Whether multiparametric MRI improves the detection of clinically significant prostate cancer and avoids the need for systematic biopsy in biopsy-naive patients remains controversial. We aimed to ...investigate whether using this approach before biopsy would improve detection of clinically significant prostate cancer in biopsy-naive patients.
In this prospective, multicentre, paired diagnostic study, done at 16 centres in France, we enrolled patients aged 18–75 years with prostate-specific antigen concentrations of 20 ng/mL or less, and with stage T2c or lower prostate cancer. Eligible patients had been referred for prostate multiparametric MRI before a first set of prostate biopsies, with a planned interval of less than 3 months between MRI and biopsies. An operator masked to multiparametric MRI results did a systematic biopsy by obtaining 12 systematic cores and up to two cores targeting hypoechoic lesions. In the same patient, another operator targeted up to two lesions seen on MRI with a Likert score of 3 or higher (three cores per lesion) using targeted biopsy based on multiparametric MRI findings. Patients with negative multiparametric MRI (Likert score ≤2) had systematic biopsy only. The primary outcome was the detection of clinically significant prostate cancer of International Society of Urological Pathology grade group 2 or higher (csPCa-A), analysed in all patients who received both systematic and targeted biopsies and whose results from both were available for pathological central review, including patients who had protocol deviations. This study is registered with ClinicalTrials.gov, number NCT02485379, and is closed to new participants.
Between July 15, 2015, and Aug 11, 2016, we enrolled 275 patients. 24 (9%) were excluded from the analysis. 53 (21%) of 251 analysed patients had negative (Likert ≤2) multiparametric MRI. csPCa-A was detected in 94 (37%) of 251 patients. 13 (14%) of these 94 patients were diagnosed by systematic biopsy only, 19 (20%) by targeted biopsy only, and 62 (66%) by both techniques. Detection of csPCa-A by systematic biopsy (29·9%, 95% CI 24·3–36·0) and targeted biopsy (32·3%, 26·5–38·4) did not differ significantly (p=0·38). csPCa-A would have been missed in 5·2% (95% CI 2·8–8·7) of patients had systematic biopsy not been done, and in 7·6% (4·6–11·6) of patients had targeted biopsy not been done. Four grade 3 post-biopsy adverse events were reported (3 cases of prostatitis, and 1 case of urinary retention with haematuria).
There was no difference between systematic biopsy and targeted biopsy in the detection of ISUP grade group 2 or higher prostate cancer; however, this detection was improved by combining both techniques and both techniques showed substantial added value. Thus, obtaining a multiparametric MRI before biopsy in biopsy-naive patients can improve the detection of clinically significant prostate cancer but does not seem to avoid the need for systematic biopsy.
French National Cancer Institute.
Cardiolipin is a mitochondrion-specific phospholipid that stabilizes the assembly of respiratory chain complexes, favoring full-yield operation. It also mediates key steps in apoptosis. In Barth ...syndrome, an X chromosome-linked cardiomyopathy caused by tafazzin mutations, cardiolipins display acyl chain modifications and are present at abnormally low concentrations, whereas monolysocardiolipin accumulates. Using immortalized lymphoblasts from Barth syndrome patients, we showed that the production of abnormal cardiolipin led to mitochondrial alterations. Indeed, the lack of normal cardiolipin led to changes in electron transport chain stability, resulting in cellular defects. We found a destabilization of the supercomplex (respirasome) I+III2+IVn but also decreased amounts of individual complexes I and IV and supercomplexes I+III and III+IV. No changes were observed in the amounts of individual complex III and complex II. We also found decreased levels of complex V. This complex is not part of the supercomplex suggesting that cardiolipin is required not only for the association/stabilization of the complexes into supercomplexes but also for the modulation of the amount of individual respiratory chain complexes. However, these alterations were compensated by an increase in mitochondrial mass, as demonstrated by electron microscopy and measurements of citrate synthase activity. We suggest that this compensatory increase in mitochondrial content prevents a decrease in mitochondrial respiration and ATP synthesis in the cells. We also show, by extensive flow cytometry analysis, that the type II apoptosis pathway was blocked at the mitochondrial level and that the mitochondria of patients with Barth syndrome cannot bind active caspase-8. Signal transduction is thus blocked before any mitochondrial event can occur. Remarkably, basal levels of superoxide anion production were slightly higher in patients' cells than in control cells as previously evidenced via an increased protein carbonylation in the taz1Δ mutant in the yeast. This may be deleterious to cells in the long term. The consequences of mitochondrial dysfunction and alterations to apoptosis signal transduction are considered in light of the potential for the development of future treatments.
•Barth syndrome lymphoblasts have impaired mitochondrial functions.•The lack of mature cardiolipin led to changes in electron transport chain stability.•A compensatory increase in mitochondrial content prevents a decrease ATP synthesis.•Apoptotic signal transduction for type II apoptosis is blocked before mitochondrial events can occur.•The basal levels of superoxide anion were slightly higher in patient's cells than in normal cells.
Neuronal ceroid lipofuscinoses (NCLs) are rare, progressive disorders. Through this series of 20 patients with NCL, we illustrate differences between subtypes in their presenting symptoms and ...clinical, imaging, and electrophysiological results to raise awareness of symptom diversity. Data were available on presenting symptoms, genetics, magnetic resonance imaging (MRI), electroencephalography (including with low‐frequency intermittent photic stimulation), visual responses, and electron microscopy. Causal mutations were identified in 10 patients. Eleven patients had neuronal ceroid lipofuscinosis type 2 (CLN2) disease and their most common presenting symptom was seizures, although motor and language defects were also reported. Five patients with CLN2 disease showed abnormalities at initial MRI, but only three showed a photic response with low‐frequency stimulation. Seizures were not as common a presenting symptom in other NCL subtypes. Patients with NCLs present with diverse symptoms, which may not be characteristic in early disease stages. These signs and symptoms should lead to rapid diagnostic confirmatory testing for NCLs.
What this paper adds
Disease presentation is not uniform for neuronal ceroid lipofuscinoses.
Characteristic clinical test results may not be identified in early disease stages.
What this paper adds
Disease presentation is not uniform for neuronal ceroid lipofuscinoses.
Characteristic clinical test results may not be identified in early disease stages.
This article is commented on by Trivisano and Specchio on page 414 of this issue.
Lysosome membrane recycling occurs at the end of the autophagic pathway and requires proteins that are mostly encoded by genes mutated in neurodegenerative diseases. However, its implication in ...neuronal death is still unclear. Here, we show that spatacsin, which is required for lysosome recycling and whose loss of function leads to hereditary spastic paraplegia 11 (SPG11), promotes clearance of gangliosides from lysosomes in mouse and human SPG11 models. We demonstrate that spatacsin acts downstream of clathrin and recruits dynamin to allow lysosome membrane recycling and clearance of gangliosides from lysosomes. Gangliosides contributed to the accumulation of autophagy markers in lysosomes and to neuronal death. In contrast, decreasing ganglioside synthesis prevented neurodegeneration and improved motor phenotype in a SPG11 zebrafish model. Our work reveals how inhibition of lysosome membrane recycling leads to the deleterious accumulation of gangliosides, linking lysosome recycling to neurodegeneration.
Display omitted
•Loss of spatacsin promotes accumulation of simple gangliosides in lysosomes•Inhibition of lysosome membrane recycling leads to accumulation of gangliosides•Gangliosides promote accumulation of autophagy markers in lysosomes•Gangliosides contribute to neurodegeneration when lysosome recycling is compromised
Boutry et al. show that inhibition of lysosome membrane recycling leads to lysosomal accumulation of some glycosphingolipids (simple gangliosides), which contributes to neuronal death.
Abstract Background Focal ablative therapy may be a suboptimal option for anterior prostate cancers (APCs) reaching the prostate apex due to concerns for thermal injury to the external sphincter. ...Objective To explore the technical feasibility of anterior partial prostatectomy (APP) for isolated APCs detected by magnetic resonance imaging (MRI), and to report short-term oncologic and functional outcomes. Design, setting, and participants Following institutional review board approval, over an 8-yr period (2008–2015) 17 consenting patients were enrolled in a prospective single-arm single-center Innovation, Development, Exploration, Assessment, Long-term (IDEAL) phase 2a study. Inclusion criteria comprised preurethral, low- to intermediate-risk APC diagnosed by MRI, and targeted biopsies. Robotic template APP was performed; posterolateral aspect of the submontanal urethra, peripheral zone, and periprostatic tissues were preserved intact. Median follow-up was 30 mo (interquartile range IQR: 25–70). Outcome measurements and statistical analysis We noted the incidence of perioperative complications and examined reports of pathology, prostate-specific antigen (PSA), imaging, biopsies, and questionnaires. Results and limitations Preoperatively, median PSA was 9.8 ng/ml, Gleason score was 6–7 (3 + 4), and cancer volume was 3.7 cm3 (IQR: 1.7–4.6). The technique was feasible in all cases. Perioperative complications included anastomotic leak (12%; G2), urinary tract infection (6%; G2), and transient intestinal ileus in one case (6%; G2). At 3 mo, continence and potency rates were 100% and 83%, respectively. Median nadir PSA was 0.4 ng/ml (IQR: 0.3–0.7). All margins and posterolateral margins rates were 55% and 35%, respectively. APC recurrence-free survival at 2 yr was 0.86 (95% confidence interval CI, 0.55–0.96). Four patients (24%) who recurred underwent an uncomplicated completion of robot-assisted prostatectomy. Regarding limitations, CIs are quite wide for reported outcomes. Conclusions Robotic partial prostatectomy for isolated APC is feasible with good functional results. While promising, much more research is needed to verify our initial outcomes and appropriately position APP in the treatment paradigms for APC. Patient summary We explored a novel approach for partial prostatic surgical ablation for prostate cancer located in the anterior part of the prostate as an alternative to other focal ablative techniques.
Abstract
Sandhoff disease (SD) is a rare inherited disorder caused by a deficiency of β-hexosaminidase activity which is fatal because no effective treatment is available. A mouse model of Hexb ...deficiency reproduces the key pathognomonic features of SD patients with severe ubiquitous lysosomal dysfunction, GM2 accumulation, neuroinflammation and neurodegeneration, culminating in death at 4 months. Here, we show that a single intravenous neonatal administration of a self-complementary adeno-associated virus 9 vector (scAAV9) expressing the Hexb cDNA in SD mice is safe and sufficient to prevent disease development. Importantly, we demonstrate for the first time that this treatment results in a normal lifespan (over 700 days) and normalizes motor function assessed by a battery of behavioral tests, with scAAV9-treated SD mice being indistinguishable from wild-type littermates. Biochemical analyses in multiple tissues showed a significant increase in hexosaminidase A activity, which reached 10–15% of normal levels. AAV9 treatment was sufficient to prevent GM2 and GA2 storage almost completely in the cerebrum (less so in the cerebellum), as well as thalamic reactive gliosis and thalamocortical neuron loss in treated Hexb−/− mice. In summary, this study demonstrated a widespread protective effect throughout the entire CNS after a single intravenous administration of the scAAV9-Hexb vector to neonatal SD mice.
To report the preliminary results of salvage re-irradiation in the prostatic bed after radical prostatectomy and salvage external beam radiation therapy (EBRT) using robotic stereotactic body ...radiation therapy (SBRT) with Cyberknife® for local recurrence of prostate cancer.
Retrospective monocentric analysis was performed on patients treated with SBRT for isolated macroscopic recurrence in the prostatic bed. All patients had radical prostatectomy and salvage or adjuvant EBRT. Local recurrence was documented using magnetic resonance imaging (MRI) and positron emission tomography (PET). Biochemical recurrence was defined as 2 rises in prostate-specific antigen (PSA) of ≥ 0.2 ng/mL above nadir. Internal gold fiducials were used for the tracking of tumor motion during SBRT. The prescription dose was 36 Gy in 6 fractions for all patients. Toxicity was scored according to the CTCAE v4.0.
Between July 2011 and November 2017, 12 patients were treated with SBRT for prostatic bed recurrence with a median follow-up of 34.2 (range, 3.5-64.4) months. Isolated non-metastatic recurrence in the prostatic bed was seen at MRI and PET imaging. Two patients were treated with 6 months androgen deprivation therapy (ADT) concomitant with re-irradiation. The median planning target volume was 4.5 cm
(range, 1.2-13.3). A PSA decrease after SBRT was found in 10 (83%) patients. The 1 and 2 years biochemical recurrence-free survival rates were 79 and 56%, respectively. Biochemical recurrence was observed for 6 patients (50%) after a median time of 18 (4-42) months. Toxicity showed: 3 patients (25%) with grade 1 cystitis and 1 patient (8%) with acute grade 2 proctitis at 4 months. One patient (13%) had grade 1 cystitis at 12 months.
Re-irradiation for local recurrence in the prostatic bed using Cyberknife® after surgery and salvage or adjuvant EBRT is well-tolerated and associated with 2 years biochemical recurrence-free survival rates of 56%. Longer follow-up and larger series are necessary.
Neuronal ceroid lipofuscinoses (NCLs) represent the most common group of inherited progressive encephalopathies in children. They are characterized by progressive loss of vision, mental and motor ...deterioration, epileptic seizures, and premature death. Rare adult forms of NCL with late onset are known as Kufs' disease. Loci underlying these adult forms remain unknown due to the small number of patients and genetic heterogeneity. Here we confirm that a late-onset form of NCL recessively segregates in US and French pedigrees of American Staffordshire Terrier (AST) dogs. Through combined association, linkage, and haplotype analyses, we mapped the disease locus to a single region of canine chromosome 9. We eventually identified a worldwide breed-specific variant in exon 2 of the Arylsulfatase G (ARSG) gene, which causes a p.R99H substitution in the vicinity of the catalytic domain of the enzyme. In transfected cells or leukocytes from affected dogs, the missense change leads to a 75% decrease in sulfatase activity, providing a functional confirmation that the variant might be the NCL-causing mutation. Our results uncover a protein involved in neuronal homeostasis, identify a family of candidate genes to be screened in patients with Kufs' disease, and suggest that a deficiency in sulfatase is part of the NCL pathogenesis.
Purpose
Using a limited temporal resolution dynamic contrast‐enhanced (DCE) magnetic resonance imaging (MRI) dataset to assess the impact of the arterial input function (AIF) choice on the transfer ...constant (Ktrans) to distinguish prostate carcinoma (PCa) from benign tissue.
Materials and Methods
Thirty‐eight patients with clinically important peripheral PCa (≥0.5 cc) were retrospectively studied. These patients underwent 1.5T multiparametric prostate MR with PCa and benign regions of interest (ROIs) selected using a visual registration with morphometric reconstruction obtained from radical prostatectomy. Using three pharmacokinetic (PK) analysis software programs, the mean Ktrans of ROIs was computed using three AIFs: an individual AIF (Ind‐AIF) and two literature population average AIFs of Weinmann (W‐AIF) and of Fritz‐Hansen (FH‐AIF). A pairwise comparison of the area under the receiver operating characteristic curves (AUROCC) obtained with different AIFs was performed.
Results
AUROCCs obtained with W‐AIF (ranging from 0.801 to 0.843) were significantly higher than FH‐AIF (ranging from 0.698 to 0.780, 0.002 ≤ P ≤ 0.045) and similar to or higher than Ind‐AIF (ranging from 0.591 to 0.839, 0.014 ≤ P ≤ 0.9). Ind‐AIF and FH‐AIF provided similar AUROCC (0.34 ≤ P ≤ 0.81). The pairwise correlation of Ktrans values was moderate to very strong when comparing W‐AIF with FH‐AIF (the Spearman's correlation coefficients SCCs ranged from 0.55 to 0.93) and very weak to moderate when comparing W‐AIF with Ind‐AIF (the SCCs ranged from 0.018 to 0.59) or FH‐AIF with Ind‐AIF (the SCCs ranged from 0.30 to 0.51).
Conclusion
W‐AIF yielded a higher performance than FH‐AIF and a similar or higher performance than Ind‐AIF in distinguishing PCa from benign tissue. J. MAGN. RESON. IMAGING 2016;43:737–749.
This study demonstrates that both in situ and ex vivo autotransplantation methods are effective and safe for treating complex renal artery aneurysms, with in situ surgery showing marginally better ...outcomes. Further multicenter research is needed to confirm these findings.
Renal artery aneurysm (RAA) is a rare condition. Our study investigates the effectiveness and outcomes of surgical treatments for complex RAA, comparing the in situ (IS) and ex vivo autotransplantation (AT) methods.
We conducted a retrospective study from June 2015 to March 2023, including all consecutive patients treated surgically for complex RAA in our center. We focused on patients with complex RAA locations requiring open surgical multidisciplinary treatment, excluding those with simple aneurysms or who were treated endovascularly. Preoperative data including demographics, comorbidities, and cardiovascular risk factors were collected. The measured primary outcome was the absence of residual aneurysm and main renal arterial thrombosis after surgery. The secondary outcomes included pre- and postoperative kidney perfusion analyses and surgical complications as per Clavien-Dindo classification. Differences between AT and IS were assessed by Wilcoxon, chi-square, or Fischer’s exact test.
Twenty-seven aneurysms were treated in 25 patients. No residual aneurysm or main artery thrombosis was found after surgery. Ten (40%) patients underwent AT surgery. The median kidney perfusion differences were 2 cc (-12; 13), 0 cc (-13; 10), and 2 cc (-10; 13; p = 0.41) in the whole, AT, and IS cohorts, respectively. Clavien-Dindo grade 1 and 2 complications occurred in 11% and 30% of patients, respectively, with no grade 3 or 4 complications observed.
Complex RAA can be managed effectively through open surgery, ensuring good ipsilateral renal preservation and tolerable toxicity. Both AT and IS surgeries yielded similar outcomes. Further multicenter studies are warranted to confirm our findings.
This study explored the treatment of a rare kidney blood vessel condition called renal artery aneurysm using two surgical approaches. Our findings suggest that both surgical techniques are effective in treating this condition without major complications, ensuring good kidney preservation. These promising results need further confirmation through larger studies across different medical centers.
PDF
