Nicola J. Mabjeesh

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.

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.

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. 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. 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. 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.

The aim of the current study was to assess whether and to what extent monitoring response to treatment using prostate-specific membrane antigen (PSMA)-based positron-emitting tomography/computerized tomography (PET/CT) studies contribute clinically relevant data to routine clinical follow-up during treatment of patients with metastatic prostate cancer (PCa). Fifty-two patients with metastatic PCa who underwent [68Ga]Ga-PSMA-11 PET/CT imaging and serum prostate-specific antigen (PSA) level measurements before and during treatment were investigated. Response was categorized by serum PSA dynamics according to improvement, stable disease, and disease progression and compared to change in imaging findings on pre- and post-treatment PET/CTs. McNemar’s test was used to assess agreement between PET/CT- and PSA-based responses to treatment. Thirty-four patients (65.4%) had compatible biochemical- and imaging-based response to treatment. However, the imaging and biochemical responses were discrepant in 18/52 patients (34.6%). PET/CT showed progressive disease in 5/52 patients (9.6%) and improvement/stable disease in 13/52 (25%) compared to biochemical assessment results. Discrepancy between imaging and biochemical response was most prominent in biochemically stable patients (90.9%), followed by patients with biochemical progression (33.3%), and in only few (8.7%) patients with biochemical improvement. The imaging-based response was suitable for choosing subsequent treatment in 22 of 30 patients (73.3%) with longer follow-up (median time of 10.3 months (IQR 6.3–18.2)). The relevance of the imaging methodology was reflected by its ability to assess individual lesions in cases of heterogeneous lesion responses, reveal the appearance of new lesions, and identify lesions that required specific consideration, such as targeted radiotherapy. Results of this retrospective analysis showed that biochemical responses to treatment and [68Ga]Ga-PSMA-11 PET/CT-based responses to treatment differ in one third of metastatic PCa patients. The latter additionally enabled lesion-based and not solely patient-based analysis. Monitoring response during treatment by [68Ga]Ga-PSMA-11 PET/CT is suitable for decision-making in patient management and choice of treatment in the majority of patients.

Brachytherapy is a well-established treatment of localized prostate cancer. Few studies have documented long-term results, specifically biochemical progression-free survival (bPFS) in men with brachytherapy alone, with or without short-term androgen deprivation therapy (ADT), or in combination with external beam radiotherapy (EBRT). Our aim was to analyze long-term bPFS of brachytherapy treated patients. Retrospective analysis of 1457 patients with low and intermediate risk prostate cancer treated with brachytherapy alone (1255) or combined with EBRT (202). Six-months ADT was administrated for all EBRT combined patients and for prostate volume downsizing when >55 cc (328). Failure was by the Phoenix definition. Kaplan-Meier analysis and multivariate Cox regression estimated and compared 10-yr and 15-yr rates of bPFS. Median follow-up was 6.1 yr. Ten and 15-yr bPFS rates of the entire cohort were 93.2% and 89.2%, respectively. On multivariate analysis, PSA density (PSAD), ADT and clinical stage were significantly associated with failure. The most powerful independent factor was PSAD with a HR of 3.5 (95% CI, 1.7–7.4) for PSAD above 0.15. No significant difference was found between low and intermediate risks patients regardless of treatment regimen. However, comparison of two intermediate risk groups, Gleason score (GS) 7, PSAP = 0.022), respectively. ADT improved bPFS rates in low risk patients. The ten and 15-yr bPFS rates were 97.6% and 94.6% compared to 92.3% and 88.2%, (P = 0.020), respectively. Our retrospective large scale study suggests that brachytherapy provides excellent long-term bPFS rates in low and intermediate risk disease. Combination of brachytherapy with EBRT yields favorable outcomes in GS 7 intermediate risk patients and short-term ADT has a positive effect on outcomes in low risk patients. Further prospective studies are warranted to discriminate the role of adding either EBRT and/or ADT to brachytherapy protocols.

ON THE FRONT COVER: The front cover image is based on the Research Article Septin 9 isoform 1 (SEPT9_i1) specifically interacts with importin‐α7 to drive hypoxia‐inducible factor (HIF)‐1α nuclear translocation by Keren Tazat et al., DOI: 10.1002/cm.21511. image

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 (β‐TrCP) on the hypoxic pathway in cancer cells. β‐TrCP is overexpressed in many tumors and regulates various cellular processes through mediating the degradation of important targets. Unexpectedly, we found that β‐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 β‐TrCP interferes with the association between HIF‐1α and HSP70/CHIP, a HIF‐1α established E3 ligase complex. Whereas the E3 ligase activity of β‐TrCP is well known, antagonizing another E3 ligase is a new mechanism of action of this important E3. We suggest that destroying or suppressing β‐TrCP and thereby interrupting the HIF‐1 pathway, could be valuable antitumor therapy.

// <![CDATA[ $('.header-date').hide();$('#titleAuthors').hide();$('#abstractHeader').hide(); // ]]> Maya Golan1, Nicola J. Mabjeesh1 1Prostate Cancer Research Laboratory, Department of Urology, Tel Aviv Sourasky Medical Center, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel Correspondence to: Nicola J. Mabjeesh, email: nicolam@tlvmc.gov.il Keywords: hypoxia-inducible factor 1α, septin 9, bimolecular fluorescence complementation, cancer, imaging Received: June 30, 2016 Accepted: March 15, 2017 Published: March 23, 2017 ABSTRACT Hypoxia-inducible factor 1 (HIF-1) is a major mediator of the hypoxic response involved in tumor progression. We had earlier described the interaction between septin 9 isoform 1 (SEPT9_i1) protein and the oxygen-regulated subunit, HIF-1α. SEPT9_i1 is a member of the conserved family of GTP-binding cytoskeleton septins. SEPT9_i1 stabilizes HIF-1α and facilitates its cytoplasmic-nuclear translocation. We utilized split yellow fluorescent protein (YFP) bimolecular fluorescence complementation (BiFC) methodology to monitor the interaction between HIF-1α and SEPT9_i1 in live cells. N-terminal (YN) and C-terminal (YC) split YFP chimeras with HIF-1α and SEPT9_i1 on both their amino and carboxyl termini were generated. HIF-1α and SEPT9_i1 chimeras were expressed in cancer cells and screened for functional complementation. SEPT9_i1-YN and YC-HIF-1α formed a long-lived highly stable complex upon interaction. The BiFC signal was increased in the presence of hypoxia-mimicking agents. In contrast, YC-ΔHLH-HIF-1α chimera, which lacked the helix-loop-helix domain that is essential for the interaction with SEPT9_i1 as well as the expression of SEPT9_i1 252-379 amino acids fragment required for the interaction with HIF-1α, significantly reduced the BiFC signal. The signal was also reduced when cells were treated with 17-N-allylamino-17-demethoxygeldanamycin, an HSP90 inhibitor that inhibits HIF-1α. It was increased with fourchlorfenuron, a small molecule that increases the interaction between HIF-1α and SEPT9_i1. These results reconfirmed the interaction between HIF-1α and SEPT9_i1 that was imaged in live cells. This BiFC system represents a novel approach for studying the real-time interaction between these two proteins and will allow high-throughput drug screening to identity compounds that disrupt this interaction.