMRI lesions is uncertain and clinically relevant during the COVID-19 crisis. We evaluated the association between biopsy delay time and pathologic findings on subsequent prostate biopsy. MATERIALS AND METHODS: After obtaining IRB approval we reviewed the medical records of 214 patients who underwent image-guided transperineal fusion biopsy of the prostate biopsy between 2017 and 2019. Study outcomes included clinically significant (ISUP grade group ≥2) and any prostate cancer on biopsy. Logistic regression was used to evaluate the association between biopsy delay time and outcomes while adjusting for known predictors of cancer on biopsy. RESULTS: The study cohort included 195 men with a median age of 68. Median delay between mpMRI and biopsy was 5 months, and 90% of patients had a ≤8 months delay. A significant association was found between PI-RADS 5 lesions and no previous biopsies and shorter delay time. Delay time was not associated with clinically significant or any cancer on biopsy. A higher risk of significant cancer was associated with older age (P = 0.008), higher PSA (0.003), smaller prostate volume (<0.001), no previous biopsy (0.012) and PI-RADS 5 lesions (0.015). CONCLUSIONS: Our findings suggest that under current practice, where men with PI-RADS 5 lesions and no previous biopsies undergo earlier evaluation, a delay of up to 8 months between imaging and biopsy does not affect biopsy findings. In the current COVID-19 crisis, selectively delaying image-guided prostate biopsies is unlikely to result in a higher rate of significant cancer.

Preoperative 68Ga-PSMA PET/CT defines a subgroup of high-risk prostate cancer patients with favorable outcomes after radical prostatectomy and lymph node dissection.

BACKGROUND: High-risk prostate cancer is associated with adverse pathology and unfavorable outcomes after radical prostatectomy. 68Ga-PSMA PET/CT is more accurate than conventional imaging for preoperative staging. We aimed to evaluate whether lymph node involvement on 68Ga-PSMA PET/CT prior to radical prostatectomy in patients with high-risk prostate cancer is associated with worse short-term oncologic outcomes. METHODS: We retrospectively reviewed 149 patients with high-risk localized or locoregional prostate cancer who underwent 68Ga-PSMA PET/CT prior to radical prostatectomy between 2015 and 2020. None of the patients received neoadjuvant or adjuvant treatment. The study endpoints were PSA persistence and biochemical recurrence. Logistic regression models were used to identify preoperative predictors of PSA persistence. Kaplan-Meier analyses were used to estimate biochemical recurrence-free survival. RESULTS: Of 149 identified patients, 19 (13%) were found to have lymph node involvement on preoperative 68Ga-PSMA PET/CT. The sensitivity, specificity, and accuracy of 68Ga-PSMA PET/CT for identifying pathologic lymph node involvement were 68%, 95%, and 92%, respectively. PSA persistence rate was lower among patients with PET-negative lymph nodes than those with PET-positive nodes (15 vs. 84%, p < 0.001). Positive nodes on imaging (OR = 41.03, p < 0.001) and clinical T2c-T3 stage (OR = 6.96, p = 0.002) were associated with PSA persistence on multivariable analysis. Among patients with PET-negative nodes the 1- and 2-year biochemical recurrence-free survival rates were 87% and 76%, respectively. CONCLUSIONS: Preoperative staging with 68Ga-PSMA PET/CT may identify a subgroup of high-risk prostate cancer patients with favorable short-term outcomes after radical prostatectomy without adjuvant treatment. Future studies will evaluate whether these results are sustained during long-term follow-up.

The use of prostate specific antigen density to predict clinically significant prostate cancer.

The purpose of this study was to assess the predictive value of prostate specific antigen density (PSAD) for detection of clinically significant prostate cancer in men undergoing systematic transrectal ultrasound (TRUS)-guided prostate biopsy. We retrospectively analyzed data of men who underwent TRUS-guided prostate biopsy because of elevated PSA (≤ 20 ng/ml) or abnormal digital rectal examination. Receiver operating characteristic curve analysis to compare PSA and PSAD performance and chi-square automatic interaction detector methodologies were used to identify predictors of clinically significant cancer (Gleason score ≥ 7 or international society of urological pathology grade group ≥ 2). Nine-hundred and ninety-two consecutive men with a median age of 66 years (IQR 61-71) were included in the study. Median PSAD was 0.10 ng/ml2 (IQR 0.10-0.22). Prostate adenocarcinoma was diagnosed in 338 men (34%). Clinically significant prostate adenocarcinoma was diagnosed in 167 patients (50% of all cancers and 17% of the whole cohort). The AUC to predict clinically significant prostate cancer was 0.64 for PSA and 0.78 for PSAD (P < 0.001). The highest Youden's index for PSAD was at 0.20 ng/ml2 with 70% sensitivity and 79% specificity for the diagnosis of clinically significant cancer. Men with PSAD < 0.09 ng/ml2 had only 4% chance of having clinically significant disease. The detection rate of clinically significant prostate cancer in patients with PSAD between 0.09 and 0.19 ng/ml2 was significantly higher when prostate volume was less than 33 ml. In conclusion, PSAD was a better predictor than PSA alone of clinically significant prostate cancer in patients undergoing TRUS-guided biopsy. Patients with PSAD below 0.09 ng/ml2 were unlikely to harbor clinically significant prostate cancer. Combining PSAD in the gray zone (0.09-0.19) with prostate volume below 33 ml adds diagnostic value of clinically significant prostate cancer.

Delivery of Radiation at the Lowest Dose Rate by a Modern Linear Accelerator is Most Effective in Inhibiting Prostate Cancer Growth.

PURPOSE: External beam radiotherapy is one of the treatment options for organ-confined prostate cancer. A total dose of 70 to 81 Gray (Gy) is given daily (1.8-2.5 Gy/d), with a dose rate of 3 to 6 Gy/min over 28 to 45 treatments during 8 to 9 weeks. We applied the latest technological development in linear accelerators for enabling a wide range of dose rates (from 0.2-21 Gy/min) to test the effect of different delivery dose rates on prostate tumor growth in an animal xenograft model. MATERIALS AND METHODS: A prostate cancer xenograft model was established in CD1/nude mice by means of PC-3 and CL-1 cells. The animals were radiated by a TrueBeam linear accelerator that delivered 4 dose rates ranging from 0.6 to 14 Gy/min, and reaching a total dose of 20 Gy. The mice were weighed and monitored for tumor development twice weekly. A 2-way analysis of variance was used to compare statistical differences between the groups. RESULTS: Tumor growth was inhibited by radiation at all 4 dose rates in the 20 study mice compared to no radiation (n = 5, controls). The most significant reduction in tumor volumes was observed when the same dose of radiation was delivered at a rate of 0.6 Gy/min (P < .01). The animals' weights were not affected by any dose rate. CONCLUSIONS: Delivery of radiation with a TrueBeam linear accelerator at the lowest possible rate was most effective in prostate cancer growth inhibition and might be considered a preferential treatment mode for localized prostate cancer.

Head-to-Head Comparison of 68Ga-PSMA-11 with 18F-PSMA-1007 PET/CT in Staging Prostate Cancer Using Histopathology and Immunohistochemical Analysis as a Reference Standard.

18F-PSMA-1007 is a novel prostate-specific membrane antigen (PSMA)-based radiopharmaceutical for imaging prostate cancer (PCa). The aim of this study was to compare the diagnostic accuracy of 18F-PSMA-1007 with 68Ga-PSMA-11 PET/CT in the same patients presenting with newly diagnosed intermediate- or high-risk PCa. Methods: Sixteen patients with intermediate- or high-risk PCa underwent 18F-PSMA-1007 and 68Ga-PSMA-11 PET/CT within 15 d. PET findings were compared between the 2 radiotracers and with reference-standard pathologic specimens obtained from radical prostatectomy. The Cohen κ-coefficient was used to assess the concordance between 18F-PSMA-1007 and 68Ga-PSMA-11 for detection of intraprostatic lesions. The McNemar test was used to assess agreement between intraprostatic PET/CT findings and histopathologic findings. Sensitivity, specificity, positive predictive value, and negative predictive value were reported for each radiotracer. SUVmax was measured for all lesions, and tumor-to-background activity was calculated. Areas under receiver-operating-characteristic curves were calculated for discriminating diseased from nondiseased prostate segments, and optimal SUV cutoffs were calculated using the Youden index for each radiotracer. Results: PSMA-avid lesions in the prostate were identified in all 16 patients with an almost perfect concordance between the 2 tracers (κ ranged from 0.871 to 1). Aside from the dominant intraprostatic lesion, similarly detected by both radiotracers, a second less intense positive focus was detected in 4 patients only with 18F-PSMA-1007. Three of these secondary foci were confirmed as Gleason grade 3 lesions, whereas the fourth was shown on pathologic examination to represent chronic prostatitis. Conclusion: This pilot study showed that both 18F-PSMA-1007 and 68Ga-PSMA-11 identify all dominant prostatic lesions in patients with intermediate- or high-risk PCa at staging. 18F-PSMA-1007, however, may detect additional low-grade lesions of limited clinical relevance.

Detection of prostate specific transcripts in the peripheral blood during brachytherapy predicts postoperative PSA kinetics.

BACKGROUND: We evaluated whether detection of prostate-specific antigen (PSA) and human kallikrein 2 (hK2) transcripts in the peripheral blood during brachytherapy could predict biochemical outcome. METHODS: Eighty-one patients who underwent (125)Iodine-based brachytherapy for localized prostate cancer (Gleason score <8, PSA <20 ng/ml, stage

Septin 9 isoform 1 (SEPT9_i1) specifically interacts with importin-α7 to drive hypoxia-inducible factor (HIF)-1α nuclear translocation.

We have shown previously that septin 9 isoform 1 (SEPT9_i1) protein associates with hypoxia-inducible factor (HIF)-1α to augment HIF-1 transcriptional activity by driving its importin-α-mediated nuclear translocation. Using in vitro and in vivo binding assays we identified that HIF-1α interacts with importin-α5 and importin-α7 in prostate cancer cells but only importin-α7 interacts with SEPT9_i1. The interaction with importin-α7 was dependent on the first 25 amino acids of SEPT9_i1 that are unique compared to other members of the mammalian septin family. Depletion of endogenous importin-α7 reduced HIF-1α levels in the nucleus. Our results provide evidence that there are importin-α specificities in the cytosolic/nuclear translocation process of HIF-1α protein, which may act differently under certain pathophysiological circumstances where SEPT9_i1 is overexpressed.