Citations

Abstract Delivery of therapeutics to solid tumors with high bioavailability remains a challenge and is likely the main contributor to the ineffectiveness of immunotherapy and chemotherapy. Here, a catheter‐directed ionic liquid embolic (ILE) is bioengineered to achieve durable vascular embolization, uniform tissue ablation, and drug delivery in non‐survival and survival porcine models of embolization, outperforming the clinically used embolic agents. To simulate the clinical scenario, rabbit VX2 orthotopic liver tumors are treated showing successful trans‐arterial delivery of Nivolumab and effective tumor ablation. Furthermore, similar results are also observed in human ex vivo tumor tissue as well as significant susceptibility of highly resistant patient‐derived bacteria is seen to ILE, suggesting that ILE can prevent abscess formation in embolized tissue. ILE represents a new class of liquid embolic agents that can treat tumors, improve the delivery of therapeutics, prevent infectious complications, and potentially increase chemo‐ and immunotherapy response in solid tumors.

A 13-year-old male undergoing maintenance chemotherapy with methotrexate and 6-mercaptopurine (6MP), for very high-risk B-cell acute lymphoblastic leukemia (ALL), presented with vomiting due to severe hypoglycemia with metabolic acidosis. While his laboratory values were concerning for a critically ill child, the patient was relatively well appearing. Hypoglycemia is a rare but serious side effect of 6MP with an unexpectedly variable presentation; therefore, a high index of suspicion is needed for its prompt detection and treatment. This patient also had severe metabolic acidosis, likely secondary to hypoglycemia, creating a serious clinical picture despite a well-appearing child. This example of incongruity between laboratory tests and clinical appearance adds nuance to the existing literature. Moreover, although 6MP-associated hypoglycemia is rare, it may be more prevalent than the literature suggests, as symptoms of hypoglycemia—nausea, vomiting, and somnolence—mirror common chemotherapy side effects. 6MP-induced hypoglycemia can be ameliorated with the addition of allopurinol to shunt metabolism in favor of the production of therapeutic metabolites over hepatotoxic metabolites. Additionally, a morning administration of 6MP and frequent snacks may also help to prevent hypoglycemia. Overall, this case adds to the literature of unusual reactions to 6MP including hypoglycemia in an older child without traditional risk factors.

BACKGROUND: Little is known about the impact of prior prostate radiation therapy (RT) on the Bacille Calmette-Guerin (BCG) immunotherapy response in patients with non-muscle invasive bladder cancer (NMIBC). OBJECTIVE: We hypothesized that the damaging radiation effects on the bladder could negatively influence BCG efficacy. METHODS: Men with a history of high-risk NMIBC were identified within the Surveillance, Epidemiology, and End Results–Medicare database. All patients completed adequate BCG defined as at least 5 plus 2 treatments completed within 12 months. Patients were stratified into 2 groups: with prior RT for prostate cancer and without prior RT before the diagnosis of NMIBC. The primary endpoint was a 5-year composite for progression defined as disease progression requiring systemic chemotherapy, checkpoint inhibitors, radical or partial cystectomy, or cancer-specific death. RESULTS: We identified 3,466 patients with NMIBC, including 145 with prior RT for prostate cancer. Five-year progression occurred in 471 patients (13.6%). Patients with prior RT were older than patients without prior RT (77.0 vs 75.0 years; P < .001). The distribution of T stage was significantly different at diagnosis between the RT and non-RT groups (RT: Ta, 44.8%; Tis, 18.6%; T1, 36.6%; without RT: Ta, 40.9%; Tis, 10.8%; T1, 48.3%; P = .002). No difference in the risk of total progression was observed between patients with and without prior RT ( P = .67). Similarly, no difference was observed after multivariable adjustment (hazard ratio, 0.99; 95% CI, 0.61-1.58; P = .95). CONCLUSION: For patients with NMIBC who undergo adequate BCG treatment, prior RT for prostate cancer was not associated with worse 5-year progression-free survival.

Background: Dofetilide and sotalol are potassium channel antagonists that require inpatient QTc monitoring during initiation, due to increased risk of fatal arrhythmias. Elderly patients are especially subject to an increased risk of fatal arrhythmias due to polypharmacy, comorbidities, and physiologic cardiac changes with aging. This study will describe the tolerability and risk factors associated with the initiation of sotalol or dofetilide in patients ≥80 years of age. Methodology: This is a multicenter, retrospective, descriptive study of patients ≥80 years old who were initiated on either dofetilide or sotalol between May 8, 2018 and July 31, 2021 at institutions within the Mayo Clinic Health System. The percentage of patients who received nonpackage insert recommended doses was identified. Incidence of and reasons for dose reductions or discontinuations due to safety-related events or clinical concerns during the initial loading period were collected. Results: The final analysis included 104 patients. The majority of patients (75%) received nonstandard initial doses of dofetilide or sotalol based on baseline estimated creatinine clearance or QTc. Overall, 39% ( N = 41) of patients experienced a dose reduction or discontinuation due to a safety-related event or concern. Patients who received nonstandard initial doses of dofetilide or sotalol had 4.7 times greater odds of experiencing a safety-related event requiring dose reduction or discontinuation. Conclusion: Following package insert dosing in elderly patients increases safety and tolerability relative to more aggressive dosing of dofetilide or sotalol.

Abstract Background: Much has been published about barriers to research participation for under-represented minority (URM) yet we know little about the experiences, motivations, and decision-making of the URM patients who were successfully treated on clinical trial (CT). The purpose of this study is to draw on the experiences of URM patients as insiders of practical knowledge of CT through photo elicitation to comprehensively understand the current state of recruitment and treatment of URM patients on interventional cancer CTs across the Mayo Clinic enterprise with a short-term goal of informing mechanisms to enrich CT participation and a long-term goal of building a patient-centered cancer practice and clinical trial patient population that is reflective of the diverse communities served by Mayo Clinic. Method: An Appreciative inquiry approach was adapted for this study which acknowledges that existing strengths and everyday experiences of URM patients has the potential to allow a more nuanced view as it pertains to our cancer populations. A total of 138 URM were invited to participate. Using photo elicitation technique, patients were asked to take photographs to portray factors that motivated them and/or facilitated their enrollment, barriers to enrollment and recommendations to improve the process for CT recruitment for other URM. Participant-generated photographs (59) and accompanying 13 interview narratives were analyzed using layered analysis. Results: A total of 13 patients (female =9) participated in the photo interviews. URM detailed their overall experiences around CT participation, motivations for participating in clinical trials; facilitators to clinical trial participation; and opportunities and considerations for increasing minority patients CT participation. Photo analyses provided symbolic representation of patients’ general experiences around CT including celebrating their “new identity”, finding peace in moments of nostalgia, their journey through the trial, lost times and finances and yet finding a new purpose to live through CT participation. Importantly patients described decision making in CT participation as a relational approach. Patients suggested opportunities and considerations for increasing minority patients trial participation, which included minimizing logistical barriers, decentralizing cancer clinical trials, increasing awareness via patient narratives, diversifying research staff, minimizing cost, and being clear on purpose and benefit of the trial. Conclusion: Our study highlights the potential to utilize visual data and narratives from URM in CT recruitment and education programming. It provided valuable insights from the URM community for the URM community on key issues on motivations of CT participation and decision-making in CT participation. Citation Format: Gladys B. Asiedu, Rahma Warsame, Mary O’Shea, Yong-hun Kim, Sara A. Ellingson, Katharine A. Price. Trial participation in pictures: Using photo elicitation to explore minority patients’ experiences on therapeutic cancer clinical trials [abstract]. In: Proceedings of the 16th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2023 Sep 29-Oct 2;Orlando, FL. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2023;32(12 Suppl):Abstract nr A076.

Importance Gestational diabetes is a common complication of pregnancy and the optimal management is uncertain. Objective To test whether early initiation of metformin reduces insulin initiation or improves fasting hyperglycemia at gestation weeks 32 or 38. Design, Setting, and Participants Double-blind, placebo-controlled trial conducted in 2 centers in Ireland (one tertiary hospital and one smaller regional hospital). Participants were enrolled from June 2017 through September 2022 and followed up until 12 weeks’ postpartum. Participants comprised 510 individuals (535 pregnancies) diagnosed with gestational diabetes based on World Health Organization 2013 criteria. Interventions Randomized 1:1 to either placebo or metformin (maximum dose, 2500 mg) in addition to usual care. Main Outcomes And Measures The primary outcome was a composite of insulin initiation or a fasting glucose level of 5.1 mmol/L or greater at gestation weeks 32 or 38. Results Among 510 participants (mean age, 34.3 years), 535 pregnancies were randomized. The primary composite outcome was not significantly different between groups and occurred in 150 pregnancies (56.8%) in the metformin group and 167 pregnancies (63.7%) in the placebo group (between-group difference, −6.9% [95% CI, −15.1% to 1.4%]; relative risk, 0.89 [95% CI, 0.78-1.02]; P = .13). Of 6 prespecified secondary maternal outcomes, 3 favored the metformin group, including time to insulin initiation, self-reported capillary glycemic control, and gestational weight gain. Secondary neonatal outcomes differed by group, with smaller neonates (lower mean birth weights, a lower proportion weighing &amp;gt;4 kg, a lower proportion in the &amp;gt;90% percentile, and smaller crown-heel length) in the metformin group without differences in neonatal intensive care needs, respiratory distress requiring respiratory support, jaundice requiring phototherapy, major congenital anomalies, neonatal hypoglycemia, or proportion with 5-minute Apgar scores less than 7. Conclusion and relevance Early treatment with metformin was not superior to placebo for the composite primary outcome. Prespecified secondary outcome data support further investigation of metformin in larger clinical trials. Trial Registration ClinicalTrials.gov Identifier: NCT02980276 ; EudraCT: 2016-001644-19

Abstract Ruptured wide‐neck aneurysms (WNAs), especially in a setting of coagulopathy, are associated with significant morbidity and mortality. It is shown that by trapping a sub‐millimeter clinical catheter inside the aneurysm sac using a flow diverter stent (FDS), instant hemostasis can be achieved by filling the aneurysm sac using a novel biomaterial, rescuing catastrophic bleeding in large‐animal models. Multiple formulations of a biomaterial comprising gelatin, nanoclay (NC), and iohexol are developed, optimized, and extensively tested in vitro to select the lead candidate for further testing in vivo in murine, porcine, and canine models of WNAs, including in a subset with aneurysm rupture. The catheter‐injectable and X‐ray visible versions of the gel embolic agent (GEA) with the optimized mechanical properties outperform control groups, including a subset that receive a clinically used liquid embolic (Onyx, Medtronic), with and without aneurysm rupture. A combinatorial approach to ruptured WNAs with GEA and FDS may change the standard of medical practice and save lives.

Background The tumor lysate, particle-loaded, dendritic cell (TLPLDC) vaccine is made by ex vivo priming matured autologous dendritic cells (DCs) with yeast cell wall particles (YCWPs) loaded with autologous tumor lysate (TL). The tumor lysate, particle only (TLPO) vaccine uses autologous TL-loaded YCWPs coated with silicate for in vivo DC loading. Here we report the 36-month prespecified analyses of this prospective, randomized, double-blind trial investigating the ability of the TLPO and TLPLDC (±granulocyte-colony stimulating factor (G-CSF)) vaccines to prevent melanoma recurrence in high-risk patients. Methods Patients with clinically disease-free stage III/IV melanoma were randomized 2:1 initially to TLPLDC versus placebo (n=124) and subsequently TLPO versus TLPLDC (n=63). All patients were randomized and blinded; however, the placebo control arm was replaced in the second randomization scheme with another novel vaccine; some analyses in this paper therefore reflect a combination of the two randomization schemes. Patients receiving the TLPLDC vaccine were further divided by their method of DC harvest (with or without G-CSF pretreatment); this was not randomized. The use of standard of care checkpoint inhibitors was not stratified between groups. Safety was assessed and Kaplan-Meier and log-rank analyses compared disease-free (DFS) and overall survival (OS). Results After combining the two randomization processes, a total of 187 patients were allocated between treatment arms: placebo (n=41), TLPLDC (n=103), or TLPO (n=43). The allocation among arms created by the addition of patients from the two separate randomization schemes does not reflect concurrent randomization among all treatment arms. TLPLDC was further divided by use of G-CSF in DC harvest: no G-CSF (TLPLDC) (n=47) and with G-CSF (TLPLDC+G) (n=56). Median follow-up was 35.8 months. Only two patients experienced a related adverse event ≥grade 3, one each in the TLPLDC+G and placebo arms. DFS was 27.2% (placebo), 55.4% (TLPLDC), 22.9% (TLPLDC+G), and 60.9% (TLPO) (p<0.001). OS was 62.5% (placebo), 93.6% (TLPLDC), 57.7% (TLPLDC+G), and 94.6% (TLPO) (p=0.002). Conclusions The TLPO and TLPLDC (without G-CSF) vaccines were associated with improved DFS and OS in this clinical trial. Given production and manufacturing advantages, the efficacy of the TLPO vaccine will be confirmed in a phase 3 trial. Trial registration number NCT02301611 .

Abstract Importance and Objective Despite a decreasing incidence of cervical cancer in North America overall, disparities in screening and cervical cancer rates persist, especially in the postmenopausal age group. Methods We reviewed the literature regarding cervical cancer screening considerations for postmenopausal persons, with a focus on cervical cancer in postmenopausal persons, existing guidelines, screening methods, and gaps in care. Discussion and Conclusion Postmenopausal persons are an important population at risk because age 65 years in the United States and up to 70 years in some parts of Canada is a milestone for screening cessation if the criteria are met. Unfortunately, inadequate screening is common, with most women 65 years or older discontinuing (exiting) screening despite not meeting the criteria to do so. Screening cessation recommendations are nuanced, and if not all criteria are met, screening should be continued until they are. Cervical cancer screening should be stopped at the recommended age if adequate screening has occurred or at any age if life expectancy is limited or the patient has had a hysterectomy in the absence of high-grade preinvasive cervical lesions or cervical cancer. Human papillomavirus infection, which is causally linked to almost all cervical cancer cases, can persist or reactivate from a prior infection or can be newly acquired from sexual contact. With more persons aging with a cervix in place, the potential for cervical cancer has increased, and higher cancer rates may be observed if recommended screening is not adhered to. We propose an algorithm based on current cervical cancer screening guidelines to aid providers in identifying whether exit criteria have been met. Until adequate screening has been confirmed, cervical cancer screening should continue.