Endoluminal Biopsy for Vein of Galen Malformation.

BACKGROUND AND OBJECTIVES: Vein of Galen malformation (VOGM), the result of arteriovenous shunting between choroidal and/or subependymal arteries and the embryologic prosencephalic vein, is among the most severe cerebrovascular disorders of childhood. We hypothesized that in situ analysis of the VOGM lesion using endoluminal tissue sampling (ETS) is feasible and may advance our understanding of VOGM genetics, pathogenesis, and maintenance. METHODS: We collected germline DNA (cheek swab) from patients and their families for genetic analysis. In situ VOGM "endothelial" cells (ECs), defined as CD31+ and CD45-, were obtained from coils through ETS during routine endovascular treatment. Autologous peripheral femoral ECs were also collected from the access sheath. Single-cell RNA sequencing of both VOGM and peripheral ECs was performed to demonstrate feasibility to define the transcriptional architecture. Comparison was also made with a published normative cerebrovascular transcriptome atlas. A subset of VOGM ECs was reserved for future DNA sequencing to assess for somatic and second-hit mutations. RESULTS: Our cohort contains 6 patients who underwent 10 ETS procedures from arterial and/or venous access during routine VOGM treatment (aged 12 days to ∼6 years). No periprocedural complications attributable to ETS occurred. Six unique coil types were used. ETS captured 98 ± 88 (mean ± SD; range 17-256) experimental ECs (CD31+ and CD45-). There was no discernible correlation between cell yield and coil type or route of access. Single-cell RNA sequencing demonstrated hierarchical clustering and unique cell populations within the VOGM EC compartment compared with peripheral EC controls when annotated using a publicly available cerebrovascular cell atlas. CONCLUSION: ETS may supplement investigations aimed at development of a molecular-genetic taxonomic classification scheme for VOGM. Moreover, results may eventually inform the selection of personalized pharmacologic or genetic therapies for VOGM and cerebrovascular disorders more broadly.

Editorial Commentary: Biceps Management During Rotator Cuff Tear: Confounding Variables Result in Unclear Indications.

Is "killing the biceps" during rotator cuff repair a capital crime or a lawful act? One of the most passionately debated topics in shoulder surgery is what to do with the biceps during rotator cuff repair: save it, tenotomize it, or perform tenodesis. Results of repair are not very successful, and given that repair of massive rotator cuff tears shows a 40% to 57% failure rate, there is renewed interest in sparing the biceps tendon as a humeral head depressor-or so that it may be used as a local graft for revision rotator cuff repair. The literature regarding tenodesis versus biceps sparing during rotator cuff repair is controversial. There are so many confounding variables affecting rotator cuff repair outcomes (tear size, comorbidities, age, tissue quality, etc.) that we do not believe that anything less than a randomized, prospective study that matches groups is likely to provide a conclusive verdict.

Computational Pathology Assessments of Cardiac Stromal Remodeling: Clinical Correlates and Prognostic Implications in Heart Transplantation.

Both overt and indolent inflammatory insults in heart transplantation can accelerate pathologic cardiac remodeling, but there are few tools for monitoring the speed and severity of remodeling over time. To address this need, we developed an automated computational pathology system to measure pathologic remodeling in transplant biopsy samples in a large, retrospective cohort of n=2167 digitized heart transplant biopsy slides. Biopsy images were analyzed to identify the pathologic stromal changes associated with future allograft loss or advanced allograft vasculopathy. Biopsy images were then analyzed to assess which historical allo-inflammatory events drive progression of these pathologic stromal changes over time in serial biopsy samples. The top-5 features of pathologic stromal remodeling most strongly associated with adverse outcomes were also strongly associated with histories of both overt and indolent inflammatory events. Our findings identify previously unappreciated subgroups of higher- and lower-risk transplant patients, and highlight the translational potential of digital pathology analysis.

Distinct genomic and immunologic tumor evolution in germline TP53-driven breast cancers.

Pathogenic germline TP53 alterations cause Li-Fraumeni Syndrome (LFS), and breast cancer is the most common cancer in LFS females. We performed first of its kind multimodal analysis of LFS breast cancer (LFS-BC) compared to sporadic premenopausal BC. Nearly all LFS-BC underwent biallelic loss of TP53 with no recurrent oncogenic variants except ERBB2 (HER2) amplification. Compared to sporadic BC, in situ and invasive LFS-BC exhibited a high burden of short amplified aneuploid segments (SAAS). Pro-apoptotic p53 target genes BAX and TP53I3 failed to be up-regulated in LFS-BC as was seen in sporadic BC compared to normal breast tissue. LFS-BC had lower CD8+ T-cell infiltration compared to sporadic BC yet higher levels of proliferating cytotoxic T-cells. Within LFS-BC, progression from in situ to invasive BC was marked by an increase in chromosomal instability with a decrease in proliferating cytotoxic T-cells. Our study uncovers critical events in mutant p53-driven tumorigenesis in breast tissue.

Preresidency research output among US neurological surgery residents.

OBJECTIVE: Research productivity is often used to evaluate candidates for neurosurgery residency. Official annual reports describe the mean total number of research products of successful applicants for each match cycle; however, the average number of indexed publications, the highest-valued research product, is not reported separately from other research products. The primary objectives of this study were to describe the distribution of preresidency indexed publication quantity among successful neurosurgery applicants from 2017 to 2021 and determine whether any change in publication quantity across application cycles existed. Secondary objectives included determining the rate at which the average publication quantity is increasing across application cycles, whether this increase is driven by high-output applicants alone, and if a performance ceiling has been reached. METHODS: US doctor of medicine seniors applying to the senior author's institution between 2017 and 2021 and who successfully matched into any US neurosurgery program were included. Publication quantities were extracted using Scopus. Additional variables were extracted from residency applications. Mean (SD) and median (IQR) publication quantities were used to describe the distribution and compare across years. Applicants were ranked by descending publication count and divided into quartiles. Averages within each quartile were compared with respective quartiles across years. Averages of the top 10% most productive applicants were compared across years to determine if a performance ceiling existed. RESULTS: Overall, 93.2% of matched applicants were captured. The mean and median total numbers of publications for applicants who matched from 2017 to 2021 were 5.6 ± 8.3 and 3.0 (1.0, 7.0), respectively. The mean and median numbers of publications increased from 3.7 ± 5.3 and 2.0 (0.0, 5.0) in 2016-2017 to 8.1 ± 10.0 and 5.0 (2.0, 11.0) in 2020-2021 (p < 0.001). The distribution of publication quantity was right-skewed. Multivariable analysis determined the application year to be independently and positively correlated with publication quantity (ß 1.07 [95% CI 0.71-1.42], p < 0.001). All quartiles observed an increased average number of publications across years (p < 0.001). The mean and median numbers for the top 10% increased from 15.8 ± 8.7 and 13.0 (10.8, 15.5) in 2016-2017, respectively, to 31.3 ± 16.0 and 25.0 (21.0, 35.5) in 2020-2021 (p < 0.001). CONCLUSIONS: Indexed publications account for a small portion of the total research products that successful neurosurgery candidates list on applications. A high number of publications is not necessary for candidates to match, with approximately 50% of all applicants who successfully matched having ≤ 5 publications and 25% having ≤ 2 publications. The average preresidency publication quantity has been increasing yearly among neurosurgery applicants. This increase was present across the applicant pool. Additionally, no performance ceiling was observed.

Global Economic Evaluation of the Reported Costs of Deep Brain Stimulation.

INTRODUCTION: Despite the known benefits of deep brain stimulation (DBS), the cost of the procedure can limit access and can vary widely. Our aim was to conduct a systematic review of the reported costs associated with DBS, as well as the variability in reporting cost-associated factors to ultimately increase patient access to this therapy. METHODS: A systematic review of the literature for cost of DBS treatment was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. PubMed and Embase databases were queried. Olsen & Associates (OANDA) was used to convert all reported rates to USD. Cost was corrected for inflation using the US Bureau of Labor Statistics Inflation Calculator, correcting to April 2022. RESULTS: Twenty-six articles on the cost of DBS surgery from 2001 to 2021 were included. The median number of patients across studies was 193, the mean reported age was 60.5 ± 5.6 years, and median female prevalence was 38.9%. The inflation- and currency-adjusted mean cost of the DBS device was USD 21,496.07 ± USD 8,944.16, the cost of surgery alone was USD 14,685.22 ± USD 8,479.66, the total cost of surgery was USD 40,942.85 ± USD 17,987.43, and the total cost of treatment until 1 year of follow-up was USD 47,632.27 ± USD 23,067.08. There were no differences in costs observed across surgical indication or country. CONCLUSION: Our report describes the large variation in DBS costs and the manner of reporting costs. The current lack of standardization impedes productive discourse as comparisons are hindered by both geographic and chronological variations. Emphasis should be put on standardized reporting and analysis of reimbursement costs to better assess the variability of DBS-associated costs in order to make this procedure more cost-effective and address areas for improvement to increase patient access to DBS.

Rare subclonal sequencing of breast cancers indicates putative metastatic driver mutations are predominately acquired after dissemination.

BACKGROUND: Evolutionary models of breast cancer progression differ on the extent to which metastatic potential is pre-encoded within primary tumors. Although metastatic recurrences often harbor putative driver mutations that are not detected in their antecedent primary tumor using standard sequencing technologies, whether these mutations were acquired before or after dissemination remains unclear. METHODS: To ascertain whether putative metastatic driver mutations initially deemed specific to the metastasis by whole exome sequencing were, in actuality, present within rare ancestral subclones of the primary tumors from which they arose, we employed error-controlled ultra-deep sequencing (UDS-UMI) coupled with FFPE artifact mitigation by uracil-DNA glycosylase (UDG) to assess the presence of 132 "metastasis-specific" mutations within antecedent primary tumors from 21 patients. Maximum mutation detection sensitivity was ~1% of primary tumor cells. A conceptual framework was developed to estimate relative likelihoods of alternative models of mutation acquisition. RESULTS: The ancestral primary tumor subclone responsible for seeding the metastasis was identified in 29% of patients, implicating several putative drivers in metastatic seeding including LRP5 A65V and PEAK1 K140Q. Despite this, 93% of metastasis-specific mutations in putative metastatic driver genes remained undetected within primary tumors, as did 96% of metastasis-specific mutations in known breast cancer drivers, including ERRB2 V777L, ESR1 D538G, and AKT1 D323H. Strikingly, even in those cases in which the rare ancestral subclone was identified, 87% of metastasis-specific putative driver mutations remained undetected. Modeling indicated that the sequential acquisition of multiple metastasis-specific driver or passenger mutations within the same rare subclonal lineage of the primary tumor was highly improbable. CONCLUSIONS: Our results strongly suggest that metastatic driver mutations are sequentially acquired and selected within the same clonal lineage both before, but more commonly after, dissemination from the primary tumor, and that these mutations are biologically consequential. Despite inherent limitations in sampling archival primary tumors, our findings indicate that tumor cells in most patients continue to undergo clinically relevant genomic evolution after their dissemination from the primary tumor. This provides further evidence that metastatic recurrence is a multi-step, mutation-driven process that extends beyond primary tumor dissemination and underscores the importance of longitudinal tumor assessment to help guide clinical decisions.

Failing to Make the Grade: Conventional Cardiac Allograft Rejection Grading Criteria Are Inadequate for Predicting Rejection Severity.

BACKGROUND: Cardiac allograft rejection is the leading cause of early graft failure and is a major focus of postheart transplant patient care. While histological grading of endomyocardial biopsy samples remains the diagnostic standard for acute rejection, this standard has limited diagnostic accuracy. Discordance between biopsy rejection grade and patient clinical trajectory frequently leads to both overtreatment of indolent processes and delayed treatment of aggressive ones, spurring the need to investigate the adequacy of the current histological criteria for assessing clinically important rejection outcomes. METHODS: N=2900 endomyocardial biopsy images were assigned a rejection grade label (high versus low grade) and a clinical trajectory label (evident versus silent rejection). Using an image analysis approach, n=370 quantitative morphology features describing the lymphocytes and stroma were extracted from each slide. Two models were constructed to compare the subset of features associated with rejection grades versus those associated with clinical trajectories. A proof-of-principle machine learning pipeline-the cardiac allograft rejection evaluator-was then developed to test the feasibility of identifying the clinical severity of a rejection event. RESULTS: The histopathologic findings associated with conventional rejection grades differ substantially from those associated with clinically evident allograft injury. Quantitative assessment of a small set of well-defined morphological features can be leveraged to more accurately reflect the severity of rejection compared with that achieved by the International Society of Heart and Lung Transplantation grades. CONCLUSIONS: Conventional endomyocardial samples contain morphological information that enables accurate identification of clinically evident rejection events, and this information is incompletely captured by the current, guideline-endorsed, rejection grading criteria.

Cost considerations for vestibular schwannoma screening and imaging: a systematic review.

Vestibular schwannomas (VS) account for approximately 8% of all intracranial neoplasms. Importantly, the cost of the diagnostic workup for VS, including the screening modalities most commonly used, has not been thoroughly investigated. Our aim is to conduct a systematic review of the published literature on costs associated with VS screening. A systematic review of the literature for cost of VS treatment was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. The terms "vestibular schwannoma," "acoustic neuroma," and "cost" were queried using the PubMed and Embase databases. Studies from all countries were considered. Cost was then corrected for inflation using the US Bureau of Labor Statistics Inflation Calculator, correcting to April 2022. The search resulted in an initial review of 483 articles, of which 12 articles were included in the final analysis. Screening criteria were used for non-neurofibromatosis type I and II patients who complained of asymmetric hearing loss, tinnitus, or vertigo. Patients included in the studies ranged from 72 to 1249. The currency and inflation-adjusted mean cost was $418.40 (range, $21.81 to $487.03, n = 5) for auditory brainstem reflex and $1433.87 (range, $511.64 to $1762.15, n = 3) for non-contrasted computed tomography. A contrasted magnetic resonance imaging (MRI) scan was found to have a median cost of $913.27 (range, $172.25-$2733.99; n = 8) whereas a non-contrasted MRI was found to have a median cost of $478.62 (range, $116.61-$3256.38, n = 4). In terms of cost reporting, of the 12 articles, 1 (8.3%) of them separated out the cost elements, and 10 (83%) of them used local prices, which include institutional costs and/or average costs of multiple institutions. Our findings describe the limited data on published costs for screening and imaging of VS. The paucity of data and significant variability of costs between studies indicates that this endpoint is relatively unexplored, and the cost of screening is poorly understood.

Clinically Significant Outcome Scores in Orthopaedic Sports Medicine Shoulder and Knee Surgery Are Increasing in Prevalence but Often Reported Incorrectly.

PURPOSE: To study the prevalence and quality of application of minimal clinically important difference (MCID), substantial clinical benefit (SCB), patient-acceptable symptomatic state (PASS), and maximum outcome improvement (MOI), reported in the orthopaedic sports medicine knee and shoulder literature in recent years and to bring awareness of proper use of such metrics. METHODS: A literature review of all shoulder and knee articles published from the American Journal of Sports Medicine (AJSM), Journal of Shoulder and Elbow Surgery (JSES), and Arthroscopy from 2016 to 2020 was performed, specifically investigating whether MCID, SCB, PASS, or MOI were used or reported. Additionally, the way these metrics were reported and interpreted was recorded. RESULTS: Out of 5,039 studies, 889 shoulder and knee studies met the inclusion criteria. Overall, 16.7% reported either MCID, PASS, or SCB. MCID was the most reported across all 3 journals. MCID was reported 12.4% of the time throughout the 5 years. PASS was reported 3.2% and SCB 1.1% of the time over the 5 years. MOI was not reported by any of the journals during this period. There was a statistically significant increase in MCID reporting in 2 of the 3 journals over the 5-year course, Arthroscopy (P = .02) and AJSM (P = .05). There was no statistically significant increase in PASS or SCB reporting rates in all 3 journals. Only 39.1% of studies reported MCID correctly (i.e., defined as the number of individual patients meeting MCID/total patients in the study). CONCLUSIONS: This study shows an increasing trend in the use of clinically significant outcome metrics, such as MCID, for interpretation of patient-reported outcomes; however, these individual metrics are often not being used on the individual level and subsequently not reported accurately. We recommend determining whether the specific metric met the threshold per individual patient and then reporting those as a percentage of the sample population to achieve the full potential of these metrics and translate them accurately across various studies. CLINICAL RELEVANCE: As the usage of clinically significant outcome metrics rises, so does the need for accurate reporting. These findings will encourage future studies to follow a more standardized format.

Emerging Landscape of Targeted Therapy of Breast Cancers With Low Human Epidermal Growth Factor Receptor 2 Protein Expression.

CONTEXT.­: Human epidermal growth factor receptor 2 (HER2) status in breast cancer is currently classified as negative or positive for selecting patients for anti-HER2 targeted therapy. The evolution of the HER2 status has included a new HER2-low category defined as an HER2 immunohistochemistry score of 1+ or 2+ without gene amplification. This new category opens the door to a targetable HER2-low breast cancer population for which new treatments may be effective. OBJECTIVE.­: To review the current literature on the emerging category of breast cancers with low HER2 protein expression, including the clinical, histopathologic, and molecular features, and outline the clinical trials and best practice recommendations for identifying HER2-low-expressing breast cancers by immunohistochemistry. DATA SOURCES.­: We conducted a literature review based on peer-reviewed original articles, review articles, regulatory communications, ongoing and past clinical trials identified through ClinicalTrials.gov, and the authors' practice experience. CONCLUSIONS.­: The availability of new targeted therapy potentially effective for patients with breast cancers with low HER2 protein expression requires multidisciplinary recognition. In particular, pathologists need to recognize and identify this category to allow the optimal selection of patients for targeted therapy.

Orthopedic surgery residents reported increased shoulder procedure volumes during the COVID-19 pandemic.

Background: The purpose of this study is to evaluate the impact of the COVID-19 pandemic on shoulder procedure volumes reported to the Accreditation Council for Graduate Medical Education by orthopedic surgery residents. Methods: We performed a retrospective review of Accreditation Council for Graduate Medical Education case logs reporting data from graduating orthopedic surgery residents during the academic years of 2006-2022. Data were queried for all patients for the following shoulder Current Procedural Terminology codes: incision, excision, intro or removal, repair/revision/reconstruction, fracture and/or dislocation, manipulation, arthroscopy, trauma, and total procedures performed. Individual t-tests were used to compare case log trends of graduating academic years before (classes of 2018 and 2019) and during (classes of 2020, 2021, and 2022) the COVID-19 pandemic. Statistical significance was established to be P <.05 for total procedure types, but at P <.005 during category comparisons to protect against alpha errors. Results: Reported mean total shoulder procedures per resident steadily increased each year from 2017 to 2022, but the only significant increase was seen when comparing the graduating classes of 2020 to 2021 (157.9 vs. 165.7, P =.02). Stratification of these procedures by subgroup revealed a significant increase in manipulation procedures from 2021 to 2022 (7.3 vs. 8.8, P =.001). Discussion/Conclusion: COVID-19 did not have a negative impact on logged shoulder procedure volume. Orthopedic surgery residents graduating during the COVID-19 pandemic reported more shoulder procedures than those graduating prepandemic. However, shoulder procedure log trends should be longitudinally investigated, as preceding years of procedural opportunities may underestimate the pandemic's impact.

Chimeric kinase ALK induces expression of NAMPT and selectively depends on this metabolic enzyme to sustain its own oncogenic function.

As we show in this study, NAMPT, the key rate-limiting enzyme in the salvage pathway, one of the three known pathways involved in NAD synthesis, is selectively over-expressed in anaplastic T-cell lymphoma carrying oncogenic kinase NPM1::ALK (ALK + ALCL). NPM1::ALK induces expression of the NAMPT-encoding gene with STAT3 acting as transcriptional activator of the gene. Inhibition of NAMPT affects ALK + ALCL cells expression of numerous genes, many from the cell-signaling, metabolic, and apoptotic pathways. NAMPT inhibition also functionally impairs the key metabolic and signaling pathways, strikingly including enzymatic activity and, hence, oncogenic function of NPM1::ALK itself. Consequently, NAMPT inhibition induces cell death in vitro and suppresses ALK + ALCL tumor growth in vivo. These results indicate that NAMPT is a novel therapeutic target in ALK + ALCL and, possibly, other similar malignancies. Targeting metabolic pathways selectively activated by oncogenic kinases to which malignant cells become "addicted" may become a novel therapeutic approach to cancer, alternative or, more likely, complementary to direct inhibition of the kinase enzymatic domain. This potential therapy to simultaneously inhibit and metabolically "starve" oncogenic kinases may not only lead to higher response rates but also delay, or even prevent, development of drug resistance, frequently seen when kinase inhibitors are used as single agents.

Biallelic BRCA Loss and Homologous Recombination Deficiency in Nonbreast/Ovarian Tumors in Germline BRCA1/2 Carriers.

PURPOSE: Breast and ovarian tumors in germline BRCA1/2 carriers undergo allele-specific loss of heterozygosity, resulting in homologous recombination deficiency (HRD) and sensitivity to poly-ADP-ribose polymerase (PARP) inhibitors. This study investigated whether biallelic loss and HRD also occur in primary nonbreast/ovarian tumors that arise in germline BRCA1/2 carriers. METHODS: A clinically ascertained cohort of BRCA1/2 carriers with a primary nonbreast/ovarian cancer was identified, including canonical (prostate and pancreatic cancers) and noncanonical (all other) tumor types. Whole-exome sequencing or clinical sequencing results (n = 45) were analyzed. A pan-cancer analysis of nonbreast/ovarian primary tumors from germline BRCA1/2 carriers from The Cancer Genome Atlas (TCGA, n = 73) was used as a validation cohort. RESULTS: Ages of nonbreast/ovarian cancer diagnosis in germline BRCA1/2 carriers were similar to controls for the majority of cancer types. Nine of 45 (20%) primary nonbreast/ovarian tumors from germline BRCA1/2 carriers had biallelic loss of BRCA1/2 in the clinical cohort, and 23 of 73 (32%) in the TCGA cohort. In the combined cohort, 35% and 27% of primary canonical and noncanonical BRCA tumor types, respectively, had biallelic loss. High HRD scores (HRDex > 42) were detected in 81% of tumors with biallelic BRCA loss compared with 22% (P < .001) of tumors without biallelic BRCA loss. No differences in genomic profile, including mutational signatures, mutation spectrum, tumor mutational burden, or microsatellite instability, were found in primary nonbreast/ovarian tumors with or without biallelic BRCA1/2 loss. CONCLUSION: A proportion of noncanonical primary tumors have biallelic loss and evidence of HRD. Our data suggest that assessment of biallelic loss and HRD could supplement identification of germline BRCA1/2 mutations in selection of patients for platinum or PARP inhibitor therapy.

Efficacy of a prolonged stability melphalan formulation for intra-arterial treatment of retinoblastoma.

BACKGROUND: Melphalan, which is poorly soluble at room temperature, is widely used for the treatment of retinoblastoma by selective ophthalmic artery infusion. Evomela, a propylene glycol-free formulation of melphalan with improved solubility and stability, has recently been used as an alternative.To compare the safety and efficacy of Evomela with standard-formulation melphalan (SFM) in the treatment of retinoblastoma by selective ophthalmic artery infusion. METHODS: We performed a retrospective case-control study of patients with retinoblastoma undergoing selective ophthalmic artery infusion with SFM or Evomela at a single institution. Cycle-specific percent tumor regression (CSPTR) was estimated by comparing photos obtained during pretreatment examination under anesthesia (EUA) with those obtained during post-treatment EUA 3-4 weeks later. CSPTR, ocular salvage rates, complication rates, operation times (unadjusted and adjusted for difficulty of ophthalmic artery catheterization), and intraprocedural dose expiration rates were compared between Evomela- and SFM-treated groups. Univariate and multivariate analyses were performed. RESULTS: Ninety-seven operations (melphalan: 45; Evomela: 52) for 23 patients with 27 retinoblastomas were studied. The ocular salvage rate was 79% in the SFM-treated group and 69% in the Evomela-treated group. Multivariate regression controlling for tumor grade, patient age, and treatment history revealed no significant differences in ocular salvage rate, CSPTR, complication rates, or operation times. Although the dose expiration rate was higher for the SFM-treated group, the difference was not statistically significant. Notably, there were no ocular or cerebral ischemic complications. CONCLUSION: Evomela has non-inferior safety and efficacy relative to SFM when used for the treatment of retinoblastoma by selective ophthalmic artery infusion.

A metagenomic analysis of the virome of inverted papilloma and squamous cell carcinoma.

INTRODUCTION: Inverted papilloma (IP) is a sinonasal tumor with a well-known potential for malignant transformation. The role of human papillomavirus (HPV) in its pathogenesis has been controversial. The purpose of this study was to determine the virome associated with IP, with progression to carcinoma in situ (CIS), and invasive carcinoma. METHODS: To determine the HPV-specific types, a metagenomics assay that contains 62,886 probes targeting viral genomes in a microarray format was used. The platform screens DNA and RNA from fixed tissues from eight controls, 16 IP without dysplasia, five IP with CIS, and 13 IP-associated squamous cell carcinoma (IPSCC). Paired with next-generation sequencing, 48 types of HPV with 857 region-specific probes were interrogated against the tumors. RESULTS: The prevalence of HPV-16 was 14%, 42%, 70%, and 73% in control tissue, IP without dysplasia, IP with CIS, and IPSCC, respectively. The prevalence of HPV-18 had a similar progressive increase in prevalence, with 14%, 27%, 67%, and 74%, respectively. The assay allowed region-specific analysis, which identified the only oncogenic HPV-18 E6 to be statistically significant when compared with control tissue. The prevalence of HPV-18 E6 was 0% in control tissue, 25% in IP without dysplasia, 60% in IP with CIS, and 77% in IPSCC. CONCLUSIONS: There are over 200 HPV types that infect human epithelial cells, of which only a few are known to be high-risk. Our study demonstrated a trend of increasing prevalence of HPV-18 E6 that correlated with histologic severity, which is novel and supports a potential role for HPV in the pathogenesis of IP.

Computational pathology improves risk stratification of a multi-gene assay for early stage ER+ breast cancer.

Prognostic markers currently utilized in clinical practice for estrogen receptor-positive (ER+) and lymph node-negative (LN-) invasive breast cancer (IBC) patients include the Nottingham grading system and Oncotype Dx (ODx). However, these biomarkers are not always optimal and remain subject to inter-/intra-observer variability and high cost. In this study, we evaluated the association between computationally derived image features from H&E images and disease-free survival (DFS) in ER+ and LN- IBC. H&E images from a total of n = 321 patients with ER+ and LN- IBC from three cohorts were employed for this study (Training set: D1 (n = 116), Validation sets: D2 (n = 121) and D3 (n = 84)). A total of 343 features relating to nuclear morphology, mitotic activity, and tubule formation were computationally extracted from each slide image. A Cox regression model (IbRiS) was trained to identify significant predictors of DFS and predict a high/low-risk category using D1 and was validated on independent testing sets D2 and D3 as well as within each ODx risk category. IbRiS was significantly prognostic of DFS with a hazard ratio (HR) of 2.33 (95% confidence interval (95% CI) = 1.02-5.32, p = 0.045) on D2 and a HR of 2.94 (95% CI = 1.18-7.35, p = 0.0208) on D3. In addition, IbRiS yielded significant risk stratification within high ODx risk categories (D1 + D2: HR = 10.35, 95% CI = 1.20-89.18, p = 0.0106; D1: p = 0.0238; D2: p = 0.0389), potentially providing more granular risk stratification than offered by ODx alone.

Angiographic analysis of ophthalmic artery flow direction in children undergoing chemosurgery for retinoblastoma compared to age-matched controls.

PURPOSE: Catheter-based intra-arterial chemotherapy (IAC) has revolutionized the treatment of retinoblastoma (RB). Variability in ophthalmic artery (OA) flow, either retrograde from external carotid artery branches, or anterograde from the internal carotid artery, necessitates multiple IAC techniques. We evaluated the direction of OA flow and identify OA flow reversal events over the course of IAC treatment as well in comparison to OA flow direction in non-RB children. MATERIALS AND METHODS: We performed a retrospective analysis of OA flow direction in all RB patients treated with IAC, along with an age-matched control group who underwent cerebral angiography at our center from 2014 to 2020. RESULTS: IAC was administered to a total of 18 eyes (15 patients). Initial anterograde OA flow was demonstrated in 66% (n = 12) of eyes. Five OA reversal events were identified (3/5 anterograde-to-retrograde). All five events were in patients receiving multiagent chemotherapy. No correlation was found between OA flow reversal events and the initial IAC technique. A control group of 88 angiograms representing 82 eyes (41 patients) was utilized. The anterograde flow was observed in 76 eyes (86.4%). Our control group included 19 patients with sequential angiograms. One OA flow reversal event was identified. CONCLUSION: OA flow direction is dynamic in IAC patients. Anterograde and retrograde OA directional switches do occur and may necessitate delivery technique variation. In our analysis, all OA flow reversal events were associated with multiagent chemotherapy regimens. Both anterograde and retrograde OA flow patterns were observed in our control cohort, suggesting bidirectional flow can occur in non-RB children.

The cost of a plastic surgery team assisting with cranioplasty.

OBJECTIVES: Cranioplasty is a commonly performed neurosurgical procedure that restores cranial anatomy. While plastic surgeons are commonly involved with cranioplasties, the cost of performing a cranioplasty with neurosurgery alone (N) vs. neurosurgery and plastic surgery (N + P) is unknown. METHODS: A single-center, multi-surgeon, retrospective cohort study was undertaken on all cranioplasties performed from 2012 to 22. The primary exposure variable of interest was operating team, comparing N vs. N + P. Cost data was inflation-adjusted to January 2022 using Healthcare Producer Price Index as calculated by the US Bureau of Labor Statistics. RESULTS: 186 patients (105 N vs. 81 N + P) underwent cranioplasties. The N + P group has a significantly longer length-of-stay (LOS) 4.5 ± 1.6days, vs. 6.0 ± 1.3days (p < 0.001), but no significant difference in reoperation, readmission, sepsis, or wound breakdown. N was significantly less expensive than N + P during both the initial cranioplasty cost ($36,739 ± $4592 vs. $41,129 ± $4374, p 0.014) and total cranioplasty costs including reoperations ($38,849 ± $5017 vs. $53,134 ± $6912, p < 0.001). Univariable analysis (threshold p = 0.20) was performed to justify inclusion into a multivariable regression model. Multivariable analysis for initial cranioplasty cost showed that sepsis (p = 0.024) and LOS (p = 0.003) were the dominant cost contributors compared to surgeon type (p = 0.200). However, surgeon type (N vs. N + P) was the only significant factor (p = 0.011) for total cost including revisions. CONCLUSIONS: Higher costs to N + P involvement without obvious change in outcomes were found in patients undergoing cranioplasty. Although other factors are more significant for the initial cranioplasty cost (sepsis, LOS), surgeon type proved the independent dominant factor for total cranioplasty costs, including revisions.