Somatic mutations in 3929 HPV positive cervical cells associated with infection outcome and HPV type.

Invasive cervical cancers (ICC), caused by HPV infections, have a heterogeneous molecular landscape. We investigate the detection, timing, and HPV type specificity of somatic mutations in 3929 HPV-positive exfoliated cervical cell samples from individuals undergoing cervical screening in the U.S. using deep targeted sequencing in ICC cases, precancers, and HPV-positive controls. We discover a subset of hotspot mutations rare in controls (2.6%) but significantly more prevalent in precancers, particularly glandular precancer lesions (10.2%), and cancers (25.7%), supporting their involvement in ICC carcinogenesis. Hotspot mutations differ by HPV type, and HPV18/45-positive ICC are more likely to have multiple hotspot mutations compared to HPV16-positive ICC. The proportion of cells containing hotspot mutations is higher (i.e., higher variant allele fraction) in ICC and mutations are detectable up to 6 years prior to cancer diagnosis. Our findings demonstrate the feasibility of using exfoliated cervical cells for detection of somatic mutations as potential diagnostic biomarkers.

Hip Arthroscopy Versus Physical Therapy for the Treatment of Symptomatic Acetabular Labral Tears in Patients Older Than 40 Years: 24-Month Results From a Randomized Controlled Trial.

BACKGROUND: The indications for hip arthroscopy in patients aged ≥40 years remain controversial, as observational studies have suggested that advanced age portends poor functional outcomes, poor durability of improvement, and high rates of conversion to total hip arthroplasty. PURPOSE: To compare hip arthroscopy versus nonoperative management for symptomatic labral tears in patients aged ≥40 years with limited radiographic osteoarthritis. STUDY DESIGN: Randomized controlled trial; Level of evidence, 1. METHODS: This single-surgeon, parallel randomized controlled trial included patients aged ≥40 years with limited osteoarthritis (Tönnis grades 0-2) who were randomized 1:1 to arthroscopic surgery with postoperative physical therapy (SPT) or physical therapy alone (PTA). Patients who received PTA and achieved unsatisfactory improvement were permitted to cross over to SPT after completing ≥14 weeks of physical therapy (CO). The primary outcomes were the International Hip Outcome Tool-33 score and modified Harris Hip Score at 24 months after surgery, and secondary outcomes included other patient-reported outcome measures and the visual analog scale for pain. The primary analysis was performed on an intention-to-treat basis using linear mixed-effects models. Sensitivity analyses included modified as-treated and treatment-failure analyses. RESULTS: A total of 97 patients were included, with 52 (53.6%) patients in the SPT group and 45 (46.4%) patients in the PTA group. Of the patients who underwent PTA, 32 (71.1%) patients crossed over to arthroscopy at a mean of 5.10 months (SD, 3.3 months) after physical therapy initiation. In both intention-to-treat and modified as-treated analyses, the SPT group displayed superior mean patient-reported outcome measure and pain scores across the study period for nearly all metrics relative to the PTA group. In the treatment-failure analysis, the SPT and CO groups showed greater improvement across all metrics compared with PTA; however, post hoc analyses revealed no significant differences in improvement between the SPT and CO groups. No significant differences were observed between groups in rates of total hip arthroplasty conversion. CONCLUSION: In patients ≥40 years of age with limited osteoarthritis, hip arthroscopy with postoperative physical therapy led to better outcomes than PTA at a 24-month follow-up. However, additional preoperative physical therapy did not compromise surgical outcomes and allowed some patients to avoid surgery. When surgery is indicated, age ≥40 years should not be considered an independent contraindication to arthroscopic acetabular labral repair. REGISTRATION: NCT03909178 (ClinicalTrials.gov identifier).

Cell-free DNA from ascites identifies clinically relevant variants and tumour evolution in patients with advanced ovarian cancer.

The emergence of targeted therapies has transformed ovarian cancer treatment. However, biomarker profiling for precision medicine is limited by access to quality, tumour-enriched tissue samples. The use of cell-free DNA (cfDNA) in ascites presents a potential solution to this challenge. In this study, next-generation sequencing was performed on ascites-derived cfDNA samples (26 samples from 15 human participants with ovarian cancer), with matched DNA from ascites-derived tumour cells (n = 5) and archived formalin-fixed paraffin-embedded (FFPE) tissue (n = 5). Similar tumour purity and variant detection were achieved with cfDNA compared to FFPE and ascites cell DNA. Analysis of large-scale genomic alterations, loss of heterozygosity and tumour mutation burden identified six cases of high genomic instability (including four with pathogenic BRCA1 and BRCA2 mutations). Copy number profiles and subclone prevalence changed between sequential ascites samples, particularly in a case where deletions and chromothripsis in Chr17p13.1 and Chr8q resulted in changes in clinically relevant TP53 and MYC variants over time. Ascites cfDNA identified clinically actionable information, concordant to tissue biopsies, enabling opportunistic molecular profiling. This advocates for analysis of ascites cfDNA in lieu of accessing tumour tissue via biopsy.

Biceps tenotomy vs. tenodesis: an ACS-NSQIP analysis of postoperative outcomes and utilization trends.

Background: While studies have assessed comparative rates of restoration of shoulder function and alleviation of symptoms, comparative systemic postoperative complication rates between biceps tenotomy and tenodesis have yet to be assessed. The purpose of the present study was to use a national administrative database to perform a comprehensive investigation into 30-day complication rates after biceps tenotomy versus tenodesis, thus providing valuable insights for informed decision-making by clinicians and patients regarding the optimal surgical approach for pathologies of the long head of the biceps tendon. Methods: The National Surgical Quality Improvement Program database was queried to analyze postoperative complication rates and metrics associated with biceps tenotomy and tenodesis. Patient data spanning from 2012 to 2021 was extracted, with relevant variables assessed to identify and compare these two surgical approaches. Adjusted and unadjusted analyses were utilized to analyze patient demographics, comorbidities, operative times, lengths of stay, readmissions, adverse events, and yearly surgical volume, along with trends in usage, across cohorts. Results: Of 11,527 total patients, 264 (2.29%), 6826 (59.22%), and 4437 (38.49%) underwent tenotomy, tenodesis with open repair, and tenodesis with arthroscopic repair, respectively. Tenotomy operative times ([mean ± SD]: 66.25 ± 44.76 minutes) were shorter than those for open tenodesis (78.83 ± 41.82) and arthroscopic tenodesis (75.98 ± 40.16). Conversely, tenotomy patients had longer hospital days (0.88 ± 4.86 days) relative to open tenodesis (.08 ± 1.55) and arthroscopic tenodesis (.12 ± 2.70). Multivariable logistic regression controlling for demographics and comorbidities demonstrated that patients undergoing tenodesis were less likely to be readmitted (adjusted odds ratio [AOR]: 0.42, 95% confidence interval [CI]: 0.17-0.98, P = .050) or sustain serious adverse events (AOR: 0.27, 95% CI: 0.13-0.57, P < .001), but equally likely to sustain minor adverse events (AOR: 0.87, CI: 0.21-3.68, P = .850), compared with patients undergoing tenotomy. Lastly, comparing utilization rates from 2012 to 2021 revealed a significant decrease in the proportion of tenotomy (from 6.2% to 1.0%) compared to open tenodesis (from 41.0% to 57.3%) and arthroscopic tenodesis (52.8% to 41.64%; P trend = .001). Conclusion: To our knowledge, this is the first large national database study investigating postoperative complication rates between the various surgical treatments for pathologies of the long head of the biceps tendon. Our results suggest that tenodesis yields fewer serious adverse events and lower readmission rates than tenotomy. We also found a shorter operative time for tenotomy. These findings support the increased utilization of tenodesis relative to tenotomy in recent years.

Comparison of Hybribio-H13 and Hybrid Capture® 2 human papillomavirus tests for detection of CIN2+ and CIN3. / Comparación de las pruebas para el virus del papiloma humano Hybribio-H13 y Hybrid Capture® 2 para la detección de NIC2+ y NIC3+

INTRODUCTION: Low-cost, accurate high-risk HPV tests are needed for cervical cancer screening in limited-resource settings. OBJECTIVE: To compare the performance of the low-cost Hybribio-H13 test with the Hybrid Capture® 2 to detect cervical intraepithelial neoplasia grade 2 or 3 (CIN2 and CIN3). MATERIALS AND METHODS: Archived baseline samples tested by the Hybrid Capture® 2 from women of the ASCUS-COL trial, aged 20 to 69 years, with biopsy-colposcopy directed diagnosis of CIN2+ (n = 143), CIN3+ (n = 51), and < CIN2 (n = 632) were blindly tested by the Hybribio-H13 test. RESULTS: The relative sensitivity of the Hybribio-H13 test versus the Hybrid Capture® 2 for detecting CIN2+ was 0.89 (90% CI = 0,80-0,98; NIT = 0,66), and for CIN3+ was 0,92 (90% CI = 0,85-0,98; NIT = 0,35). Relative specificity was 1.19 (90% CI = 1.05-1.33; NIT <0.00001). In the analysis restricted to women older than 30 years, the relative sensitivity of the Hybribio-H13 for CIN3+ was marginally below unity (ratio = 0.97; 90% CI = 0.95-0.99), and the specificity remained higher than the Hybrid Capture® 2 test. CONCLUSION: The Hybribio-H13 test was as specific as the Hybrid Capture® 2 for detecting CIN2+ or CIN3+ but less sensitive. Considering these results and the young age of the population recruited for screening because of ASCUS cytology, we suggest our results warrant the evaluation of the Hybribio-H13 for screening cervical cancer, especially in the evaluated population.

Introducción. Se necesitan pruebas para detectar genotipos de VPH de alto riesgo, precisas y de bajo costo, para la tamización del cáncer de cuello uterino en entornos de recursos limitados. Objetivo. Comparar el desempeño de la prueba de bajo costo Hybrid-H13 con la de Hybrid Capture® 2 para detectar NIC2+ y NIC3+. Materiales y métodos. Se analizaron en ciego muestras de la línea base provenientes de mujeres del estudio ASCUS-COL, entre los 20 y los 69 años, con diagnóstico dirigido por biopsia-colposcopia de NIC2+ (n = 143), NIC3 + (n = 51) y < NIC2 (n = 632) con la prueba para detección de virus de papiloma humano Hybribio-H13. Estas muestras fueron previamente evaluadas con la prueba Hybrid Capture® 2. Resultados. La sensibilidad relativa de Hybribio-13 versus la de Hybrid Capture® 2 para detectar NIC2+ fue de 0,89 (IC90%: 0,80-0,98; NIT = 0,66) y para NIC3+ fue de 0,92 (IC90%: 0,85-0,98; NIT = 0,35). La especificidad relativa fue de 1,19 (IC90%: 1,05-1,33; NIT <0,00001). En el análisis restringido a mujeres mayores de 30 años, la sensibilidad relativa de Hybribio-H13 para NIC3+ estuvo marginalmente por debajo de la unidad (proporción = 0,97; IC90%: 0,95-0,99) y la especificidad permaneció más alta que la de la prueba Hybrid Capture® 2. Conclusión. La prueba de Hybribio-H13 fue tan específica como la de Hybrid Capture® 2, pero menos sensible para detectar NIC2+ o NIC3+. Teniendo en cuenta estos resultados y la temprana edad de la población reclutada en la tamización por la presencia de ASCUS en la citología, se sugiere continuar con la evaluación de la prueba Hybribio-H13 para la detección de cáncer de cuello uterino en poblaciones con las mismas características que las de la aquí evaluada.

Association Between Severity of Chondrolabral Junction Breakdown and Functional Outcomes After Hip Arthroscopy for Acetabular Labral Tears.

BACKGROUND: Despite focus on surgical preservation of the chondrolabral junction (CLJ), the transition zone between the acetabular cartilage and labrum, the association between severity of CLJ breakdown and functional outcomes after hip arthroscopy remains unexplored. PURPOSE: To assess the influence of CLJ breakdown on patient-reported outcome measures (PROMs) at a 24-month follow-up after hip arthroscopy for symptomatic labral tears. STUDY DESIGN: Cohort study; Level of evidence, 3. METHODS: A retrospective review of prospectively collected data was conducted to identify patients ≥18 years of age with a minimum 24-month follow-up who underwent hip arthroscopy by a single surgeon for the treatment of symptomatic labral tears secondary to femoroacetabular impingement. The Beck classification of transition zone cartilage was used to grade CLJ damage; patients with grades 0 to 2 were stratified into the mild CLJ damage cohort, and those with grades 3 and 4 were stratified into the severe CLJ damage cohort. PROMs were collected at baseline and at 3, 6, 12 months, and annually thereafter postoperatively. Linear mixed-effects models were used to compare PROMs. Rates of achieving clinically meaningful thresholds and subsequent surgery rates were also compared. RESULTS: In total, 198 patients met the inclusion criteria, with a mean follow-up of 3.54 ± 1.26 years. A total of 95 patients with severe CLJ damage (mean age, 34.9 ± 10.5 years) were compared with 103 patients with mild CLJ damage (mean age, 38.2 ± 11.9 years). Hip Outcome Score-Activities of Daily Living (HOS-ADL), Non-Arthritic Hip Score (NAHS), and visual analog score for pain were inferior in the severe CLJ group at enrollment and all follow-up time points (P≤ .05). However, patients with severe CLJ breakdown exhibited greater improvements in HOS-ADL and NAHS at the 24-month follow-up and achieved clinically meaningful thresholds at equivalent rates to patients with mild CLJ breakdown. Subsequent surgery rates were 6.8% and 12.6% in patients with mild versus severe CLJ damage, respectively (P = .250). CONCLUSION: Severe CLJ breakdown is associated with increased pain and decreased functional level preoperatively and up to 24 months after hip arthroscopy. Despite this, patients with severe CLJ breakdown experienced greater improvements in functional outcomes at a 24-month follow-up and achieved clinical thresholds at similar rates to patients with mild CLJ damage. Thus, while worse baseline pain and functional levels may indicate severe CLJ breakdown, these patients still benefit substantially from hip arthroscopy.

Variation in the Cost of Hip Arthroscopy for Labral Pathological Conditions: A Time-Driven Activity-Based Costing Analysis.

BACKGROUND: Despite growing interest in delivering high-value orthopaedic care, the costs associated with hip arthroscopy remain poorly understood. By employing time-driven activity-based costing (TDABC), we aimed to characterize the cost composition of hip arthroscopy for labral pathological conditions and to identify factors that drive variation in cost. METHODS: Using TDABC, we measured the costs of 890 outpatient hip arthroscopy procedures for labral pathological conditions across 5 surgeons at 4 surgery centers from 2015 to 2022. All patients were ≥18 years old and were treated by surgeons who each performed ≥20 surgeries during the study period. Costs were normalized to protect the confidentiality of internal hospital cost data. Descriptive analyses and multivariable linear regression were performed to identify factors underlying cost variation. RESULTS: The study sample consisted of 515 women (57.9%) and 375 men (42.1%), with a mean age (and standard deviation) of 37.1 ± 12.7 years. Most of the procedures were performed in patients who were White (90.6%) or not Hispanic (93.4%). The normalized total cost of hip arthroscopy per procedure ranged from 43.4 to 203.7 (mean, 100 ± 24.2). Of the 3 phases of the care cycle, the intraoperative phase was identified as the largest generator of cost (>90%). On average, supply costs accounted for 48.8% of total costs, whereas labor costs accounted for 51.2%. A 2.5-fold variation between the 10th and 90th percentiles for total cost was attributed to supplies, which was greater than the 1.8-fold variation attributed to labor. Variation in total costs was most effectively explained by the labral management method (partial R2 = 0.332), operating surgeon (partial R2 = 0.326), osteoplasty type (partial R2 = 0.087), and surgery center (partial R2 = 0.086). Male gender (p < 0.001) and younger age (p = 0.032) were also associated with significantly increased costs. Finally, data trends revealed a shift toward labral preservation techniques over debridement during the study period (with the rate of such techniques increasing from 77.8% to 93.2%; Ptrend = 0.0039) and a strong correlation between later operative year and increased supply costs, labor costs, and operative time (p < 0.001 for each). CONCLUSIONS: By applying TDABC to outpatient hip arthroscopy, we identified wide patient-to-patient cost variation that was most effectively explained by the method of labral management, the operating surgeon, the osteoplasty type, and the surgery center. Given current procedural coding trends, declining reimbursements, and rising health-care costs, these insights may enable stakeholders to design bundled payment structures that better align reimbursements with costs. LEVEL OF EVIDENCE: Economic and Decision Analysis Level IV. See Instructions for Authors for a complete description of levels of evidence.

Revision Total Ankle Arthroplasty Using a Novel Modular Fixed-Bearing Revision Ankle System.

INTRODUCTION: Large bone defects such as those encountered after failed total ankle replacement have previously been a relative contraindication to revision ankle replacement due to inadequate bone stock. We describe our experience and patient reported outcomes with a modular ankle replacement system with tibial and talar augments. METHODS: This is a retrospective case series analysis of patients who underwent a total ankle replacement using the INVISION system across 2 centers between 2016 and 2022. Patients completed the Manchester-Oxford Foot Questionnaire (MOXFQ), Ankle Osteoarthritis Scale (AOS), and EQ-5D pre-operatively and then post-operatively at 6 months, 1 year, 2 years, 3 years, and 5 years. Medical records were reviewed for complications and re-operations. X-rays were reviewed for lucencies and alignment. RESULTS: A total of 17 patients were included in the study; 14 men and 3 women with an average age at the time of surgery of 67.9 years (range 56-80 years). The average follow-up post-operatively was 40.5 months (range 7-78) at the time of this study. The indication for surgery was revision of failed total ankle replacement (TAR) in 16 and revision of failed ankle fusion in 1. An augmented tibia was used in 13, an augmented talus in 13, and both augmented tibia and talus in 9 cases. There were no early surgical complications. One patient required debridement and implant retention for late deep infection. No implants have been revised. The average MOXFQ score improved by 19.3 points at most recent follow-up. The average AOS score improved by 25.2 points. CONCLUSION: The early results of a modular augmented ankle arthroplasty system have shown satisfactory patient outcomes with a low complication and re-operation rate and present another option for patients with larger bone defects. This is a small series, and a larger series with long-term follow-up would be beneficial. LEVELS OF EVIDENCE: Level IV: Case series.

Severus: accurate detection and characterization of somatic structural variation in tumor genomes using long reads.

Most current studies rely on short-read sequencing to detect somatic structural variation (SV) in cancer genomes. Long-read sequencing offers the advantage of better mappability and long-range phasing, which results in substantial improvements in germline SV detection. However, current long-read SV detection methods do not generalize well to the analysis of somatic SVs in tumor genomes with complex rearrangements, heterogeneity, and aneuploidy. Here, we present Severus: a method for the accurate detection of different types of somatic SVs using a phased breakpoint graph approach. To benchmark various short- and long-read SV detection methods, we sequenced five tumor/normal cell line pairs with Illumina, Nanopore, and PacBio sequencing platforms; on this benchmark Severus showed the highest F1 scores (harmonic mean of the precision and recall) as compared to long-read and short-read methods. We then applied Severus to three clinical cases of pediatric cancer, demonstrating concordance with known genetic findings as well as revealing clinically relevant cryptic rearrangements missed by standard genomic panels.

Germline pathogenic variants associated with triple-negative breast cancer in US Hispanic and Guatemalan women using hospital and community-based recruitment strategies.

PURPOSE: Recruit and sequence breast cancer subjects in Guatemalan and US Hispanic populations. Identify optimum strategies to recruit Latin American and Hispanic women into genetic studies of breast cancer. METHODS: We used targeted gene sequencing to identify pathogenic variants in 19 familial breast cancer susceptibility genes in DNA from unselected Hispanic breast cancer cases in the US and Guatemala. Recruitment across the US was achieved through community-based strategies. In addition, we obtained patients receiving cancer treatment at major hospitals in Texas and Guatemala. RESULTS: We recruited 287 Hispanic US women, 38 (13%) from community-based and 249 (87%) from hospital-based strategies. In addition, we ascertained 801 Guatemalan women using hospital-based recruitment. In our experience, a hospital-based approach was more efficient than community-based recruitment. In this study, we sequenced 103 US and 137 Guatemalan women and found 11 and 10 pathogenic variants, respectively. The most frequently mutated genes were BRCA1, BRCA2, CHEK2, and ATM. In addition, an analysis of 287 US Hispanic patients with pathology reports showed a significantly higher percentage of triple-negative disease in patients with pathogenic variants (41% vs. 15%). Finally, an analysis of mammography usage in 801 Guatemalan patients found reduced screening in women with a lower socioeconomic status (p < 0.001). CONCLUSION: Guatemalan and US Hispanic women have rates of hereditary breast cancer pathogenic variants similar to other populations and are more likely to have early age at diagnosis, a family history, and a more aggressive disease. Patient recruitment was higher using hospital-based versus community enrollment. This data supports genetic testing in breast cancer patients to reduce breast cancer mortality in Hispanic women.

Improved detection of low-frequency within-host variants from deep sequencing: A case study with human papillomavirus.

High-coverage sequencing allows the study of variants occurring at low frequencies within samples, but is susceptible to false-positives caused by sequencing error. Ion Torrent has a very low single nucleotide variant (SNV) error rate and has been employed for the majority of human papillomavirus (HPV) whole genome sequences. However, benchmarking of intrahost SNVs (iSNVs) has been challenging, partly due to limitations imposed by the HPV life cycle. We address this problem by deep sequencing three replicates for each of 31 samples of HPV type 18 (HPV18). Errors, defined as iSNVs observed in only one of three replicates, are dominated by C→T (G→A) changes, independently of trinucleotide context. True iSNVs, defined as those observed in all three replicates, instead show a more diverse SNV type distribution, with particularly elevated C→T rates in CCG context (CCG→CTG; CGG→CAG) and C→A rates in ACG context (ACG→AAG; CGT→CTT). Characterization of true iSNVs allowed us to develop two methods for detecting true variants: (1) VCFgenie, a dynamic binomial filtering tool which uses each variant's allele count and coverage instead of fixed frequency cut-offs; and (2) a machine learning binary classifier which trains eXtreme Gradient Boosting models on variant features such as quality and trinucleotide context. Each approach outperforms fixed-cut-off filtering of iSNVs, and performance is enhanced when both are used together. Our results provide improved methods for identifying true iSNVs in within-host applications across sequencing platforms, specifically using HPV18 as a case study.

Association Between Chondrolabral Junction Breakdown and Conversion to Total Hip Arthroplasty After Hip Arthroscopy for Symptomatic Labral Tears: Minimum 8-Year Follow-up.

BACKGROUND: Arthroscopic treatment of femoroacetabular impingement (FAI) and symptomatic labral tears confers short- to midterm benefits, yet further long-term evidence is needed. Moreover, despite the physiological and biomechanical significance of the chondrolabral junction (CLJ), the clinical implications of damage to this transition zone remain understudied. PURPOSE: To (1) report minimum 8-year survivorship and patient-reported outcome measures after hip arthroscopy for FAI and (2) characterize associations between outcomes and patient characteristics (age, body mass index, sex), pathological parameters (Tönnis angle, alpha angle, type of FAI, CLJ breakdown), and procedures performed (labral management, FAI treatment, microfracture). STUDY DESIGN: Cohort study; Level of evidence, 3. METHODS: This retrospective cohort study included patients who underwent primary hip arthroscopy for symptomatic labral tears secondary to FAI by a single surgeon between 2002 and 2013. All patients were ≥18 years of age with minimum 8-year follow-up and available preoperative radiographs. The primary outcome was conversion to total hip arthroplasty (THA), and secondary outcomes included revision arthroscopy, patient-reported outcome measures, and patient satisfaction. CLJ breakdown was assessed using the Beck classification. Kaplan-Meier estimates and weighted Cox regression were used to estimate 10-year survivorship (no conversion to THA) and identify risk factors associated with THA conversion. RESULTS: In this study of 174 hips (50.6% female; mean age, 37.8 ± 11.2 years) with mean follow-up of 11.1 ± 2.5 years, the 10-year survivorship rate was 81.6% (95% CI, 75.9%-87.7%). Conversion to THA occurred at a mean 4.7 ± 3.8 years postoperatively. Unadjusted analyses revealed several variables significantly associated with THA conversion, including older age; higher body mass index; higher Tönnis grade; labral debridement; and advanced breakdown of the CLJ, labrum, or articular cartilage. Survivorship at 10 years was inferior in patients exhibiting severe (43.6%; 95% CI, 31.9%-59.7%) versus mild (97.9%; 95% CI, 95.1%-100%) breakdown of the CLJ (P < .001). Multivariable analysis identified worsening CLJ breakdown (weighted hazard ratio per 1-unit increase, 6.41; 95% CI, 3.11-13.24), older age (1.09; 95% CI, 1.04-1.14), and higher Tönnis grade (4.59; 95% CI, 2.13-9.90) as independent negative prognosticators (P < .001 for all). CONCLUSION: Although most patients achieved favorable minimum 8-year outcomes, several pre- and intraoperative factors were associated with THA conversion; of these, worse CLJ breakdown, higher Tönnis grade, and older age were the strongest predictors.

Insights into the mechanisms and structure of breakage-fusion-bridge cycles in cervical cancer using long-read sequencing.

Cervical cancer is caused by human papillomavirus (HPV) infection, has few approved targeted therapeutics, and is the most common cause of cancer death in low-resource countries. We characterized 19 cervical and four head and neck cancer cell lines using long-read DNA and RNA sequencing and identified the HPV types, HPV integration sites, chromosomal alterations, and cancer driver mutations. Structural variation analysis revealed telomeric deletions associated with DNA inversions resulting from breakage-fusion-bridge (BFB) cycles. BFB is a common mechanism of chromosomal alterations in cancer, and our study applies long-read sequencing to this important chromosomal rearrangement type. Analysis of the inversion sites revealed staggered ends consistent with exonuclease digestion of the DNA after breakage. Some BFB events are complex, involving inter- or intra-chromosomal insertions or rearrangements. None of the BFB breakpoints had telomere sequences added to resolve the dicentric chromosomes, and only one BFB breakpoint showed chromothripsis. Five cell lines have a chromosomal region 11q BFB event, with YAP1-BIRC3-BIRC2 amplification. Indeed, YAP1 amplification is associated with a 10-year-earlier age of diagnosis of cervical cancer and is three times more common in African American women. This suggests that individuals with cervical cancer and YAP1-BIRC3-BIRC2 amplification, especially those of African ancestry, might benefit from targeted therapy. In summary, we uncovered valuable insights into the mechanisms and consequences of BFB cycles in cervical cancer using long-read sequencing.

The Effect of Pelvic Incidence on Outcomes After Hip Arthroscopy for Femoroacetabular Impingement and Acetabular Labral Tears.

BACKGROUND: In the setting of femoroacetabular impingement (FAI), decompression osteoplasties reconcile deleterious loading patterns caused by cam and pincer lesions. However, native variations of spinopelvic sagittal alignment may continue to perpetuate detrimental effects on the labrum, chondrolabral junction, and articular cartilage after hip arthroscopy. PURPOSE: To evaluate the effect of pelvic incidence (PI) on postoperative outcomes after hip arthroscopy for acetabular labral tears in the setting of FAI. STUDY DESIGN: Cohort study; Level of evidence, 3. METHODS: A retrospective query of prospectively collected data identified patients ≥18 years of age who underwent primary hip arthroscopy for FAI and acetabular labral tears between February 2014 and January 2022, with 3-, 6-, 12-, and 24-month follow-ups. Measurements for PI, pelvic tilt (PT), sacral slope (SS), and acetabular version were obtained via advanced diagnostic imaging. Patients were stratified into low-PI (<45°), moderate-PI (45°≤ PI ≤ 60°), and high-PI (>60°) cohorts. Patient-reported outcome measures (PROMs), clinically meaningful outcomes (ie, minimal clinically important difference, Patient Acceptable Symptom State, substantial clinical benefit, and maximal outcome improvement), visual analog scale (VAS) pain scores, and patient satisfaction were compared across cohorts. RESULTS: A total of 74 patients met eligibility criteria and were stratified into low-PI (n = 28), moderate-PI (n = 31), and high-PI (n = 15) cohorts. Correspondingly, patients with high PI displayed significantly greater values for PT (P = .001), SS (P < .001), acetabular version (P < .001), and acetabular inclination (P = .049). By the 12- and 24-month follow-ups, the high-PI cohort was found to have significantly inferior PROMs, VAS pain scores, rates of clinically meaningful outcome achievement, and satisfaction relative to patients with moderate and/or low PI. No significant differences were found between cohorts regarding rates of revision arthroscopy, subsequent spine surgery, or conversion to total hip arthroplasty. CONCLUSION: After hip arthroscopy, patients with a high PI (>60°) exhibited inferior PROMs, rates of achieving clinically meaningful thresholds, and satisfaction at 12 and 24 months relative to patients with low or moderate PI. Conversely, the outcomes of patients with low PI (<45°) were found to match the trajectory of those with a neutral spinopelvic alignment (45°≤ PI ≤ 60°). These findings highlight the importance of analyzing spinopelvic parameters preoperatively to prognosticate outcomes before hip arthroscopy for acetabular labral tears and FAI.

Preoperative Paralabral Cysts Predict More Significant Chondral Damage but Not 2-Year Functional Outcomes Following Arthroscopic Labral Repair.

PURPOSE: To investigate whether paralabral cysts identified incidentally on preoperative magnetic resonance imaging (MRI/MRA) predict 2-year functional outcomes after arthroscopic acetabular labral repair. METHODS: Prospectively collected data for patients undergoing primary hip arthroscopy by a single surgeon from 2014 to 2020 were retrospectively reviewed. Included patients were ≥18 years and completed baseline patient-reported outcome measures (PROMs) with additional follow-up at 3, 6, 12, and 24 months. Exclusion criteria were labral debridement, hip dysplasia, advanced hip osteoarthritis (Tönnis >1), or previous ipsilateral hip surgery. Patients were stratified based on the presence of paralabral cysts identified on MRI/MRA. Primary outcomes were International Hip Outcome Tool (iHOT-33) and modified Harris Hip Score (mHHS). Secondary outcomes included other PROMs and the visual analog pain scale. Outcomes were compared between cohorts using linear mixed-effects models and Fisher's exact tests. Sensitivity analyses accounted for preoperative PROMs, nonlinear improvement trajectories, and relevant baseline characteristics. RESULTS: Of the 182 included hips (47.8% female; mean ± standard deviation age, 36.9 ± 11.4), 30 (16.4%) had paralabral cysts. During the 2-year study period, there were no significant differences between patients with and without paralabral cysts in terms of iHOT-33 scores (weighted difference = 1.60; 95% confidence interval [CI], -5.09, 8.28; P = .64), mHHS scores (weighted difference = 0.56; 95% CI, -4.16, 5.28; P = .82), or any secondary outcomes (except for HOS-Sports Subscale at 3 months [mean difference = -11.85; 95% CI, -22.85, -0.84; P = .035]). Furthermore, there were no significant differences in clinically meaningful outcomes (P > .05 for all), revision rates (P = 1.00), or conversion to total hip arthroplasty between cohorts (P = 1.00). These results held across all sensitivity analyses. CONCLUSIONS: Although preoperative paralabral cysts were associated with worse cam impingement and more severe chondral damage observed intraoperatively, they did not predict 2-year functional outcomes or clinically meaningful improvements, suggesting that incidentally discovered paralabral cysts are not a contraindication for arthroscopic labral repair. LEVEL OF EVIDENCE: Level III, retrospective cohort study.

Insights into the Mechanisms and Structure of Breakage-Fusion-Bridge Cycles in Cervical Cancer using Long-Read Sequencing.

Cervical cancer is caused by human papillomavirus (HPV) infection, has few approved targeted therapeutics, and is the most common cause of cancer death in low-resource countries. We characterized 19 cervical and four head and neck cell lines using long-read DNA and RNA sequencing and identified the HPV types, HPV integration sites, chromosomal alterations, and cancer driver mutations. Structural variation analysis revealed telomeric deletions associated with DNA inversions resulting from breakage-fusion-bridge (BFB) cycles. BFB is a common mechanism of chromosomal alterations in cancer, and this is one of the first analyses of these events using long-read sequencing. Analysis of the inversion sites revealed staggered ends consistent with exonuclease digestion of the DNA after breakage. Some BFB events are complex, involving inter- or intra-chromosomal insertions or rearrangements. None of the BFB breakpoints had telomere sequences added to resolve the dicentric chromosomes and only one BFB breakpoint showed chromothripsis. Five cell lines have a Chr11q BFB event, with YAP1/BIRC2/BIRC3 gene amplification. Indeed, YAP1 amplification is associated with a 10-year earlier age of diagnosis of cervical cancer and is three times more common in African American women. This suggests that cervical cancer patients with YAP1/BIRC2/BIRC3-amplification, especially those of African American ancestry, might benefit from targeted therapy. In summary, we uncovered new insights into the mechanisms and consequences of BFB cycles in cervical cancer using long-read sequencing.

Outcomes of Hip Arthroscopy in the Setting of Concomitant Symptomatic Lumbosacral Spine Pathology: A Matched Control Study With Minimum 24-Month Follow-up.

BACKGROUND: The overlapping biomechanical relationship between the lumbosacral spine and pelvis poses unique challenges to patients with concomitant pathologies limiting spinopelvic range of motion. PURPOSE: To assess the influence of concomitant, symptomatic lumbosacral spine pathology on patient-reported outcome measures (PROMs) after hip arthroscopy for the treatment of femoroacetabular impingement (FAI) and symptomatic labral tears. STUDY DESIGN: Cohort study; Level of evidence, 3. METHODS: A retrospective query of prospectively collected data identified patients aged ≥18 years with a minimum 24-month follow-up who underwent hip arthroscopy by a single surgeon for the treatment of symptomatic labral tears secondary to FAI. Patients were stratified into cohorts based on the presence (hip-spine [HS]) or absence (matched control [MC]) of symptomatic lumbosacral spine pathology. Inclusion within the HS cohort required confirmation of lower back pain/symptoms on preoperative surveys plus a diagnosis of lumbosacral spine pathology verified by radiology reports and correlating clinical documentation. Patients with previous spine surgery were excluded. PROMs were compared between groups, along with rates of achieving minimal clinically important difference (MCID) thresholds, Patient Acceptable Symptom State (PASS) thresholds, revision arthroscopy, and conversion to total hip arthroplasty (THA). RESULTS: A total of 70 patients with lumbosacral pathology were coarsened exact matched to 87 control patients without spinal pathology. The HS cohort had preoperative baseline scores that were significantly worse for nearly all PROMs. Follow-ups at 3, 6, 12, and 24 months displayed similar trends, with the HS cohort demonstrating significantly worse scores for most collected outcomes. However, at every time point, HS and MC patients exhibited similar magnitudes of improvement across all PROM and pain metrics. Furthermore, while significantly fewer HS patients achieved PASS for nearly all PROMs at 12- and 24-month follow-ups, MCID thresholds were reached at similar or greater rates across all PROMs relative to the MC cohort. Finally, there were no significant differences in rates of revision or THA between cohorts at maximum available follow-up. CONCLUSION: After hip arthroscopy to address labral tears in the setting of FAI, patients with symptomatic lumbosacral pathologies and no history of spine surgery were found to exhibit inferior pre- and postoperative PROMs but achieved statistically similar clinical benefit and rates of PROM improvement through 24-month follow-up compared with the MC cohort with isolated hip disease. These findings aid in providing a realistic recovery timeline and evidence that coexisting hip and spine disorders are not a contraindication for arthroscopic hip preservation surgery.

Labral Reconstruction via Capsular Augmentation Maintains Perfusion to the Acetabular Labrum and Locally Transferred Autograft: An in Vivo Laser Doppler Flowmetry Analysis.

Background: The purpose of the present study was to examine the effects of arthroscopic labral repair with capsular augmentation on blood flow in vivo with use of laser Doppler flowmetry (LDF) to measure microvascular perfusion of the labrum and autograft tissue. Methods: The present prospective case series included patients ≥18 years old who underwent arthroscopic acetabular labral repair with capsular augmentation; all procedures were performed by a single surgeon between 2018 and 2022. The LDF probe measured microvascular blood flow flux within 1 mm3 of the surrounding labral and capsular tissue of interest. Mean baseline measurements of flux were compared with readings immediately following capsular elevation and after completing labral augmentation. Blood flux changes were expressed as the percent change from the baseline measurements. Results: The present study included 41 patients (24 men [58.5%] and 17 women [41.5%]) with a mean age (and standard deviation) of 31.3 ± 8.4 years, a mean BMI of 24.6 ± 3.4 kg/m2, a mean lateral center-edge of angle 35.3° ± 4.9°, a mean Tönnis angle of 5.8° ± 5.8°, and a mean arterial pressure of 93.7 ± 10.9 mm Hg. Following capsular elevation, the mean percent change in capsular blood flow flux was significantly different from baseline (-9.24% [95% confidence interval (CI), -18.1% to -0.04%]; p < 0.001). Following labral augmentation, the mean percent change in labral blood flow flux was significantly different from baseline both medially (-22.3% [95% CI, -32.7% to -11.9%]; p < 0.001) and laterally (-32.5% [95% CI, -41.5% to -23.6%]; p = 0.041). There was no significant difference between the changes in medial and lateral perfusion following repair (p = 0.136). Conclusions: Labral repair with capsular augmentation sustains a reduced blood flow to the native labrum and capsular tissue at the time of fixation. The biological importance of this reduction is unknown, but these findings may serve as a benchmark for other labral preservation techniques and support future correlations with clinical outcomes. Level of Evidence: Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence.

Analysis of Several Common APOBEC-type Mutations in Bladder Tumors Suggests Links to Viral Infection.

FGFR3 and PIK3CA are among the most frequently mutated genes in bladder tumors. We hypothesized that recurrent mutations in these genes might be caused by common carcinogenic exposures such as smoking and other factors. We analyzed 2,816 bladder tumors with available data on FGFR3 and/or PIK3CA mutations, focusing on the most recurrent mutations detected in ≥10% of tumors. Compared to tumors with other FGFR3/PIK3CA mutations, FGFR3-Y375C was more common in tumors from smokers than never-smokers (P = 0.009), while several APOBEC-type driver mutations were enriched in never-smokers: FGFR3-S249C (P = 0.013) and PIK3CA-E542K/PIK3CA-E545K (P = 0.009). To explore possible causes of these APOBEC-type mutations, we analyzed RNA sequencing (RNA-seq) data from 798 bladder tumors and detected several viruses, with BK polyomavirus (BKPyV) being the most common. We then performed IHC staining for polyomavirus (PyV) Large T-antigen (LTAg) in an independent set of 211 bladder tumors. Overall, by RNA-seq or IHC-LTAg, we detected PyV in 26 out of 1,010 bladder tumors with significantly higher detection (P = 4.4 × 10-5), 25 of 554 (4.5%) in non-muscle-invasive bladder cancers (NMIBC) versus 1 of 456 (0.2%) of muscle-invasive bladder cancers (MIBC). In the NMIBC subset, the FGFR3/PIK3CA APOBEC-type driver mutations were detected in 94.7% (18/19) of PyV-positive versus 68.3% (259/379) of PyV-negative tumors (P = 0.011). BKPyV tumor positivity in the NMIBC subset with FGFR3- or PIK3CA-mutated tumors was also associated with a higher risk of progression to MIBC (P = 0.019). In conclusion, our results support smoking and BKPyV infection as risk factors contributing to bladder tumorigenesis in the general patient population through distinct molecular mechanisms. PREVENTION RELEVANCE: Tobacco smoking likely causes one of the most common mutations in bladder tumors (FGFR3-Y375C), while viral infections might contribute to three others (FGFR3-S249C, PIK3CA-E542K, and PIK3CA-E545K). Understanding the causes of these mutations may lead to new prevention and treatment strategies, such as viral screening and vaccination.