MRI at diagnostic versus confirmatory biopsy during MRI-based active surveillance of prostate cancer.

OBJECTIVES: Active surveillance (AS) is a management strategy for patients with favorable risk prostate cancer. Multi-parametric magnetic resonance imaging (mpMRI) may impact upgrading rates, but there is mixed evidence on the appropriate timing to introduce mpMRI. We evaluated timing of initial mpMRI use for patients on AS and compared upgrading and intervention rates for AS candidates who received initial mpMRI before diagnostic biopsy vs. confirmatory biopsy. SUBJECTS AND METHODS: Patients enrolled in AS captured by the Prospective Loyola Urology mpMRI (PLUM) Prostate Biopsy Cohort which captures men undergoing MRI-fusion prostate biopsy. We included patients enrolled in AS between January 2014 and October 2022. We conducted a retrospective analysis of patients who underwent MRI-fusion prostate biopsy while on AS at our institution. The cohort was stratified by men who underwent first mpMRI prior to diagnostic biopsy (MRI-DBx), confirmatory biopsy (MRI-CBx), or a subsequent surveillance biopsy. Oncologic outcomes including pathologic reclassification, intervention-free survival, progression-free survival, and overall survival were evaluated. RESULTS: Of 346 patients identified on AS, 94 (27.2%) received mpMRI at the time of diagnostic biopsy, 182 (52.6%) at confirmatory biopsy, and 70 (20.2%) at a later biopsy. At confirmatory biopsy (median 14 months), there was no difference in upgrading (HR 0.95, P = 0.78) or intervention rates (HR 0.97, P = 0.88) between MRI-DBx and MRI-CBx. PI-RADS score on initial mpMRI was associated with upgrading during AS follow-up relative to men with negative mpMRI (HR 4.20 (P = 0.04), 3.24 (P < 0.001), and 1.99 (P < 0.001) for PI-RADS 5, 4, and 3, respectively), and PSA density was associated with intervention (HR 1.52, P = 0.03). CONCLUSION: mpMRI can serve as a prognostic tool to select and monitor AS patients, but there was no difference in upgrading or intervention rates based on initial timing of MRI.

Efficacy of Intravesical Nadofaragene Firadenovec for Patients With Bacillus Calmette-Guérin-Unresponsive Nonmuscle-Invasive Bladder Cancer: 5-Year Follow-Up From a Phase 3 Trial.

PURPOSE: Nadofaragene firadenovec-vncg is a nonreplicating adenoviral vector-based gene therapy for bacillus Calmette-Guérin (BCG)-unresponsive carcinoma in situ (CIS) with/without high-grade Ta/T1. We report outcomes following 5 years of planned follow-up. MATERIALS AND METHODS: This open-label phase 3 trial (NCT02773849) enrolled patients with BCG-unresponsive nonmuscle-invasive bladder cancer in 2 cohorts: CIS ± Ta/T1 (CIS; n = 107) and Ta/T1 without CIS (Ta/T1 cohort; n = 50). Patients received 75 mL (3 × 1011 vp/mL) nadofaragene firadenovec intravesically once every 3 months with cystoscopy and cytology assessments, with continued treatment offered to those remaining high grade recurrence-free (HGRF). RESULTS: One hundred fifty-seven patients were enrolled from 33 US sites (n = 151 included in efficacy analyses). Median follow-up was 50.8 months (interquartile range 39.1-60.0), with 27% receiving ≥ 5 instillations and 7.6% receiving treatment for ≥ 57 months. Of patients with CIS 5.8% (95% CI 2.2-12.2) were HGRF at month 57, and 15% (95% CI 6.1-27.8) of patients with high-grade Ta/T1 were HGRF at month 57. Kaplan-Meier-estimated HGRF survival at 57 months was 13% (95% CI 6.9-21.5) and 33% (95% CI 19.5-46.6) in the CIS and Ta/T1 cohorts, respectively. Cystectomy-free survival at month 60 was 49% (95% CI 40.0-57.1): 43% (95% CI 32.2-53.7) in the CIS cohort and 59% (95% CI 43.1-71.4) in the Ta/T1 cohort. Overall survival at 60 months was 80% (71.0, 86.0): 76% (64.6-84.5) and 86% (70.9-93.5) in the CIS and Ta/T1 cohorts, respectively. Only 5 patients (4 with CIS and 1 with Ta/T1) experienced clinical progression to muscle-invasive disease. CONCLUSIONS: At 60 months, nadofaragene firadenovec-vncg allowed bladder preservation in nearly half of the patients and proved to be a safe option for BCG-unresponsive nonmuscle-invasive bladder cancer.

Natural compounds from freshwater mussels disrupt fungal virulence determinants and influence fluconazole susceptibility in the presence of macrophages in Cryptococcus neoformans.

Cryptococcus neoformans is a human fungal pathogen responsible for fatal infections, especially in patients with a depressed immune system. Overexposure to antifungal drugs due to prolonged treatment regimens and structure-similar applications in agriculture have weakened the efficacy of current antifungals in the clinic. The rapid evolution of antifungal resistance urges the discovery of new compounds that inhibit fungal virulence determinants, rather than directly killing the pathogen, as alternative strategies to overcome disease and reduce selective pressure toward resistance. Here, we evaluated the efficacy of freshwater mussel extracts (crude and clarified) against the production of well-defined virulence determinants (i.e., thermotolerance, melanin, capsule, and biofilm) and fluconazole resistance in C. neoformans. We demonstrated the extracts' influence on fungal thermotolerance, capsule production, and biofilm formation, as well as susceptibility to fluconazole in the presence of macrophages. Additionally, we measured the inhibitory activity of extracts against commercial peptidases (family representatives of cryptococcal orthologs) related to fungal virulence determinants and fluconazole resistance, and integrated these phenotypic findings with quantitative proteomics profiling. Our approach defined distinct signatures of each treatment and validated a new mechanism of anti-virulence action toward the polysaccharide capsule from a selected extract following fractionation. By understanding the mechanisms driving the antifungal activity of mussels, we may develop innovative treatment options to overcome fungal infections and promote susceptibility to fluconazole in resistant strains. IMPORTANCE: As the prevalence and severity of global fungal infections rise, along with an increasing incidence of antifungal resistance, new strategies to combat fungal pathogens and overcome resistance are urgently needed. Critically, our current methods to overcome fungal infections are limited and drive the evolution of resistance forward; however, an anti-virulence approach to disarm virulence factors of the pathogen and promote host cell clearance is promising. Here, we explore the efficacy of natural compounds derived from freshwater mussels against classical fungal virulence determinants, including thermotolerance, capsule production, stress response, and biofilm formation. We integrate our phenotypic discoveries with state-of-the-art mass spectrometry-based proteomics to identify mechanistic drivers of these antifungal properties and propose innovative avenues to reduce infection and support the treatment of resistant strains.

Robotic versus open radical cystectomy for bladder cancer: evaluation of complications, survival, and opioid prescribing patterns.

We aim to compare complications, readmission, survival, and prescribing patterns of opioids for post-operative pain management for Robotic-assisted laparoscopic radical cystectomy (RARC) as compared to open radical cystectomy (ORC). Patients that underwent RARC or ORC for bladder cancer at a tertiary care center from 2005 to 2021 were included. Recurrence-free survival (RFS) and overall survival (OS) were evaluated with Kaplan-Meier curves and multivariable Cox proportional hazards regression models. Comparisons of narcotic usage were completed with oral morphine equivalents (OMEQ). Multivariable linear regression was used to assess predictors of OMEQ utilization. A total of 128 RARC and 461 ORC patients were included. There was no difference in rates of Clavien-Dindo grade ≥ 3 complications between RARC and ORC (36.7 vs 30.1%, p = 0.16). After a mean follow up of 3.4 years, RFS (HR 0.96, 95%CI 0.58-1.56) and OS (HR 0.69, 95%CI 0.46-1.05) were comparable between RARC and ORC. There was no difference in the narcotic usage between patients in the RARC and ORC groups during the last 24 h of hospitalization (median OMEQ: 0 vs 0, p = 0.33) and upon discharge (median OMEQ: 178 vs 210, p = 0.36). Predictors of higher OMEQ discharge prescriptions included younger age [(- )3.46, 95%CI (-)5.5-(-)0.34], no epidural during hospitalization [- 95.85, 95%CI (- )144.95-(- )107.36], and early time-period of surgery [(- )151.04, 95%CI (- )194.72-(- )107.36]. RARC has comparable 90-day complication rates and early survival outcomes to ORC and remains a viable option for bladder cancer. RARC results in comparable levels of opioid utilization for pain management as ORC.

Novel insights into genetic susceptibility for colorectal cancer from transcriptome-wide association and functional investigation.

BACKGROUND: Transcriptome-wide association studies have been successful in identifying candidate susceptibility genes for colorectal cancer (CRC). To strengthen susceptibility gene discovery, we conducted a large transcriptome-wide association study and an alternative splicing transcriptome-wide association study in CRC using improved genetic prediction models and performed in-depth functional investigations. METHODS: We analyzed RNA-sequencing data from normal colon tissues and genotype data from 423 European descendants to build genetic prediction models of gene expression and alternative splicing and evaluated model performance using independent RNA-sequencing data from normal colon tissues of the Genotype-Tissue Expression Project. We applied the verified models to genome-wide association studies (GWAS) summary statistics among 58 131 CRC cases and 67 347 controls of European ancestry to evaluate associations of genetically predicted gene expression and alternative splicing with CRC risk. We performed in vitro functional assays for 3 selected genes in multiple CRC cell lines. RESULTS: We identified 57 putative CRC susceptibility genes, which included the 48 genes from transcriptome-wide association studies and 15 genes from splicing transcriptome-wide association studies, at a Bonferroni-corrected P value less than .05. Of these, 16 genes were not previously implicated in CRC susceptibility, including a gene PDE7B (6q23.3) at locus previously not reported by CRC GWAS. Gene knockdown experiments confirmed the oncogenic roles for 2 unreported genes, TRPS1 and METRNL, and a recently reported gene, C14orf166. CONCLUSION: This study discovered new putative susceptibility genes of CRC and provided novel insights into the biological mechanisms underlying CRC development.

A multi-national, video-based qualitative study to refine training guidelines for assigning an "unsafe" score in laparoscopic cholecystectomy critical view of safety.

BACKGROUND: The critical view of safety (CVS) was incorporated into a novel 6-item objective procedure-specific assessment for laparoscopic cholecystectomy (LC-CVS OPSA) to enhance focus on safe completion of surgical tasks and advance the American Board of Surgery's entrustable professional activities (EPAs) initiative. To enhance instrument development, a feasibility study was performed to elucidate expert surgeon perspectives regarding "safe" vs. "unsafe" practice. METHODS: A multi-national consortium of 11 expert LC surgeons were asked to apply the LC-CVS OPSA to ten LC videos of varying surgical difficulty using a "safe" vs. "unsafe" scale. Raters were asked to provide written rationale for all "unsafe" ratings and invited to provide additional feedback regarding instrument clarity. A qualitative analysis was performed on written responses to extract major themes. RESULTS: Of the 660 ratings, 238 were scored as "unsafe" with substantial variation in distribution across tasks and raters. Analysis of the comments revealed three major categories of "unsafe" ratings: (a) inability to achieve the critical view of safety (intended outcome), (b) safe task completion but less than optimal surgical technique, and (c) safe task completion but risk for potential future complication. Analysis of reviewer comments also identified the potential for safe surgical practice even when CVS was not achieved, either due to unusual anatomy or severe pathology preventing safe visualization. Based upon findings, modifications to the instructions to raters for the LC-CVS OPSA were incorporated to enhance instrument reliability. CONCLUSIONS: A safety-based LC-CVS OPSA has the potential to significantly improve surgical training by incorporating CVS formally into learner assessment. This study documents the perspectives of expert biliary tract surgeons regarding clear identification and documentation of unsafe surgical practice for LC-CVS and enables the development of training materials to improve instrument reliability. Learnings from the study have been incorporated into rater instructions to enhance instrument reliability.

Laparoscopic cholecystectomy critical view of safety (LC-CVS): a multi-national validation study of an objective, procedure-specific assessment using video-based assessment (VBA).

BACKGROUND: A novel 6-item objective, procedure-specific assessment for laparoscopic cholecystectomy incorporating the critical view of safety (LC-CVS OPSA) was developed to support trainee formative and summative assessments. The LC-CVS OPSA included two retraction items (fundus and infundibulum retraction) and four CVS items (hepatocystic triangle visualization, gallbladder-liver separation, cystic artery identification, and cystic duct identification). The scoring rubric for retraction consisted of poor (frequently outside of defined range), adequate (minimally outside of defined range) and excellent (consistently inside defined range) and for CVS items were "poor-unsafe", "adequate-safe", or "excellent-safe". METHODS: A multi-national consortium of 12 expert LC surgeons applied the OPSA-LC CVS to 35 unique LC videos and one duplicate video. Primary outcome measure was inter-rater reliability as measured by Gwet's AC2, a weighted measure that adjusts for scales with high probability of random agreement. Analysis of the inter-rater reliability was conducted on a collapsed dichotomous scoring rubric of "poor-unsafe" vs. "adequate/excellent-safe". RESULTS: Inter-rater reliability was high for all six items ranging from 0.76 (hepatocystic triangle visualization) to 0.86 (cystic duct identification). Intra-rater reliability for the single duplicate video was substantially higher across the six items ranging from 0.91 to 1.00. CONCLUSIONS: The novel 6-item OPSA LC CVS demonstrated high inter-rater reliability when tested with a multi-national consortium of LC expert surgeons. This brief instrument focused on safe surgical practice was designed to support the implementation of entrustable professional activities into busy surgical training programs. Instrument use coupled with video-based assessments creates novel datasets with the potential for artificial intelligence development including computer vision to drive assessment automation.

Neoadjuvant Chemotherapy Before Radical Cystectomy for Muscle-Invasive Bladder Cancer: Elective and Eligibility Factors Impacting Utilization.

INTRODUCTION: We aimed to assess utilization of neoadjuvant chemotherapy (NAC) and etiologies for lack of NAC receipt among patients with muscle-invasive bladder cancer (MIBC). METHODS: Patients diagnosed with MIBC undergoing radical cystectomy at a single institution (2005-2021) were included. Patients were categorized by receipt of NAC, and reasons for no NAC were categorized into eligibility and elective factors. Overall survival was analyzed using univariable and multivariable Cox proportional hazards regression models and modeled with Kaplan-Meier curves. RESULTS: Three hundred eighty patients with MIBC were included; 154 (40.5%) received NAC. Patients were not candidates for NAC due to renal dysfunction (16.6%), clinical contraindications (4.7%), salvage setting (2.1%), and histology (5.3%; total N = 109). Among 271 (71.3%) who were eligible, utilization increased from early (2005-2016) to recent (2016-2021) time periods (34.2% to 85.7% among NAC-eligible, P < .001; 22.8% vs 67.1% among all MIBC, P < .001). Elective factors for not receiving NAC included patient symptoms (7.8%), disease progression concern (7.0%), patient preference/refusal (20.3%) and provider discretion (8.1%) among 271 NAC-eligible patients. Notably, patient preference/refusal decreased from 33.6% to 3.4% in recent years (P < .001). On multivariable analysis, lack of NAC utilization due to renal dysfunction (HR 2.18, P = .002), clinical contraindications (HR 2.62, P = .01), and elective factors (HR 1.88, P = .01) were associated with worse overall survival. CONCLUSIONS: NAC utilization increased over time with 85.7% of eligible patients with MIBC receiving NAC in recent years. Renal dysfunction, patient preference, and clinical contraindications were primary etiologies for lack of NAC. Fewer patients refused NAC in recent years leading to a potential ceiling for NAC utilization.

CT Navigation for Percutaneous Needle Placement: How I Do It.

CT navigation (CTN) has recently been developed to combine many of the advantages of conventional CT and CT-fluoroscopic guidance for needle placement. CTN systems display real-time needle position superimposed on a CT dataset. This is accomplished by placing electromagnetic (EM) or optical transmitters/sensors on the patient and needle, combined with fiducials placed within the scan field to superimpose a known needle location onto a CT dataset. Advantages of CTN include real-time needle tracking using a contemporaneous CT dataset with the patient in the treatment position, reduced radiation to the physician, facilitation of procedures outside the gantry plane, fewer helical scans during needle placement, and needle guidance based on diagnostic-quality CT datasets. Limitations include the display of a virtual (vs actual) needle position, which can be inaccurate if the needle bends, the fiducial moves, or patient movement occurs between scans, and limitations in anatomical regions with a high degree of motion such as the lung bases. This review summarizes recently introduced CTN technologies in comparison to historical methods of CT needle guidance. A "How I do it" section follows, which describes how CT navigation has been integrated into the study center for both routine and challenging procedures, and includes step-by-step explanations, technical tips, and pitfalls.

Using video-based assessment (VBA) to document fellow improvement in safely completing the jejunojejunostomy portion of laparoscopic Roux-en-Y gastric bypass (RYGB) surgery.

BACKGROUND: Surgical assessment instruments are used for formative and summative trainee evaluations. To characterize the features of existing instruments and a novel 12-item objective, procedure-specific assessment tool for Roux-en-Y Gastric Bypass (RYGB-OPSA), we evaluated the progress of a single surgical fellow over 17 consecutive surgeries. METHODS: Seventeen consecutive RYGB videos completed between 8/2021 and 1/2022 by an academic hospital surgical fellow were de-identified and assessed by four board-certified bariatric surgeons using Global Operative Assessment of Laparoscopic Skills (GOALS), General Assessment of Surgical Skill (GASS), and RYGB-OPSA which includes the reflection of transverse colon, identification of ligament of Treitz, biliopancreatic and Roux limbs orientation, jejunal division point selection, stapler use, mesentery division, bleeding control, jejunojejunostomy (JJ) anastomotic site selection, apposition of JJ anastomotic site, JJ creation, common enterotomy closure of JJ, and integrity of anastomosis. The GASS measured economy of motion, tissue handling, appreciating operative anatomy, bimanual dexterity, and achievement of hemostasis. RYGB-OPSA and GASS items were scored "poor-unsafe," "acceptable-safe," or "good-safe." Change in performance was measured by linear trendline slope. RESULTS: Over the course of 17 procedures, significant improvement was demonstrated by three GOALS items, GOALS overall score, GASS bimanual dexterity, and three RYGB-OPSA tasks: JJ creation, jejunal division point selection, and stapler use. Achievement of hemostasis declined but never rated "poor-unsafe." Overall RYGB-OPSA and GOALS trendlines documented significant increase across the 17 procedures. CONCLUSION: This examination of a bariatric surgery fellow's operative training experience as measured by three surgical assessment instruments demonstrated anticipated improvements in general skills and safe completion of procedure-specific tasks. Effective surgical assessment instruments have enough sensitivity to show improvement to enable meaningful trainee feedback (low-stakes assessments) as well as the ability to determine safe surgical practice to enable promotion to greater autonomous practice.

Differences in incidence, staging, and survival of urologic cancers in patients under 65 living in the US-Mexico border region.

Objectives: To describe and compare the incidence, stage at diagnosis, and survival for genitourinary cancers in the border regions and in Hispanic-Americans. Materials and methods: A population-based search was performed using the Surveillance, Epidemiology, and End Results Program 18 database and the Texas Cancer Registry from 2000 to 2017. Cox regression models were performed with adjusted for age, gender, race, cancer type, cancer stage, insurance status, and cause of death were used to compare cancer-specific survival. Results: A total of 63,236 kidney and renal pelvis, 38,398 bladder, 170,640 prostate, 24,313 testicular cancer cases were identified. Cancer-specific survival was found to be improved in Hispanic-Americans in kidney and renal pelvis (hazard ratio [HR], 0.903, 95% confidence interval [CI], 0.856-0.952, p = 0.0001), and bladder cancers (HR, 0.817, 95% CI, 0.743-0.898, p < 0.001), despite a more advanced stage at diagnosis in Hispanics with bladder cancer (p < 0.0074). Testicular cancer has a survival disadvantage for individuals living in the border region (HR, 1.315, 95% CI, 1.124-1.539, p = 0.0006). Conclusions: Disparities exist between Hispanic-Americans and Non-Hispanic White and also between individuals living in the border counties when compared to other regions. This is most significant in individuals with testicular cancer residing in the border region who demonstrate worse overall survival.

A Practical Approach to Predicting Surgical Site Infection Risk Among Patients Before Leaving the Operating Room.

A surgical site infection (SSI) prediction model that identifies at-risk patients before leaving the operating room can support efforts to improve patient safety. In this study, eight pre-operative and five perioperative patient- and procedure-specific characteristics were tested with two scoring algorithms: 1) count of positive factors (manual), and 2) logistic regression model (automated). Models were developed and validated using data from 3,440 general and oncologic surgical patients. In the automated algorithm, two pre-operative (procedure urgency, odds ratio [OR]: 1.7; and antibiotic administration >2 hours before incision, OR: 1.6) and three intraoperative risk factors (open surgery [OR: 3.7], high-risk procedure [OR: 3.5], and operative time OR: [2.6]) were associated with SSI risk. The manual score achieved an area under the curve (AUC) of 0.831 and the automated algorithm achieved AUC of 0.868. Open surgery had the greatest impact on prediction, followed by procedure risk, operative time, and procedure urgency. At 80% sensitivity, the manual and automated scores achieved a positive predictive value of 16.3% and 22.0%, respectively. Both the manual and automated SSI risk prediction algorithms accurately identified at-risk populations. Use of either model before the patient leaves the operating room can provide the clinical team with evidence-based guidance to consider proactive intervention to prevent SSIs.

Engineering the HK97 virus-like particle as a nanoplatform for biotechnology applications.

The research described here looks at the development of virus-like particles (VLPs) derived from bacteriophage HK97 as versatile scaffolds for bionanomaterials construction. Based on molecular models, the Prohead I HK97 VLP was engineered to allow attachment of small molecules to the interior by introducing a reactive cysteine into the genetic sequence of the HK97 GP5 protein that self assembles to form the VLP structure. In addition, methods for entrapping large protein macromolecules were evaluated and found to produce high encapsulation numbers of green fluorescent proteins (GFP) in the internal space of the HK97 VLP. A method for modular modification of the external surface was engineered by constructing a plasmid allowing the addition of peptide sequences to the C-terminus of the GP5 protein, which was validated by appending the sortase recognition peptide sequence, LPETG, to the C-terminus of GP5 and showing the attachment of a polyglycine-GFP to the HK97 VLP through sortase mediated ligation. To demonstrate the potential for advanced applications, an HK97 VLP covalently labeled on the interior surface with fluorescein and containing an externally displayed integrin binding peptide sequence (RGD) was evaluated and found to be preferentially localized at C2C12 cells relative to the HK97 VLP lacking the RGD peptide. Together, these results support the potential of the HK97 VLP as a versatile nanoparticle platform that can be modified internally and externally in a modular fashion for the purpose of programming the VLP for desired applications.

Association between Surgical Technical Skills and Clinical Outcomes: A Systematic Literature Review and Meta-Analysis.

Background: A systematic literature review and meta-analysis was conducted to assess the association between intraoperative surgical skill and clinical outcomes. Methods: Peer-reviewed, original research articles published through August 31, 2021 were identified from PubMed and Embase. From the 1,513 potential articles, seven met eligibility requirements, reporting on 151 surgeons and 17,932 procedures. All included retrospective assessment of operative videos. Associations between surgical skill and outcomes were assessed by pooling odds ratios (OR) using random-effects models with the inverse variance method. Eligible studies included pancreaticoduodenectomy, gastric bypass, laparoscopic gastrectomy, prostatectomy, colorectal, and hemicolectomy procedures. Results: Meta-analytic pooling identified significant associations between the highest vs. lowest quartile of surgical skill and reoperation (OR: 0.44; 95% confidence interval [CI]: 0.23, 0.83), hemorrhage (OR: 0.66; 95% CI, 0.65, 0.68), obstruction (OR: 0.33; 95% CI, 0.30, 0.35), and any medical complication (OR: 0.23, 95% CI, 0.19, 0.27). Nonsignificant inverse associations were noted between skill and readmission, emergency department visit, mortality, leak, infection, venous thromboembolism, and cardiac and pulmonary complications. Conclusions: Overall, surgeon technical skill appears to predict clinical outcomes. However, there are surprisingly few articles that evaluate this association. The authors recommend a thoughtful approach for the development of a comprehensive surgical quality infrastructure that could significantly reduce the challenges identified by this study.

Molecular Characteristics of Early-Onset Colorectal Cancer According to Detailed Anatomical Locations: Comparison With Later-Onset Cases.

INTRODUCTION: Early-onset colorectal cancer diagnosed before the age of 50 years has been increasing. Likely reflecting the pathogenic role of the intestinal microbiome, which gradually changes across the entire colorectal length, the prevalence of certain tumor molecular characteristics gradually changes along colorectal subsites. Understanding how colorectal tumor molecular features differ by age and tumor location is important in personalized patient management. METHODS: Using 14,004 cases with colorectal cancer including 3,089 early-onset cases, we examined microsatellite instability (MSI), CpG island methylator phenotype (CIMP), and KRAS and BRAF mutations in carcinomas of the cecum, ascending colon, transverse colon, descending colon, sigmoid colon, and rectum and compared early-onset cases with later-onset cases. RESULTS: The proportions of MSI-high, CIMP-high, and BRAF -mutated early-onset tumors were lowest in the rectum (8.8%, 3.4%, and 3.5%, respectively) and highest in the ascending colon (46% MSI-high; 15% CIMP-high) or transverse colon (8.6% BRAF -mutated) (all Ptrend <0.001 across the rectum to ascending colon). Compared with later-onset tumors, early-onset tumors showed a higher prevalence of MSI-high status and a lower prevalence of CIMP-high status and BRAF mutations in most subsites. KRAS mutation prevalence was higher in the cecum compared with that in the other subsites in both early-onset and later-onset tumors ( P < 0.001). Notably, later-onset MSI-high tumors showed a continuous decrease in KRAS mutation prevalence from the rectum (36%) to ascending colon (9%; Ptrend <0.001), followed by an increase in the cecum (14%), while early-onset MSI-high cancers showed no such trend. DISCUSSION: Our findings support biogeographical and pathogenic heterogeneity of colorectal carcinomas in different colorectal subsites and age groups.

Genetic Predictors for Fecal Propionate and Butyrate-Producing Microbiome Pathway Are Not Associated with Colorectal Cancer Risk: A Mendelian Randomization Analysis.

BACKGROUND: Mechanistic data indicate the benefit of short-chain fatty acids (SCFA) produced by gut microbial fermentation of fiber on colorectal cancer, but direct epidemiologic evidence is limited. A recent study identified SNPs for two SCFA traits (fecal propionate and butyrate-producing microbiome pathway PWY-5022) in Europeans and showed metabolic benefits. METHODS: We conducted a two-sample Mendelian randomization analysis of the genetic instruments for the two SCFA traits (three SNPs for fecal propionate and nine for PWY-5022) in relation to colorectal cancer risk in three large European genetic consortia of 58,131 colorectal cancer cases and 67,347 controls. We estimated the risk of overall colorectal cancer and conducted subgroup analyses by sex, age, and anatomic subsites of colorectal cancer. RESULTS: We did not observe strong evidence for an association of the genetic predictors for fecal propionate levels and the abundance of PWY-5022 with the risk of overall colorectal cancer, colorectal cancer by sex, or early-onset colorectal cancer (diagnosed at <50 years), with no evidence of heterogeneity or pleiotropy. When assessed by tumor subsites, we found weak evidence for an association between PWY-5022 and risk of rectal cancer (OR per 1-SD, 0.95; 95% confidence intervals, 0.91-0.99; P = 0.03) but it did not surpass multiple testing of subgroup analysis. CONCLUSIONS: Genetic instruments for fecal propionate levels and the abundance of PWY-5022 were not associated with colorectal cancer risk. IMPACT: Fecal propionate and PWY-5022 may not have a substantial influence on colorectal cancer risk. Future research is warranted to comprehensively investigate the effects of SCFA-producing bacteria and SCFAs on colorectal cancer risk.

Cancer prevention in cancer predisposition syndromes: A protocol for testing the feasibility of building a hereditary cancer research registry and nurse navigator follow up model.

Monogenic, high penetrance syndromes, conferring an increased risk of malignancies in multiple organs, are important contributors to the hereditary burden of cancer. Early detection and risk reduction strategies in patients with a cancer predisposition syndrome can save their lives. However, despite evidence supporting the benefits of early detection and risk reduction strategies, most Canadian jurisdictions have not implemented programmatic follow up of these patients. In our study site in the province of Newfoundland and Labrador (NL), Canada, there is no centralized, provincial registry of high-risk individuals. There is no continuity or coordination of care providing cancer genetics expertise and no process to ensure that patients are referred to the appropriate specialists or risk management interventions. This paper describes a study protocol to test the feasibility of obtaining and analyzing patient risk management data, specifically patients affected by hereditary breast ovarian cancer syndrome (HBOC; BRCA 1 and BRCA 2 genes) and Lynch syndrome (LS; MLH1, MSH2, MSH6, and PMS2 genes). Through a retrospective cohort study, we will describe these patients' adherence to risk management guidelines and test its relationship to health outcomes, including cancer incidence and stage. Through a qualitative interviews, we will determine the priorities and preferences of patients with any inherited cancer mutation for a follow up navigation model of risk management. Study data will inform a subsequent funding application focused on creating and evaluating a research registry and follow up nurse navigation model. It is not currently known what proportion of cancer mutation carriers are receiving care according to guidelines. Data collected in this study will provide clinical uptake and health outcome information so gaps in care can be identified. Data will also provide patient preference information to inform ongoing and planned research with cancer mutation carriers.

Interactions between folate intake and genetic predictors of gene expression levels associated with colorectal cancer risk.

Observational studies have shown higher folate consumption to be associated with lower risk of colorectal cancer (CRC). Understanding whether and how genetic risk factors interact with folate could further elucidate the underlying mechanism. Aggregating functionally relevant genetic variants in set-based variant testing has higher power to detect gene-environment (G × E) interactions and may provide information on the underlying biological pathway. We investigated interactions between folate consumption and predicted gene expression on colorectal cancer risk across the genome. We used variant weights from the PrediXcan models of colon tissue-specific gene expression as a priori variant information for a set-based G × E approach. We harmonized total folate intake (mcg/day) based on dietary intake and supplemental use across cohort and case-control studies and calculated sex and study specific quantiles. Analyses were performed using a mixed effects score tests for interactions between folate and genetically predicted expression of 4839 genes with available genetically predicted expression. We pooled results across 23 studies for a total of 13,498 cases with colorectal tumors and 13,918 controls of European ancestry. We used a false discovery rate of 0.2 to identify genes with suggestive evidence of an interaction. We found suggestive evidence of interaction with folate intake on CRC risk for genes including glutathione S-Transferase Alpha 1 (GSTA1; p = 4.3E-4), Tonsuko Like, DNA Repair Protein (TONSL; p = 4.3E-4), and Aspartylglucosaminidase (AGA: p = 4.5E-4). We identified three genes involved in preventing or repairing DNA damage that may interact with folate consumption to alter CRC risk. Glutathione is an antioxidant, preventing cellular damage and is a downstream metabolite of homocysteine and metabolized by GSTA1. TONSL is part of a complex that functions in the recovery of double strand breaks and AGA plays a role in lysosomal breakdown of glycoprotein.

Intravascular US: Applications in Interventional Radiology.

Interventional radiology applications of intravascular US (IVUS) continue to expand, complementing intraprocedural angiography and providing a unique vantage from which to guide endovascular interventions. Vascular pathologic conditions become sonographically visualized rather than inferred from the planar appearance of the opacified vascular lumen. Perivascular targets become sonographically visualized rather than approximated on the basis of fluoroscopic landmarks. The authors introduce broad categories of IVUS catheters, namely radial and side-firing varieties, as well as prevailing options for each and their technical specifications. Common applications within interventional radiology are covered in a systems approach, including deep venous thrombosis, May-Thurner syndrome, nutcracker syndrome, transjugular intrahepatic portosystemic shunts, aortic interventions, peripheral arterial disease, and endovascular or perivascular biopsy. Discussions are accompanied by technical pearls from the authors, and summarized evidence where IVUS has been shown to reduce procedural time, intravascular contrast agent dose, radiation exposure, and morbidity in each space is presented. Finally, emerging applications and future directions are discussed. ©RSNA, 2022.