Citations

Abstract Background Diet modulates inflammation and insulin response and may be an important modifiable factor in the primary prevention of hepatocellular carcinoma (HCC) and chronic liver disease (CLD). We developed the empirical dietary inflammatory pattern (EDIP) and empirical dietary index for hyperinsulinemia (EDIH) scores to assess the inflammatory and insulinemic potentials of diet. We prospectively examined the associations of EDIP and EDIH at baseline with the following HCC risk and CLD mortality. Design We followed 485 931 individuals in the National Institutes of Health–American Association of Retired Persons Diet and Health Study since 1995. Cox proportional hazards regression was used to calculate multivariable hazard ratios (HRs) and 95% confidence intervals (CIs). Results We confirmed 635 incident HCC cases and 993 CLD deaths. Participants in the highest compared with those in the lowest EDIP quartile had a 1.35 times higher risk of developing HCC (95% CI = 1.08 to 1.70, Ptrend = .0005) and a 1.70 times higher CLD mortality (95% CI = 1.41 to 2.04, Ptrend < .0001). For the same comparison, participants with the highest EDIH were at increased risk of HCC (HR = 1.53, 95% CI = 1.20 to 1.95, Ptrend = .0004) and CLD mortality (HR = 1.72, 95% CI = 1.42 to 2.01, Ptrend < .0001). Similar positive associations of scores with HCC risk and CLD mortality were observed for both women and men. Moreover, individuals in both the highest EDIP and EDIH tertiles had a 92% increased HCC risk (95% CI = 1.43 to 2.58) and 98% increased CLD mortality (95% CI = 1.27 to 3.08) compared with those in both lowest tertiles. Conclusions Our findings suggest that inflammation and hyperinsulinemia are potential mechanisms linking diet to HCC development and CLD mortality.

Abstract Background Surgery is the mainstay of treatment for meningioma, the most common primary intracranial tumor, but improvements in meningioma risk stratification are needed and current indications for postoperative radiotherapy are controversial. Recent studies have proposed prognostic meningioma classification systems using DNA methylation profiling, copy number variants, DNA sequencing, RNA sequencing, histology, or integrated models based on multiple combined features. Targeted gene expression profiling has generated robust biomarkers integrating multiple molecular features for other cancers, but is understudied for meningiomas. Methods Targeted gene expression profiling was performed on 173 meningiomas and an optimized gene expression biomarker (34 genes) and risk score (0 to 1) was developed to predict clinical outcomes. Clinical and analytical validation was performed on independent meningiomas from 12 institutions across 3 continents (N = 1856), including 103 meningiomas from a prospective clinical trial. Gene expression biomarker performance was compared to 9 other classification systems. Results The gene expression biomarker improved discrimination of postoperative meningioma outcomes compared to all other classification systems tested in the independent clinical validation cohort for local recurrence (5-year area under the curve [AUC] 0.81) and overall survival (5-year AUC 0.80). The increase in area under the curve compared to the current standard of care, World Health Organization 2021 grade, was 0.11 for local recurrence (95% confidence interval [CI] 0.07–0.17, P < 0.001). The gene expression biomarker identified meningiomas benefiting from postoperative radiotherapy (hazard ratio 0.54, 95% CI 0.37–0.78, P = 0.0001) and re-classified up to 52.0% meningiomas compared to conventional clinical criteria, suggesting postoperative management could be refined for 29.8% of patients. Conclusions A targeted gene expression biomarker improves discrimination of meningioma outcomes compared to recent classification systems and predicts postoperative radiotherapy responses.

Background: Adults with cardiovascular co-morbidities and risk factors are at greater risk of severe COVID-19. These same risk factors may also be associated with an attenuated antibody response to COVID-19 vaccines, although studies in diverse, U.S. population-based cohorts have been limited. Methods: The Collaborative Cohort of Cohorts for COVID-19 Research (C4R) conducted a serosurvey for SARS-CoV-2 antibodies via dried blood spot (DBS) in 14 U.S. cohorts. IgG antibodies to SARS-CoV-2 spike subunit 1 (S1) and nucleocapsid (N) were measured from DBS using a semi-quantitative microsphere immunoassay and reported as median fluorescence intensity (MFI). Multivariable adjusted linear models regressed log-transformed anti-S1 MFI on age, sex, race/ethnicity, education attainment, self-reported diabetes, hypertension, cardiovascular disease (CVD), chronic kidney disease, smoking history, body mass index (BMI), asthma, obstructive lung diseases, DBS batch, anti-N MFI, vaccine type, time between vaccine and DBS, and vaccine dose at time of DBS collection. Results are presented as the percent difference in anti-S1 MFI compared with a reference group. Results: There were 6614 vaccinated participants prior to booster regimens and DBS collection (April 2021-July 2022) with 50%, 48%, and 2% of the cohort who received BNT162b2, mRNA-1273, or other vaccines, respectively. The mean (SD) time between vaccination and DBS was 3.8 (1.8) months. Over 10% of the cohort had self-reported a history of diabetes, 55% had hypertension, and 74% had a BMI>25 kg/m 2 . Anti-S1 MFI decreased as the time between vaccine dose and DBS collection increased. Diabetes was associated with a 16.1% lower anti-S1 MFI (95%CI:-22.4,-9.5) whereas neither hypertension (-3.8%;95%CI:-9.3,2.1), nor cardiovascular disease history (-5.3%;95%CI:-16.3,7.4) were associated with anti-S1 MFI. Former and current smoking history were each associated with a lower anti-S1 MFI: (-6.6%;95%CI:-12.1,-0.8) and (-16.1%;95%CI:-24.7,-6.6), respectively. Participants with a BMI 25-29.9 kg/m 2 had a 7.6% higher anti-S1 MFI (95%CI:0.3,15.4) whereas those with a BMI of 30-35 kg/m 2 and >35 kg/m 2 had 6.2% (95%CI:-2.4,15.5) higher and 8.9% lower (95%CI:-17.6,0.7) MFI levels, respectively. Older age and male sex were each associated with a lower anti-S1 MFI and mRNA-1273 vaccine, Asian subgroup, higher anti-N titer, and prior COVID-19 infection were each associated with higher anti-S1 MFI. Chronic kidney disease, education attainment, and lung disease were not associated with anti-S1 MFI. Conclusions: Several traditional cardiovascular disease risk factors were associated with diminished humoral responses to the initial COVID-19 vaccine regimens in a diverse U.S. population-based cohort and may have implications on strategies to improve vaccine responses.

PURPOSE The long-term toxicities of chemotherapy and radiotherapy can represent a significant burden to testicular cancer survivors. Retroperitoneal lymph node dissection (RPLND) is an established treatment for testicular germ cell tumors with minimal late morbidity although little data exist on its efficacy in early metastatic seminoma. Surgery in early metastatic seminoma is a prospective phase II single-arm, multi-institutional trial of RPLND as first-line treatment for testicular seminoma with clinically low-volume retroperitoneal lymphadenopathy. PATIENTS AND METHODS Twelve sites in the United States and Canada prospectively enrolled adult patients with testicular seminoma and isolated retroperitoneal lymphadenopathy (1-3 cm). Open RPLND was performed by certified surgeons with a primary end point of 2-year recurrence-free survival (RFS). Complication rates, pathologic up/downstaging, recurrence patterns, adjuvant therapies, and treatment-free survival were assessed. RESULTS A total of 55 patients were enrolled, with a median (IQR) largest clinical lymph node size of 1.6 cm (1.3-1.9). RPLND pathology demonstrated a median (IQR) largest lymph node size of 2.3 cm (0.9-3.5); nine patients (16%) were pN0, 12 (22%) pN1, 31 (56%) pN2, and 3 (5%) pN3. One patient received adjuvant chemotherapy. With a median (IQR) follow-up of 33 months (12.0-61.6), 12 patients experienced recurrence, with a 2-year RFS of 81% and a recurrence rate of 22%. Of the patients who experienced recurrence, 10 were treated with chemotherapy and two underwent additional surgery. At last follow-up, all patients who experienced a recurrence were disease-free and the 2-year overall survival was 100%. Four patients (7%) experienced short-term complications, and four patients experienced long-term complications including incisional hernia (1) and anejaculation (3). CONCLUSION RPLND is a treatment option for testicular seminoma with clinically low-volume retroperitoneal lymphadenopathy and is associated with low long-term morbidity.

OBJECTIVE The rates of women and underrepresented racial and ethnic minority (UREM) students successfully matching into neurosurgical residency are extremely low and do not reflect the makeup of the general population. As of 2019, only 17.5% of neurosurgical residents in the United States were women, 4.95% were Black or African American, and 7.2% were Hispanic or Latinx. Earlier recruitment of UREM students will help to diversify the neurosurgical workforce. Therefore, the authors developed a virtual educational event for undergraduate students entitled "Future Leaders in Neurosurgery Symposium for Underrepresented Students’’ (FLNSUS). The primary objectives of the FLNSUS were to expose attendees to 1) neurosurgeons from diverse gender, racial, and ethnic backgrounds; 2) neurosurgical research; 3) opportunities for neurosurgical mentorship; and 4) information about life as a neurosurgeon. The authors hypothesized that the FLNSUS would increase student self-confidence, provide exposure to the specialty, and reduce perceived barriers to a neurosurgical career. METHODS To measure the change in participant perceptions of neurosurgery, pre- and postsymposium surveys were administered to attendees. Of the 269 participants who completed the presymposium survey, 250 participated in the virtual event and 124 completed the postsymposium survey. Paired pre- and postsurvey responses were used for analysis, yielding a response rate of 46%. To assess the impact of participant perceptions of neurosurgery as a field, pre- and postsurvey responses to questions were compared. The change in response was analyzed, and a nonparametric sign test was performed to check for significant differences. RESULTS According to the sign test, applicants showed increased familiarity with the field (p < 0.001), increased confidence in their abilities to become neurosurgeons (p = 0.014), and increased exposure to neurosurgeons from diverse gender, racial, and ethnic backgrounds (p < 0.001 for all categories). CONCLUSIONS These results reflect a significant improvement in student perceptions of neurosurgery and suggest that symposiums like the FLNSUS may promote further diversification of the field. The authors anticipate that events promoting diversity in neurosurgery will lead to a more equitable workforce that will ultimately translate to enhanced research productivity, cultural humility, and patient-centered care in neurosurgery.

Abstract Palliative care (PC) benefits patients undergoing hematopoietic stem cell transplantation (HSCT), but it remains underutilized. Although transplant physicians report concerns regarding how patients perceive PC, HSCT recipients’ perceptions about PC remain unaddressed. We conducted a multisite, cross-sectional survey of autologous and allogeneic HSCT recipients 3 to 12 months after transplant to assess their familiarity, knowledge, and perception of PC, as well as their unmet PC needs. We computed a composite score of patients’ perceptions of PC and used a generalized linear regression model to examine factors associated with these perceptions. We enrolled 69.6% (250/359) of potential participants (median age = 58.1; 63.1% autologous HSCT). Overall, 44.3.8% (109/249) reported limited knowledge about PC and 52% (127/245) endorsed familiarity with PC. Most patients felt hopeful (54%) and reassured (50%) when they heard the term PC; 83% saw referral as a sign their doctor cared about what was happening to them. In multivariate analyses, patients who were more knowledgeable about PC were more likely to have positive perceptions of PC (B = 7.54, standard error = 1.61, P &lt; .001). Patients’ demographics, HSCT features, quality of life, and symptom burden were not significantly associated with perceptions of PC. HSCT recipients have positive perceptions of PC, though many have limited knowledge about its role. Patients who were more knowledgeable about PC were more likely to have positive perceptions of PC. These data do not support transplant physicians’ negative concerns about how patients perceive PC and underscore the need to further educate patients and transplant physicians about PC.

AbstractBiofilms formed by antibiotic‐resistant bacteria in wound beds challenge the treatment of wound infections. In this work, the activity of a novel electrochemical bandage (e‐bandage) composed of carbon fabric and controlled by a wearable potentiostat, designed to continuously deliver low amounts of hydrogen peroxide (H2O2), is evaluated against methicillin‐resistant Staphylococcus aureus (MRSA), multidrug‐resistant Pseudomonas aeruginosa (MDR‐PA) and mixed‐species (MRSA and MDR‐PA) wound infections. Wounds created on Swiss Webster mice are infected with the above‐named bacteria and biofilms allow to establish in wound beds for 3 days. e‐Bandages, which electrochemically reduce dissolved oxygen to H2O2 when polarized at −0.6 VAg/AgCl, are placed atop infected wound beds and polarized continuously for 48 h. Polarized e‐bandage treatment results in significant reductions (p <0.001) of both monospecies and mixed‐species wound infections. After e‐bandage treatment, electron microscopy shows degradation of bacterial cells, and histopathology shows no obvious alterations to the inflammatory host response. Blood biochemistries show no abnormalities. Taken all together, results of this work suggest that the described H2O2‐producing e‐bandage can reduce in vivo MRSA, MDR‐PA, and mixed‐species wound biofilms, and should be further developed as a potential antibiotic‐free strategy for treatment of wound infections.

Abstract Aims Hyperlipidemia and T cell driven inflammation are important drivers of atherosclerosis, the main underlying cause of cardiovascular disease. Here, we detailed the effects of hyperlipidemia on T cells. Methods and results In vitro, exposure of human and murine CD4+ T cells to very low-density lipoprotein (VLDL), but not to low-density lipoprotein (LDL) resulted in upregulation of Th1 associated pathways. VLDL was taken up via a CD36-dependent pathway and resulted in membrane stiffening and a reduction in lipid rafts. To further detail this response in vivo, T cells of mice lacking the LDL receptor (LDLr), which develop a strong increase in VLDL cholesterol and triglyceride levels upon high cholesterol feeding were investigated. CD4+ T cells of hyperlipidemic Ldlr-/- mice exhibited an increased expression of the C-X-C-chemokine receptor 3 (CXCR3) and produced more interferon-γ (IFN-γ). Gene set enrichment analysis identified IFN-γ-mediated signaling as the most upregulated pathway in hyperlipidemic T cells. However, the classical Th1 associated transcription factor profile with strong upregulation of Tbet and Il12rb2 was not observed. Hyperlipidemia did not affect levels of the CD4+ T cell's metabolites involved in glycolysis or other canonical metabolic pathways but enhanced amino acids levels. However, CD4+ T cells of hyperlipidemic mice showed increased cholesterol accumulation and an increased arachidonic acid (AA) to docosahexaenoic acid (DHA) ratio, which was associated with inflammatory T cell activation. Conclusions Hyperlipidemia, and especially its VLDL component induces an atypical Th1 response in CD4+ T cells. Underlying mechanisms include CD36 mediated uptake of VLDL, and an altered AA/DHA ratio.

Abstract Background Breast conserving therapy (BCT) is accepted as a preferred option for unifocal breast cancer. However, the oncologic safety of BCT for multiple ipsilateral breast cancer (MIBC), has not been demonstrated in a prospective study. The ACOSOG (Alliance) Z11102 phase II single arm prospective trial was designed to evaluate outcomes with BCT for MIBC. Methods Women age 40+ with 2 or 3 foci of biopsy proven breast cancer (BC) (each site &lt; 5cm in size with at least 1 site invasive) separated by &gt;2-3 cm of normal breast tissue and disease limited to two quadrants of the breast with cN0 or cN1 disease were eligible. All patients had pre-operative mammogram and breast MRI was initially required and subsequently made optional. Neoadjuvant therapy was not allowed. Patients were treated with lumpectomy resected to negative margins followed by whole breast radiation with boost to all lumpectomy beds. The primary endpoint of Z11102 is the cumulative incidence of local recurrence (LR, defined as histologic evidence of ductal carcinoma in situ or invasive BC in the ipsilateral breast or chest wall) at 5 years (treating death and distant and nodal/regional recurrence as competing risks) to assess whether the rate is greater than 8%. Data were frozen 5/25/2022. Results From 11/2012-8/2016, 270 women were enrolled. Of these, 33 were ineligible, 14 converted to mastectomy, 11 were unable to meet protocol-specific radiation endpoints, 1 had no definable tumor, 1 had 4 sites of cancer and 16 withdrew before completing surgery and radiation, leaving 194 patients [median age 61 (range 40-87)] eligible who completed breast conserving surgery and radiation therapy. With median follow-up of alive patients of 66.6 months (range: 4.1, 90.6), 6 patients have developed LR (5 ipsilateral breast and 1 chest wall), corresponding to an estimated cumulative incidence of local recurrence of 3.2% (95% CI: 1.3, 6.4) at 5 years. No patients have developed regional recurrence, 5 patients developed distant recurrence, 0 patients developed local and distant recurrence, 5 patients developed contralateral BC, 3 new non-BC primaries and 8 patients have died (1 related to BC). The rate of local recurrence in patients without a breast pre-op MRI (n=14) was 22.6% at 5 years compared to 1.7% among the 180 patients with a preop MRI (p=0.002). Patient age, number of sites of preoperative biopsy proven BC, HER2 status, pathologic T and N category were not statistically significantly associated with risk of LR. Conclusion The Z11102 clinical trial demonstrates that for women with MIBC breast conserving surgery with adjuvant radiation with lumpectomy site boosts has an acceptably low LR rate (3.2% at 5 years), making this a reasonable consideration for women with 2-3 ipsilateral foci. The LR rate was significantly higher in the small cohort of patients without preoperative breast MRI. Support: U10CA180821, U10CA180882; https://acknowledgments.alliancefound.org. ClinicalTrials.gov Identifier: NCT01556243 Table 1: Factors associated with LR after BCT for MIBC Citation Format: Judy C. Boughey, Kari M. Rosenkranz, Karla V. Ballman, Linda McCall, Bruce G. Haffty, Laurie W. Cuttino, Charlotte D. Kubicky, H. T. Carisa Le-Petross, Kimberly Van Zee, Armando E. Giuliano, Olwen M. Hahn, Kelly K. Hunt, Lisa Carey, Ann Partridge. Impact of Breast Conservation Therapy on Local Recurrence in Patients with Multiple Ipsilateral Breast Cancer – Results from ACOSOG Z11102 (Alliance) [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr GS4-01.