Racial and Ethnic Inequities at the Practice and Physician Levels in Timely Next-Generation Sequencing for Patients With Advanced Non-Small-Cell Lung Cancer Treated in the US Community Setting.

PURPOSE: Racial/ethnic inequities in next-generation sequencing (NGS) were examined for patients with advanced non-small-cell lung cancer (aNSCLC) at the practice and physician levels to inform policies to improve equitable quality of care. METHODS: This retrospective study used a nationwide electronic health record-derived deidentified database for patients with aNSCLC diagnosed between April 2018 and March 2022 in the community setting. Timely NGS was an NGS result between initial diagnosis and ≤60 days after advanced diagnosis. We studied how inequities were driven by (1) non-Latinx Black (Black) and Latinx patient under-representation at high testing practices versus (2) Black and Latinx patients being tested at lower rates than non-Latinx White (White) patients, even at the same practice. We defined these two concepts as across inequity and within inequity, respectively, with total inequity as their summation. Mean percentage point inequities were estimated using a Bayesian approach. RESULTS: A total of 12,045 patients (9,981 White; 1,528 Black; 536 Latinx) met study criteria. At the practice level, versus White patients, the mean percentage point difference in NGS testing total inequity was 7.49 for Black and 8.26 for Latinx. Within- and across-practice inequities contributed to total inequity in NGS testing for Black (48% v 52%) and Latinx patients (60% v 40%). At the physician level, versus White patients, the mean percentage point difference in total inequity was 7.73 for Black and 8.81 for Latinx patients. Within- versus across-physician inequities contributed to total inequity for Black and Latinx patients (77% v 23% and 67% v 33%). CONCLUSION: Within-practice, across-practice, and across-physician inequities were main contributors to total inequity in NGS testing, requiring a suite of interventions to effectively address inequities.

Why seemingly more difficult test conditions produce more accurate recognition of semantic prototype words: A recognition memory paradox?

Subjects studied Deese-Roediger-McDermott semantic-associate lists and took a recognition test. The makeup and number of test probes were manipulated. In Experiments 1 and 2A, one of three or all three distractors were semantically related to the list theme. In Experiment 2B, 6 or 30 related probes were used at test. Results showed that semantically related distractors and a longer list of test words both had a beneficial effect on the accurate discrimination of the prototype lures from the studied semantic associates and on the discrimination of studied from unstudied prototype words. These findings are inconsistent with predictions of memory interference and activation theories. We propose that the counterintuitive findings can be explained by the notion of old/new recognition as categorization learning and that relatedness and a larger number of test probes provide more accurate information about the prototype lure as a distractor, thereby improving its classification as a distractor.

Hypoxia-activated evofosfamide for treatment of recurrent bevacizumab-refractory glioblastoma: a phase I surgical study.

Background: Anti-angiogenic therapy is known to induce a greater degree of hypoxia, including in glioblastoma (GBM). Evofosfamide (Evo) is a hypoxia-activated prodrug which is reduced, leading to the release of the alkylating agent bromo-isophosphoramide mustard. We assessed the safety, tolerability, preliminary efficacy, and biomarkers of Evo plus bevacizumab (Bev) in Bev-refractory GBM. Methods: Twenty-eight patients with Bev-refractory GBM were enrolled in a dose escalation study receiving from 240 mg/m2 (cohort 1) to 670 mg/m2 (cohort 4) of Evo every 2 weeks in combination with Bev. Patients deemed surgical candidates underwent a single dose of Evo or placebo with pimonidazole immediately prior to surgery for biomarker evaluation, followed by dose escalation upon recovery. Assessments included adverse events, response, and survival. Results: Evo plus Bev was well tolerated up to and including the maximum dose of 670 mg/m2, which was determined to be the recommended phase II dose. Overall response rate was 17.4%, with disease control (complete response, partial response, and stable disease) observed in 14 (60.9%) of the 23 patients. The ratio of enhancement to non-enhancement was significant on log-rank analysis with time to progression (P = 0.023), with patients having a ratio of less than 0.37 showing a median progression-free survival of 98 days versus 56 days for those with more enhancement. Conclusions: Evo plus Bev was well tolerated in patients with Bev-refractory GBM, with preliminary evidence of activity that merits further investigation.

The role of decision criterion in the Deese-Roediger-McDermott (DRM) false recognition memory: False memory falls and rises as a function of restriction on criterion setting.

How much of the Deese-Roediger-McDermott (DRM) false memory is attributable to decision criterion is so far a controversial issue. Previous studies typically used explicit warnings against accepting the critical lure to investigate this issue. The assumption is that if the false memory results from using a liberally biased criterion, it should be greatly reduced or eliminated by an explicit warning against accepting the critical lure. Results showed that warning was generally ineffective. We asked the question of whether subjects can substantially reduce false recognition without being warned when the test forces them to make a distinction between true and false memories. Using a two-alternative forced choice in which criterion plays a relatively smaller role, we showed that subjects could indeed greatly reduce the rate of false recognition. However, when the forced-choice restriction was removed from the two-item choice test, the rate of false recognition rebounded to that of the hit for studied list words, indicating the role of criterion in false recognition.

The effects of increasing semantic-associate list length on the Deese-Roediger-McDermott false recognition memory: Dual false-memory process in retrieval from sub- and supraspan lists.

In this study, the number of semantic associates in Deese-Roediger-McDermott (DRM) lists was varied from 4 to 14 in a modified Sternberg paradigm. The false alarm (FA) and correct rejection (CR) reaction time (RT)/memory-set size (MSS) functions of critical lures showed a cross-over interaction at approximately MSS 7, suggesting a reversal of the relative dominance between these two responses to the critical lure at this point and also indicating the location of the boundary between the sub- and supraspan MSS. For the subspan lists, FA to critical lures was slower than CR, suggesting a slow, strategic mechanism driving the false memory. Conversely, for the supraspan lists, critical lure FA was faster than its CR, suggesting a spontaneous mechanism driving the false memory. Results of two experiments showed that an automatic, fast, and a slow, controlled process could be error-prone or error-corrective, depending on the length of the DRM memory list. Thus there is a dual retrieval process in false memory as in true memory. The findings can be explained by both the activation/monitoring and the fuzzy-trace theories.

Rhenium-186 liposomes as convection-enhanced nanoparticle brachytherapy for treatment of glioblastoma.

Although external beam radiation is an essential component to the current standard treatment of primary brain tumors, its application is limited by toxicity at doses more than 80 Gy. Recent studies have suggested that brachytherapy with liposomally encapsulated radionuclides may be of benefit, and we have reported methods to markedly increase the specific activity of rhenium-186 ((186)Re)-liposomes. To better characterize the potential delivery, toxicity, and efficacy of the highly specific activity of (186)Re-liposomes, we evaluated their intracranial application by convection-enhanced delivery in an orthotopic U87 glioma rat model. After establishing an optimal volume of 25 µL, we observed focal activity confined to the site of injection over a 96-hour period. Doses of up to 1850 Gy were administered without overt clinical or microscopic evidence of toxicity. Animals treated with (186)Re-liposomes had a median survival of 126 days (95% confidence interval [CI], 78.4-173 days), compared with 49 days (95% CI, 44-53 days) for controls. Log-rank analysis between these 2 groups was highly significant (P = .0013) and was even higher when 100 Gy was used as a cutoff (P < .0001). Noninvasive luciferase imaging as a surrogate for tumor volume showed a statistically significant separation in bioluminescence by 11 days after 100 Gy or less treatment between the experimental group and the control animals (χ(2)[1, N= 19] = 4.8; P = .029). MRI also supported this difference in tumor size. Duplication of tumor volume differences and survival benefit was possible in a more invasive U251 orthotopic model, with clear separation in bioluminescence at 6 days after treatment (χ(2)[1, N= 9] = 4.7; P = .029); median survival in treated animals was not reached at 120 days because lack of mortality, and log-rank analysis of survival was highly significant (P = .0057). Analysis of tumors by histology revealed minimal areas of necrosis and gliosis. These results support the potential efficacy of the highly specific activity of brachytherapy by (186)Re-liposomes convection-enhanced delivery in glioma.

Rebound tumour progression after the cessation of bevacizumab therapy in patients with recurrent high-grade glioma.

After withdrawal of bevacizumab in patients with recurrent high-grade glioma, we have observed a rapid tumour re-growth or "rebound" radiographic phenomenon with accelerated clinical decline. We retrospectively reviewed 11 patients treated at the Henry Ford Hermelin Brain Tumor Center with recurrent high-grade glioma who demonstrated a rebound progression pattern after the discontinuation of bevacizumab. The original tumour area-of-enhancement increased by a mean of 158%, when compared to the rebound magnetic resonance imaging. After rebound, no patients (0/8) showed a response to next-line treatments that did not include bevacizumab. The median survival of those re-treated with bevacizumab was 149 and 32 days for those who received other regimens. Abrupt discontinuation of bevacizumab after recurrence often leads to a dramatic rebound phenomenon and rapid clinical decline. Slow tapering of the bevacizumab dose after tumour progression may prevent this from occurring and improve responsiveness to next-line therapies.

Initial experience with bevacizumab treatment for biopsy confirmed cerebral radiation necrosis.

BACKGROUND: Cerebral radiation necrosis is a serious complication of radiation treatment for brain tumors. Therapeutic options include corticosteroids, anticoagulation and hyperbaric oxygen with limited efficacy. Bevacizumab, an antibody against VEGF had been reported to reduce edema in patients with suspected radiation necrosis. We retrospectively reviewed 6 patients with biopsy proven cerebral radiation necrosis treated with bevacizumab between 2006 and 2008. RESULTS: Interval MRI follow-up demonstrated radiographic response in all patients with an average reduction of 79% for the post gadolinium studies and 49% for the FLAIR images. The initial partial radiographic response was noted for up to a mean follow-up time of 5.9 months (6 weeks to 18 months). CONCLUSION: Bevacizumab appears to produce radiographic response and clinical benefits in the treatment of patients with cerebral radionecrosis.

Bevacizumab and irinotecan treatment for progressive diffuse brainstem glioma: case report.

Diffuse brainstem glioma carries a dismal prognosis. The current cornerstone of treatment is radiation therapy. Chemotherapy appears to be ineffective and the role of this treatment in the recurrent or progressive setting is not known. Bevacizumab and irinotecan have been reported to have shown radiographic response and improvement in progression-free survival among patients with malignant supratentorial gliomas. In this paper, we report our experience in an adult patient with progressive diffuse brainstem glioma treated with bevacizumab and irinotecan.