Citations

Abstract Background: Two PARP inhibitors are approved for germline BRCA1/2 mutant metastatic breast cancer (MBC), based on clinical trials demonstrating an improvement in patient outcomes and quality of life. However, germline BRCA1/2 mutations are identified in 5-10% of breast cancer, limiting their potential applicability. Our prior work demonstrated that somatic BRCA1/2 mutations can be detected in cell-free DNA (cfDNA) in a proportion of patients with MBC who are not germline BRCA1/2 carriers, and that a PARP inhibitor caused growth inhibition in a circulating tumor cell line generated from a patient with MBC and a pathogenic somatic BRCA1 mutation (Vidula, Dubash, CCR, 2020). Thus, we hypothesize that a PARP inhibitor may have efficacy in somatic BRCA1/2 mutant MBC identified by cfDNA. Trial Design: This phase II investigator initiated open label clinical trial is enrolling 30 patients who have pathogenic somatic BRCA1/2 mutations found in cfDNA. Patients must not be known germline BRCA1/2 carriers. Patients receive treatment with the PARP inhibitor, talazoparib, until disease progression. Serial imaging (CT chest, abdomen, pelvis, and bone scan) occurs every 3 months, and cfDNA is collected monthly to evaluate changes in the genomic environment. Patients will also have blood collected at baseline for the Cancer Risk B assay (CR-B), a novel flow variant assay to assess double strand break repair mutations in circulating blood cells (Syeda, Genetics, 2017). Eligibility criteria: Patients with MBC (TNBC with ≥ 1 prior chemotherapy or HR+/HER2- with ≥ 1 prior hormone therapy or ineligible for hormone therapy) with a somatic BRCA1/2 mutation identified in cfDNA (established pathogenic variant) are being enrolled. Patients should not be known germline BRCA1/2 carriers (genetic testing is not required but can be obtained per physician discretion) and may not have previously received a PARP inhibitor. There is no limit on the number of prior therapies, and a prior platinum chemotherapy is allowed in the absence of disease progression on the platinum. Patients must have adequate performance status and organ function. Specific Aims: The primary endpoint is progression-free survival (PFS) using RECIST 1.1. Secondary endpoints include objective response rate and toxicity (NCI CTCAE v 5.0). Exploratory objectives include evaluating serial changes in BRCA1/2 mutant allelic frequency in cfDNA, evaluating the impact of BRCA1/2 reversion mutations, comparing pre- and post-treatment cfDNA results to identify markers of resistance, evaluating the CR-B assay positivity rate, and ultimately correlating these analyses with treatment response. Statistical Methods: A two-stage design with 80% power to demonstrate that talazoparib is associated with “success” (PFS > 12 weeks) in ≥53% patients (4% alpha) is being used. Accrual: This study (NCT03990896) is currently open at Massachusetts General Hospital, where 4 patients are completing screening for enrollment. This study will be activated soon at the University of California San Francisco, MD Anderson, Mayo Clinic Rochester and Jacksonville, Northwestern, and Emory (7 academic centers). Funding: Support for this study is provided by a Pfizer ASPIRE award and Conquer Cancer Foundation of ASCO–Breast Cancer Research Foundation- Career Development Award. Contact information: Neelima Vidula, MD, Massachusetts General Hospital, nvidula@mgh.harvard.edu Citation Format: Neelima Vidula, Erica Blouch, Erin Basile, Nathan Royce Ruffle-Deignan, Nora Horick, Senthil Damodaran, Alvaro Moreno Aspitia, Manali Bhave, Ami Shah, Minetta C. Liu, Joseph Sparano, Harry Ostrer, Hope Rugo, Leif W. Ellisen, Aditya Bardia. Phase II study of a PARP inhibitor in metastatic breast cancer with somaticBRCA1/2mutations identified by cell-free DNA: Genotyping based clinical trial [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr OT2-24-03.

Background The landmark study of durvalumab as consolidation therapy in NSCLC patients (PACIFIC trial) demonstrated significantly longer progression-free survival (PFS) in patients with locally advanced, unresectable non-small cell lung cancer (NSCLC) treated with durvalumab (immunotherapy, IO) therapy after chemoradiotherapy (CRT). In clinical practice in the USA, durvalumab continues to be used in patients across all levels of programmed cell death ligand-1 (PD-L1) expression. While immune therapies have shown promise in several cancers, some patients either do not respond to the therapy or have cancer recurrence after an initial response. It is not clear so far who will benefit of this therapy or what the mechanisms behind treatment failure are. Methods A total of 133 patients with unresectable stage III NSCLC who underwent durvalumab after CRT or CRT alone were included. Patients treated with durvalumab IO after CRT were randomly split into training (D1=59) and test (D2=59) sets and the remaining 15 patients treated with CRT alone were grouped in D3. Radiomic textural patterns from within and around the target nodules were extracted. A radiomic risk score (RRS) was built and was used to predict PFS and overall survival (OS). Patients were divided into high-risk and low-risk groups based on median RRS. Results RRS was found to be significantly associated with PFS in D1 (HR=2.67, 95% CI 1.85 to 4.13, p<0.05, C-index=0.78) and D2 (HR=2.56, 95% CI 1.63 to 4, p<0.05, C-index=0.73). Similarly, RRS was associated with OS in D1 (HR=1.89, 95% CI 1.3 to 2.75, p<0.05, C-index=0.67) and D2 (HR=2.14, 95% CI 1.28 to 3.6, p<0.05, C-index=0.69), respectively. RRS was found to be significantly associated with PFS in high PD-L1 (HR=3.01, 95% CI 1.41 to 6.45, p=0.0044) and low PD-L1 (HR=2.74, 95% CI 1.8 to 4.14, p=1.77e-06) groups. Moreover, RRS was not significantly associated with OS in the high PD-L1 group (HR=2.08, 95% CI 0.98 to 4.4, p=0.054) but was significantly associated with OS in the low PD-L1 group (HR=1.61, 95% CI 1.14 to 2.28, p=0.0062). In addition, RRS was significantly associated with PFS (HR=2.77, 95% CI 1.17 to 6.52, p=0.019, C-index=0.77) and OS (HR=2.62, 95% CI 1.25 to 5.51, p=0.01, C-index=0.77) in D3, respectively. Conclusions Tumor radiomics of pretreatment CT images from patients with stage III unresectable NSCLC were prognostic of PFS and OS to CRT followed by durvalumab IO and CRT alone.

Background Hypotension with endotracheal intubation (ETI) is common and associated with adverse outcomes. We sought to evaluate whether a previously described hypotension prediction score (HYPS) for ETI is associated with worse patient outcomes and/or clinical conditions. Methods This study is a post hoc analysis of a prospective observational multicenter study involving adult (age ≥18 years) intensive care unit (ICU) patients undergoing ETI in which the HYPS was derived and validated on the entire cohort and a stable subset (ie, patients in stable condition). We evaluated the association between increasing HYPSs in both subsets and several patient-centered outcomes and clinical conditions. Results Complete data for HYPS calculations were available for 783 of 934 patients (84%). Logistic regression analysis showed increasing odds ratios (ORs) for the highest risk category for new-onset acute kidney injury (OR, 7.37; 95% CI, 2.58-21.08); new dialysis need (OR, 8.13; 95% CI, 1.74-37.91); ICU mortality (OR, 16.39; 95% CI, 5.99-44.87); and hospital mortality (OR, 18.65; 95% CI, 6.81-51.11). Although not increasing progressively, the OR for the highest risk group was significantly associated with new-onset hypovolemic shock (OR, 6.06; 95% CI, 1.47-25.00). With increasing HYPSs, median values (interquartile ranges) decreased progressively (lowest risk vs. highest risk) for ventilator-free days (23 [18-26] vs. 1 [0-21], P < .001) and ICU-free days (20 [11-24] vs. 0 [0-13], P < .001). Of the 729 patients in the stable subset, 598 (82%) had complete data for HYPS calculations. Logistic regression analysis showed significantly increasing ORs for the highest risk category for new-onset hypovolemic shock (OR, 7.41; 95% CI, 2.06-26.62); ICU mortality (OR, 5.08; 95% CI, 1.87-13.85); and hospital mortality (OR, 7.08; 95% CI, 2.63-19.07). Conclusions As the risk for peri-intubation hypotension increases, according to a validated hypotension prediction tool, so does the risk for adverse clinical events and certain clinical conditions. Trial Registration The study was registered at ClinicalTrials.gov (NCT02508948).

AbstractAimsThe MicraTM transcatheter pacing system (TPS) (Medtronic) is the only leadless pacemaker that promotes atrioventricular (AV) synchrony via accelerometer‐based atrial sensing. Data regarding the real‐world experience with this novel system are scarce. We sought to characterize patients undergoing MicraTM‐AV implants, describe percentage AV synchrony achieved, and analyze the causes for suboptimal AV synchrony.MethodsIn this retrospective cohort study, electronic medical records from 56 consecutive patients undergoing MicraTM‐AV implants at the Mayo Clinic sites in Minnesota, Florida, and Arizona with a minimum follow‐up of 3 months were reviewed. Demographic data, comorbidities, echocardiographic data, and clinical outcomes were compared among patients with and without atrial synchronous ventricular pacing (AsVP) ≥ 70%.ResultsSixty‐five percent of patients achieved AsVP ≥ 70%. Patients with adequate AsVP had smaller body mass indices, a lower proportion of congestive heart failure, and prior cardiac surgery. Echocardiographic parameters and procedural characteristics were similar across the two groups. Active device troubleshooting was associated with higher AsVP. The likely reasons for low AsVP were small A4‐wave amplitude, high ventricular pacing burden, and inadequate device reprogramming. Importantly, in patients with low AsVP, subjective clinical worsening was not noted during follow‐up.ConclusionWith the increasing popularity of leadless pacemakers, it is paramount for device implanting teams to be familiar with common predictors of AV synchrony and troubleshooting with MicraTM‐AV devices.

Slow deep breathing (SDB) may help patients with acute pain. The primary aim of this systematic review and meta-analysis is to investigate the effects of SDB on acute pain. Secondary aims include investigating the effects of SDB on acute pain-related physical and emotional functioning. An a priori protocol was registered and a database search was conducted by a reference librarian. Randomized controlled trials (RCT) were eligible for inclusion and exclusion criteria included studies of SDB for non-pain indications and studies that applied SDB as a component of an encompassing intervention. The risk or bias was assessed using the Cochrane Collaboration's revised tool for assessing risk of bias in randomized trials. Meta-analysis was conducted using the random effects model. A total of 11 968 studies were screened and seven RCTs met inclusion criteria; five were judged to have low risk of bias. Meta-analysis of post-intervention pain scores demonstrated that SDB was associated with significantly lower pain scores compared with a control group, but with high levels of heterogeneity. Subgroup analyzes demonstrated that trials of burn pain were associated with a larger reduction in pain which partially explains the heterogeneity. Very low certainty evidence suggests that SDB may reduce acute pain intensity. Further research is needed to identify patients who are candidates for SDB and determine the best approach to deliver this therapy.

Abstract Chiari malformation is a relatively rare condition involving herniation of the brain out of the skull and into the spinal canal. The purpose of this review was to identify top contributors to the world of Chiari research, as well as to highlight the publications which have shaped our perception of this condition.We performed a search of the Web of Science between the years 1900 and 2021 using the terms “Chiari I malformation”, “Arnold Chiari malformation”, “Chiari II malformation”, “Chiari malformation type 1”, and “Chiari malformation type 2”. After screening for duplicates and assessing for relevance using two independent reviewers, the top 100 most frequently cited articles were collected and sorted. These articles were published between the years 1938 and 2015 and were cited 145.7 times on average, ranging from 79 to 724 citations per article. Authored by Milhorat et al., the 1999 Neurosurgery article “Chiari I Malformation Redefined: Clinical and Radiographic Findings for 364 Symptomatic Patients” received most citations (724 citations). Journal of Neurosurgery contributed the most articles to the top-100 with 21 publications. The University of California system accounted for the most articles by institution (8 of 100) and the USA was the highest contributing country (62%). In this study, we identified and analyzed the most cited articles on Chiari malformations to gain a better understanding of the publications contributing our knowledge of this disorder. This analysis serves both as a way of gauging the current state of research and of recognizing gaps where further research is necessary.

Abstract Background This North Central Cancer Treatment Group (NCCTG) N064A (Alliance) phase II trial evaluated upfront chemoradiotherapy incorporating the EGFR inhibitor panitumumab, followed by gemcitabine and panitumumab for unresectable, non-metastatic pancreatic cancer. Methods The treatment consisted of fluoropyrimidine and panitumumab given concurrently with radiotherapy followed by gemcitabine and panitumumab for 3 cycles followed by maintenance panitumumab. The primary endpoint was the 12-month overall survival (OS) rate and secondary endpoints included confirmed response rate (RR), OS, progression-free survival (PFS), and adverse events. Enrollment of 50 patients was planned and the study fully accrued. Results Fifty-two patients were enrolled, but only 51 were treated and included in the analysis. The median age of patients was 65 years and 54.9% were women. Twenty-two patients received at least 1 cycle of systemic therapy following radiotherapy, but 29 patients received chemoradiotherapy only without receiving subsequent chemotherapy after completion of chemoradiotherapy. The overall RR was 5.9% (95% CI: 1.2%-16.2%). The 12-month OS rate was 50% (95% CI: 38%-67%) which fell short of the per-protocol goal for success (51.1%). The median PFS was 7.4 months (95% CI: 4.5-8.6) and the median OS was 12.1 months (95% CI 7.9-15.9). Grade 3 or higher adverse events were reported by 88%. Conclusion The combination of panitumumab, chemotherapy, and external beam radiation therapy was associated with very high rates of grades 3-4 toxicities and survival results did not meet the trial’s goal for success. This regimen is not recommended for further study (ClinicalTrials.gov Identifier NCT00601627).