Citations

Abstract BACKGROUND Recurrent anaplastic astrocytoma (AA), a grade 3 brain cancer, remains an unmet medical need. STELLAR was a phase III randomized, open-label trial of eflornithine (ornithine decarboxylase inhibitor) with lomustine versus lomustine alone, originally for patients with recurrent AA. However, as the WHO definition of AA evolved during trial conduct (e.g., excluding IDH wild-type disease), we determined results in both the original ITT population and by revised molecularly defined WHO 2021 diagnoses in pre-planned analyses. METHOD Key eligibility: age ≥ 18, AA (2016 WHO criteria), first recurrence ≥ 6 months after radiation and temozolomide, KPS ≥ 70, no imaging findings consistent with grade 4 glioblastoma. Stratification: IDH, age, resection extent, and geography. Patients were randomized to Arm A: eflornithine (2.8 g/m2 TID Q 2/3 weeks) with lomustine (90 mg/m2 Q 6 weeks) or Arm B: lomustine (110 mg/m2 Q 6 weeks). Primary endpoint was OS. The pre-specified hazard ratio (HR) goal was 0.667 based on projected median OS (mOS) increase to 18 months from 12 months. RESULTS 343 pts (172/171 Arms A/B) were randomized (105 sites, 8 countries). ITT analysis found no difference between arms (mOS 23.4 vs. 20.3 months, HR = 0.94). However, a pre-specified subset analysis in IDH mutant, 2021 WHO-defined grade 3 astrocytoma (n=194), showed significant improvement with eflornithine (mOS 34.9 vs. 23.5 months, HR = 0.64, log rank p = 0.016) and PFS (15.8 vs. 7.2 months, HR = 0.58, log rank p = 0.015). No difference was observed in the IDH wild-type subset. AEs were consistent with historic data. CONCLUSION There was no difference in OS between arms in the ITT analysis. However, medically meaningful and statistically significant OS and PFS benefits were observed with eflornithine in the pre-planned analysis of patients with molecularly defined 2021 WHO CNS grade 3 astrocytoma.

Abstract GBM AGILE(NCT03970447) is a phase 2/3 Bayesian adaptive registration platform trial testing multiple therapies against a common control. Paxalisib, a PI3K/mTOR inhibitor, is the 3rd arm in the trial to conclude evaluation. METHODS Paxalisib was open to patients with newly diagnosed unmethylated (NDU) and recurrent (RD) glioblastoma, with three possible signatures: NDU, RD, and All(NDU+RD). Arm enrollment occurred Dec2020 through May2022. Control patients were enrolled from study initiation (July2019) and were treated with temozolomide(NDU) or lomustine(RD). GBM AGILE investigational arms have 1 or 2 stages, with adaptive randomization in stage 1 and fixed randomization if arms continue to stage 2. Efficacy is based on OS hazard ratio(HR) of Arm/Control. Efficacy goal is final Bayesian probability ≥ 98% for HR<1.00 in combined Stages. An Arm continues to Stage 2 if Bayesian predictive power (PP) ≥ 0.8. An Arm stops accruing in Stage 1 if it reaches maximal sample size(N) or does not meet a minimum efficacy threshold (PP<0.25 for all signatures when N>50). Clinical cut-off is 12 months after accrual stops. The maximum N for paxalisib was approximately 150(Stage 1) and 50(Stage 2). RESULTS After paxalisib reached >150 patients in Stage 1, accrual stopped [Paxalisib/control N 54/75(NDU), 100/188(RD)]. Neither PP thresholds for moving to Stage 2 nor stopping for minimum efficacy were met. Following an unplanned public disclosure that the arm did not continue to stage 2, clinical cut-off for final analysis (planned May2023) was updated to public disclosure date (August2022). At final analysis mean HRs were 0.89(NDU), 1.25(RD), 1.05(All), probabilities of HR<1.00 of 0.72(NDU), 0.076(RD), 0.398(All). Model estimated median OS paxalisib/control (months) were 14.77/13.84(NDU) and 8.58/10.06(RD). CONCLUSION Paxalisib did not show survival benefit over cumulative control in final primary analysis; additional secondary analyses are being considered. GBM AGILE continues to rapidly and efficiently assess therapies in ND and RD glioblastoma.

Background/Objectives: Overall survival for patients with Stage 3 pancreatic ductal adenocarcinoma (PDAC) remains limited, with a median survival of 12 to 15 months. Irreversible electroporation (IRE) is a local tumor ablation method that induces cancerous cell death by disrupting cell membrane homeostasis. The DIRECT Registry study was designed to assess the effectiveness and safety of IRE when combined with standard of care (SOC) treatment for Stage 3 PDAC versus SOC alone in a real-world setting after at least 3 months of induction chemotherapy; Methods: Patients with Stage 3 PDAC treated with IRE plus SOC or SOC alone were prospectively enrolled in a multicenter registry study. Enrollment required 3 months of active multi-agent chemotherapy with no progression before enrollment. Endpoints were 30- and 90-day mortality and adverse events (AEs). Results: Eighty-seven IRE and 27 SOC subjects were enrolled in the registry. Mean ages were 64.0 ± 8.4 and 66.4 ± 9.9 years, and mean anterior/posterior tumor diameters were 2.2 ± 0.7 cm and 3.2 ± 1.3 for the IRE and SOC groups respectively (p = 0.0066). All IRE procedures were performed using an open approach. The 90-day all-cause mortality was 5/83 (6.0%) and 2/27 (7.4%) for the IRE and SOC groups, respectively. Two subjects in the IRE group died from treatment-related complications, and one patient in the SOC group died due to chemotherapy-related complications. Conclusions: Initial results from the DIRECT registry study indicate the use of IRE for curative intent tumor ablation in combination with induction chemotherapy has equivalent morbidity and mortality rates when compared to standard-of-care chemotherapy alone.

ABSTRACTIn this first annual review article, the American Society for Apheresis (ASFA) Attending Physician Subcommittee (APSc) of the Physicians' Committee (PC) curated key apheresis literature in 2023 and presented their choices for the 10 most seminal apheresis articles. PubMed and OVID search engines were used to identify manuscripts from four topic areas: donor apheresis, therapeutic apheresis, education, and cellular therapy. To further identify seminal criteria, they had to present at least one of the following: novel findings, practice‐altering outcomes, international scope, randomized controlled trial, relevant to current clinical practice, and/or provide evidence for category III or IV indications based on the ASFA ninth special issue of the Guidelines on the Use of Therapeutic Apheresis in Clinical Practice‐Evidence‐Based Approach. Inclusion criteria included: full‐length, peer‐reviewed, English language, and human subjects. Case reports, review articles, and meta‐analyses were excluded.

Background: Pathologic reflux is a common debilitating digestive condition and anti-reflux surgery is an effective treatment option. Depending on the specifics of the procedure, anti-reflux surgery leads to distinct changes in the endoscopic appearance of the esophagogastric junction (EGJ). This American Foregut Society (AFS) white paper develops nomenclature for describing the endoscopic characteristics of the EGJ after commonly performed laparoscopic antireflux operations. Methods: The AFS Anti-Reflux Barrier Collaborative analyzed the anatomic manipulation and corresponding endoscopic appearance of the EGJ after commonly performed anti-reflux surgery including: (1) 360° anterior/posterior (AP) fundoplication (Nissen); (2) posterior partial fundoplication (Toupet); (3) anterior partial fundoplication (Watson, Dor); (4) magnetic sphincter augmentation; and (5) concomitant hiatal hernia repair with transoral fundoplication (cTIF). Results: Characteristics common to the anti-reflux surgery procedures include restoration of intra-abdominal esophageal length and crural diaphragm repair such that the hiatal aperture is no longer visible in the retroflexed endoscopic view. With regard to the geometry of anti-reflux procedures, the Collaborative established that when evaluated endoscopically in retroflection, the surgically constructed valve should be described in reference to the angle of His and the extent of anatomic change described in terms of (1) the depth of the anterior and posterior grooves, (2) the apposition of the valve collar to the endoscope, (3) the length of the valve, and (4) the position of the squamocolumnar junction relative to the lip of the valve. Conclusions: Current anti-reflux operations share much in common but employ varying degrees of valvular reconstruction leading to distinct endoscopic characteristics. Developing a consistent nomenclature for describing the appearance of the post-surgical valve is essential to develop a better understanding of how variables such as the tightness of the hiatal repair, tightness of the valve collar, and length of the valve can impact the outcome of anti-reflux surgery and predict reflux recurrence.

The Autosomal Dominant Polycystic Kidney Disease (ADPKD) Centers of Excellence (COE) Program, launched by the Polycystic Kidney Disease Foundation in 2022, aims to bridge the gap in specialized care for individuals with ADPKD. This program seeks to enhance the availability of specialized clinicians and simplify the process for patients seeking expert care. It is founded on three pillars: improving care for all individuals with ADPKD, educating and empowering the community, and advancing polycystic kidney disease research. The program draws inspiration from successful models in other diseases, such as cystic fibrosis and muscular dystrophy, which have demonstrated the effectiveness of standardized care centers in improving patient outcomes. Patient and clinician stakeholder interviews have identified key areas where a national program could make a significant effect, including the need for a core care team with defined referral processes, mentorship and shared care models, patient navigation services, and education around expert consensus and care guidelines. The program introduces two designations to accommodate diverse care settings and enhance patient access to specialists: COE and Partner Clinic. The Partner Clinic designation ensures that patients in smaller community practices have access to specialized care through mentorship and guidance from experts at COE. The program also emphasizes the importance of specialized services, especially in underserved communities experiencing health disparities, to manage the complexities of ADPKD care. Patient focus groups have highlighted the need for care navigation services, centralized sources of knowledge, and access to local care. The program aims to address these needs by providing a structured framework for care coordination, enhancing patient self-advocacy, and improving overall outcomes for individuals with ADPKD. Key Points The Autosomal Dominant Polycystic Kidney Disease Centers of Excellence Program aims to improve specialized care for autosomal dominant polycystic kidney disease patients. It introduces two designations to accommodate diverse care settings and enhance patient access to specialists: Center of Excellence and Partner Clinic. The program draws inspiration from successful models in other diseases, such as cystic fibrosis and muscular dystrophy, which have demonstrated the effectiveness of standardized care centers in improving patient outcomes. Key needs and programmatic goals identified through patient and clinician stakeholder interviews include establishing a core care team with defined referral processes, implementing mentorship and shared care models, providing patient navigation services, and offering education on expert consensus and care guidelines.

Study Design: A meta-analysis approach to a systematic review. Objective: Perform a systematic review to identify all reports directly comparing outcomes of lateral lumbar interbody fusion (LLIF) using static versus expandable interbody cages. Specifically focusing on periprocedural complications, intraoperative morbidity, and fusion outcomes. Summary of Background Data: Minimally invasive surgical techniques, particularly LLIF, have gained popularity for their potential to reduce muscle and soft tissue dissection, leading to faster postoperative recovery. LLIF has been associated with fewer complications compared with open posterior approaches. The introduction of expandable lumbar interbody devices aims to further reduce surgical difficulty and potential complications. However, concerns include a small graft window due to the expansion mechanism and higher costs. Methods: The Web of Science, Scopus, and PubMed databases were systematically queried in accordance with PRISMA guidelines to identify articles comparing outcomes following LLIF using static and expandable interbodies. The Newcastle-Ottawa Scale (NOS) was employed to assess the risk of bias (ROB) in the selected studies. Extracted data underwent effect-size meta-analysis with the PyMARE library, using P<0.05 to define statistical significance. Results: Of the 77 identified articles, 4 studies comprising 283 patients (mean age: 67.1 y, 55.8% female) met the inclusion and exclusion criteria. A total of 150 patients (53%) were treated with static interbodies compared with 133 (47%) receiving expandable interbodies. The groups did not differ significantly with respect to operative time (P=0.59), blood loss (P=0.89), length of stay (P=0.78), subsidence (P=0.49), 24-month mean disc height (P=0.11), 24-month mean ODI (P=0.58), or 24-month mean visual analog scale (VAS) back pain (P=0.81). The expandable group saw a trend toward improved fusion rates (97% vs. 92%, P=0.06). Conclusions: The present meta-analysis suggests the use of expandable (vs. static) interbodies in LLIF surgery may result in similar surgical morbidity, subsidence, and decompression. Further prospective comparative studies are merited to validate these results.

Abstract Task Group (TG) 314 of the American Association of Physicists in Medicine (AAPM) was charged to develop guidance for recovering from fault states in radiation therapy, specifically regarding the delivery of photon or electron beams using a linear accelerator (linac) including ancillary systems. The fault conditions addressed may involve software, hardware, or a combination of causes. The report provides detailed recommendations for the proactive steps to be taken before a fault, the actions to be taken at the time of a fault, and the safety steps before returning a linac to clinical service, as well as the activities that device manufacturers and standard organizations can do to prevent and resolve the faults. A user‐maintained log of prior faults; establishment of remote access by the vendor; and user training in emergency gantry, couch, and door motions are all useful proactive steps. At the moment of downtime and after ensuring the safety of the patient, the report stresses the importance of capturing fault information, prompt contact with the service engineer after the initial assessment, and considerations for communicating the estimated duration before the linac is returned to service. The medical physicist has a critical responsibility to assess the impact of the fault on patient care. Before resuming clinical use, the medical physicist must both determine the level of testing required to ensure safe operation of the linac and ensure any partially or totally delivered treatments have been correctly saved for accurate completion of the treatment fraction. The report stresses the roles of the radiation therapist, medical physicist, and service engineer to efficiently and safely address linac downtime. The appendices contain a description of the efforts of several organizations regarding linac safety: Integrating the Healthcare Enterprise—Radiation Oncology, International Standards Organization/International Electrotechnical Commission, Radiation Oncology Safety Stakeholder Initiative, and the AAPM Vendor Relations and Product Usability Subcommittee. Disclaimer: The recommendations of this TG should not be used to establish regulations. These recommendations are guidelines for Qualified Medical Physicists and others to use and appropriately interpret for their institution and clinical setting. Each institution may have site‐specific or state‐mandated needs and requirements which may modify their usage of these recommendations.

Background: Acute limb ischemia (ALI) requires prompt revascularization to preserve the extremity and minimize the effects of systemic reperfusion. Once ALI is recognized, delays in revascularization are generally due to system issues (e.g., transfer) and there is a need for a method of temporary extremity perfusion to reduce warm ischemic time. Lower Extremity Extracorporeal Distal Revascularization (LEEDR) is a percutaneous technique that uses a pump and circuit to deliver oxygenated blood into a pedal artery. Hypothesis: Extracorporeal perfusion can improve survival from ALI. Aims: The aim of this study is to use a swine model of prolonged hindlimb ischemia to compare survival and functional outcomes of LEEDR versus control (warm ischemia). Methods: Anesthetized female Yorkshire swine (40-60kg) underwent hindlimb ischemia using endovascular balloon occlusion and were randomized to control (n=6) or LEEDR (n=6). Controls underwent 9 hours of ischemia. LEEDR animals underwent contralateral femoral and ipsilateral posterior tibial artery cannulation followed by 8 hours of extracorporeal perfusion into the ischemic limb. Subjects were revascularized by removing the endovascular balloons, restoring extremity blood flow, and undergoing a 4-hour critical care period before extubation and observation for 48 hours. Primary outcome was survival and secondary outcomes included functional extremity scores (Tarlov Gait Score), compartment pressures (mmHg) and biochemical markers of reperfusion. Results: Survival was higher in animals undergoing LEEDR (83% vs. 0%; p=0.001), with most control animals succumbing to acute lung injury. LEEDR animals had a higher functional gait score (5.9±0.3 vs. 2.5±0.7; p<0.001) and lower compartment pressure (8±2 vs. 28±4; p=0.002) compared to controls. Biochemically, the LEEDR group had lower potassium (4.5±0.3 vs. 5.3±0.4; p=0.001) and lactate (1.2±0.5 vs. 2.0±0.7; p<0.001) measurements compared to controls during reperfusion and recovery. Conclusion: LEEDR can effectively mitigate 8 hours of extremity ischemia in a swine model, reducing mortality from reperfusion, while improving functional gait score and eliminating compartment syndrome. This percutaneous approach to ALI opens a new field of extracorporeal limb salvage, which can temporize extremity perfusion improving outcomes in patients who have traditionally had limited options due to prolonged warm ischemia.

Background: VICTORION-INITIATE (NCT04929249) showed significantly greater LDL-C lowering in patients (pts) with ASCVD with an inclisiran first (IF) strategy (adding inclisiran immediately on failure to achieve LDL-C <70 mg/dL on maximally tolerated statin therapy) vs usual care (UC). Tokenization can be leveraged to link clinical trial data to pt-level real-world data (RWD) to provide a comprehensive overview of the pt journey pre- and post-trial and enhance understanding of clinical trial and long-term pt outcomes. Aim: To utilize tokenization and linked RWD to characterize the pt journey pre-VICTORION-INITIATE enrollment. Methods: Eligible pts from VICTORION-INITIATE were deidentified and tokenized with unique IDs, allowing linking to RWD (EMR, claims, hospital, and lab records) to follow the pt journey in the 3-year pre-trial and 2-year post-trial periods. Here we present demographics, clinical characteristics, and lipid-lowering therapy (LLT) use of pts with linked pre-trial RWD. Results: Of 450 pts randomized, 383 (85.1%) were linked with pre-trial RWD (IF arm, n=193; UC arm, n=190); 26.9% were female, first available recorded mean (SD) age was 64 (9.36) years. Among the 74.2% (n=284) of pts with linked, pre-trial, lipid test RWD, mean (SD) earliest and latest LDL-C values were 100.1 mg/dL (35.70) and 99.3 mg/dL (30.06), respectively, for pts in the IF arm vs 97.3 mg/dL (40.43) and 97.8 mg/dL (27.60) for pts in the UC arm ( Table ). Overall, in the pre-trial period, LLT was dispensed/prescribed to 66.1% of pts, statins to 64.5%, ezetimibe to 4.4%, and PCSK9i to 4.4%. Of pts with ≥1 recorded ASCVD events in the pre-trial period (n=141), 53.2% and 68.8% had available LLT dispensing/prescription records pre- and post-event, respectively. Conclusions: In the 3 years pre-VICTORION-INITIATE, mean LDL-C levels were above recommended goals, non-statin LLT prescription was infrequent, and ~31% of pts with ≥1 recorded ASCVD event had no evidence of post-event LLT use, highlighting a need for more aggressive LDL-C management. Full data visibility for each pt is a limitation of this approach. Tokenization post-trial will allow for long-term evaluation of LLT practices.