Citations

Background. Surgical-site infection (SSI) is the most common early infectious complication after pancreas transplantation (PT). Although SSI has been shown to worsen outcomes, little data exist to guide optimal choices in perioperative prophylaxis. Methods. We performed a retrospective cohort study of PT recipients from 2010–2020 to examine the effect of perioperative antibiotic prophylaxis with Enterococcus coverage. Enterococcus coverage included antibiotics that would be active for penicillin-susceptible Enterococcus isolates. The primary outcome was SSI within 30 d of transplantation, and secondary outcomes were Clostridioides difficile infection (CDI) and a composite of pancreas allograft failure or death. Outcomes were analyzed by multivariable Cox regression. Results. Of 477 PT recipients, 217 (45.5%) received perioperative prophylaxis with Enterococcus coverage. Eighty-seven recipients (18.2%) developed an SSI after a median of 15 d from transplantation. In multivariable Cox regression analysis, perioperative Enterococcus prophylaxis was associated with reduced risk of SSI (hazard ratio [HR] 0.58; 95% confidence interval [CI], 0.35-0.96; P = 0.034). Anastomotic leak was also significantly associated with elevated risk of SSI (HR 13.95; 95% CI, 8.72-22.32; P < 0.001). Overall, 90-d CDI was 7.4%, with no difference between prophylaxis groups (P = 0.680). SSI was associated with pancreas allograft failure or death, even after adjusting for clinical factors (HR 1.94; 95% CI, 1.16-3.23; P = 0.011). Conclusions. Perioperative prophylaxis with Enterococcus coverage was associated with reduced risk of 30-d SSI but did not seem to influence risk of 90-d CDI after PT. This difference may be because of the use of beta-lactam/beta-lactamase inhibitor combinations, which provide better activity against enteric organisms such as Enterococcus and anaerobes compared with cephalosporin. Risk of SSI was also related to anastomotic leak from surgery, and SSI itself was associated with subsequent risk of a poor outcome. Measures to mitigate or prevent early complications are warranted.

TPS4199 Background: Tumor Treating Fields (TTFields) therapy is a locoregional antimitotic treatment approved for newly diagnosed and recurrent glioblastoma GBM and pleural mesothelioma. TTFields (150 kHz) therapy, with/without chemotherapy, had antiproliferative and anticlonogenic activity in pancreatic cancer cell lines, and reduced tumor volume and weight more than chemotherapy alone in in vivo models. TTFields therapy with gemcitabine and nab-paclitaxel (GnP) was well-tolerated, with promising efficacy in metastatic and locally advanced pancreatic adenocarcinoma (LAPC) in the phase 2 PANOVA study (NCT01971281). LAPC prognosis remains poor despite available therapies, which can negatively impact quality of life (QoL). As such, there remains a need for effective and tolerable treatments. Methods: PANOVA-3 (EF-27, NCT03377491) is a prospective, randomized, phase 3 study investigating the efficacy and safety of TTFields therapy with GnP in patients with LAPC, with a planned enrollment of 556 patients. Key inclusion criteria are: a diagnosis of unresectable LAPC (per NCCN guidelines), ECOG PS of 0–2, and no prior treatment. Patients will be stratified by performance status and geographical region and assigned 1:1 to treatment groups to receive TTFields therapy + GnP or GnP alone. GnP will be administered at a standard dose per standard of care. TTFields therapy (150 kHz, 18h/day) will be delivered by the NovoTTF-200T System until local disease progression per RECIST v1.1. Usage will be tracked by the device. Follow-up will be performed every 4 weeks and computed tomography scans of the chest and abdomen will be taken every 8 weeks until disease progression. Patients will be followed every month until death. The primary endpoint is overall survival and key secondary endpoints include QoL, pain-free survival, and puncture-free survival, which will be compared between treatment groups. Other secondary endpoints include progression-free survival (PFS), local PFS, objective response rate, 1-year survival rate, rate of resectability, and safety. Guidance around usage, lifestyle integration and prevention and management of skin adverse events will be provided by Device Support Specialists and field personnel. Usage information will be provided to patients and physicians to facilitate discussions to optimize outcomes by maximizing time on therapy. Together, these novel support approaches aim to optimize patient usage and outcomes. The trial is currently recruiting at 149 sites, globally. The DMC last reviewed the trial in August 2022, and suggested that the trial continue as planned. Clinical trial information: NCT03377491 .

4006 Background: Liposomal irinotecan + 5-fluorouracil/leucovorin (5-FU/LV) is approved in the USA and Europe for mPDAC following progression with gemcitabine-based therapy. A phase 1/2 study (NCT02551991) demonstrated promising anti-tumor activity in patients with mPDAC who received first-line liposomal irinotecan 50 mg/m2 + 5-FU 2400 mg/m2 + LV 400 mg/m2 + oxaliplatin 60 mg/m2 (NALIRIFOX). Here, we present results from NAPOLI 3 (NCT04083235), a randomized, open-label, phase 3 study investigating the efficacy and safety of NALIRIFOX compared with nab-paclitaxel 125 mg/m2 + gemcitabine 1000 mg/m2 (Gem+NabP) as first-line therapy in patients with mPDAC. Methods: Eligible patients with histopathologically/cytologically confirmed untreated mPDAC were randomized (1:1; stratified by Eastern Cooperative Oncology Group [ECOG] performance status, geographic region and presence/absence of liver metastases) to receive NALIRIFOX on days 1 and 15 of a 28-day cycle or Gem+NabP on days 1, 8 and 15 of a 28-day cycle. The primary endpoint was overall survival (OS); secondary endpoints were progression-free survival (PFS), overall response rate (ORR) and safety. OS was evaluated when at least 543 events were observed using a stratified log-rank test with an overall one-sided significance level of 0.025. Results: Overall, 770 patients (NALIRIFOX, n = 383; Gem+NabP, n = 387) were included. Baseline characteristics were balanced between arms. At a median follow-up of 16.1 months, 544 events had occurred. Median OS was 11.1 months in the NALIRIFOX group versus 9.2 months in the Gem+NabP group; median PFS was 7.4 months versus 5.6 months. Median (95% CI) duration of response was 7.3 (5.8–7.6) and 5.0 (3.8–5.6) months in patients who received NALIRIFOX and Gem+NabP, respectively. Grade 3/4 treatment-emergent adverse events occurring in at least 10% of patients receiving NALIRIFOX versus Gem+NabP included diarrhea (20.3% vs 4.5%), nausea (11.9% vs 2.6%), hypokalemia (15.1% vs 4.0%), anemia (10.5% vs 17.4%) and neutropenia (14.1% vs 24.5%). Conclusions: First-line NALIRIFOX demonstrated clinically meaningful and statistically significant improvement in OS and PFS compared with Gem+NabP in patients with mPDAC. The NALIRIFOX safety profile was consistent with the profiles of the regimen components and generally manageable. Clinical trial information: NCT04083235 . [Table: see text]

Abstract Two inherited autosomal dominant cancer predisposition conditions - BRCA related hereditary breast and ovarian cancer (HBOC) and Lynch syndrome (LS) - are termed Centers for Disease Control and Prevention Tier 1 (CDCT1) genetic conditions, for which early identification and intervention have a positive impact on public health. Selection of individuals for genetic testing for these conditions is based on personal and family history. The goal of this study was to evaluate whether screening in a tertiary medical center using exome sequencing could efficiently identify carriers of HBOC and LS and to determine the frequency of incremental carriers identified outside of traditional clinical practice guidelines. Participants from three geographically diverse Mayo Clinic practices in the USA (Rochester MN, Phoenix AZ, Jacksonville FL) consented to clinical “Exome+” sequencing (Helix, San Mateo, CA; Mayo GeneGuide, Rochester, MN) in the TAPESTRY study (NCT05212428), which links sequencing data with electronic health records and the return of CDCT1 genetic findings. For this study we focused on two inherited cancer predisposition conditions: BRCA-related HBOC (BRCA1 and BRCA2) and LS (MLH1, MSH2, MSH6, PMS2 and EPCAM). Detailed chart review to collect demographic information, personal and family history, and assessment of clinical practice guidelines for genetic evaluation (National Cancer Control Network 2021). To date, 44,306 patients have enrolled and sequenced in TAPESTRY. Annotation and interpretation of all variants in 7 genes for HBOC and LS resulted in identification of 550 carriers (prevalence 1.24%) which included 387 with HBOC (27.2% BRCA1, 42.8% BRCA2) and 163 with LS (12.3% MSH6, 8.8% PMS2, 4.5% MLH1, 3.8% MSH2 and 0.2% EPCAM). Demographics of the cohort included: 62.7% female, mean age 55.2 years, non-white race 9.6% and 3.8% Hispanic/Latino ethnicity. A personal history of cancer was present in 46.4% of test positive patients, including 22.5% of HBOC patients with breast or ovarian cancer and 20.9% of LS patients with colorectal or uterine cancer. More than half of the patients (52.1%) were newly diagnosed with HBOC and LS based on the results of this study. Overall, 39.2% of HBOC/LS carriers identified through Exome+ sequencing did not satisfy NCCN criteria for genetic evaluation, this was higher for LS (56.2%) compared to HBOC (32%). Amongst those newly diagnosed with HBOC/LS (n=286), NCCN criteria were not satisfied in 60% of cases (78% for LS and 51% for HBOC). Of the pathogenic germline variant carriers who met NCCN guidelines for testing, 34.2% were not aware of their diagnosis prior to participation in this study. Our results emphasize the need for wide genomic screening for CDCT1 cancer predisposition syndromes. Such screening could identify at-risk carriers of HBOC and LS, who would not otherwise be identified through clinical practice guidelines. Citation Format: Emily Gay, Niloy Jewel Samadder, Michelle L. Bublitz, Melanie M. Peterson, Tammy A. Wilson, Lorelei A. Bandel, Sebastian M. Armasu, Robert A. Vierkant, Matthew J. Ferber, Eric W. Klee, Nicholas B. Larson, Teresa M. Kruisselbrink, Timothy B. Curry, Jan B. Egan, Jennifer L. Kemppainen, Jessa S. Bidwell, Jennifer L. Anderson, Tammy M. McAllister, T'Nita S. Walker, Katie L. Kunze, Vanda Lindpere, Michael A. Golafshar, Margaret Klint, Richard J. Presutti, William V. Bobo, Aleksander Sekulic, Jolene M. Summer Bolster, Cheryl L. Willman, Konstantinos N. Lazaridis. Genetic screening in a tertiary medical center identifies carriers of cancer predisposition diseases that would be missed by clinical guidelines [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5768.

AbstractRight heart (RH) structure and function are major determinants of symptoms and prognosis in pulmonary arterial hypertension (PAH). RH imaging provides detailed information, but evidence and guidelines on the use of RH imaging in treatment decisions are limited. We conducted a Delphi study to gather expert opinion on the role of RH imaging in decision‐making for treatment escalation in PAH. A panel of 17 physicians with expertise in PAH and RH imaging used three surveys in a modified Delphi process to reach consensus on the role of RH imaging in PAH. Survey 1 used open‐ended questions to gather information. Survey 2 contained Likert scale and other questions intended to identify consensus on topics identified in Survey 1. Survey 3 contained Likert scale questions derived from Survey 2 and summary information on the results of Survey 2. The Delphi panel reached consensus that RH imaging is likely to improve the current risk stratification algorithms and help differentiate risk levels in patients at intermediate risk. Tricuspid annular plane systolic excursion, right ventricular fractional area change, right atrial area, tricuspid regurgitation, inferior venae cavae diameter, and pericardial effusion should be part of routine echocardiography in PAH. Cardiac magnetic resonance imaging is valuable but limited by cost and access. A pattern of abnormal RH imaging results should prompt consideration of hemodynamic evaluation and possible treatment escalation. RH imaging is an important tool for decisions about treatment escalation in PAH, but systematically collected evidence is needed to clarify its role.

Importance Whether vigorous intensity exercise is associated with an increase in risk of ventricular arrhythmias in individuals with hypertrophic cardiomyopathy (HCM) is unknown. Objective To determine whether engagement in vigorous exercise is associated with increased risk for ventricular arrhythmias and/or mortality in individuals with HCM. The a priori hypothesis was that participants engaging in vigorous activity were not more likely to have an arrhythmic event or die than those who reported nonvigorous activity. Design, Setting, and Participants This was an investigator-initiated, prospective cohort study. Participants were enrolled from May 18, 2015, to April 25, 2019, with completion in February 28, 2022. Participants were categorized according to self-reported levels of physical activity: sedentary, moderate, or vigorous-intensity exercise. This was a multicenter, observational registry with recruitment at 42 high-volume HCM centers in the US and internationally; patients could also self-enroll through the central site. Individuals aged 8 to 60 years diagnosed with HCM or genotype positive without left ventricular hypertrophy (phenotype negative) without conditions precluding exercise were enrolled. Exposures Amount and intensity of physical activity. Main Outcomes and Measures The primary prespecified composite end point included death, resuscitated sudden cardiac arrest, arrhythmic syncope, and appropriate shock from an implantable cardioverter defibrillator. All outcome events were adjudicated by an events committee blinded to the patient’s exercise category. Results Among the 1660 total participants (mean [SD] age, 39 [15] years; 996 male [60%]), 252 (15%) were classified as sedentary, and 709 (43%) participated in moderate exercise. Among the 699 individuals (42%) who participated in vigorous-intensity exercise, 259 (37%) participated competitively. A total of 77 individuals (4.6%) reached the composite end point. These individuals included 44 (4.6%) of those classified as nonvigorous and 33 (4.7%) of those classified as vigorous, with corresponding rates of 15.3 and 15.9 per 1000 person-years, respectively. In multivariate Cox regression analysis of the primary composite end point, individuals engaging in vigorous exercise did not experience a higher rate of events compared with the nonvigorous group with an adjusted hazard ratio of 1.01. The upper 95% 1-sided confidence level was 1.48, which was below the prespecified boundary of 1.5 for noninferiority. Conclusions and Relevance Results of this cohort study suggest that among individuals with HCM or those who are genotype positive/phenotype negative and are treated in experienced centers, those exercising vigorously did not experience a higher rate of death or life-threatening arrhythmias than those exercising moderately or those who were sedentary. These data may inform discussion between the patient and their expert clinician around exercise participation.

Beta-hemolytic streptococci are common causes of bloodstream infection (BSI). There is emerging data regarding oral antibiotics for BSI but limited for beta-hemolytic streptococcal BSI.

Background Our prior work demonstrated that questionnaires assessing psychosocial symptoms have utility for predicting improvement in patients with acute post-traumatic headache following mild traumatic brain injury. In this cohort study, we aimed to determine whether prediction accuracy can be refined by adding structural magnetic resonance imaging (MRI) brain measures to the model. Methods Adults with acute post-traumatic headache (enrolled 0–59 days post-mild traumatic brain injury) underwent T1-weighted brain MRI and completed three questionnaires (Sports Concussion Assessment Tool, Pain Catastrophizing Scale, and the Trait Anxiety Inventory Scale). Individuals with post-traumatic headache completed an electronic headache diary allowing for determination of headache improvement at three- and at six-month follow-up. Questionnaire and MRI measures were used to train prediction models of headache improvement and headache trajectory. Results Forty-three patients with post-traumatic headache (mean age = 43.0, SD = 12.4; 27 females/16 males) and 61 healthy controls were enrolled (mean age = 39.1, SD = 12.8; 39 females/22 males). The best model achieved cross-validation Area Under the Curve of 0.801 and 0.805 for predicting headache improvement at three and at six months. The top contributing MRI features for the prediction included curvature and thickness of superior, middle, and inferior temporal, fusiform, inferior parietal, and lateral occipital regions. Patients with post-traumatic headache who did not improve by three months had less thickness and higher curvature measures and notably greater baseline differences in brain structure vs. healthy controls (thickness: p < 0.001, curvature: p = 0.012) than those who had headache improvement. Conclusions A model including clinical questionnaire data and measures of brain structure accurately predicted headache improvement in patients with post-traumatic headache and achieved improvement compared to a model developed using questionnaire data alone.