Citations

AbstractBackgroundThe development of systemic treatment options leveraging the molecular landscape of advanced thyroid cancer is a burgeoning field. This is a multidisciplinary evidence‐based statement on the definition of advanced thyroid cancer and its targeted systemic treatment.MethodsAn expert panel was assembled, a literature review was conducted, and best practice statements were developed. The modified Delphi method was applied to assess the degree of consensus for the statements developed by the author panel.ResultsA review of the current understanding of thyroid oncogenesis at a molecular level is presented and characteristics of advanced thyroid cancer are defined. Twenty statements in topics including the multidisciplinary management, molecular evaluation, and targeted systemic treatment of advanced thyroid cancer are provided.ConclusionsWith the growth in targeted treatment options for thyroid cancer, a consensus definition of advanced disease and statements regarding the utility of molecular testing and available targeted systemic therapy is warranted.

AbstractBackgroundThough infrequent, incomplete left atrial appendage closure (LAAC) may result from residual leaks. Percutaneous closure has been described though data is limited.MethodsWe compiled a registry from four centers of patients undergoing percutaneous closure of residual leaks following LAAC via surgical means or with the Watchman device. Leak severity was classified as none (no leak), mild (1–2 mm), moderate (3–4 mm), or severe (≥5 mm). Procedural and clinical success was defined as the elimination of leak or mild residual leak at the conclusion of the procedure or follow‐up, respectively.ResultsOf 72 (age 72.2 ± 9.2 years; 67% male) patients, 53 had undergone prior LAAC using the Watchman device and 19 patients surgical LAAC. Mean CHADS2‐VA2Sc score was 4.0 ± 1.8. The median leak size was 5 mm, range: 2–13). A total of 13 received Amplatzer Vascular Plug‐II, 18 received Amplatzer Duct Occluder‐II and 40 patients received coils. One underwent closure using a 21 mm‐Watchman. Procedural success was 94%. Zero surgical and nine Watchman patients (13%) had a residual leak at procedural‐end (five mild, three moderate, and one severe)—only one patient had no reduction in leak size. Overall leak size reduction was 94%. Two (3%) had intraoperative pericardial effusion. There were no device embolizations, device‐related thrombi, or procedural deaths. Clinical success was maintained at 94%. Two had cerebrovascular accidents—at 2 days (transient ischemic attack) and 10 months postprocedure. Two had major bleeding outside the 30‐day periprocedural window.ConclusionPercutaneous closure of residual leaks following left atrial appendage closure is feasible and associated with good outcomes. The procedural risk appears to be satisfactory.

Abstract Pulsed electric fields (PEFs) have emerged as an ideal cardiac ablation modality. At present numerous clinical trials in humans are exploring PEF as an ablation strategy for both atrial and ventricular arrhythmias, with early data showing significant promise. As this is a relatively new technology there is limited understanding of its principles and biophysics. Importantly, PEF biophysics and principles are starkly different to current energy modalities (radiofrequency and cryoballoon). Given the relatively novel nature of PEFs, this review aims to provide an understanding of the principles and biophysics of PEF ablation. The goal is to enhance academic research and ultimately enable optimization of ablation parameters to maximize procedure success and minimize risk.

Background and objectives The progression of polycystic liver disease is not well understood. The purpose of the study is to evaluate the associations of polycystic liver progression with other disease progression variables and classify liver progression on the basis of patient's age, height-adjusted liver cystic volume, and height-adjusted liver volume. Design, setting, participants, & measurements Prospective longitudinal magnetic resonance images from 670 patients with early autosomal dominant polycystic kidney disease for up to 14 years of follow-up were evaluated to measure height-adjusted liver cystic volume and height-adjusted liver volume. Among them, 245 patients with liver cyst volume >50 ml at baseline were included in the longitudinal analysis. Linear mixed models on log-transformed height-adjusted liver cystic volume and height-adjusted liver volume were fitted to approximate mean annual rate of change for each outcome. The association of sex, body mass index, genotype, baseline height-adjusted total kidney volume, and Mayo imaging class was assessed. We calculated height-adjusted liver cystic volume ranges for each specific age and divided them into five classes on the basis of annual percentage increase in height-adjusted liver cystic volume. Results The mean annual growth rate of height-adjusted liver cystic volume was 12% (95% confidence interval, 11.1% to 13.1%; P <0.001), whereas that for height-adjusted liver volume was 2% (95% confidence interval, 1.9% to 2.6%; P <0.001). Women had higher baseline height-adjusted liver cystic volume than men, but men had higher height-adjusted liver cystic volume growth rate than women by 2% (95% confidence interval, 0.4% to 4.5%; P =0.02). Whereas the height-adjusted liver cystic volume growth rate decreased in women after menopause, no decrease was observed in men at any age. Body mass index, genotype, and baseline height-adjusted total kidney volume were not associated with the growth rate of height-adjusted liver cystic volume or height-adjusted liver volume. According to the height-adjusted liver cystic volume growth rate, patients were classified into five classes (number of women, men in each class): A (24, six); B (44, 13); C (43, 48); D (28, 17); and E (13, nine). Conclusions Compared with height-adjusted liver volume, the use of height-adjusted liver cystic volume showed greater separations in volumetric progression of polycystic liver disease. Similar to the Mayo imaging classification for the kidney, the progression of polycystic liver disease may be categorized on the basis of patient’s age and height-adjusted liver cystic volume.

Background and objectives Documentation is important for quality improvement, education, and research. There is currently a lack of recommendations regarding key aspects of documentation in regional anesthesia. The aim of this study was to establish recommendations for documentation in regional anesthesia. Methods Following the formation of the executive committee and a directed literature review, a long list of potential documentation components was created. A modified Delphi process was then employed to achieve consensus amongst a group of international experts in regional anesthesia. This consisted of 2 rounds of anonymous electronic voting and a final virtual round table discussion with live polling on items not yet excluded or accepted from previous rounds. Progression or exclusion of potential components through the rounds was based on the achievement of strong consensus. Strong consensus was defined as ≥75% agreement and weak consensus as 50%–74% agreement. Results Seventy-seven collaborators participated in both rounds 1 and 2, while 50 collaborators took part in round 3. In total, experts voted on 83 items and achieved a strong consensus on 51 items, weak consensus on 3 and rejected 29. Conclusion By means of a modified Delphi process, we have established expert consensus on documentation in regional anesthesia.

TPS194 Background: Despite a growing number of treatment options for first line mCRPC, approximately 40% of patients (pts) have radiographic progression within the first year. Androgen receptor (AR) signaling inhibition increases genomic instability with double-strand DNA breaks & co-inhibition of AR & PARP induces synthetic lethality in multiple preclinical models. Homologous recombination repair (HRR) gene aberrations do not appear to be necessary for this synergy as demonstrated in a ph 2 clinical trial of abiraterone & olaparib where this combination improved radiographic progression-free survival (rPFS) in HRR-wild-type pts compared with abiraterone alone. A ph 1b trial has since shown that enzalutamide plus rucaparib has acceptable safety profile & no significant drug-drug interactions (S-DDI). Methods: CASPAR/A031902 (NCT04455750) is a ph 3 study in which 984 pts will be randomized 1:1 to enzalutamide plus rucaparib or placebo. HRR gene aberration is not required for enrollment. All pts will undergo next-generation targeted-exome sequencing from archival tumor tissue (new biopsy only required if no archival tissue available). Treatment will be continued until disease progression & crossover is not allowed. Key eligibility criteria are age ≥ 18 years, ECOG PS 0-2, biopsy-proven prostate adenocarcinoma, progressive (PSA or radiographic) disease per Prostate Cancer Working Group 3 guidelines, measurable or nonmeasurable disease per RECIST 1.1, no prior treatment for mCRPC (prior docetaxel, abiraterone, darolutamide, or apalutamide in non-mCRPC setting is allowed), no significant uncontrolled comorbidity, & no medications with S-DDI with enzalutamide/rucaparib. Hierarchical co-primary endpoints are rPFS & overall survival (OS). The OS analysis will be undertaken as a primary endpoint if the rPFS endpoint is met. For a one-sided logrank test with a type 1 error rate equal to 0.025, the study has 90% power to detect a hazard ratio (HR) of 0.71 in rPFS (median rPFS of 15 & 21 months in control & combination arms, respectively) & 80% power to detect an HR of 0.80 in OS (median OS of 32 & 40 months, respectively). Key secondary endpoints are rPFS & OS in pts with vs without pathogenic BRCA1, BRCA2, or PALB2 alterations; & differences in adverse events & quality of life (QOL) outcomes between the treatment arms. QOL assessments include Functional Assessment of Cancer Therapy–Prostate (FACT-P), Brief Pain Inventory Short Form (BPI-SF) & EQ-5D-5L. A key correlative endpoint is the sensitivity of ctDNA-based testing for alterations in HRR genes. Enrollment to CASPAR began in July 2021 & the study is available for participation to all US-NCTN sites with a projected enrollment of 3 years. Support: U10CA180821, U10CA180882, U24CA196171; U10CA180888; Clovis Oncology; http://acknowledgments.alliancefound.org Clinical trial information: NCT04455750.

518 Background: Cisplatin (C) based neoadjuvant chemotherapy (NAC) has been the mainstay treatment for muscle invasive bladder cancer (MIBC). However, the optimal choice of NAC is not well-established. We therefore conducted a network-meta-analysis (NMA) to assess comparative efficacy of different treatment options. Methods: Several electronic databases (MEDLINE, and EMBASE) and conference proceedings were systematically used to identify randomized trials evaluating first-line treatments in neoadjuvant MIBC. Outcomes of interest included overall survival (OS), progression-free survival (PFS), objective response rate (ORR) and pathologic complete response (pCR). DerSimonian-Laird random-effects meta-analysis was used to compute direct comparisons between NAC and local therapy (LT) only. Fixed effect NMA was conducted within the frequentist framework for mixed treatment comparisons. P-scores were used to assess relative treatment rankings. All statistical analyses were conducted in R (v 4.1.1). Results: This systematic review included 23 trials (25 references) with a total of 5313 patients with 10 unique treatments. Direct comparisons showed significant benefit in PFS (HR: 0.82; 95% CI: 0.71-0.94), and in OS (HR: 0.85; 95% CI: 0.78-0.92) with NAC when compared to LT only. However, the likelihood of achieving an objective response (RR: 1.18; 95% CI: 0.72-1.95: I2: 85%) or CR (RR: 1.51; 95% CI: 0.87-2.61; I2: 79%) was not different between the two arms. Data available in 15 trials contributed to the network for PFS outcome while only eight trials contributed to OS outcome. Mixed treatment comparisons showed significantly improved PFS with nintedanib-gemcitabine-cisplatin (NinGC; HR: 0.42; 95% CI: 0.20-0.87) and dose-dense-methotrexate-vinblastine-doxorubicin-cisplatin (ddMVAC; HR: 0.61; 95% CI: 0.43-0.88) compared to LT only. Consistent benefit was observed when NinGC (HR: 0.48; 95% CI: 0.24-0.97) and ddMVAC (HR: 0.70; 95% CI: 0.51-0.96) were compared to GC only. However, no significant differences were observed between NinGC (rank 1) and ddMVAC (rank 2) or among other mixed treatment comparisons. Similarly, OS was significantly improved with NinGC (rank 1) relative to MVAC (HR: 0.41; 95% CI: 0.17-0.97), MVC (HR: 0.37; 95% CI: 0.16-0.88), MC (HR: 0.38; 95% CI: 0.16-0.92), AC (HR: 0.36; 95% CI: 0.15-0.91), and GC (HR: 0.39; 95% CI: 0.17-0.90). While similar results were observed with ddMVAC (rank 2) when compared to MVC (HR: 0.63; 95% CI: 0.42-0.94), MC (HR: 0.64; 95% CI: 0.42-0.98), and GC (HR: 0.66; 95% CI: 0.47-0.92), no significant differences were observed with ddMVAC when compared to MVAC (HR: 0.62; 95% CI: 0.38-1.01) and NinGC (HR: 1.70; 95% CI: 0.69-4.19). Conclusions: Current evidence shows improved PFS and OS with the use of neoadjuvant ddMVAC and Nin-GC in patients with MIBC relative to other treatment options.

360 Background: Pembrolizumab has been established as an effective treatment option in adjuvant renal cell carcinoma after the publication of KEYNOTE-564. However, the magnitude of benefit based on different risk categories is not well defined. Methods: We included full-text publications of phase II/III randomized controlled trials (RCTs) evaluating immune checkpoint inhibitors or tyrosine kinase inhibitors (TKIs) in adjuvant renal cell carcinoma after a systematic search. The outcomes of interest included disease free survival (DFS), overall survival (OS), all grade or grade ≥3 treatment related, and all cause adverse events. Mixed treatment comparisons were computed through a fixed-effect multivariate meta-regression within the frequent framework. Relative treatment rankings were assessed using P-scores. We used stratified baseline risks of disease progression from observational data and at 5, 10, 15 years from the Leibovich risk stratification system (based on risk scores ranging from 0 to ≥15). Corresponding intervention risks (CIRs) were then approximated using relative effect estimates (from NMA) and baseline risks. The difference between CIRs and baseline risks were calculated to present absolute risk differences in each baseline category. Results: This NMA included six RCTs with a total of 7525 participants and five unique treatment options. Mixed treatment comparisons showed significant DFS and OS benefit with pembrolizumab (rank 1) when compared against sunitinib (DFS HR 0.74 [0.55-0.99]; OS HR 0.51 [0.27-0.94]). However, there were no significant differences with pembrolizumab compared to pazopanib (DFS HR 0.81 [0.60- 1.09]; OS HR 0.54[0.29-1.01]) and axitinib (DFS HR 0.78 [0.54-1.14]; OS HR 0.52 [0.24-1.16]). The safety profiles were comparable. Absolute benefit of TKIs in adjuvant setting was minimal whereas this benefit increased with higher T and N patients in patients treated with pembrolizumab (Table). Similarly, the treatment benefit increased with higher Leibovich’s risk scores at 5, 10 and 15 years of follow up. Conclusions: The current analysis suggests that a risk adapted approach may be useful when considering adjuvant pembrolizumab in RCC patients.[Table: see text]

165 Background: A prior study of patients with advanced cancers treated with immune checkpoint inhibitors (ICI) associated improved overall survival with tissue tumor mutational burden above the 80th percentile in each histology (tTMB-H). TMB can also reliably be calculated via liquid biopsy (bTMB), and trends higher than tTMB in analogous tumors. Here, we generate a plasma-informed benchmark for bTMB-H in advanced prostate cancer and report preliminary data from an ongoing multi-institutional case series of patients treated with ICI. Methods: Circulating tumor DNA (ctDNA) next generation sequencing (NGS) results from 3,504 patients with advanced prostate cancer who received a Guardant360 liquid biopsy within a 12-month period were analyzed. The 80th percentile of TMB was defined as the benchmark for bTMB-H in this cohort, and prevalence of microsatellite instability (MSI-H) was determined. Subsequently, clinical data were collected from patients across five institutions who received pembrolizumab based on bTMB scores or other tumor characteristics (i.e. CDK12 mutation). Results: Overall, mean and median bTMB were calculated as 12.34 mut/Mb and 8.61 mut/Mb, respectively (range: 0 – 1164.75 mut/Mb). The 80th percentile of bTMB was 13.4 mut/Mb and the 90th percentile was 16.6 mut/Mb. 2.6% of patients were both MSI-H and bTMB-H. No patients with bTMB < 13.4 mut/Mb (TMB-L) were found to be MSI-H. Ten patients from five institutions received pembrolizumab (8 monotherapy) after a median of 4.5 lines of prior therapy (Table). Four patients were MSI-H. The 3 patients in the cohort with PSA decreases > 50% had both MSI-H and bTMB ≥ 13.4 mut/Mb. Per RECIST criteria, disease was controlled (CR, PR, SD) in 6 of 7 (86%) patients with bTMB scores ≥ 13.4 mut/Mb. Conclusions: These data continue to affirm that ctDNA NGS is a practical and cost-effective means of assessing potential predictors of ICI activity in patients with advanced prostate cancer. Preliminary data from this growing cohort of patients who have received ICI guided by bTMB scores and other molecular parameters identified via ctDNA NGS, including MSI-H, demonstrate a clinical benefit from therapy. Further studies are warranted for contextualizing individual tumor bTMB scores with established, pathology-specific benchmarks.[Table: see text]