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Organochlorine pesticide exposure and risk of prostate cancer development and progression: a systematic review
Background: There is an increasing body of evidence linking the exposure of an individual to pesticides such as organochlorine pesticides (OPCs) and an increased risk of developing diseases such as cancer. Exposure to OPCs has been suggested to increase the risk of developing hormone-dependant cancers such as prostate cancer (PCa). However, there is a relative paucity of information about the influence of exposure to these pesticides on the evolution of PCa, including risk of tumour development, progression to metastasis, and disease recurrence following therapy. Methods: We used several databases such as PubMed MEDLINE Database, Web of Science, and Scopus, in order to conduct a systematic review of the available epidemiological data implicating an association between exposure to OCPs and biochemical recurrence (BCR) of PCa. We searched all peer-reviewed articles published up to July 31 st 2020. Pre-defined eligibility criteria for the inclusion of studies were that they be original studies, reviews, previous meta-analyses, or case–control or cohort studies. Results: Agent Orange is the most widely-studied OCP in the context of any possible causal role in the recurrence of PCa following radical prostatectomy, or in the progression to advanced disease. Only two studies didn’t demonstrate a significant association between exposure to OCPs and subsequent BCR following radical prostatectomy. Another study identified a significant association between exposure to Oxychlordane and PCB44 and progression to advanced PCa. Conclusion: This review confirmed a relative lack of high-quality evidence regarding this topic. However, the available evidence to date suggests the presence of a potential causal relationship between exposure to OPCs and PCa development and progression.
Multiple novel prostate cancer predisposition loci confirmed by an international study: the PRACTICAL Consortium.
A recent genome-wide association study found that genetic variants on chromosomes 3, 6, 7, 10, 11, 19 and X were associated with prostate cancer risk. We evaluated the most significant single-nucleotide polymorphisms (SNP) in these loci using a worldwide consortium of 13 groups (PRACTICAL). Blood DNA from 7,370 prostate cancer cases and 5,742 male controls was analyzed by genotyping assays. Odds ratios (OR) associated with each genotype were estimated using unconditional logistic regression. Six of the seven SNPs showed clear evidence of association with prostate cancer (P = 0.0007-P = 10(-17)). For each of these six SNPs, the estimated per-allele OR was similar to those previously reported and ranged from 1.12 to 1.29. One SNP on 3p12 (rs2660753) showed a weaker association than previously reported [per-allele OR, 1.08 (95% confidence interval, 1.00-1.16; P = 0.06) versus 1.18 (95% confidence interval, 1.06-1.31)]. The combined risks associated with each pair of SNPs were consistent with a multiplicative risk model. Under this model, and in combination with previously reported SNPs on 8q and 17q, these loci explain 16% of the familial risk of the disease, and men in the top 10% of the risk distribution have a 2.1-fold increased risk relative to general population rates. This study provides strong confirmation of these susceptibility loci in multiple populations and shows that they make an important contribution to prostate cancer risk prediction.
Systemic Lupus Erythematosus With Cardiac Tamponade and Myocardial Edema in the Early Postpartum Period.
BACKGROUND: Pericardial effusions are frequently caused by inflammatory diseases. In cases of serosal inflammation, which often present with concomitant systemic symptoms, cardiac tamponade can occur, requiring emergency drainage. Nevertheless, it is rare for the index presentation of a previously undiagnosed inflammatory disease to be with cardiac tamponade. CASE SUMMARY: We describe a case of a young woman who presented in the postpartum period with cardiac tamponade. Further investigations confirmed that the underlying diagnosis was systemic lupus erythematosus (SLE). DISCUSSION: SLE can be associated with pericardial effusion but rarely causes cardiac tamponade. Herein, we describe a case of an index presentation of SLE in the postpartum period with a large pericardial effusion and tamponade. Cardiac imaging showed myocardial edema, reflective of associated myocarditis. TAKE-HOME MESSAGES: SLE can present in the immediate postpartum period, and acute management of tamponade in this context includes drainage of the effusion and immunosuppressive therapy.
Ductal adenocarcinoma of the prostate: A systematic review and meta-analysis of incidence, presentation, prognosis, and management
Abstract Context Ductal adenocarcinoma (DAC) is relatively rare, but is nonetheless the second most common subtype of prostate cancer. First described in 1967, opinion is still divided regarding its biology, prognosis, and outcome. Objectives To systematically interrogate the literature to clarify the epidemiology, diagnosis, management, progression, and survival statistics of DAC. Materials and methods We conducted a literature search of five medical databases from inception to May 04 2020 according to PRISMA criteria using search terms ?prostate ductal adenocarcinoma? OR ?endometriod adenocarcinoma of prostate? and variations of each. Results Some 114 studies were eligible for inclusion, presenting 2 907 170 prostate cancer cases, of which 5911 were DAC. [Correction added on 16 January 2021 after the first online publication: the preceding statement has been corrected in this current version.] DAC accounts for 0.17% of prostate cancer on meta-analysis (range 0.0837%-13.4%). The majority of DAC cases were admixed with predominant acinar adenocarcinoma (AAC). Median Prostate Specific Antigen at diagnosis ranged from 4.2 to 9.6 ng/mL in the case series. DAC was more likely to present as T3 (RR1.71; 95%CI 1.53-1.91) and T4 (RR7.56; 95%CI 5.19-11.01) stages, with far higher likelihood of metastatic disease (RR4.62; 95%CI 3.84-5.56; all P-values < .0001), compared to AAC. Common first treatments included surgery (radical prostatectomy (RP) or cystoprostatectomy for select cases) or radiotherapy (RT) for localized disease, and hormonal or chemo-therapy for metastatic disease. Few studies compared RP and RT modalities, and those that did present mixed findings, although cancer-specific survival rates seem worse after RP. Biochemical recurrence rates were increased with DAC compared to AAC. Additionally, DAC metastasized to unusual sites, including penile and peritoneal metastases. Where compared, all studies reported worse survival for DAC compared to AAC. Conclusion When drawing conclusions about DAC it is important to note the heterogenous nature of the data. DAC is often diagnosed incidentally post-treatment, perhaps due to lack of a single, universally applied histopathological definition. As such, DAC is likely underreported in clinical practice and the literature. Poorer prognosis and outcomes for DAC compared to AAC merit further research into genetic composition, evolution, diagnosis, and treatment of this surprisingly common prostate cancer sub-type. Patient summary Ductal prostate cancer is a rare but important form of prostate cancer. This review demonstrates that it tends to be more serious at detection and more likely to spread to unusual parts of the body. Overall survival is worse with this type of prostate cancer and urologists need to be aware of the presence of ductal prostate cancer to alter management decisions and follow-up.
A PSA SNP associates with cellular function and clinical outcome in men with prostate cancer.
Genetic variation at the 19q13.3 KLK locus is linked with prostate cancer susceptibility in men. The non-synonymous KLK3 single nucleotide polymorphism (SNP), rs17632542 (c.536 T > C; Ile163Thr-substitution in PSA) is associated with reduced prostate cancer risk, however, the functional relevance is unknown. Here, we identify that the SNP variant-induced change in PSA biochemical activity mediates prostate cancer pathogenesis. The 'Thr' PSA variant leads to small subcutaneous tumours, supporting reduced prostate cancer risk. However, 'Thr' PSA also displays higher metastatic potential with pronounced osteolytic activity in an experimental metastasis in-vivo model. Biochemical characterisation of this PSA variant demonstrates markedly reduced proteolytic activity that correlates with differences in in-vivo tumour burden. The SNP is associated with increased risk for aggressive disease and prostate cancer-specific mortality in three independent cohorts, highlighting its critical function in mediating metastasis. Carriers of this SNP allele have reduced serum total PSA and a higher free/total PSA ratio that could contribute to late biopsy decisions and delay in diagnosis. Our results provide a molecular explanation for the prominent 19q13.3 KLK locus, rs17632542 SNP, association with a spectrum of prostate cancer clinical outcomes.
Clonal phylogenies inferred from bulk, single cell, and spatial transcriptomic analysis of epithelial cancers.
Epithelial cancers are typically heterogeneous with primary prostate cancer being a typical example of histological and genomic variation. Prior studies of primary prostate cancer tumour genetics revealed extensive inter and intra-patient genomic tumour heterogeneity. Recent advances in machine learning have enabled the inference of ground-truth genomic single-nucleotide and copy number variant status from transcript data. While these inferred SNV and CNV states can be used to resolve clonal phylogenies, however, it is still unknown how faithfully transcript-based tumour phylogenies reconstruct ground truth DNA-based tumour phylogenies. We sought to study the accuracy of inferred-transcript to recapitulate DNA-based tumour phylogenies. We first performed in-silico comparisons of inferred and directly resolved SNV and CNV status, from single cancer cells, from three different cell lines. We found that inferred SNV phylogenies accurately recapitulate DNA phylogenies (entanglement = 0.097). We observed similar results in iCNV and CNV based phylogenies (entanglement = 0.11). Analysis of published prostate cancer DNA phylogenies and inferred CNV, SNV and transcript based phylogenies demonstrated phylogenetic concordance. Finally, a comparison of pseudo-bulked spatial transcriptomic data to adjacent sections with WGS data also demonstrated recapitulation of ground truth (entanglement = 0.35). These results suggest that transcript-based inferred phylogenies recapitulate conventional genomic phylogenies. Further work will need to be done to increase accuracy, genomic, and spatial resolution.
Local anaesthetic transperineal biopsy versus transrectal prostate biopsy in prostate cancer detection (TRANSLATE): a multicentre, randomised, controlled trial.
BACKGROUND: Prostate cancer diagnosis requires biopsy, traditionally performed under local anaesthetic with ultrasound guidance via a transrectal approach (TRUS). Local anaesthetic ultrasound-guided transperineal biopsy (LATP) is gaining popularity in this setting; however, there is uncertainty regarding prostate sampling, infection rates, tolerability, side-effects, and cost-effectiveness. TRANSLATE was a randomised clinical trial that aimed to compare detection of Gleason Grade Group (GGG) 2 or higher prostate cancer, side-effects, tolerability, and patient-reported outcomes, after LATP versus TRUS biopsy. METHODS: In this randomised clinical trial which was done at ten hospitals in the UK, patients aged 18 years or older were eligible if investigated for suspected prostate cancer based on elevated age-specific prostate-specific antigen or abnormal digital rectal examination, and if biopsy-naive having received pre-biopsy MRI on a 1·5 or higher Tesla scanner. Individuals were excluded if they had any previous prostate biopsy, extensive local disease easily detectable by any biopsy (prostate-specific antigen >50 ng/mL or entire gland replaced by tumour on MRI), symptoms of concurrent or recent urinary tract infection, history of immunocompromise, need for enhanced antibiotic prophylaxis, absent rectum, or inability to position in lithotomy. Participants were randomly assigned in a 1:1 ratio to receive LATP or TRUS biopsy, using web-based software with a randomisation sequence using a minimisation algorithm to ensure balanced allocation across biopsy groups for minimisation factors (recruitment site, and location of the MRI lesion). The primary outcome was detection of GGG 2 or higher prostate cancer, analysed in the modified intention-to-treat population (all randomly assigned to treatment who had a biopsy result available). Key secondary endpoints assessing post-biopsy adverse events were infection, bleeding, urinary and sexual function, tolerability, and patient-reported outcomes. This trial is registered with ClinicalTrials.gov (NCT05179694) and at ISRCTN (ISRCTN98159689), and is complete. FINDINGS: Between Dec 3, 2021, and Sept 26, 2023, 2078 (76%) of 2727 assessed individuals were eligible, and 1126 (41%) of 2727 agreed to participate. 1044 (93%) of the 1126 participants were White British. Participants were allocated to TRUS (n=564) or LATP (n=562) biopsy, and were followed up at time of biopsy, and at 7 days, 35 days, and 4 months post-biopsy. We found GGG 2 or higher prostate cancer in 329 (60%) of 547 participants with biopsy results randomly assigned to LATP compared with 294 (54%) of 540 participants with biopsy results randomly assigned to TRUS biopsy (odds ratio [OR] 1·32 [95% CI 1·03-1·70]; p=0·031). Infection requiring admission to hospital within 35 days post-biopsy occurred in 2 (<1%) of 562 participants in the LATP group compared with 9 (2%) of 564 in the TRUS group. No statistically significant difference was observed in the reporting of overall biopsy-related complications (LATP 454 [81%] of 562 vs TRUS 436 [77%] of 564, OR 1·23 [95% CI 0·93 to 1·65]), urinary retention requiring catheterisation (LATP 35 [6%] of 562 vs TRUS 27 [5%] of 564), urinary symptoms (median International Prostate Symptom Score: LATP 8 [IQR 4-14] vs TRUS 8 [4-13], OR 0·36 [95% CI -0·38 to 1·10]), nor sexual function (median International Index of Erectile Function score: LATP 5 [2-25] vs TRUS 8 [3-24], OR -0·60 [-1·79 to 0·58]) at 4 months after biopsy. Trial participants more commonly reported LATP biopsy to be immediately painful and embarrassing compared with TRUS (LATP 216 [38%] of 562 vs TRUS 153 [27%] of 564; OR 1·84 [95% CI 1·40 to 2·43]). Serious adverse events occurred in 14 (2%) of 562 participants in the LATP group and 25 (4%) of 564 in the TRUS group. INTERPRETATION: Among biopsy-naive individuals being investigated for possible prostate cancer, biopsy with LATP led to greater detection of GGG 2 or higher disease compared with TRUS. These findings will help to inform patients, clinicians, clinical guidelines, and policy makers regarding the important trade-offs between LATP and TRUS prostate biopsy. FUNDING: National Institute for Health and Care Research (NIHR) Health Technology Assessment.
Change in Early Patient-Reported Sexual Function After Periacetabular Osteotomy: A Study Utilizing the UK Non-Arthroplasty Hip Registry.
BACKGROUND: Periacetabular osteotomy (PAO) is an established treatment for symptomatic developmental dysplasia of the hip (DDH) and femoroacetabular impingement (FAI; principally acetabular retroversion) in adults who are commonly of reproductive age. PURPOSE: To describe the effect of PAO on patient-reported sexual function (SF) using data from the UK Non-Arthroplasty Hip Registry (NAHR). STUDY DESIGN: Cohort study: Level of evidence, 3. METHODS: Adult patients who underwent isolated PAO between January 2012 and July 2022 were extracted from the NAHR. The EuroQol-5 Dimensions (EQ-5D) and International Hip Outcome Tool 12 (iHOT-12) questionnaires were collected preoperatively and at 6 and 12 months postoperatively. This included responses to 2 questions from the iHOT-12 questionnaire relevant to SF: (1) "Are questions about SF relevant to you?" and (2) "How much trouble do you have with sexual activity because of your hip?" (0 = severe; 100 = none). RESULTS: A total of 773 patients (median age, 29 years (IQR, 23-37), 92.5% female) who underwent PAO for DDH (n = 703; 90.9%) or FAI (n = 70; 9.1%) were identified after exclusions. Of iHOT-12 respondents, 88.2% indicated that SF was relevant to them. Baseline median iHOT-12 SF scores were 33 (IQR, 18-53) for female and 73 (IQR, 36-90) for male patients. Female iHOT-12 SF improved by a mean of +19.9 points (95% CI, 16.5-23.2) at 6 months (P < .0001), with continued improvement to +26.4 points (95% CI, 23.0-29.8) at 12 months (P < .0001) versus preoperative SF scores. At 12 months, median iHOT-12 SF scores were 70 (IQR, 40-90) and 89 (IQR, 70-99) for female and male patients, respectively. Preoperative SF scores were significantly lower (P = .001) in patients who underwent PAO for indication of FAI (female median score 22; IQR, 10-38) compared with DDH (female median score: 34; IQR, 18-54); however, both indications saw significant improvement in SF scores at 12 months. iHOT-12 SF scores improved for 77.1% and worsened for 19.1% of female respondents with DDH. A strong positive association was seen between health-related quality of life (EQ-5D) and SF scores, and there was significant improvement in SF across studied ages. CONCLUSION: PAO was associated with significant improvement in patient-reported SF for the majority of patients. Some patients may have trouble with sexual activity even 1 year after PAO for DDH, with almost 20% reporting poorer SF compared with preoperative baseline.
Trends in prescription opioid use in Europe: A DARWIN EU® multinational cohort study including seven European countries
BackgroundThe opioid crisis has been a serious public health challenge in North America for decades, despite numerous efforts to mitigate its devastating consequences. As concerns grow about a similar situation developing in Europe, we evaluated the trends in opioid use and characterized prescribing indications across seven European countries.MethodsWe conducted a multinational cohort study using electronic health records from various healthcare settings: primary care [Clinical Practice Research Datalink (CPRD) GOLD (United Kingdom), Sistema d’Informació per al Desenvolupament de la Investigació en Atenció Primària (SIDIAP, Spain), and Integrated Primary Care Information Project (IPCI, the Netherlands)]; primary and outpatient specialist care [IQVIA Disease Analyzer (DA) Germany and IQVIA Longitudinal Patient Database (LPD) Belgium]; hospital care [Clinical Data Warehouse of Bordeaux University Hospital (CHUBX, France)]; and the Estonian Biobank (EBB). All data were mapped to the Observational Medical Outcomes Partnership (OMOP) Common Data Model (CDM). All people registered in a contributing database for ≥365 days between 2012 and 2022 were included. Annual period prevalence and incidence rates of opioid prescriptions were estimated, and long-term trends were quantified as the percent change from 2012 to 2019. New opioid users were characterized, including potential prescribing indications.ResultsBetween 2012 and 2019, the incidence of opioid prescriptions in primary care decreased by −50·7% (CPRD GOLD) and −2·0% (SIDIAP), while it increased in EBB (+52·8%) and CHUBX (+25·3%) data. The incidence of codeine and tramadol use decreased in most databases. However, the prevalence of oxycodone, morphine, and fentanyl increased. Opioid use was highest among older age groups, and the majority of prescriptions were for oral formulations. Respiratory and pain-related conditions were the most common indications for new opioid users in outpatient settings.ConclusionDespite a decrease in new opioid prescriptions in many European countries, the prevalence of opioid use remained largely stable over the last decade. More data are needed to monitor evolving opioid prescription patterns in Europe, particularly in the post-pandemic era.