Asymmetric Hsp90 N domain SUMOylation recruits Aha1 and ATP-competitive inhibitors.

The stability and activity of numerous signaling proteins in both normal and cancer cells depends on the dimeric molecular chaperone heat shock protein 90 (Hsp90). Hsp90's function is coupled to ATP binding and hydrolysis and requires a series of conformational changes that are regulated by cochaperones and numerous posttranslational modifications (PTMs). SUMOylation is one of the least-understood Hsp90 PTMs. Here, we show that asymmetric SUMOylation of a conserved lysine residue in the N domain of both yeast (K178) and human (K191) Hsp90 facilitates both recruitment of the adenosine triphosphatase (ATPase)-activating cochaperone Aha1 and, unexpectedly, the binding of Hsp90 inhibitors, suggesting that these drugs associate preferentially with Hsp90 proteins that are actively engaged in the chaperone cycle. Importantly, cellular transformation is accompanied by elevated steady-state N domain SUMOylation, and increased Hsp90 SUMOylation sensitizes yeast and mammalian cells to Hsp90 inhibitors, providing a mechanism to explain the sensitivity of cancer cells to these drugs.

Lack of Impact of Robotic Assisted Laparoscopic Radical Prostatectomy on Intraoperative Levels of Prostate Cancer Circulating Tumor Cells.

PURPOSE: While the significance of circulating tumor cells in clinically localized cancer remains controversial, it has been reported that surgical tumor manipulation can increase circulating tumor cells, including during open prostatectomy. To our knowledge it is unknown whether this cell shedding also occurs during minimally invasive prostatectomy, which minimizes tumor palpation and uses earlier vascular control. We tested the impact of robotic assisted laparoscopic radical prostatectomy on intraoperative circulating tumor cell levels. MATERIALS AND METHODS: Circulating tumor cell counts were compared in peripheral blood specimens from 25 patients treated with robotic assisted laparoscopic radical prostatectomy preoperatively vs intraoperatively after prostate excision, in addition to 11 healthy blood donors. Circulating tumor cell detection was performed using EpCAM immunomagnetic enrichment and multiparametric flow cytometry quantification of viable EpCAM positive/prostate specific membrane antigen positive/CD45 negative cells. Intraoperative cell counts and increases were tested in univariable analyses for associations with perioperative variables, histopathology and postoperative progression. RESULTS: Circulating tumor cells were detected in 0% of healthy controls compared to 48% and 52% of prostatectomy cases preoperatively and intraoperatively, respectively (range 1 to 8 cells). There was no difference in the incidence or mean number of circulating tumor cells preoperatively vs intraoperatively. Of the patients 60% had no intraoperative change from preoperative levels. Intraoperative cell increases vs decreases were equally infrequent (each 20%) with no intraoperative increase greater than 1 circulating tumor cell. Intraoperative circulating tumor cell detection was not significantly associated with prostatectomy operative characteristics, histopathology or early postoperative progression at a median 21-month followup. CONCLUSIONS: Robotic assisted laparoscopic radical prostatectomy does not cause significant intraoperative increases in circulating tumor cells in contrast to historical reports of open prostatectomy. These findings may aid urologists in counseling candidates for robotic assisted laparoscopic radical prostatectomy regarding the possibility of intraoperative tumor cell shedding.

Diagnostic value of biparametric magnetic resonance imaging (MRI) as an adjunct to prostate-specific antigen (PSA)-based detection of prostate cancer in men without prior biopsies.

OBJECTIVES: To determine the diagnostic yield of analysing biparametric (T2- and diffusion-weighted) magnetic resonance imaging (B-MRI) for prostate cancer detection compared with standard digital rectal examination (DRE) and prostate-specific antigen (PSA)-based screening. PATIENTS AND METHODS: Review of patients who were enrolled in a trial to undergo multiparametric-prostate (MP)-MRI and MR/ultrasound fusion-guided prostate biopsy at our institution identified 143 men who underwent MP-MRI in addition to standard DRE and PSA-based prostate cancer screening before any prostate biopsy. Patient demographics, DRE staging, PSA level, PSA density (PSAD), and B-MRI findings were assessed for association with prostate cancer detection on biopsy. RESULTS: Men with detected prostate cancer tended to be older, with a higher PSA level, higher PSAD, and more screen-positive lesions (SPL) on B-MRI. B-MRI performed well for the detection of prostate cancer with an area under the curve (AUC) of 0.80 (compared with 0.66 and 0.74 for PSA level and PSAD, respectively). We derived combined PSA and MRI-based formulas for detection of prostate cancer with optimised thresholds. (i) for PSA and B-MRI: PSA level + 6 x (the number of SPL) > 14 and (ii) for PSAD and B-MRI: 14 × (PSAD) + (the number of SPL) >4.25. AUC for equations 1 and 2 were 0.83 and 0.87 and overall accuracy of prostate cancer detection was 79% in both models. CONCLUSIONS: The number of lesions positive on B-MRI outperforms PSA alone in detection of prostate cancer. Furthermore, this imaging criteria coupled as an adjunct with PSA level and PSAD, provides even more accuracy in detecting clinically significant prostate cancer.

Clinical significance of ureteric 'skip lesions' at the time of radical cystectomy: the M.D. Anderson experience and literature review.

OBJECTIVE: To assess the incidence and clinical significance of 'skip lesions' that are present in proximal but not in distal ureteric sections, which are occasionally found during the pathological examination of ureteric margins during radical cystectomy (RC). PATIENTS AND METHODS: We identified 660 patients who underwent a RC and had at least two permanent margins for a given ureter. In all, 1173 ureters were analysed and classified as follows: 'normal' (no tumour, reactive atypia, mild or moderate dysplasia) or 'abnormal' (severe dysplasia, carcinoma in situ (CIS), or tumour). Transitions from 'normal' distal pathology to 'abnormal' on proximal section(s) determined frequency of skip lesions. Fisher's exact test and the log-rank test were used to study correlations. RESULTS: Ureteric skip lesions were found in 4.8% patients (2.9% ureters). Pathology of skip lesions was CIS in 55.9%, transitional cell carcinoma in 23.5% and severe dysplasia in 20.6%. Skip lesions were associated with lymphovascular invasion (34.4% vs 13.7%, P = 0.004) and advanced pT stage (P = 0.007). On multivariate analysis, skip lesions correlated with lower median overall survival (OS) (inestimable vs 8.2 years, P = 0.014) in patients with pT0 or pTa disease and a trend towards lower OS (2.7 vs 8.8 years, P = 0.066) in pTis disease. Concordance between frozen distal margin and permanent proximal margin varied; sensitivity was 80% in those without and 20% in those with skip lesions. CONCLUSIONS: The presence of a ureteric skip lesion may be associated with lower survival in patients with pT0, pTa or pTis urothelial carcinoma. Thus, while uncommon, ureteric skip lesions should be reported in pathological findings.

Multiparametric magnetic resonance imaging (MRI) and subsequent MRI/ultrasonography fusion-guided biopsy increase the detection of anteriorly located prostate cancers.

OBJECTIVE: To describe the detection rate of anteriorly located prostate cancer (PCa) with the addition of magnetic resonance imaging (MRI)/ultrasonography (US) fusion-guided biopsy (FGB) to the standard transrectal ultrasonography (TRUS)-guided biopsy. PATIENTS AND METHODS: All patients, regardless of their biopsy history, who were referred for clinical suspicion of PCa (i.e elevated prostate-specific antigen (PSA) level and abnormal digital rectal examination) underwent 3T multiparametric-MRI (mpMRI) screening; and those with suspicious lesions in the anterior region of the prostate were identified. Patients then received a FGB of all suspicious lesions in addition to a systematic 12-core extended sextant TRUS-guided biopsy. We conducted a lesion-based analysis comparing cancer detection rates of anterior targets using FGB vs systematic cores taken from the same anatomic sextant within the prostate. Lengths of cancer in the most involved core were also compared between the two biopsy techniques used. Patients with only anterior targets were analysed separately. RESULTS: Of 499 patients undergoing FGB, 162 had a total of 241 anterior lesions. The mean age, PSA level and prostate volume in this group were 62 years, 12.7 ng/dL, and 57 mL, respectively. In total, PCa was diagnosed in 121 anterior lesions (50.2%) identified on mpMRI. Sixty-two (25.7%) of these anterior lesions were documented as positive for cancer on systematic 12-core TRUS-guided biopsy cores, while 97 (40.2%) were positive on the targeted FGB cores (P = 0.001). In lesions that were positive on both FGB and TRUS biopsy, the most involved core was 112% longer on FGB (3.7 vs 1.6 mm, P ≤ 0.01). Forty-two patients had only anterior lesions on mpMRI; of these, 24 (57.1%) were found to have cancer on the FGB + TRUS biopsy platform. Six patients were positive on FGB only and 13 were positive on both biopsy techniques; however, 7/13 patients were upgraded to a higher Gleason score after FGB. All five patients positive on TRUS biopsy only were candidates for active surveillance. CONCLUSION: The results showed that FGB detects significantly more anteriorly located PCa than does TRUS-guided biopsy alone and it may serve as an effective tool for the subset of patients with such tumours.

Mechanism of anion exchange and small-molecule inhibition of pendrin.

Pendrin (SLC26A4) is an anion exchanger that mediates bicarbonate (HCO3-) exchange for chloride (Cl-) and is crucial for maintaining pH and salt homeostasis in the kidney, lung, and cochlea. Pendrin also exports iodide (I-) in the thyroid gland. Pendrin mutations in humans lead to Pendred syndrome, causing hearing loss and goiter. Inhibition of pendrin is a validated approach for attenuating airway hyperresponsiveness in asthma and for treating hypertension. However, the mechanism of anion exchange and its inhibition by drugs remains poorly understood. We applied cryo-electron microscopy to determine structures of pendrin from Sus scrofa in the presence of either Cl-, I-, HCO3- or in the apo-state. The structures reveal two anion-binding sites in each protomer, and functional analyses show both sites are involved in anion exchange. The structures also show interactions between the Sulfate Transporter and Anti-Sigma factor antagonist (STAS) and transmembrane domains, and mutational studies suggest a regulatory role. We also determine the structure of pendrin in a complex with niflumic acid (NFA), which uncovers a mechanism of inhibition by competing with anion binding and impeding the structural changes necessary for anion exchange. These results reveal directions for understanding the mechanisms of anion selectivity and exchange and their regulations by the STAS domain. This work also establishes a foundation for analyzing the pathophysiology of mutations associated with Pendred syndrome.

Accuracy of multiparametric magnetic resonance imaging in confirming eligibility for active surveillance for men with prostate cancer.

BACKGROUND: Active surveillance (AS) is an attempt to avoid overtreatment of clinically insignificant prostate cancer (PCa); however, patient selection remains controversial. Multiparametric prostate magnetic resonance imaging (MP-MRI) may help better select AS candidates. METHODS: We reviewed a cohort of men who underwent MP-MRI with MRI/Ultrasound fusion-guided prostate biopsy and selected potential AS patients at entry using Johns Hopkins criteria. MP-MRI findings were assessed, including number of lesions, dominant lesion diameter, total lesion volume, prostate volume, and lesion density (calculated as total lesion volume/prostate volume). Lesions were assigned a suspicion score for cancer by MRI. AS criteria were reapplied based on the confirmatory biopsy, and accuracy of MP-MRI in predicting AS candidacy was assessed. Logistic regression modeling and chi-square statistics were used to assess associations between MP-MRI interpretation and biopsy results. RESULTS: Eighty-five patients qualified for AS with a mean age of 60.2 years and mean prostate-specific antigen level of 4.8 ng/mL. Of these, 25 patients (29%) were reclassified as not meeting AS criteria based on confirmatory biopsy. Number of lesions, lesion density, and highest MRI lesion suspicion were significantly associated with confirmatory biopsy AS reclassification. These MRI-based factors were combined to create a nomogram that generates a probability for confirmed AS candidacy. CONCLUSION: As clinicians counsel patients with PCa, MP-MRI may contribute to the decision-making process when considering AS. Three MRI-based factors (number of lesions, lesion suspicion, and lesion density) were associated with confirmatory biopsy outcome and reclassification. A nomogram using these factors has promising predictive accuracy for which future validation is necessary. Cancer 2013;119:3359-66. Published 2013. This article is a U.S. Government work and is in the public domain in the USA.

Prostate cancer: can multiparametric MR imaging help identify patients who are candidates for active surveillance?

PURPOSE: To determine whether multiparametric magnetic resonance (MR) imaging can help identify patients with prostate cancer who would most appropriately be candidates for active surveillance (AS) according to current guidelines and to compare the results with those of conventional clinical assessment scoring systems, including the D'Amico, Epstein, and Cancer of the Prostate Risk Assessment (CAPRA) systems, on the basis of findings at prostatectomy. MATERIALS AND METHODS: This institutional review board-approved HIPAA-compliant retrospectively designed study included 133 patients (mean age, 59.3 years) with a mean prostate-specific antigen level of 6.73 ng/mL (median, 4.39 ng/mL) who underwent multiparametric MR imaging at 3.0 T before radical prostatectomy. Informed consent was obtained from all patients. Patients were then retrospectively classified as to whether they would have met AS eligibility criteria or were better served by surgery. AS eligibility criteria for prostatectomy specimens were a dominant tumor smaller than 0.5 mL without Gleason 4 or 5 patterns or extracapsular or seminal vesicle invasion. Conventional clinical assessment scores (the D'Amico, Epstein, and CAPRA scoring systems) were compared with multiparametric MR imaging findings for predicting AS candidates. The level of significance of difference between scoring systems was determined by using the χ(2) test for categoric variables with the level of significance set at P < .05. RESULTS: Among 133 patients, 14 were eligible for AS on the basis of prostatectomy results. The sensitivity, positive predictive value (PPV), and overall accuracy, respectively, were 93%, 25%, and 70% for the D'Amico system, 64%, 45%, and 88% for the Epstein criteria, and 93%, 20%, and 59% for the CAPRA scoring system for predicting AS candidates (P < .005 for all, χ(2) test), while multiparametric MR imaging had a sensitivity of 93%, a PPV of 57%, and an overall accuracy of 92% (P < .005). CONCLUSION: Multiparametric MR imaging provides useful additional information to existing clinicopathologic scoring systems of prostate cancer and improves the assignment of treatment (eg, AS or active treatment).

Utility of multiparametric magnetic resonance imaging suspicion levels for detecting prostate cancer.

PURPOSE: We determine the usefulness of multiparametric magnetic resonance imaging in detecting prostate cancer, with a specific focus on detecting higher grade prostate cancer. MATERIALS AND METHODS: Prospectively 583 patients who underwent multiparametric magnetic resonance imaging and subsequent prostate biopsy at a single institution were evaluated. On multiparametric magnetic resonance imaging, lesions were identified and scored as low, moderate or high suspicion for prostate cancer based on a validated scoring system. Magnetic resonance/ultrasound fusion guided biopsies of magnetic resonance imaging lesions in addition to systematic 12-core biopsies were performed. Correlations between the highest assigned multiparametric magnetic resonance imaging suspicion score and presence of cancer and biopsy Gleason score on the first fusion biopsy session were assessed using univariate and multivariate logistic regression models. Sensitivity, specificity, negative predictive value and positive predictive value were calculated and ROC curves were developed to assess the discriminative ability of multiparametric magnetic resonance imaging as a diagnostic tool for various biopsy Gleason score cohorts. RESULTS: Significant correlations were found between age, prostate specific antigen, prostate volume, and multiparametric magnetic resonance imaging suspicion score and the presence of prostate cancer (p<0.0001). On multivariate analyses controlling for age, prostate specific antigen and prostate volume, increasing multiparametric magnetic resonance imaging suspicion was an independent prognosticator of prostate cancer detection (OR 2.2, p<0.0001). Also, incremental increases in multiparametric magnetic resonance imaging suspicion score demonstrated stronger associations with cancer detection in patients with Gleason 7 or greater (OR 3.3, p<0.001) and Gleason 8 or greater (OR 4.2, p<0.0001) prostate cancer. Assessing multiparametric magnetic resonance imaging as a diagnostic tool for all prostate cancer, biopsy Gleason score 7 or greater, and biopsy Gleason score 8 or greater separately via ROC analyses demonstrated increasing accuracy of multiparametric magnetic resonance imaging for higher grade disease (AUC 0.64, 0.69, and 0.72, respectively). CONCLUSIONS: Multiparametric magnetic resonance imaging is a clinically useful modality to detect and characterize prostate cancer, particularly in men with higher grade disease.

Can magnetic resonance-ultrasound fusion biopsy improve cancer detection in enlarged prostates?

PURPOSE: Patients with an enlarged prostate and suspicion of prostate cancer pose a diagnostic dilemma. The prostate cancer detection rate of systematic 12-core transrectal ultrasound guided biopsy is between 30% and 40%. For prostates greater than 40 cc this decreases to 30% or less. Magnetic resonance-ultrasound fusion biopsy has shown superior prostate cancer detection rates. We defined the detection rate of magnetic resonance-ultrasound fusion biopsy in men with an enlarged prostate gland. MATERIALS AND METHODS: We retrospectively analyzed the records of patients who underwent multiparametric prostate magnetic resonance imaging followed by magnetic resonance-ultrasound fusion biopsy at our institution. Whole prostate volumes were calculated using magnetic resonance imaging reconstructions. Detection rates were analyzed with respect to age, prostate specific antigen and whole prostate volumes. Multivariable logistic regression was used to assess these parameters as independent predictors of prostate cancer detection. RESULTS: We analyzed 649 patients with a mean±SD age of 61.8±7.9 years and a median prostate specific antigen of 6.65 ng/ml (IQR 4.35-11.0). Mean whole prostate volume was 58.7±34.3 cc. The overall detection rate of the magnetic resonance-ultrasound fusion platform was 55%. For prostates less than 40 cc the detection rate was 71.1% compared to 57.5%, 46.9%, 46.9% 33.3%, 36.4% and 30.4% for glands 40 to 54.9, 55 to 69.9, 70 to 84.9, 85 to 99.9, 100 to 114.9 and 115 cc or greater, respectively (p<0.0001). Multivariable logistic regression showed a significant inverse association of magnetic resonance imaging volume with prostate cancer detection, controlling for age and prostate specific antigen. CONCLUSIONS: Transrectal ultrasound guided and fusion biopsy cancer detection rates decreased with increasing prostate volume. However, magnetic resonance-ultrasound fusion biopsy had a higher prostate cancer detection rate compared to that of transrectal ultrasound guided biopsy in the literature. Magnetic resonance-ultrasound fusion biopsy represents a promising solution for patients with suspicion of prostate cancer and an enlarged prostate.

Magnetic resonance imaging (MRI)-guided transurethral ultrasound therapy of the prostate: a preclinical study with radiological and pathological correlation using customised MRI-based moulds.

OBJECTIVE: To characterise the feasibility and safety of a novel transurethral ultrasound (US)-therapy device combined with real-time multi-plane magnetic resonance imaging (MRI)-based temperature monitoring and temperature feedback control, to enable spatiotemporally precise regional ablation of simulated prostate gland lesions in a preclinical canine model. To correlate ablation volumes measured with intra-procedural cumulative thermal damage estimates, post-procedural MRI, and histopathology. MATERIALS AND METHODS: Three dogs were treated with three targeted ablations each, using a prototype MRI-guided transurethral US-therapy system (Philips Healthcare, Vantaa, Finland). MRI provided images for treatment planning, guidance, real-time multi-planar thermometry, as well as post-treatment evaluation of efficacy. After treatment, specimens underwent histopathological analysis to determine the extent of necrosis and cell viability. Statistical analyses (Pearson's correlation, Student's t-test) were used to evaluate the correlation between ablation volumes measured with intra-procedural cumulative thermal damage estimates, post-procedural MRI, and histopathology. RESULTS: MRI combined with a transurethral US-therapy device enabled multi-planar temperature monitoring at the target as well as in surrounding tissues, allowing for safe, targeted, and controlled ablations of prescribed lesions. Ablated volumes measured by cumulative thermal dose positively correlated with volumes determined by histopathological analysis (r(2) 0.83, P < 0.001). Post-procedural contrast-enhanced and diffusion-weighted MRI showed a positive correlation with non-viable areas on histopathological analysis (r(2) 0.89, P < 0.001, and r(2) 0.91, P = 0.003, respectively). Additionally, there was a positive correlation between ablated volumes according to cumulative thermal dose and volumes identified on post-procedural contrast-enhanced MRI (r(2) 0.77, P < 0.01). There was no difference in mean ablation volumes assessed with the various analysis methods (P > 0.05, Student's t-test). CONCLUSIONS: MRI-guided transurethral US therapy enabled safe and targeted ablations of prescribed lesions in a preclinical canine prostate model. Ablation volumes were reliably predicted by intra- and post-procedural imaging. Clinical studies are needed to confirm the feasibility, safety, oncological control, and functional outcomes of this therapy in patients in whom focal therapy is indicated.

MRI characterization of the dynamic effects of 5α-reductase inhibitors on prostate zonal volumes.

INTRODUCTION: Prior studies of volumetric effects of 5α-reductase inhibitors (5ARIs) on the prostate have used transrectal ultrasound which provides poor differentiation of prostatic zones. We utilized high-resolution prostate MRI to evaluate the true dynamic effects of 5ARI in men who underwent multiple MRIs. MATERIALS AND METHODS: A retrospective study of patients who underwent serial 3.0 Tesla prostate MRI from 2007 to 2012 and were treated with 5ARI were studied. Nineteen patients who had a baseline MRI prior to 5ARI initiation and subsequent MRI follow up were selected. A randomly selected group of 40 patients who had not received any form of therapy was selected as the control cohort. Total prostate volume (TPV), transition zone volume (TZV), and peripheral zone volume (PZV) were calculated using 3D reconstructions and prostate segmentation from T2-weighted MRI. Changes in volumes were correlated with the duration of treatment using linear regression analysis. RESULTS: Following over 2 years of treatment, 5ARI decreased TPV significantly (16.7%, p < 0.0001). There were similar decreases in TZV (7.5%, p < 0.001) and PZV (27.4%, p = 0.0002) from baseline. In the control group, TPV and TZV increased (p < 0.0001) while PZV remained stable. When adjusted for the natural growth of prostate zonal volume dynamics seen in the control cohort, approximately 60% of the reduction of the TPV from 5ARI resulted from changes in the TZV and 40% of the reduction from changes in the PZV. CONCLUSIONS: 3.0 Tesla MRI characterizations of the dynamic effects of 5ARI on prostate zonal volumes demonstrate significant decreases in TPV, TZV, and PZV. 5ARI blocks the natural growth of TZV as men age and decreases both TZV and PZV below their baselines. As imaging technology improves, prostate MRI allows for more accurate assessment of drug effects on dynamic prostate volumes.

Analysis and comparison of SARS-CoV-2 variant antibodies and neutralizing activity for 6 months after a booster mRNA vaccine in a healthcare worker population.

Introduction: In the context of recurrent surges of SARS-CoV-2 infections, a detailed characterization of antibody persistence over a 6-month period following vaccine booster dose is necessary to crafting effective public health policies on repeat vaccination. Methods: To characterize the SARS-CoV-2 antibody profile of a healthcare worker population over a 6-month period following mRNA vaccination and booster dose. 323 healthcare workers at an academic medical center in Orange County, California who had completed primary vaccination and booster dose against SARS-CoV-2 were recruited for the study. A total of 690 blood specimens over a 6-month period were collected via finger-stick blood and analyzed for the presence of antibodies against 9 SARS-CoV-2 antigens using a coronavirus antigen microarray. Results: The primary outcome of this study was the average SARS-CoV-2 antibody level as measured using a novel coronavirus antigen microarray. Additional outcomes measured include levels of antibodies specific to SARS-CoV-2 variants including Delta, Omicron BA.1, and BA.2. We also measured SARS-CoV-2 neutralization capacity for a subset of the population to confirm correlation with antibody levels. Although antibodies against SARS-CoV-2 wane throughout the 6-month period following a booster dose, antibody levels remain higher than pre-boost levels. However, a booster dose of vaccine based on the original Wuhan strain generates approximately 3-fold lower antibody reactivity against Omicron variants BA.1 and BA.2 as compared to the vaccine strain. Despite waning antibody levels, neutralization activity against the vaccine strain is maintained throughout the 6-month period. Discussion: In the context of recurrent surges of SARS-CoV-2 infections, our data indicate that breakthrough infections are likely driven by novel variants with different antibody specificity and not by time since last dose of vaccination, indicating that development of vaccinations specific to these novel variants is necessary to prevent future surges of SARS-CoV-2 infections.

Very distal apical prostate tumours: identification on multiparametric MRI at 3 Tesla.

UNLABELLED: What's known on the subject? and What does the study add? MRI has been shown to improve prostate cancer detection rates. Pinto et al. (J Urol 2011; 86: 1281-5) reported their outcomes on 101 patients with low, moderate or high suspicion lesions on multiparametric MRI that were subsequently targeted via an MRI/ultrasound fusion biopsy platform. The prostate cancer detection rates were 27%, 66% and 89% respectively. Sciarra et al. (Clin Cancer Res 2010; 16: 1875-83) performed a prospective trial in 180 patients with prior negative biopsy and persistent PSA elevation. Patients were randomized to either MRI targeted biopsy followed by random 12-core TRUS biopsy vs random TRUS guided biopsy alone. Prostate cancer detection in the MRI targeted group was 45.5% vs 24.4% in the random group. Although MRI has been shown to improve prostate cancer detection rates, there has not previously been any work looking at the ability of MRI to detect prostate cancer localized to the very distal apex of the prostate. This is an important topic in that it might lead clinicians to counsel their patients in treatment decisions if it is felt that a treatment might not treat this section of the prostate well, e.g. high intensity focused ultrasound therapy that might spare the distal apex. OBJECTIVE: • To describe an undescribed 'very distal' apical prostate cancer on multiparametric MRI (mpMRI) since apical prostate cancer can be difficult to detect in transrectal ultrasound guided biopsy and might therefore be missed in treatment decisions such as high intensity focused ultrasound or surgical therapy. PATIENTS AND METHODS: • From January 2011 to December 2012 a total of 210 consecutive patients underwent 3 T mpMRI with endorectal coil followed by our previously described MRI/ultrasound image fused and directed TRUS biopsies. • Patients also underwent 12-core TRUS sextant biopsies. • The inclusion criteria required at least one distal apical prostate lesion visualized on mpMRI and targeted for biopsy. RESULTS: • A total of 38 men (median age 62 years, median PSA 7.68 ng/dL) were identified as having distal apical prostate cancer on mpMRI. • Thirteen patients (34%) had a prior diagnosis of cancer and were on active surveillance protocols while 25 (66%) did not. Of those patients, 21 (55%) had undergone a median of two prior negative biopsies. • Twenty-two patients (58%) were positive on biopsy for prostate cancer. On breakdown of patients who were positive, 17 (77%) were positive on TRUS random biopsies and 21 (95%) were positive on MRI targeted biopsies with the majority of patients having multifocal disease. • At the distal apical lesions of interest, 80% were positive on MRI targeted biopsy. In addition 33% of these patients were upgraded based on MRI targeted biopsy at the distal lesion. CONCLUSIONS: • Very distal apical prostate cancer can be accurately detected and sampled with mpMRI and subsequent MRI/ultrasound fusion biopsy. • This may aid clinicians and patients in decision making for therapeutic modalities.

Low suspicion lesions on multiparametric magnetic resonance imaging predict for the absence of high-risk prostate cancer.

UNLABELLED: What's known on the subject? and What does the study add? Over-treatment of indolent prostate cancer lesions is a problem which can result in increased human and medical costs. Lesions with a low suspician level at mpMRI of the prostate have low risk of including high risk prostate cancer. OBJECTIVE: To determine whether multiparametric magnetic resonance imaging (mpMRI) has the potential to identify patients at low risk for cancer, thus obviating the need for biopsy. Prostate cancer is currently diagnosed by random biopsies, resulting in the discovery of multiple low-risk cancers that often lead to overtreatment. PATIENTS AND METHODS: We reviewed 800 consecutive patients who underwent a 3 Tesla mpMRI of the prostate with an endorectal coil from March 2007 to November 2011. All suspicious lesions were independently reviewed by two radiologists using T2-weighted, diffusion-weighted, spectroscopic and dynamic contrast-enhanced MRI sequences. Patients with only low suspicion lesions (maximum of two positive parameters on mpMRI) who subsequently underwent transrectal ultrasonography (TRUS)/MRI fusion targeted biopsy were selected for analysis. RESULTS: In total, 125 patients with only low suspicion prostatic lesions on mpMRI were identified. On TRUS/MRI fusion biopsy, 77 (62%) of these patients had no cancer detected, 38 patients had Gleason 6 disease and 10 patients had Gleason 7 (3+4) disease. There were 30 patients with cancer detected on biopsy who qualified for active surveillance using 2011 National Comprehensive Cancer Network guidelines. No cases of high-risk (≥ Gleason 4+3) cancer were identified on biopsy and, of the fifteen patients who underwent radical prostatectomy at our institution, none were pathologically upgraded to high-risk cancer. Thus, for patients with only low suspicion lesions, 107 (88%) patients either had no cancer or clinically insignificant disease. CONCLUSIONS: The results obtained in the present study show that low suspicion lesions on mpMRI are associated with either negative biopsies or low-grade tumours suitable for active surveillance. Such patients have a low risk of harbouring high-risk prostate cancers.

Image guidance in the focal treatment of prostate cancer.

PURPOSE OF REVIEW: The advent of prostate-specific antigen screening has led to a seven-fold increase in the incidence of prostate cancer without a resultant decrease in mortality rate. This has led to the belief that urologists are overdetecting and overtreating clinically insignificant disease. To maintain the delicate balance between high cancer cure rate and overtreatment, which could potentially lead to unnecessary morbidities, focal therapy has emerged as the reasonable middle ground. In this article, we present the conceptual basis and the challenges of focal therapy, while emphasizing the critical role of imaging in focal treatment of prostate cancer. RECENT FINDINGS: Multiple phase I trials have demonstrated the feasibility, short-term efficacy, and safety of focal therapy. Fundamental to the success of these trials and the ultimate acceptance of focal therapy is the integral role of imaging in optimal patient selection. Among the different imaging modalities, only ultrasound and multiparametric MRI are intimately involved in the detection, diagnosis, staging, and treatment of prostate cancer. Each modality has its own unique advantages and shortcomings. Recent advances in enhanced ultrasound modalities, functional MRIs, and biopsy platforms have taken focal therapy one step closer to becoming the standard of care. SUMMARY: Although early results of phase I focal therapy trials are encouraging, long-term oncological outcomes remain to be elucidated. Incorporation of these technological advances into large prospective trials is needed to establish focal therapy as an important asset in the urologist's armamentarium against prostate cancer.

Structural basis of HIV inhibition by L-nucleosides: Opportunities for drug development and repurposing.

Infection with HIV can cripple the immune system and lead to AIDS. Hepatitis B virus (HBV) is a hepadnavirus that causes human liver diseases. Both pathogens are major public health problems affecting millions of people worldwide. The polymerases from both viruses are the most common drug target for viral inhibition, sharing common architecture at their active sites. The L-nucleoside drugs emtricitabine and lamivudine are widely used HIV reverse transcriptase (RT) and HBV polymerase (Pol) inhibitors. Nevertheless, structural details of their binding to RT(Pol)/nucleic acid remained unknown until recently. Here, we discuss the implications of these structures, alongside related complexes with L-dNTPs, for the development of novel L-nucleos(t)ide drugs, and prospects for repurposing them.

Analysis and comparison of SARS-CoV-2 variant antibodies and neutralizing activity for 6 months after a booster mRNA vaccine in a healthcare worker population.

In the context of recurrent surges of SARS-CoV-2 infections, a detailed characterization of antibody persistence over a 6-month period following vaccine booster dose is necessary to crafting effective public health policies on repeat vaccination. To characterize the SARS-CoV-2 antibody profile of a healthcare worker population over a 6-month period following mRNA vaccination and booster dose. 323 healthcare workers at an academic medical center in Orange County, California who had completed primary vaccination and booster dose against SARS-CoV-2 were recruited for the study. A total of 690 blood specimens over a 6-month period were collected via finger-stick blood and analyzed for the presence of antibodies against 9 SARS-CoV-2 antigens using a coronavirus antigen microarray. The primary outcome of this study was the average SARS-CoV-2 antibody level as measured using a novel coronavirus antigen microarray. Additional outcomes measured include levels of antibodies specific to SARS-CoV-2 variants including Delta, Omicron BA.1, and BA.2. We also measured SARS-CoV-2 neutralization capacity for a subset of the population to confirm correlation with antibody levels. Although antibodies against SARS-CoV-2 wane throughout the 6-month period following a booster dose, antibody levels remain higher than pre-boost levels. However, a booster dose of vaccine generates approximately 3-fold lower antibody reactivity against Omicron variants BA.1 and BA.2 as compared to the original Wuhan strain. Despite waning antibody levels, neutralization activity against the original Wuhan strain is maintained throughout the 6-month period. In the context of recurrent surges of SARS-CoV-2 infections despite vaccination with booster doses, our data indicate that breakthrough infections are likely driven by novel variants with different antibody specificity and not by time since last dose of vaccination, indicating that development of vaccinations specific to these novel variants is necessary to prevent future surges of SARS-CoV-2 infections.

Evaluation of Histone Deacetylase Inhibitors as Radiosensitizers for Proton and Light Ion Radiotherapy.

Significant opportunities remain for pharmacologically enhancing the clinical effectiveness of proton and carbon ion-based radiotherapies to achieve both tumor cell radiosensitization and normal tissue radioprotection. We investigated whether pretreatment with the hydroxamate-based histone deacetylase inhibitors (HDACi) SAHA (vorinostat), M344, and PTACH impacts radiation-induced DNA double-strand break (DSB) induction and repair, cell killing, and transformation (acquisition of anchorage-independent growth in soft agar) in human normal and tumor cell lines following gamma ray and light ion irradiation. Treatment of normal NFF28 primary fibroblasts and U2OS osteosarcoma, A549 lung carcinoma, and U87MG glioma cells with 5-10 µM HDACi concentrations 18 h prior to cesium-137 gamma irradiation resulted in radiosensitization measured by clonogenic survival assays and increased levels of colocalized gamma-H2AX/53BP1 foci induction. We similarly tested these HDACi following irradiation with 200 MeV protons, 290 MeV/n carbon ions, and 350 MeV/n oxygen ions delivered in the Bragg plateau region. Unlike uniform gamma ray radiosensitization, effects of HDACi pretreatment were unexpectedly cell type and ion species-dependent with C-12 and O-16 ion irradiations showing enhanced G0/G1-phase fibroblast survival (radioprotection) and in some cases reduced or absent tumor cell radiosensitization. DSB-associated foci levels were similar for proton-irradiated DMSO control and SAHA-treated fibroblast cultures, while lower levels of induced foci were observed in SAHA-pretreated C-12 ion-irradiated fibroblasts. Fibroblast transformation frequencies measured for all radiation types were generally LET-dependent and lowest following proton irradiation; however, both gamma and proton exposures showed hyperlinear transformation induction at low doses (≤25 cGy). HDACi pretreatments led to overall lower transformation frequencies at low doses for all radiation types except O-16 ions but generally led to higher transformation frequencies at higher doses (>50 cGy). The results of these in vitro studies cast doubt on the clinical efficacy of using HDACi as radiosensitizers for light ion-based hadron radiotherapy given the mixed results on their radiosensitization effectiveness and related possibility of increased second cancer induction.

MRI-guided focal laser ablation of prostate cancer: a prospective single-arm, single-center trial with 3 years of follow-up.

PURPOSE: We aimed to assess post-interventional and 36-month follow-up results of a single-center, single-arm, in-bore phase I trial of focal laser ablation (FLA) guided by multiparametric magnetic resonance imaging (mpMRI). METHODS: FLA procedures were done in-bore MRI using a transperineal approach. Primary endpoints were feasibility and safety expressed as lack of grade 3 complications. Secondary endpoints were changes in international prostate symptom score (IPSS), sexual health inventory for men (SHIM), quality of life (QoL) scores, and serum prostate specific antigen (PSA) levels. Treatment outcomes were assessed by combined mpMRI-ultrasound fusion-guided and extended sextant systematic biopsy after 12, 24, and optionally after 36 months. RESULTS: Fifteen participants were included. Seven patients (46.67%) had Gleason 3+3 and 8 patients (53.33%) had Gleason 3+4 cancer. All patients tolerated the procedure well, and no grade 3/4 complications occurred. All grade 1 and 2 complications were transient and resolved completely. There was no significant change in mean IPSS from baseline (-1, p = 0.460) and QoL (0, p = 0.441) scores following FLA but there was a significant drop in mean SHIM scores (-2, p = 0.010) compared to pretreatment baselines. Mean PSA significantly decreased after FLA (-2.5, p < 0.001). Seven out of 15 patients (46.67%) had residual cancer in, adjacent, or in close proximity to the treatment area (1 × 4+3=7, 1 × 3+4=7, and 5 × 3+3=6). Four out of 15 patients (26.67%) underwent salvage therapy (2 repeat FLA, 2 radical prostatectomy). CONCLUSION: After 3 years of follow-up we conclude focal laser ablation is safe and feasible without significant complications.