Citations

Background: Severe intracranial atherosclerosis, in excess of 70% luminal stenosis, is an established cause of recurrent stroke. Collateral circulation and the hemodynamic effects of such stenoses, however, may further delineate such risk. We conducted angiographic analyses in the SAMMPRIS trial to correlate the degree of collaterals and hemodynamic effects of such stenoses with baseline clinical and imaging characteristics of enrolled subjects. Methods: Baseline angiography of SAMMPRIS subjects was submitted for blinded review to grade collaterals with the ASITN/SIR scale and antegrade flow across the lesion with TICI. Hemodynamic effect was defined as any flow reduction (a partial TICI score). The association of these angiographic scores (dichotomized as none/partial versus complete collaterals and partial versus complete TICI) and baseline demographic, clinical and imaging variables were evaluated using chi-square tests for percentages and independent group t-tests for means. Results: 424/451 subjects enrolled in SAMMPRIS had baseline angiography available for review, with adequate information to score collaterals in 376 cases. Complete collaterals were noted in 117 (31%). Hemodynamic effects (partial TICI scores) were noted in only 188 (50%) of these lesions, which were all in excess of 70% luminal stenosis. Mean lesion length (n=184, from stenting arm) did not differ between the two categories of either collaterals or hemodynamic impairment. Mean percent stenosis was higher for patients with complete collaterals (none/partial, mean 73.7%; complete, 77.4%; p<0.001) and hemodynamic impairment was more common (p<0.001). More robust collaterals (complete versus none/partial) were associated with patients who at baseline were younger (mean age 58.0 versus 61.5 years; p=0.009), had higher serum HDL (40.0 versus 37.7 mg /dL, p=0.035), participated in moderate exercise (43.1 versus 27.9%, p=0.004) and did not smoke (79.5 versus 69.4%, p=0.042). Previously reported associations with collateral circulation (diabetes, statins, presence of infarction on CT or MRI) were inapparent. These relationships of collaterals with hemodynamic impairment and other baseline variables were established across all anatomical distributions of intracranial stenosis. Conclusions: Severe intracranial atherosclerotic lesions are not always associated with hemodynamic effects. Collateral circulation may also frequently compensate for severe stenosis, with more robust collaterals in younger and healthier individuals.

Background: The degree of collateral circulation is a powerful risk factor for recurrent stroke in the setting of medical therapy for symptomatic intracranial atherosclerosis. The impact of collaterals on the short-term risk for stroke in patients treated by stenting or intensive medical therapies is not known. We systematically evaluated baseline angiographic features of collateral circulation and antegrade flow across intracranial stenoses in randomized subjects of the multicenter SAMMPRIS trial and correlated these to their 30-day risk of ischemic stroke. Methods: Digital review of baseline angiograms in SAMMPRIS was conducted to score ASITN/SIR collateral grade and TICI antegrade flow, blind to other data. Dichotomized collateral and TICI scores (none/partial versus complete) were analyzed independently and in combinations with trial endpoints of territorial ischemic stroke or stroke in territory (SIT) and intracranial hemorrhage (ICH) within 30 days in the intensive medical and stenting arms of the study. Log-rank tests with follow-up time censored at 30 days were used in the analysis. Results: Collaterals could be assessed on 376/424 baseline angiography studies available for digital imaging review for the 451 randomized subjects in SAMMPRIS (186 medical, 190 stenting). Early territorial stroke (SIT) occurred in 6/186 (3.2%) subjects in the medical arm and 20/190 (10.5%) after stenting. SIT was not associated with TICI in either arm, whereas collaterals exerted a potent protective influence in medical (p=0.067) and stented (p=0.004) cases, with 0/66 (0%) SIT in the medical arm and 0/51 (0%) SIT in the stented arm when collaterals were complete. SIT in medical cases was associated with partial TICI/partial collaterals (5/25 (20.0%)) versus complete TICI/partial collaterals (1/95 (1.1%)) and partial TICI/complete collaterals (0/66 (0%)), p<0.001. SIT in stented cases was associated with partial TICI/partial collaterals (11/46 (23.9%)) versus complete TICI/partial collaterals (9/93 (9.7%)) and partial TICI/complete collaterals (0/51 (0%)), p<0.001. ICH within 30 days occurred in 0/186 (0%) subjects randomized to medical therapy. In the stenting arm, early ICH occurred in 8/190 (4.2%) and was associated with TICI (p=0.036) and collaterals (p=0.077). Overall, early ICH after stenting was associated with partial TICI/partial collaterals (7/46 (15.2%)) versus complete TICI/partial collaterals (1/93 (1.1%)) and partial TICI/complete collaterals (0/51 (0%)), p<0.001. Conclusions: Patients with impaired collateral flow associated with severe intracranial stenosis had the highest risk for stroke within 30 days, both with intensive medical therapy and as a complication of angioplasty and stenting.

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 &gt; 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.

We hypothesized that elevation in muscle sympathetic nervous system activity (MSNA) during hyperinsulinemia is mediated by its peripheral vasodilator effect on the arterial baroreflex. Using three separate protocols in humans, we observed increases in both MSNA and cardiac output during hyperinsulinemia, which we attributed to the baroreflex response to peripheral vasodilation induced by insulin. Results show that peripheral vasodilation induced by insulin contributes to increased MSNA during hyperinsulinemia.

PURPOSE Chemotherapy outcomes in older patients with Philadelphia (Ph) chromosome–negative B-acute lymphoblastic leukemia (ALL) are very poor. Here, we evaluated blinatumomab as induction and consolidation therapy followed by prednisone, vincristine, 6-mercaptopurine, and methotrexate (POMP) maintenance chemotherapy in this patient population. PATIENTS AND METHODS Patients were treated at National Clinical Trial Network sites. Eligibility criteria included age ≥ 65 years and newly diagnosed Ph chromosome–negative B-ALL. Patients received blinatumomab as induction for one-two cycles until attainment of response (complete remission (CR) and CR with incomplete count recovery). Patients then received three cycles of consolidation with blinatumomab followed by 18 months of POMP maintenance chemotherapy. Eight doses of intrathecal methotrexate were administered as central nervous system prophylaxis. RESULTS Twenty-nine eligible patients were enrolled. The median age was 75 years, and the median bone marrow blast count at diagnosis was 87%. Cytogenetic risk was poor in 10 patients (34%), and five of 14 patients (36%) tested had the Ph-like ALL gene signature. Nineteen patients (66%; 95% CI, 46 to 82) achieved CR. Kaplan-Meier 3-year disease-free survival and overall survival estimates were 37% (95% CI, 17 to 57) and 37% (95% CI, 20 to 55), respectively. CONCLUSION Blinatumomab was well tolerated and effective in the treatment of older patients with newly diagnosed Ph chromosome–negative B-ALL, including patients with poor-risk cytogenetics. The 3-year disease-free survival and overall survival results are encouraging and suggest that this approach should be further explored.

Abstract Background and purpose Cognitive complaints are common in patients recovering from Coronavirus Disease 2019 (COVID-19), yet their etiology is often unclear. We assess factors that contribute to cognitive impairment in ambulatory versus hospitalized patients during the sub-acute stage of recovery. Methods Participants were prospectively recruited from a hospital-wide registry. All patients tested positive for SARS-CoV-2 infection using a real-time reverse transcriptase polymerasechain-reaction assay. Patients ≤ 18 years-of-age and those with a pre-existing major neurocognitive disorder were excluded. Participants completed an extensive neuropsychological questionnaire and a computerized cognitive screen via remote telemedicine platform. Rates of subjective and objective neuropsychological impairment were compared between the ambulatory and hospitalized groups. Factors associated with impairment were explored separately within each group. Results A total of 102 patients (76 ambulatory, 26 hospitalized) completed the symptom inventory and neurocognitive tests 24 ± 22 days following laboratory confirmation of SARSCoV-2 infection. Hospitalized and ambulatory patients self-reported high rates of cognitive impairment (27-40%), without differences between the groups. However, hospitalized patients showed higher rates of objective impairment in visual memory (30% vs. 4%; p=0.001) and psychomotor speed (41% vs. 15%; p=0.008). Objective cognitive test performance was associated with anxiety, depression, fatigue, and pain in the ambulatory but not the hospitalized group. Conclusions Focal cognitive deficits are more common in hospitalized than ambulatory patients. Cognitive performance is associated with neuropsychiatric symptoms in ambulatory but not hospitalized patients. Objective neurocognitive measures can provide essential information to inform neurologic triage and should be included as endpoints in clinical trials.

Gastric cancer is the third leading cause of cancer-related deaths worldwide. Over 95% of gastric cancers are adenocarcinomas, which are typically classified based on anatomic location and histologic type. Gastric cancer generally carries a poor prognosis because it is often diagnosed at an advanced stage. Systemic therapy can provide palliation, improved survival, and enhanced quality of life in patients with locally advanced or metastatic disease. The implementation of biomarker testing, especially analysis of HER2 status, microsatellite instability (MSI) status, and the expression of programmed death-ligand 1 (PD-L1), has had a significant impact on clinical practice and patient care. Targeted therapies including trastuzumab, nivolumab, and pembrolizumab have produced encouraging results in clinical trials for the treatment of patients with locally advanced or metastatic disease. Palliative management, which may include systemic therapy, chemoradiation, and/or best supportive care, is recommended for all patients with unresectable or metastatic cancer. Multidisciplinary team management is essential for all patients with localized gastric cancer. This selection from the NCCN Guidelines for Gastric Cancer focuses on the management of unresectable locally advanced, recurrent, or metastatic disease.