Polymerase theta is a synthetic lethal target for killing Epstein-Barr virus lymphomas.

Treatment options for Epstein-Barr virus (EBV)-cancers are limited, underscoring the need for new therapeutic approaches. We have previously shown that EBV-transformed cells and cancers lack homologous recombination (HR) repair, a prominent error-free pathway that repairs double-stranded DNA breaks; instead, EBV-transformed cells demonstrate genome-wide scars of the error-prone microhomology-mediated end joining (MMEJ) repair pathway. This suggests that EBV-cancers are vulnerable to synthetic lethal therapeutic approaches that target MMEJ repair. Indeed, we have previously found that targeting PARP, an enzyme that contributes to MMEJ, results in the death of EBV-lymphoma cells. With the emergence of clinical resistance to PARP inhibitors and the recent discovery of inhibitors of Polymerase theta (POLθ), the polymerase essential for MMEJ, we investigated the role of POLθ in EBV-lymphoma cells. We report that EBV-transformed cell lines, EBV-lymphoma cell lines, and EBV-lymphomas in AIDS patients demonstrate greater abundance of POLθ, driven by the EBV protein EBNA1, compared to EBV-uninfected primary lymphocytes and EBV-negative lymphomas from AIDS patients (a group that also abundantly expresses POLθ). We also find POLθ enriched at cellular DNA replication forks and exposure to the POLθ inhibitor Novobiocin impedes replication fork progress, impairs MMEJ-mediated repair of DNA double-stranded breaks, and kills EBV-lymphoma cells. Notably, cell killing is not due to Novobiocin-induced activation of the lytic/replicative phase of EBV. These findings support a role for POLθ not just in DNA repair but also DNA replication and as a therapeutic target in EBV-lymphomas and potentially other EBV-cancers as EBNA1 is expressed in all EBV-cancers.IMPORTANCEEpstein-Barr virus (EBV) contributes to ~2% of the global cancer burden. With a recent estimate of >200,000 deaths a year, identifying molecular vulnerabilities will be key to the management of these frequently aggressive and treatment-resistant cancers. Building on our earlier work demonstrating reliance of EBV-cancers on microhomology-mediated end-joining repair, we now report that EBV lymphomas and transformed B cell lines abundantly express the MMEJ enzyme POLθ that likely protects cellular replication forks and repairs replication-related cellular DNA breaks. Importantly also, we show that a newly identified POLθ inhibitor kills EBV-cancer cells, revealing a novel strategy to block DNA replication and repair of these aggressive cancers.

Associations of Long-term Sleep Duration Trajectories with Overall and Cause-Specific Mortality Among Middle-to-older Aged Black and White Adults.

Background: Both short and long sleep durations are adversely associated with numerous chronic conditions, including cardiovascular disease (CVD), diabetes, hypertension, and mortality. The American Academy of Sleep Medicine recommends adults in the United States sleep at least 7 hours and less than 9 hours per night to maintain optimal health. It remains unclear how sleep duration trajectories over time are associated with mortality. Methods: This observational cohort study includes 46,928 Black and White adults (mean age: 53 ± 9 years) who enrolled in the Southern Community Cohort Study between 2002-2009 and completed a follow-up survey in 2008-2013. Participants were categorized into nine sleep duration trajectory categories based on the reported average sleep duration between study enrollment and at follow-up. Participant vital status and date and cause of death were ascertained via linkage to the National Death Index through 2022. Cox regression analysis was performed to estimate hazard ratios (HR) and 95% confidence intervals (CI) for the association between sleep duration trajectory and all-cause and cause-specific mortality (CVD, cancer, and neurodegenerative disease) after adjustment for sociodemographic characteristics, health behaviors, and clinical factors. Results: During a median 12.6 years of follow-up, we documented 13,579 deaths, including 4,135 from CVD, 3,067 from cancer, and 544 from neurodegenerative diseases. Compared to the optimal sleep duration trajectory (maintaining 7-9 hours), all sub-optimal trajectories were associated with significant 6 to 33% greater risk of all-cause mortality in fully adjusted models. Compared to the optimal sleep trajectory, three of the sub-optimal trajectories were associated with increased CVD mortality, with HRs ranging from 1.20 to 1.34. The short-long trajectory was associated with the greatest risk of all-cause mortality (HR:1.33; 95%CI: 1.21, 1.46) and the long-short trajectory was associated with the greatest CVD mortality risk (HR:1.34; 95%CI: 1.10, 1.65). The healthy-long trajectory was associated with the greatest risk of cancer mortality (HR: 1.19; 95%CI:1.00, 1.41). None of the sub-optimal trajectories was associated with neurodegenerative disease mortality. Conclusions: Suboptimal sleep duration trajectories were associated with increased risk of all-cause mortality as well as CVD mortality. Findings highlight the importance of maintaining healthy sleep duration throughout midlife to reduce mortality risk.

Simultaneous screening of overexpressed genes in breast cancer for oncogenic drivers and tumor dependencies.

There are hundreds of genes typically overexpressed in breast cancer cells and it's often assumed that their overexpression contributes to cancer progression. However, the precise proportion of these overexpressed genes contributing to tumorigenicity remains unclear. To address this gap, we undertook a comprehensive screening of a diverse set of seventy-two genes overexpressed in breast cancer. This systematic screening evaluated their potential for inducing malignant transformation and, concurrently, assessed their impact on breast cancer cell proliferation and viability. Select genes including ALDH3B1, CEACAM5, IL8, PYGO2, and WWTR1, exhibited pronounced activity in promoting tumor formation and establishing gene dependencies critical for tumorigenicity. Subsequent investigations revealed that CEACAM5 overexpression triggered the activation of signaling pathways involving ß-catenin, Cdk4, and mTOR. Additionally, it conferred a growth advantage independent of exogenous insulin in defined medium and facilitated spheroid expansion by inducing multiple layers of epithelial cells while preserving a hollow lumen. Furthermore, the silencing of CEACAM5 expression synergized with tamoxifen-induced growth inhibition in breast cancer cells. These findings underscore the potential of screening overexpressed genes for both oncogenic drivers and tumor dependencies to expand the repertoire of therapeutic targets for breast cancer treatment.

Nonoperative Versus Operative Treatment of Z-Type Comminuted Clavicle Fractures in Adolescents: A Prospective Substratified Cohort Analysis.

OBJECTIVES: To compare the clinical, radiographic, and patient-reported outcomes of nonoperative and operative treatment of adolescents with comminuted "Z-type" midshaft clavicle fractures. DESIGN: Prospective observational cohort. SETTING: Eight tertiary care pediatric centers. PATIENT SELECTION CRITERIA: Patients aged 10-18 years who were treated either operatively or nonoperatively for a diaphyseal clavicle fracture between 2013 and 2017 were screened/enrolled at the time of injury. The current subcohort analysis was derived from a larger adolescent clavicle study population of 907 patients. OUTCOME MEASUREMENTS AND COMPARISONS: Complications and validated patient-reported outcome measures (PROs):(ASES, QuickDASH, Marx Shoulder Activity Score, EQ-5D, EQ-VAS, and patient satisfaction score) were compared between operative and nonoperative cohorts. RESULTS: Eighty-one patients (69 male [85.2%], 12 female; average age 15 years [11.1-18.7]; 78 with sports participation [96.2%]) were followed through bony healing and return to sports, while 59 patients (73%) completed 2-year follow-up with PROs, 26 of whom were treated nonoperatively and 33 treated operatively. All demographic and fracture characteristics were similar (P > 0.05) between the 2-year follow-up cohorts except for fracture shortening, which was greater in the operative cohort (23 vs. 29 mm, P = 0.01). After controlling for this potential confounder through both regression and propensity matched subgroup analysis, nonoperative versus operative cohorts showed no difference in rates of nonunion (0%), delayed union (0% vs. 2.3%, P = 1.0), symptomatic malunion (2.7% vs. 0%, P = 0.4), refracture (2.7% vs. 2.2%, P = 1.0), unexpected subsequent surgery (5.4% vs. 11.4%, P = 0.45), or clinically significant complications (5.4% vs. 16%, P = 0.17). There were no differences in any PROs between cohorts, both before and after controlling for the difference in fracture shortening (all P-values >0.05). CONCLUSIONS: In this prospective comparison of complications and 2-year PROs in adolescents with comminuted Z-type clavicle fractures, nonoperative and operative treatment yielded similar outcomes. LEVEL OF EVIDENCE: Therapeutic Level II. See Instructions for Authors for a complete description of levels of evidence.

Surgical treatment of cystic pituitary adenomas: literature-based definitions and postoperative outcomes.

BACKGROUND AND OBJECTIVES: To survey the applied definitions of 'cystic' among pituitary adenomas and evaluate whether postoperative outcomes differ relative to non-cystic counterparts. METHODS: A literature search and meta-analysis was performed using PRISMA guidelines. Studies were eligible if novel data were reported regarding the applied definition of 'cystic' and postoperative outcomes among cases of surgically treated pituitary adenomas. Data were pooled with random effects meta-analysis models into cohorts based on the applied definition of 'cystic'. Categorical meta-regressions were used to investigate differences between cohorts. Among studies comparing cystic and non-cystic pituitary adenomas, meta-analysis models were applied to determine the Odds Ratio [95% Confidence Interval]. Statistical analyses were performed using Comprehensive Meta-Analysis (CMA, 4.0), with a priori significance defined as P < 0.05. RESULTS: Ten studies were eligible yielding 283 patients with cystic pituitary adenomas. The definitions of 'cystic' mainly varied between the visual appearance of cystic components on preoperative magnetic resonance imaging and a volumetric definition requiring 50% or greater of tumor volume exhibiting cystic components. Tumor diameter was seldom reported with an associated standard deviation/error, limiting meta-analyses. When the data were pooled in accordance with the definition applied, there were no significant differences in the rates of gross total resection (P = 0.830), endocrinologic remission (P = 0.563), and tumor recurrence (P = 0.320). Meta-analyses on studies comparing cystic versus non-cystic pituitary adenomas indicated no significant difference in the rates of gross total resection (P = 0.729), endocrinologic remission (P = 0.857), and tumor recurrence (P = 0.465). CONCLUSION: Despite some individual studies describing a significant influence of pituitary adenoma texture on postoperative outcomes, meta-analyses revealed no such differences between cystic and non-cystic pituitary adenomas. This discrepancy may be explained in part by the inconsistent definition of 'cystic' and between-group differences in tumor size. A notion of a field-standard definition of 'cystic' among pituitary adenomas should be established to facilitate inter-study comparisons.

A preliminary examination of the effects of childhood abuse and resilience on pain and physical functioning in patients with knee osteoarthritis.

OBJECTIVES: We examined associations of a self-reported history of childhood abuse with pain and physical functioning in patients with knee osteoarthritis (KOA) awaiting total knee arthroplasty (TKA). We also explored the potential moderating effects of positive childhood experiences (PCEs), an index of resilience, on these associations. METHODS: Prior to TKA, participants with KOA awaiting surgery (N = 239) completed self-report measures of adverse childhood experiences (ACEs), PCEs, pain, and physical functioning. We evaluated associations of pain and physical functioning (Brief Pain Inventory [BPI] and Western Ontario and McMaster University of Osteoarthritis Index [WOMAC]) based on the experience of ACEs (childhood abuse), with PCEs (childhood happiness and supportive parental care) as potential moderators. RESULTS: Greater exposure to childhood abuse was positively correlated with BPI pain interference as well as WOMAC pain and functioning scores. Additionally, childhood happiness and supportive parental care moderated the positive associations of childhood abuse with pain and physical functioning; though, surprisingly, the adverse effects of childhood abuse on these outcomes were more pronounced among participants with high levels of childhood happiness and supportive parental care. CONCLUSION: Overall, results show an association between a self-reported history of childhood abuse and pain and functioning in patients with KOA awaiting TKA. However, PCEs did not protect against the negative consequences of childhood abuse in our cohort. Further research is needed to validate these associations and gain a more comprehensive understanding of the complex interplay between childhood abuse and PCEs and their potential influences on pain experiences in adults with chronic pain conditions, including KOA.

Nickel-Catalyzed Electrochemical Cross-Electrophile C(sp2)-C(sp3) Coupling via a NiII Aryl Amido Intermediate.

Cross-electrophile coupling (XEC) between aryl halides and alkyl halides is a streamlined approach for C(sp2)-C(sp3) bond construction, which is highly valuable in medicinal chemistry. Based on a key NiII aryl amido intermediate, we developed a highly selective and scalable Ni-catalyzed electrochemical XEC reaction between (hetero)aryl halides and primary and secondary alkyl halides. Experimental and computational mechanistic studies indicate that an amine secondary ligand slows down the oxidative addition process of the Ni-polypyridine catalyst to the aryl bromide and a NiII aryl amido intermediate is formed in-situ during the reaction process. The relatively slow oxidative addition is beneficial for enhancing the selectivity of the XEC reaction. The NiII aryl amido intermediate stabilizes the NiII-aryl species to prevent the aryl-aryl homo-coupling side reactions and acts as a catalyst to activate the alkyl bromide substrates. This electrosynthesis system provides a facile, practical, and scalable platform for the formation of (hetero)aryl-alkyl bonds using standard Ni catalysts under mild conditions. The mechanistic insights from this work could serve as a great foundation for future studies on Ni-catalyzed cross-couplings.

BCLA CLEAR Presbyopia: Management with corneal techniques.

Corneal techniques for enhancing near and intermediate vision to correct presbyopia include surgical and contact lens treatment modalities. Broad approaches used independently or in combination include correcting one eye for distant and the other for near or intermediate vision, (termed monovision or mini-monovision depending on the degree of anisometropia) and/or extending the eye's depth of focus [1]. This report provides an overview of the evidence for the treatment profile, safety, and efficacy of the range of corneal techniques currently available for managing presbyopia. The visual needs and expectations of the patient, their ocular characteristics, and prior history of surgery are critical considerations for patient selection and preoperative evaluation. Contraindications to refractive surgery include unstable refraction, corneal abnormalities, inadequate corneal thickness for the proposed ablation depth, ocular and systemic co-morbidities, uncontrolled mental health issues and unrealistic patient expectations. Laser refractive options for monovision include surface/stromal ablation techniques and keratorefractive lenticule extraction. Alteration of spherical aberration and multifocal ablation profiles are the primary means for increasing ocular depth of focus, using surface and non-surface laser refractive techniques. Corneal inlays use either small aperture optics to increase depth of field or modify the anterior corneal curvature to induce corneal multifocality. Presbyopia correction by conductive keratoplasty involves application of radiofrequency energy to the mid-peripheral corneal stroma which leads to mid-peripheral corneal shrinkage, inducing central corneal steepening. Hyperopic orthokeratology lens fitting can induce spherical aberration and correct some level of presbyopia. Postoperative management, and consideration of potential complications, varies according to technique applied and the time to restore corneal stability, but a minimum of 3 months of follow-up is recommended after corneal refractive procedures. Ongoing follow-up is important in orthokeratology and longer-term follow-up may be required in the event of late complications following corneal inlay surgery.

Ferroptosis Inhibition with Deferoxamine Alleviates Radiation-Induced Fibrosis.

Background: Radiation-induced fibrosis (RIF) is a debilitating sequelae of radiation therapy that has been shown to improve with topical treatment with the iron chelator deferoxamine (DFO). We investigated whether DFO exerts this effect through attenuation of ferroptosis, a recently described iron-dependent pathway of cell death. Methods: Adult C57BL/6J mice were treated with topical DFO or ferrostastin-1 (Fer-1) and irradiated with 30 Grays of ionizing radiation to the dorsal skin to promote development of chronic RIF. Immunofluorescent staining with 4-hydroxynonenal (4-HNE) antibody was carried out directly following irradiation to assess ferroptosis activity. Perfusion testing with laser Doppler was performed throughout the healing interval. Eight weeks following radiation, dorsal skin was harvested and analyzed histologically and biomechanically. Results: Immunohistochemical staining demonstrated lower presence of 4-HNE in non-irradiated skin, DFO-treated skin, and Fer-1-treated skin compared to irradiated, untreated skin. DFO resulted in histological measurements (dermal thickness and collagen content) that resembled normal skin, while Fer-1 treatment yielded less significant improvements. These results were mirrored by analysis of extracellular matrix ultrastructure and biomechanical testing, which recapitulated the ability of topical DFO treatment to alleviate RIF across these parameters while Fer-1 resulted in less notable improvement. Finally, perfusion levels in DFO treated irradiated skin were similar to measurements in normal skin, while Fer-1 treatment did not impact this feature. Conclusions: Ferroptosis contributes to the development of RIF and attenuation of this process leads to reduced skin injury. DFO further improves RIF through additional enhancement of perfusion not seen with Fer-1.

Multisite Study of the Management of Musculoskeletal Infection After Trauma: The MMUSKIT Study.

Background: The optimal duration and choice of antibiotic for fracture-related infection (FRI) is not well defined. This study aimed to determine whether antibiotic duration (≤6 vs >6 weeks) is associated with infection- and surgery-free survival. The secondary aim was to ascertain risk factors associated with surgery- and infection-free survival. Methods: We performed a multicenter retrospective study of patients diagnosed with FRI between 2013 and 2022. The association between antibiotic duration and surgery- and infection-free survival was assessed by Cox proportional hazard models. Models were weighted by the inverse of the propensity score, calculated with a priori variables of hardware removal; infection due to Staphylococcus aureus, Staphylococcus lugdunensis, Pseudomonas or Candida species; and flap coverage. Multivariable Cox proportional hazard models were run with additional covariates including initial pathogen, need for flap, and hardware removal. Results: Of 96 patients, 54 (56.3%) received ≤6 weeks of antibiotics and 42 (43.7%) received >6 weeks. There was no association between longer antibiotic duration and surgery-free survival (hazard ratio [HR], 0.95; 95% CI, .65-1.38; P = .78) or infection-free survival (HR, 0.77; 95% CI, .30-1.96; P = .58). Negative culture was associated with increased hazard of reoperation or death (HR, 3.52; 95% CI, 1.99-6.20; P < .001) and reinfection or death (HR, 3.71; 95% CI, 1.24-11.09; P < .001). Need for flap coverage had an increased hazard of reoperation or death (HR, 3.24; 95% CI, 1.61-6.54; P = .001). Conclusions: The ideal duration of antibiotics to treat FRI is unclear. In this multicenter study, there was no association between antibiotic treatment duration and surgery- or infection-free survival.

Preoperative decreased physical activity is associated with greater postoperative pain: the mediating role of preoperative sleep disturbance.

PURPOSE: Engagement in physical activity (PA) is often associated with better sleep quality and less pain severity among patients diagnosed with breast cancer. However, less research has focused on whether patients' PA prior to breast surgery, including their perceived decrease in PA level, is associated with worse preoperative sleep quality, and subsequently, greater postoperative pain. This longitudinal study investigated whether patients' preoperative PA was associated with their postoperative pain. We also explored whether preoperative sleep disturbance partially mediated the relationship between preoperative PA and postoperative pain. METHODS: Prior to breast surgery, patients self-reported both their overall level of PA and whether they perceived a decrease in their PA since the diagnosis/onset of treatment for cancer. Patients also completed a measure of preoperative sleep disturbance. Two weeks after surgery, patients completed a measure of postoperative surgical-area pain severity. RESULTS: Our results showed that preoperatively perceiving a decrease in PA level was significantly associated with greater preoperative sleep disturbance and postoperative pain. A mediation analysis revealed that the association between preoperative decreased PA and postoperative pain was partially mediated by preoperative sleep disturbance. Notably, patients' overall preoperative level of PA was not related to preoperative sleep disturbance or postoperative pain. CONCLUSION: These findings suggest that maintaining, or even increasing, PA after diagnosis/treatment may be more important than the absolute amount of PA that women engage in during the preoperative period. Potentially, some patients with breast cancer may benefit from a preoperative intervention focused on both maintaining PA and bolstering sleep quality.

Hematoxylin and Eosin Architecture Uncovers Clinically Divergent Niches in Pancreatic Cancer.

Pancreatic ductal adenocarcinoma (PDAC) represents one of the only cancers with an increasing incidence rate and is often associated with intra- and peri-tumoral scarring, referred to as desmoplasia. This scarring is highly heterogeneous in extracellular matrix (ECM) architecture and plays complex roles in both tumor biology and clinical outcomes that are not yet fully understood. Using hematoxylin and eosin (H&E), a routine histological stain utilized in existing clinical workflows, we quantified ECM architecture in 85 patient samples to assess relationships between desmoplastic architecture and clinical outcomes such as survival time and disease recurrence. By utilizing unsupervised machine learning (ML) to summarize a latent space across 147 local (e.g. fiber length, solidity) and global (e.g. fiber branching, porosity) H&E-based features, we identified a continuum of histological architectures that were associated with differences in both survival and recurrence. Further, we mapped H&E architectures to a CO-Detection by indEXing (CODEX) reference atlas, revealing localized cell- and protein-based niches associated with outcome-positive vs. outcome-negative scarring in the tumor microenvironment. Overall, our study utilizes standard H&E staining to uncover clinically relevant associations between desmoplastic organization and PDAC outcomes, offering a translatable pipeline to support prognostic decision-making and a blueprint of spatial-biological factors for modeling by tissue engineering methods.

Dysfunction of infiltrating cytotoxic CD8+ T cells within the graft promotes murine kidney allotransplant tolerance.

Tolerance of mouse kidney allografts arises in grafts that develop regulatory Tertiary Lymphoid Organs (rTLOs). scRNAseq data and adoptive transfer of alloreactive T cells post-transplant showed that cytotoxic CD8+ T cells are reprogrammed within the accepted graft to an exhausted/regulatory-like phenotype mediated by IFN-γ. Establishment of rTLOs was required since adoptive transfer of alloreactive T cells prior to transplantation results in kidney allograft rejection. Despite intragraft CD8+ cells with a regulatory phenotype, they were not essential for the induction and maintenance of kidney allograft tolerance since renal allotransplantation into CD8 KO recipients resulted in acceptance and not rejection. Analysis of scRNAseq data from allograft kidneys and malignant tumors identified similar regulatory-like cell types within the T cell clusters and trajectory analysis showed that cytotoxic CD8+ T cells are reprogrammed into an exhausted/regulatory-like phenotype intratumorally. Induction of cytotoxic CD8+ T cell dysfunction of infiltrating cells appears to be a beneficial mechanistic pathway that protects the kidney allotransplant from rejection through a process we call "defensive tolerance." This pathway has implications for our understanding of allotransplant tolerance and tumor resistance to host immunity.

Superficial Neurocristic EWSR1::FLI1 Fusion Tumor: A Distinctive, Clinically Indolent, S100 Protein/SOX10-Positive Neoplasm.

It is now understood that identical gene fusions may be shared by different entities. We report a distinctive neoplasm of the skin and subcutis, harboring the Ewing sarcoma-associated EWSR1::FLI1 fusion, but differing otherwise from Ewing sarcoma. Slides and blocks for 5 cutaneous neoplasms coded as other than Ewing sarcoma and harboring EWSR1::FLI1 were retrieved. Immunohistochemical and molecular genetic results were abstracted from reports. Methylation profiling was performed. Clinical information was obtained. The tumors occurred in 4 males and 1 female (median 25 years of age; range 19-69 years) and involved the skin/subcutis of the back (2), thigh, buttock, and chest wall (median 2.4 cm; range 1-11cm). Two tumors were present "years" before coming to clinical attention. The lesions were multinodular, circumscribed. and consisted of nests of bland, round cells admixed with hyalinized collagenous bands containing spindled cells. Hemorrhage and cystic change were often present; necrosis was absent. All were diffusely S100 protein/SOX10-positive; 4 of 5 were CD99-negative. One tested case was strongly positive for NKX2.2. A variety of other tested markers were either focally positive (GFAP, p63) or negative. Molecular genetic results were: EWSR1 exon 7::FLI1 exon 8, EWSR1 exon 11::FLI1 exon 5, EWSR1 exon 11::FLI1 exon 6, EWSR1 exon 7:: FLI1 exon 6, and EWSR1 exon 10::FLI1 exon 6. Methylation profiling (3 cases) showed these to form a unique cluster, distinct from Ewing sarcoma. All patients underwent excision with negative margins; one received 1 cycle of chemotherapy. Clinical follow-up showed all patients to be alive without disease (median 17 months; range 11-62 months). Despite similar gene fusions, the morphologic, immunohistochemical, epigenetic, and clinical features of these unique EWSR1::FLI1-fused neoplasms of the skin and subcutis differ substantially from Ewing sarcoma. Interestingly, EWSR1 rearrangements involved exons 10 or 11, only rarely seen in Ewing sarcoma, in a majority of cases. Superficial neurocristic EWSR1::FLI1 fusion tumors should be rigorously distinguished from true cutaneous Ewing sarcomas.

Cost-of-care discussions for individuals with advanced non-small cell lung cancer and melanoma: Findings from a large, population-based pilot study.

BACKGROUND: Costs of cancer care can result in patient financial hardship; many professional organizations recommend provider discussions about treatment costs as part of high-quality care. In this pilot study, the authors examined patient-provider cost discussions documented in the medical records of individuals who were diagnosed with advanced non-small cell lung cancer (NSCLC) and melanoma-cancers with recently approved, high-cost treatment options. METHODS: Individuals who were newly diagnosed in 2017-2018 with stage III/IV NSCLC (n = 1767) and in 2018 with stage III/IV melanoma (n = 689) from 12 Surveillance, Epidemiology, and End Results regions were randomly selected for the National Cancer Institute Patterns of Care Study. Documentation of cost discussions was abstracted from the medical record. The authors examined patient, treatment, and hospital factors associated with cost discussions in multivariable logistic regression analyses. RESULTS: Cost discussions were documented in the medical records of 20.3% of patients with NSCLC and in 24.0% of those with melanoma. In adjusted analyses, privately insured (vs. publicly insured) patients were less likely to have documented cost discussions (odds ratio [OR], 0.54; 95% confidence interval [CI], 0.37-0.80). Patients who did not receive systemic therapy or did not receive any cancer-directed treatment were less likely to have documented cost discussions than those who did receive systemic therapy (OR, 0.39 [95% CI, 0.19-0.81] and 0.46 [95% CI, 0.30-0.70], respectively), as were patients who were treated at hospitals without residency programs (OR, 0.64; 95% CI, 0.42-0.98). CONCLUSIONS: Cost discussions were infrequently documented in the medical records of patients who were diagnosed with advanced NSCLC and melanoma, which may hinder identifying patient needs and tracking outcomes of associated referrals. Efforts to increase cost-of-care discussions and relevant referrals, as well as their documentation, are warranted.

Arteriovenous malformations in the cerebellopontine angle: assessment of the "backdoor resection" technique and microsurgical results in 38 patients.

OBJECTIVE: Posterior fossa arteriovenous malformations (AVMs) represent 7% to 15% of all intracranial AVMs and are associated with an increased risk of hemorrhage, morbidity, and mortality compared with supratentorial AVMs, thus prompting urgent and definitive treatment. Cerebellopontine angle (CPA) AVMs are a unique group of posterior fossa AVMs incorporating characteristics of brainstem and cerebellar lesions, which are particularly amenable to microsurgical resection. This study reports the clinical, radiological, operative, and outcome features of patients with CPA AVMs in a large cohort. METHODS: The authors conducted a single-surgeon, 2-institution retrospective cohort study of all consecutive patients with CPA AVMs treated with microsurgical resection during a 25-year period. RESULTS: CPA AVMs represented 22% (38 of 176) of all infratentorial AVMs resected by the senior author. Overall, 38 patients (22 [58%] male and 16 [42%] female) met the study inclusion criteria and were analyzed. Most patients presented with hemorrhage (n = 29, 76%). The median age at surgery was 56 (range 6-82) years. Subtypes included 22 (58%) petrosal cerebellar AVMs, 11 (29%) lateral pontine AVMs, and 5 (13%) AVMs involving both the brainstem and cerebellum. Most AVM niduses were small (< 3 cm; n = 35, 92%) and compact (n = 31, 82%). Fourteen (37%) patients harbored flow-related aneurysms. Twenty (53%) patients underwent preoperative embolization. Complete angiographic obliteration was achieved with microsurgery in 35 (92%) patients. Five (13%) patients with poor neurological conditions at presentation died before hospital discharge. Of the 7 (18%) patients with new postoperative neurological deficits, 5 had transient deficits. The median (interquartile range) follow-up was 1.7 (0.5-3.2) years; 32 (84%) patients were alive at last follow-up, and 30 (79%) had achieved a favorable neurological outcome (modified Rankin Scale [mRS] score 0-2). The only independent predictor of unfavorable postoperative outcome (mRS score 3-6) was the preoperative mRS score (p = 0.002). CONCLUSIONS: CPA AVMs are unique posterior fossa lesions, including petrosal cerebellar and lateral pontine AVMs. The "backdoor resection" technique provides a safe and efficient strategy with high obliteration rates and a low risk of treatment-related morbidity. Microsurgical resection should be considered the frontline treatment for most CPA AVMs, except for those with a significant diffuse brainstem component.

Intrarenal pressure with hand-pump or pressurized-bag irrigation: randomized clinical trial at retrograde intrarenal surgery.

BACKGROUND: The aim was to ascertain the impact of irrigation technique on human intrarenal pressure during retrograde intrarenal surgery. METHODS: A parallel randomized trial recruited patients across three hospital sites. Patients undergoing retrograde intrarenal surgery for renal stone treatment with an 11/13-Fr ureteral access sheath were allocated randomly to 100 mmHg pressurized-bag (PB) or manual hand-pump (HP) irrigation. The primary outcome was mean procedural intrarenal pressure. Secondary outcomes included maximum intrarenal pressure, variance, visualization, HP force of usage, procedure duration, stone clearance, and clinical outcomes. Live intrarenal pressure monitoring was performed using a COMETTMII pressure guidewire, deployed cystoscopically to the renal pelvis. The operating team was blinded to the intrarenal pressure. RESULTS: Thirty-eight patients were randomized between July and November 2023 (trial closure). The final analysis included 34 patients (PB 16; HP 18). Compared with PB irrigation, HP irrigation resulted in significantly higher mean intrarenal pressure (mean(s.d.) 62.29(27.45) versus 38.16(16.84) mmHg; 95% c.i. for difference in means (MD) 7.97 to 40.29 mmHg; P = 0.005) and maximum intrarenal pressure (192.71(106.23) versus 68.04(24.16) mmHg; 95% c.i. for MD 70.76 to 178.59 mmHg; P < 0.001), along with greater variance in intrarenal pressure (log transformed) (6.23(1.59) versus 4.60(1.30); 95% c.i. for MD 0.62 to 2.66; P = 0.001). Surgeon satisfaction with procedural vision reported on a scale of 10 was higher with PB compared with HP irrigation (mean(s.d.) 8.75(0.58) versus 6.28(1.27); 95% c.i. for MD 1.79 to 3.16; P < 0.001). Subjective HP usage force did not correlate significantly with transmitted intrarenal pressure (Pearson R = -0.15, P = 0.57). One patient (HP arm) developed urosepsis. CONCLUSION: Manual HP irrigation resulted in higher and more fluctuant intrarenal pressure trace (with inferior visual clarity) than 100-mmHg PB irrigation. REGISTRATION NUMBER: osf.io/jmg2h (https://osf.io/).