Methotrexate to treat hand osteoarthritis with synovitis (METHODS): an Australian, multisite, parallel-group, double-blind, randomised, placebo-controlled trial.

BACKGROUND: Hand osteoarthritis is a disabling condition with few effective therapies. Hand osteoarthritis with synovitis is a common inflammatory phenotype associated with pain. We aimed to examine the efficacy and safety of methotrexate at 6 months in participants with hand osteoarthritis and synovitis. METHODS: In this multisite, parallel-group, double-blind, randomised, placebo-controlled trial, participants (aged 40-75 years) with hand osteoarthritis (Kellgren and Lawrence grade ≥2 in at least one joint) and MRI-detected synovitis of grade 1 or more were recruited from the community in Melbourne, Hobart, Adelaide, and Perth, Australia. Participants were randomly assigned (1:1) using block randomisation, stratified by study site and self-reported sex, to receive methotrexate 20 mg or identical placebo orally once weekly for 6 months. The primary outcome was pain reduction (measured with a 100 mm visual analogue scale; VAS) in the study hand at 6 months assessed in the intention-to-treat population. Safety outcomes were assessed in all randomly assigned participants. This trial was registered with the Australian New Zealand Clinical Trials Registry (ACTRN12617000877381). FINDINGS: Between Nov 22, 2017, and Nov 8, 2021, of 202 participants who were assessed for eligibility, 97 (48%) were randomly assigned to receive methotrexate (n=50) or placebo (n=47). 68 (70%) of 97 participants were female and 29 (30%) were male. 42 (84%) of 50 participants in the methotrexate group and 40 (85%) of 47 in the placebo group provided primary outcome data. The mean change in VAS pain at 6 months was -15·2 mm (SD 24·0) in the methotrexate group and -7·7 mm (25·3) in the placebo group, with a mean between-group difference of -9·9 (95% CI -19·3 to -0·6; p=0·037) and an effect size (standardised mean difference) of 0·45 (0·03 to 0·87). Adverse events occurred in 31 (62%) of 50 participants in the methotrexate group and 28 (60%) of 47 participants in the placebo group. INTERPRETATION: Treatment of hand osteoarthritis and synovitis with 20 mg methotrexate for 6 months had a moderate but potentially clinically meaningful effect on reducing pain, providing proof of concept that methotrexate might have a role in the management of hand osteoarthritis with an inflammatory phenotype. FUNDING: National Health and Medical Research Council of Australia.

Can 68 Ga-PSMA positron emission tomography and multiparametric MRI guide treatment for biochemical recurrence after radical prostatectomy?

OBJECTIVE: To evaluate the role of multiparametric magnetic resonance imaging (mpMRI) and Gallium-68 (68 Ga)-prostate-specific membrane antigen (PSMA) positron emission tomography (PET)/computed tomography (CT) in guiding salvage therapy for patients with biochemical recurrence (BCR) post-radical prostatectomy. PATIENTS AND METHODS: Patients were evaluated with paired mpMRI and 68 Ga-PSMA PET/CT scans for BCR (prostate-specific antigen [PSA] >0.2 ng/mL). Patient, tumour, PSA and imaging characteristics were analysed with descriptive statistics. RESULTS: A total of 117 patients underwent paired scans to investigate BCR, of whom 53.0% (62/117) had detectable lesions on initial scans and 47.0% (55/117) did not. Of those without detectable lesions, 8/55 patients proceeded to immediate salvage radiotherapy (sRT) and 47/55 were observed. Of patients with negative imaging who were initially observed, 46.8% (22/47) did not reach threshold for repeat imaging, while 53.2% were rescanned due to rising PSA levels. Of these rescanned patients, 31.9% (15/47) were spared sRT due to proven distant disease, or due to absence of disease on repeat imaging. Of the original 117 patients, 53 (45.3%) were spared early sRT due to absence of disease on imaging or presence of distant disease, while those undergoing delayed sRT still maintained good PSA responses. Of note, patients with high-risk features who underwent sRT despite negative imaging demonstrated satisfactory PSA responses to sRT. Study limitations include the observational design and absence of cause-specific or overall survival data. CONCLUSION: Our findings support the use of mpMRI and 68 Ga-PSMA PET/CT in guiding timing and necessity of salvage therapy tailored to detected lesions, with potential to reduce unnecessary sRT-related morbidity. Larger or randomized trials are warranted to validate this.

68Ga-Prostate-Specific Membrane Antigen Positron Emission Tomography Maximum Standardized Uptake Value as a Predictor of Gleason Pattern 4 and Pathological Upgrading in Intermediate-Risk Prostate Cancer.

PURPOSE: Accurate risk stratification remains a barrier for the safety of active surveillance in patients with intermediate-risk prostate cancer. [68Ga]Ga-PSMA-11 prostate-specific membrane antigen positron emission tomography/computerized tomography (68Ga-PSMA PET/CT) and the maximum standardized uptake value (SUVmax) may improve risk stratification within this population. MATERIALS AND METHODS: We reviewed men with International Society for Urological Pathology Grade Group (GG) 2-3 disease on transperineal template biopsy undergoing 68Ga-PSMA PET/CT from November 2015 to January 2021. Primary outcome was the presence of high percentage Gleason pattern 4 (GP4) disease per segment at surgery at 3 thresholds: >/<50% GP4, >/<20% GP4, and >/<10% GP4. SUVmax was compared by GP4, and multivariable logistic regression examined the relationship between SUVmax and GP4. Secondary outcome was association between SUVmax and pathological upgrading (GG 1/2 to GG ≥3 from biopsy to surgery). RESULTS: Of 220 men who underwent biopsy, 135 men underwent surgery. SUVmax was higher in high GP4 groups: 5.51 (IQR 4.19-8.49) vs 3.31 (2.64-4.41) >/<50% GP4 (p <0.001); 4.77 (3.31-7.00) vs 3.13 (2.64-4.41) >/<20% GP4 (p <0.001); and 4.54 (6.10-3.13) vs 3.03 (2.45-3.70) >/<10% GP4 (p <0.001). SUVmax remained an independent predictor of >50% (OR=1.39 [95%CI 1.18-1.65], p <0.001) and >20% (OR=1.24 [1.04-1.47], p=0.015) GP4 disease per-segment, and of pathological upgrading (OR=1.22 [1.01-1.48], p=0.036). SUVmax threshold 4.5 predicted >20% GP4 with 58% specificity, 85% sensitivity, positive predictive value 75% and negative predictive value 72%. Threshold 5.4 predicted pathological upgrading with 91% specificity and negative predictive value 94%. CONCLUSIONS: SUVmax on 68Ga-PSMA PET/CT is associated with GP4. SUVmax may improve risk stratification for men with intermediate-risk prostate cancer.

Combined Utility of 68Ga-Prostate-specific Membrane Antigen Positron Emission Tomography/Computed Tomography and Multiparametric Magnetic Resonance Imaging in Predicting Prostate Biopsy Pathology.

BACKGROUND: 68Gallium-labelled prostate-specific membrane antigen positron emission tomography (68Ga-PSMA-11 PET) is a valuable staging tool, but its utility in characterising primary prostate cancer remains unclear. The maximum standardised uptake value (SUVmax) is a quantification measure of highest radiotracer uptake within PET-avid lesions. OBJECTIVE: To assess the utility of SUVmax in detecting clinically significant prostate cancer (csPCa) on biopsy alone and in combination with multiparametric magnetic resonance imaging (mpMRI). DESIGN, SETTING, AND PARTICIPANTS: This was a retrospective analysis of 200 men who underwent 68Ga-PSMA-11 PET/CT, mpMRI, and transperineal template prostate biopsy between 2016 and 2018. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The primary and secondary outcomes were detection of grade group (GG) 3-5 and GG 2-5 prostate cancer, respectively. We used the Mann-Whitney U test to compare SUVmax by GG, and calculated sensitivity and specificity for csPCa detection via 68Ga-PSMA-11 PET/CT, mpMRI, and both. Multivariable logistic regression analyses were used to identify predictors of csPCa on biopsy. RESULTS AND LIMITATIONS: The median SUVmax was greater for GG 3-5 tumours (6.40, interquartile range [IQR] 4.47-11.0) than for benign and GG 1-2 tumours (3.14, IQR 2.55-3.91; p < 0.001). The median SUVmax was greater for GG 3 (5.70, IQR 3.68-8.67) than for GG 2 (3.47, IQR 2.70-4.74; p < 0.001). For GG 3-5 disease, sensitivity was 86.5%, 95.9%, and 98.6%, and the negative predictive value (NPV) was 88.4%, 88.5%, and 93.3% using SUVmax ≥4, a Prostate Imaging-Reporting and Data System (PI-RADS) score of 3-5, and both, respectively. This combined model detected more GG 3-5 disease than mpMRI alone (98.6% vs 95.9%; p = 0.04). SUVmax was an independent predictor of csPCa for GG 3-5 disease only (odds ratio 1.27 per unit, 95% confidence interval 1.13-1.45). Our results are limited by the retrospective study design. CONCLUSIONS: Greater SUVmax on 68Ga-PSMA-11 PET/CT is associated with detection of GG 3-5 cancer on biopsy. The combination of PI-RADS score and SUVmax provides higher sensitivity and NPV than either alone. 68Ga-PSMA-11 PET/CT may be useful alongside mpMRI in improving risk stratification for localised disease. PATIENT SUMMARY: The amount of a radioactive tracer taken up in the prostate during a type of scan called PET (positron emission tomography) can predict whether aggressive prostate cancer is likely to be found on biopsy. This may complement the more usual type of scan, MRI (magnetic resonance imaging), used to detect prostate cancer.

Focal low dose-rate brachytherapy for low to intermediate risk prostate cancer: preliminary experience at an Australian institution.

BACKGROUND: Focal treatment for prostate cancer (PCa) is a hybrid approach combining ablative treatment of the involved prostate gland and continued active surveillance (AS) of the unaffected gland. Low dose-rate (LDR) brachytherapy can be used as a lesion-targeted focal therapy, however, further studies are required to support its use. The aim of this study is to evaluate the dosimetry, toxicity and oncological outcomes of men receiving lesion-targeted focal LDR brachytherapy for low to intermediate risk PCa. METHODS: This is a retrospective cohort study of 26 men with unifocal, low to intermediate grade PCa diagnosed on a combination of multiparametric-magnetic resonance imaging (mp-MRI) and targeted plus template transperineal (TP) biopsy, who received focal LDR brachytherapy at a single institution. Brachytherapy involved a single monotherapy implant using iodine-125 seeds to deliver a prescribed dose of 145 Gy to the index lesion. RESULTS: The mean focal planning target volume (F-PTV) as a percentage of the prostate volume was 24.5%. The percentage of the focal gross tumour volume (F-GTV) receiving 100% of the prescription dose was 100% for 12 patients and ≥98% for 18 patients. The median follow-up for toxicity and biochemical control outcomes was 23.1 [interquartile range (IQR) 19.1-31.3] and 24.2 (IQR 17.9-30.0) months, respectively. Grade 2 urinary and erectile toxicities were reported by 29.2% and 45.8% of patients, respectively, with resolution of urinary symptoms to baseline by last follow-up. There were no grade ≥3 urinary or erectile toxicities or grade ≥2 rectal toxicity. All 21 patients who underwent a repeat mp-MRI and TP biopsy at 12-24 months post-treatment were negative for clinically significant disease and 25 (96.2%) patients were free from biochemical failure (FFBF). CONCLUSIONS: Focal LDR brachytherapy is associated with a favourable toxicity profile and a high rate of control of significant PCa at 12-18 months post-treatment. We have commenced the LIBERATE prospective registry in focal LDR brachytherapy based on the highly encouraging outcomes of this initial experience.

Is antibiotic treatment effective in the management of chronic low back pain with disc herniation? Study protocol for a randomised controlled trial.

BACKGROUND: There has been immense interest and debate regarding the effectiveness of antibiotic treatment for chronic low back pain. Two randomised controlled trials have examined the efficacy of antibiotics for chronic low back pain with disc herniation and Modic changes, but have reported conflicting results. The aim of this double-blind, randomised, placebo-controlled trial is to determine the efficacy of antibiotic treatment in a broader patient subgroup of chronic low back pain with disc herniation and investigate whether the presence of Modic changes predicts response to antibiotic therapy. METHODS: One hundred and seventy individuals with chronic low back pain will be recruited through hospital and private medical and allied health clinics; advertising in national, community and social media; and posting of flyers in community locations. They will be randomly allocated to receive either amoxicillin-clavulanate (500 mg/125 mg) twice per day for 90 days or placebo. The primary outcome measure of pain intensity will be assessed using the Low Back Pain Rating scale and a 100-mm visual analogue scale at 12 months. Secondary measures of self-reported low back disability and work absence and hindrance will also be examined, and an economic analysis will be conducted. Intention-to-treat analyses will be performed. DISCUSSION: There is uncertainty about whether antibiotic treatment is effective for chronic low back pain and, if effective, which patient subgroup is most likely to respond. We will conduct a clinical trial to investigate the efficacy of antibiotics compared with placebo in individuals with chronic low back pain and a disc herniation. Our findings will provide high-quality evidence to assist in answering these questions. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry ACTRN12615000958583 . Registered on 11 September 2015.

Reliability of a Novel Scoring System for MRI Assessment of Severity in Gluteal Tendinopathy: The Melbourne Hip MRI Score.

BACKGROUND: Gluteal tendinopathy is commonly reported in the literature, but there is a need for a validated magnetic resonance imaging (MRI)-based scoring system to grade the severity of the tendinopathy. PURPOSE: To use intra- and interobserver reliability to validate a new scoring system, the Melbourne Hip MRI (MHIP) score, for assessing the severity of gluteal tendinopathy. STUDY DESIGN: Cohort study (diagnosis); Level of evidence, 3. METHODS: The MHIP score assesses gluteal tendinopathy according to each 1 of 5 categories: (1) extent of tendon pathology (maximum 5 points); (2) muscle atrophy (maximum 4 points); (3) trochanteric bursitis (maximum 4 points); (4) cortical irregularity (maximum 3 points); and (5) bone marrow edema (maximum 1 point), with an overall range of 0 to 17 (most severe). A total of 41 deidentified MRI scans from 40 patients diagnosed with gluteal tendinopathy (mean baseline age, 57.44 ± 25.26 years; 4 male, 36 female) were read and graded according to MHIP criteria by 2 experienced musculoskeletal radiologists. The radiologists were blinded to previous reports, and the scans were read twice within a 2-month period. Statistical analysis using the intraclass correlation coefficient (ICC) was used to determine intra- and interobserver reliability and mean/range for the MHIP scores. RESULTS: Of a total of 123 readings, the mean MHIP score (±SD) was 3.93 ± 2.24 (range, 0-17 points). The MHIP score demonstrated excellent reliability for determining the severity of gluteal tendinopathy on MRI. The ICC for intra- and interobserver reliability was 0.81 (95% CI, 0.67-0.89) and 0.78 (95% CI, 0.62-0.87), respectively. CONCLUSION: The MHIP score had excellent intra- and interobserver reliability in scoring gluteal tendinopathy. This score allows gluteal tendon pathology to be graded prior to treatment and to be used for standardized comparisons between results in future research undertaking radiological review of gluteal tendinopathy.

Radiological Identification of Injury to the Kaplan Fibers of the Iliotibial Band in Association With Anterior Cruciate Ligament Injury.

BACKGROUND: Recent biomechanical studies have demonstrated that the Kaplan fibers (KFs) of the iliotibial band play a role in the control of anterolateral rotation of the knee. However, controversy exists regarding whether the KFs are injured in conjunction with anterior cruciate ligament (ACL) injury. PURPOSE: To establish the prevalence of radiological injury to the KFs in the ACL-injured knee; to evaluate the effect of the time interval between injury and magnetic resonance imaging (MRI) on diagnosis of KF injury; and to assess for any association between KF injury and other qualitative radiological findings. STUDY DESIGN: Cohort study (diagnosis); Level of evidence, 3. METHODS: Preoperative MRI scans were reviewed for 161 patients with ACL injury. Specific diagnostic criteria were developed and applied to identify KF injury. Chi-square testing was performed to look for associations among KF injury, the time from injury to MRI, and associated radiological knee injuries. RESULTS: Radiological evidence of KF injury was identified in 30 (18.6%) patients. The diagnosis of KF injury was higher in patients who had MRI scans performed within 90 days of injury as compared with ≥90 days after injury (23.7 vs 6.4%; P = .010). Patients with an MRI diagnosis of KF injury had significantly higher rates of lateral meniscal injury (40% vs 18%; P = .007), posteromedial tibial bone marrow edema (73% vs 44%; P = .003), and injury to the lateral collateral ligament (13% vs 3%; P = .019) or medial collateral ligament (23% vs 8%; P = .019). CONCLUSION: The prevalence of injury to the KF in patients with ACL injury as diagnosed by MRI was relatively low (18.6% of patients). However, the time interval from injury to MRI was relevant to diagnosis, with significantly higher rates of injury identification in patients with early (within 90 days) versus delayed (≥90 days) MRI. KF injury was associated with higher rates of injury to the lateral meniscal and collateral ligaments, as well as posteromedial tibial bone bruising.

Detection and localisation of primary prostate cancer using 68 gallium prostate-specific membrane antigen positron emission tomography/computed tomography compared with multiparametric magnetic resonance imaging and radical prostatectomy specimen pathology.

OBJECTIVE: To compare the accuracy of 68 gallium prostate-specific membrane antigen positron emission tomography/computed tomography (68 Ga-PSMA PET/CT) with multiparametric MRI (mpMRI) in detecting and localising primary prostate cancer when compared with radical prostatectomy (RP) specimen pathology. PATIENTS AND METHODS: Retrospective review of men who underwent 68 Ga-PSMA PET/CT and mpMRI for primary prostate cancer before RP across four centres between 2015 and 2018. Patients undergoing imaging for recurrent disease or before non-surgical treatment were excluded. We defined pathological index tumour as the lesion with highest International Society of Urological Pathology Grade Group (GG) on RP specimen pathology. Our primary outcomes were rates of accurate detection and localisation of RP specimen pathology index tumour using 68 Ga-PSMA PET/CT or mpMRI. We defined tumour detection as imaging lesion corresponding with RP specimen tumour on any imaging plane, and localisation as imaging lesion matching RP specimen index tumour in all sagittal, axial, and coronal planes. Secondary outcomes included localisation of clinically significant and transition zone (TZ) index tumours. We defined clinically significant disease as GG 3-5. We used descriptive statistics and the Mann-Whitney U-test to define and compare demographic and pathological characteristics between detected, missed and localised tumours using either imaging modality. We used the McNemar test to compare detection and localisation rates using 68 Ga-PSMA PET/CT and mpMRI. RESULTS: In all, 205 men were included in our analysis, including 133 with clinically significant disease. There was no significant difference between 68 Ga-PSMA PET/CT and mpMRI in the detection of any tumour (94% vs 95%, P > 0.9). There was also no significant difference between localisation of all index tumours (91% vs 89%, P = 0.47), clinically significant index tumours (96% vs 91%, P = 0.15) or TZ tumours (85% vs 80%, P > 0.9) using 68 Ga-PSMA PET/CT and mpMRI. Limitations include retrospective study design and non-central review of imaging and pathology. CONCLUSION: We found no significant difference in the detection or localisation of primary prostate cancer between 68 Ga-PSMA PET/CT and mpMRI. Further prospective studies are required to evaluate a combined PET/MRI model in minimising tumours missed by either modality.

The Kaplan Fibers of the Iliotibial Band Can Be Identified on Routine Knee Magnetic Resonance Imaging.

BACKGROUND: The Kaplan fibers (KFs) of the iliotibial band have been suggested to play a role in anterolateral rotational instability of the knee, particularly in the setting of an anterior cruciate ligament (ACL) rupture. Description of the normal magnetic resonance imaging (MRI) anatomy of the KFs may facilitate subsequent investigation into the MRI signs of injury. PURPOSE: To assess if the KF complex can be identified on 3-T MRI using standard knee protocols. STUDY DESIGN: Cohort study (diagnosis); Level of evidence, 3. METHODS: 3-T MRI scans of 50 ACL-intact knees were reviewed independently by a musculoskeletal radiologist and 2 orthopaedic surgeons. Identification of the KFs was based on radiological diagnostic criteria developed a priori. Identification of the KFs in the sagittal, coronal, and axial planes was recorded. Interobserver reliability was assessed using the Kappa statistic. Detailed anatomy including distance to the joint line and relationship to adjacent structures was recorded. RESULTS: The mean patient age was 43 years (range, 15-81 years), 58% were male, and 50% were right knees. The KFs were identified by at least 2 reviewers on the sagittal images in 96% of cases, on the axial images in 76% of cases, and on the coronal images in 4% of cases. The mean distance from the KF distal femoral insertion to the lateral joint line was 50.1 mm (SD, 6.6 mm) and the mean distance to the lateral gastrocnemius tendon origin was 10.8 mm (SD, 8.6 mm). The KFs were consistently identified immediately anterior to the superior lateral geniculate artery on sagittal imaging. Interobserver reliability for identification was best in the sagittal plane (Kappa 0.5) and worst in the coronal plane (Kappa 0.1). CONCLUSION: The KF complex can be identified on routine MRI sequences in the ACL-intact knee; however, there is low to moderate interobserver reliability. Imaging in the sagittal plane had the highest rate of identification and the coronal plane the lowest. There is a consistent relationship between the most distal KF femoral attachment and the lateral joint line, lateral gastrocnemius tendon, and superior lateral geniculate artery.

Cerebral amyloid angiopathy: Review of clinico-radiological features and mimics.

Cerebral amyloid angiopathy (CAA) is an important cause of lobar intracerebral haemorrhage (ICH) in the elderly, but has other clinico-radiological manifestations. In the last two decades, certain magnetic resonance imaging (MRI) sequences, namely gradient-recalled echo imaging and the newer and more sensitive susceptibility-weighted imaging, have been utilised to detect susceptibility-sensitive lesions such as cerebral microbleeds and cortical superficial siderosis. These can be utilised sensitively and specifically by the Modified Boston Criteria to make a diagnosis of CAA without the need for 'gold-standard' histopathology from biopsy. However, recently, other promising MRI biomarkers of CAA have been described which may further increase precision of radiological diagnosis, namely chronic white matter ischaemia, cerebral microinfarcts and lobar lacunes, cortical atrophy, and increased dilated perivascular spaces in the centrum semiovale. However, the radiological manifestations of CAA, as well as their clinical correlates, may have other aetiologies and mimics. It is important for the radiologist to be aware of these clinico-radiological features and mimics to accurately diagnose CAA. This is increasingly important in a patient demographic that has a high prevalence for use of antiplatelet and antithrombotic medications for other comorbidities which inherently carries an increased risk of ICH in patients with CAA.

Interpreting Prostate Multiparametric Magnetic Resonance Imaging: Urologists' Guide Including Prostate Imaging Reporting and Data System.

OBJECTIVE: To review and explain the development of multiparametric MRI and its use in prostate cancer diagnosis while educating on the implication of certain radiological findings. METHODS: The physics of magnetic resonance imaging is reviewed befor the explanation of different phase technologies in "multiparametric" scanning. Sample images of the prostate are used to display phenomena described. RESULTS: Modalities of multiparametric magnetic resonance imaging (mpMRI) of the prostate were reviewed and the interpretation of certain findings were displayed on sample images to educate clinicians about their presence and significance. CONCLUSION: Diagnosis, biopsy targeting, surveillance, operative planning and staging has led to endorsement of mpMRI and it is imperative that treating urologists have an understanding of mpMRI to appreciate the power and limitations of its findings.

Multicentre evaluation of magnetic resonance imaging supported transperineal prostate biopsy in biopsy-naïve men with suspicion of prostate cancer.

OBJECTIVES: To analyse the detection rates of primary magnetic resonance imaging (MRI)-fusion transperineal prostate biopsy using combined targeted and systematic core distribution in three tertiary referral centres. PATIENTS AND METHODS: In this multicentre, prospective outcome study, 807 consecutive biopsy-naïve patients underwent MRI-guided transperineal prostate biopsy, as the first diagnostic intervention, between 10/2012 and 05/2016. MRI was reported following the Prostate Imaging-Reporting and Data System (PI-RADS) criteria. In all, 236 patients had 18-24 systematic transperineal biopsies only, and 571 patients underwent additional targeted biopsies either by MRI-fusion or cognitive targeting if PI-RADS ≥3 lesions were present. Detection rates for any and Gleason score 7-10 cancer in targeted and overall biopsy were calculated and predictive values were calculated for different PI-RADS and PSA density (PSAD) groups. RESULTS: Cancer was detected in 68% of the patients (546/807) and Gleason score 7-10 cancer in 49% (392/807). The negative predictive value of 236 PI-RADS 1-2 MRI in combination with PSAD of <0.1 ng/mL/mL for Gleason score 7-10 was 0.91 (95% confidence interval ± 0.07, 8% of study population). In 418 patients with PI-RADS 4-5 lesions using targeted plus systematic biopsies, the cancer detection rate of Gleason score 7-10 was significantly higher at 71% vs 59% and 61% with either approach alone (P < 0.001). For 153 PI-RADS 3 lesions, the detection rate was 31% with no significant difference to systematic biopsies with 27% (P > 0.05). Limitations include variability of multiparametric MRI (mpMRI) reading and Gleason grading. CONCLUSION: MRI-based transperineal biopsy performed at high-volume tertiary care centres with a significant experience of prostate mpMRI and image-guided targeted biopsies yielded high detection rates of Gleason score 7-10 cancer. Prostate biopsies may not be needed for men with low PSAD and an unsuspicious MRI. In patients with high probability lesions, combined targeted and systematic biopsies are recommended.

MRI is not reliable in diagnosing of concomitant anterolateral ligament and anterior cruciate ligament injuries of the knee.

PURPOSE: There has been a renewed interest in the anterolateral structures of the knee, including description of the anterolateral ligament (ALL) as a distinct structure. Recognizing injury to the ALL is challenging, particularly given the subjective nature of physical examination. Consequently, focus has turned to magnetic resonance imaging (MRI) to reach a preoperative diagnosis of this region. The aim of this study was to examine the ability of 3-Tesla (3T) MRI to identify the ALL in ACL-injured patients compared to a matched control group of ACL-intact patients. The hypothesis was that the ALL would be more difficult to identify in ACL-injured patients compared to ACL-intact patients. METHODS: A prospective case control study was performed comparing 3T MRI scans of 63-patients with an ACL rupture with a control group of 64-patients without ACL injury. An experienced musculoskeletal radiologist and an orthopaedic surgeon evaluated the scans performed using standard knee protocols. The ALL was considered in three regions for analysis: femoral, meniscal, and tibial. The status of the ALL was determined as visualized or non-visualized, and the integrity was assessed as intact, attenuated, or focal discontinuity. RESULTS: The detection rate of at least a portion of the ALL was 41/64 (64%) in the control group and 45/63 (72%) in the ACL-injured cohort, respectively. The entire length of the ALL could only be identified in 15/64 (23%) of the control group and 13/63 (21%) of the ACL-injured cases. In both groups, the visibility of the ALL was poorest at the femoral region and greatest at the tibial regions. The ALL, when visualized, was deemed to be intact in 55/63 (87%) of cases. Although the inter-observer reliability was excellent for detection of the ALL in the control group (κ = 0.86), this decreased to only moderate reliability in the ACL-injured group (κ = 0.52). CONCLUSION: This study demonstrates that MRI alone should not be relied upon to make a diagnosis of ALL injury in the setting of concomitant ACL injury due to the inability to accurately visualize this structure consistently in its entirety. To make a diagnosis of ALL injury or anterolateral instability of the knee and clinical correlation remains essential. LEVEL OF EVIDENCE: Case-control study, Level III.

The natural history of Modic changes in a community-based cohort.

BACKGROUND: Vertebral endplate (Modic) lesions are gaining interest, with varied phenotypes recognised to have distinct clinical and histological correlates. Nevertheless, the natural history of these lesions is unclear. This study examined the natural history of Modic changes and their potential relationship to the intervertebral disc. METHODS: Seventy-two community-based adults not selected for low back pain had lumbar spine magnetic resonance imaging (MRI) performed at baseline (2012) and approximately 2 years later to assess Modic lesions. Fifty-six participants completed the study. Intervertebral disc pathology was assessed by disc height and the Pfirrmann grading system at baseline. RESULTS: At baseline, 6 Modic type 1 lesions were present in 3 (4.2%) participants. At follow-up, 4 persisted, 2 changed to a Modic type 2 lesion, and there were 4 incident lesions. Only 1 participant (1.4%) had a baseline Modic type 3 lesion, which persisted at follow-up, with one further incident lesion. Modic type 2 lesions were most common (n=47, in 20 of 72 [27.8%] participants). Resolution of Modic type 2 lesions was uncommon (n=1, with 2 changing to a type 1 lesion). 18 incident lesions occurred in 7 (12.5%) participants, with most occurring both sides of the intervertebral disc. A reduction in the average baseline disc height was associated with an increased risk for type 2 incident lesions (OR 1.9, 95% CI 1.1 to 3.3, P=0.03). Similarly, severe baseline disc degeneration at L3/4, L4/5 and L5/S1 was associated with an increased risk for type 2 incident lesions (all P≤0.05). CONCLUSION: This longitudinal study has demonstrated that Modic type 2 are the most common of the Modic lesions in community-based adults and while resolution of these lesions is uncommon, incident disease develops on both sides of the intervertebral disc in the setting of severe disc degeneration. These results suggest that type 2 Modic changes are a sequel of disc degeneration.

Brain lesion correlates of fatigue in individuals with traumatic brain injury.

The purpose of this study was to investigate the neurological correlates of both subjective fatigue as well as objective fatigability in individuals with traumatic brain injury (TBI). The study has a cross-sectional design. Participants (N = 53) with TBI (77% male, mean age at injury 38 years, mean time since injury 1.8 years) underwent a structural magnetic resonance imaging (MRI) scan and completed the Fatigue Severity Scale (FSS), while a subsample (N = 36) was also tested with a vigilance task. While subjective fatigue (FSS) was not related to measures of brain lesions, multilevel analyses showed that a change in the participants' decision time was significantly predicted by grey matter (GM) lesions in the right frontal lobe. The time-dependent development of the participants' error rate was predicted by total brain white matter (WM) lesion volumes, as well as right temporal GM and WM lesion volumes. These findings could be explained by decreased functional connectivity of attentional networks, which results in accelerated exhaustion during cognitive task performance. The disparate nature of objectively measurable fatigability on the one hand and the subjective experience of fatigue on the other needs further investigation.

Ovarian Cancers Harbor Defects in Nonhomologous End Joining Resulting in Resistance to Rucaparib.

Purpose: DNA damage defects are common in ovarian cancer and can be used to stratify treatment. Although most work has focused on homologous recombination (HR), DNA double-strand breaks are repaired primarily by nonhomologous end joining (NHEJ). Defects in NHEJ have been shown to contribute to genomic instability and have been associated with the development of chemoresistance.Experimental Design: NHEJ was assessed in a panel of ovarian cancer cell lines and 47 primary ascetic-derived ovarian cancer cultures, by measuring the ability of cell extracts to end-join linearized plasmid monomers into multimers. mRNA and protein expression of components of NHEJ was determined using RT-qPCR and Western blotting. Cytotoxicities of cisplatin and the PARP inhibitor rucaparib were assessed using sulforhodamine B (SRB) assays. HR function was assessed using γH2AX/RAD51 foci assay.Results: NHEJ was defective (D) in four of six cell lines and 20 of 47 primary cultures. NHEJ function was independent of HR competence (C). NHEJD cultures were resistant to rucaparib (P = 0.0022). When HR and NHEJ functions were taken into account, only NHEJC/HRD cultures were sensitive to rucaparib (compared with NHEJC/HRC P = 0.034, NHEJD/HRC P = 0.0002, and NHEJD/HRD P = 0.0045). The DNA-PK inhibitor, NU7441, induced resistance to rucaparib (P = 0.014) and HR function recovery in a BRCA1-defective cell line.Conclusions: This study has shown that NHEJ is defective in 40% of ovarian cancers, which is independent of HR function and associated with resistance to PARP inhibitors in ex vivo primary cultures. Clin Cancer Res; 23(8); 2050-60. ©2016 AACR.

Lumbar disc degeneration is associated with modic change and high paraspinal fat content - a 3.0T magnetic resonance imaging study.

BACKGROUND: Degenerative disc disease of the lumbar spine is common, with severe disease increasing the risk for chronic low back pain. This cross-sectional study examined whether disc degeneration is representative of a 'whole-organ' pathology, by examining its association with bone (vertebral endplate) and soft tissue (paraspinal muscle fat) abnormalities. METHODS: Seventy-two community-based individuals unselected for low back pain, had Magnetic Resonance Imaging (MRI). Lumbosacral disc degeneration was determined via the Pfirrmann grading system, a validated method to assess the intervertebral disc, distinguishing the nucleus and annulus, the signal intensity and the height of the intervertebral disc. Modic change and high paraspinal muscle fat content was also measured from MRI. RESULTS: Severe disc degeneration was associated, or tended to be associated with type 2 Modic change from L2 to L5 (OR range 3.5 to 25.3, p ≤ 0.06). Moreover, severe disc degeneration at all intervertebral levels was associated with or tended to be associated with high fat content of the paraspinal muscles (OR range 3.7 to 14.3, p ≤ 0.09). CONCLUSION: These data demonstrate that disc degeneration of the lumbar spine is commonly accompanied by Modic change and high fat content of paraspinal muscles, thus representing a 'whole-organ' pathology. Longitudinal studies are required to determine the temporal relationship between these structural abnormalities. Understanding this may have the potential to identify novel targets for the treatment and prevention of lumbosacral disc degeneration.

Modic changes in the lumbar spine and their association with body composition, fat distribution and intervertebral disc height - a 3.0 T-MRI study.

BACKGROUND: Vertebral endplate (Modic) abnormalities are important structural lesions in the spine, but their association with body composition and fat distribution have not been examined. Moreover, no study has examined whether Modic change are related to other structural features of low back pain, such as reduced intervertebral disc height. METHODS: Seventy-two community-based individuals not selected for low back pain had lumbar vertebral Modic change and intervertebral disc height assessed from MRI. Dual energy x-ray absorptiometry measured body composition and fat distribution. RESULTS: The predominance of Modic change was type 2. Modic change was associated with an increased fat mass index (OR 1.20, 95 % CI 1.01 to 1.43), and tended to be associated with a reduced fat-free mass index (OR 0.62, 95 % CI 0.37 to 1.03, p = 0.07). While an increased percentage of gynoid fat was associated with a reduced risk (OR 0.62, 95 % CI 0.43 to 0.89), an increased percentage of android fat was associated with an increased risk of Modic change (OR 2.11, 95 % CI 1.18 to 3.76). Modic change was also associated with reduced intervertebral disc height at L2/3, L4/5 and L5/S1 (OR range 1.4 to 1.8; all p ≤ 0.03). CONCLUSION: Modic type 2 change is associated with reduced intervertebral disc height and an increased fat mass index. Whereas gynoid fat distribution protected against Modic type 2 change, an android pattern increased the risk of this lesion. Modic type 2 change, which histologically represent fat replacement, might have a metabolic component to its aetiology.

Prevention of Adverse Drug Reactions in Hospitalised Older Patients Using a Software-Supported Structured Pharmacist Intervention: A Cluster Randomised Controlled Trial.

BACKGROUND: Proven interventions to reduce adverse drug reactions (ADRs) in older hospitalised patients are lacking. Previous randomised controlled trial (RCT) data indicate that a structured pharmacist review of medication (SPRM) can reduce inappropriate prescribing in older hospitalised patients. However, no RCT data show that an SPRM reduces ADRs in this population. METHODS: We performed a cluster RCT comparing a clinical decision support software (CDSS)-supported SPRM intervention with standard pharmaceutical care in older patients hospitalised with an acute unselected illness. Over 13 months, we screened 1833 patients aged ≥65 years admitted to specialist services other than geriatric medicine for study inclusion. We randomised 361 patients to the trial intervention arm and 376 patients to the control arm, applying the intervention at a single timepoint within 48 h of admission. The primary endpoint (ADR incidence) was assessed at 7-10 days post-admission or at discharge (whichever came first). The secondary endpoints were the median hospital length of stay (LOS) and hospital mortality rate. RESULTS: Attending clinicians in the intervention group implemented 54.8% of SPRM/CDSS prescribing recommendations. Ninety-one ADRs occurred in 78 control patients (20.7%) compared with 61 ADRs in 50 intervention patients (13.9%), i.e., an absolute risk reduction of 6.8%. The number needed to treat (NNT) to prevent one patient having one ADR was 15; the total NNT to prevent one ADR was 14. The median LOS and hospital mortality were not significantly different. CONCLUSION: An SPRM delivered on a CDSS platform significantly reduces ADR incidence in acutely hospitalised older people.