Citations

Abstract Palliative care (PC) benefits patients undergoing hematopoietic stem cell transplantation (HSCT), but it remains underutilized. Although transplant physicians report concerns regarding how patients perceive PC, HSCT recipients’ perceptions about PC remain unaddressed. We conducted a multisite, cross-sectional survey of autologous and allogeneic HSCT recipients 3 to 12 months after transplant to assess their familiarity, knowledge, and perception of PC, as well as their unmet PC needs. We computed a composite score of patients’ perceptions of PC and used a generalized linear regression model to examine factors associated with these perceptions. We enrolled 69.6% (250/359) of potential participants (median age = 58.1; 63.1% autologous HSCT). Overall, 44.3.8% (109/249) reported limited knowledge about PC and 52% (127/245) endorsed familiarity with PC. Most patients felt hopeful (54%) and reassured (50%) when they heard the term PC; 83% saw referral as a sign their doctor cared about what was happening to them. In multivariate analyses, patients who were more knowledgeable about PC were more likely to have positive perceptions of PC (B = 7.54, standard error = 1.61, P < .001). Patients’ demographics, HSCT features, quality of life, and symptom burden were not significantly associated with perceptions of PC. HSCT recipients have positive perceptions of PC, though many have limited knowledge about its role. Patients who were more knowledgeable about PC were more likely to have positive perceptions of PC. These data do not support transplant physicians’ negative concerns about how patients perceive PC and underscore the need to further educate patients and transplant physicians about PC.

Abstract The radiologically isolated syndrome (RIS) was defined in 2009 as the presence of asymptomatic, incidentally identified demyelinating-appearing white matter lesions in the CNS within individuals lacking symptoms typical of multiple sclerosis (MS). The RIS criteria have been validated and predict the transition to symptomatic MS reliably. The performance of RIS criteria that require fewer MRI lesions is unknown. 2009-RIS subjects, by definition, fulfil three to four of four criteria for 2005 dissemination in space (DIS) and subjects fulfilling only one or two lesions in at least one 2017 DIS location were identified within 37 prospective databases. Univariate and multivariate Cox regression models were used to identify predictors of a first clinical event. Performances of different groups were calculated. Seven hundred and forty-seven subjects (72.2% female, mean age 37.7 ± 12.3 years at the index MRI) were included. The mean clinical follow-up time was 46.8 ± 45.4 months. All subjects had focal T2 hyperintensities suggestive of inflammatory demyelination on MRI; 251 (33.6%) fulfilled one or two 2017 DIS criteria (designated as Groups 1 and 2, respectively), and 496 (66.4%) fulfilled three or four 2005 DIS criteria representing 2009-RIS subjects. Group 1 and 2 subjects were younger than the 2009-RIS group and were more likely to develop new T2 lesions over time (P < 0.001). Groups 1 and 2 were similar regarding survival distribution and risk factors for transition to MS. At 5 years, the cumulative probability for a clinical event was 29.0% for Groups 1 and 2 compared to 38.7% for 2009-RIS (P = 0.0241). The presence of spinal cord lesions on the index scan and CSF-restricted oligoclonal bands in Groups 1–2 increased the risk of symptomatic MS evolution at 5 years to 38%, comparable to the risk of development in the 2009-RIS group. The presence of new T2 or gadolinium-enhancing lesions on follow-up scans independently increased the risk of presenting with a clinical event (P < 0.001). The 2009-RIS subjects or Groups 1 and 2 with at least two of the risk factors for a clinical event demonstrated better sensitivity (86.0%), negative predictive value (73.1%), accuracy (59.8%) and area under the curve (60.7%) compared to other criteria studied. This large prospective cohort brings Class I evidence that subjects with fewer lesions than required in the 2009 RIS criteria evolve directly to a first clinical event at a similar rate when additional risk factors are present. Our results provide a rationale for revisions to existing RIS diagnostic criteria.

Abstract Background: Treatment of estrogen receptor (ER)-positive breast cancer with selective estrogen receptor degraders (SERDs) frequently results in the loss or reduction of ER expression. Whether these changes are due to on-target effects of SERDs degrading ER or arise as a mechanism of tumor resistance with associated changes in cellular phenotypes remains unknown. It is critical to distinguish between these possibilities to accurately assess treatment response and determine the most appropriate subsequent therapy. To this end, we created and conducted molecular analyses on patient-derived organoid cultures from post-treatment tissue in patients receiving neoadjuvant SERD therapy for early-stage ER+ breast cancer in the I-SPY2 Endocrine Optimization Protocol (EOP). Methods: The I-SPY2 EOP study is a prospective, randomized substudy within the I-SPY TRIAL testing the oral SERD amcenestrant alone or in combination with letrozole or abemaciclib in stage 2/3 ER+ Her2-negative breast cancer. Enrollment is ongoing, with patients receiving amcenestrant neoadjuvantly for 6 months until the day before surgery. Tumor tissue is collected at baseline, 3 weeks, and at surgery. Organoids were generated from post-treatment surgical samples. Organoid cultures were optimized based on established methods (Dekkers et al., Nature Protocols, 2021) to assess ER levels and activity. Pre- and post-treatment tissue samples were also assessed for ER, PR, Ki67, and GATA3, a luminal marker and transcription factor that is functionally linked with ER, via immunohistochemistry. Results: In 7 patients with both pre- and post-treatment tissue samples including fresh surgical samples for organoid generation, the ER in baseline tumor tissue was >=90% in all patients, PR ranged from 40-90%, and Ki67 ranged from 5-30%. In post-treatment surgical tissue from these cases, ER ranged from 0-30%, PR from 0-50%, Ki67 from < 1%-10%, and GATA3 was positive in 5 of 5 cases tested to-date. The creation of organoids from residual disease at surgery was attempted for these 7 patients, with organoids successfully propagated in 5 cases thus far. 3 of 5 organoid cultures were ready for analysis and in all cases strong ER and PR expression in organoids was observed after culture for > 1 month in the absence of amcenestrant. Detailed gene expression profiling (including Mammaprint/Blueprint) and gene set enrichment analyses (GSEA) to assess for intrinsic breast cancer subtype and ER activity in each sample and corresponding organoid culture are in progress and will be reported with the full dataset. Conclusion: Patient-derived organoid culturing of residual disease after neoadjuvant endocrine therapy is feasible. Neoadjuvant treatment with a SERD can render ER and PR low or absent at the time of surgical resection, which does not necessarily imply the presence of endocrine therapy resistant disease. The use of organoids and additional IHC markers (GATA3) demonstrate that receptor negativity may be an indicator of the drug hitting its target, suggesting ER signaling is still intact. In general, patient-derived tumor organoid cultures modeling residual disease states can be a useful adjunct to existing methods used to monitor the effects of neoadjuvant endocrine therapy and is being explored in the I-SPY EOP trial. Citation Format: Jennifer Rosenbluth, Christopher J. Schwartz, Tam Binh Bui, Shruti Warhadpande, Pravin Phadatare, Sigal Eini, Michael Bruck, Julissa Molina-Vega, Kami Pullakhandam, Nicole Schindler, Lamorna A. Brown Swigart, Christina Yau, Gillian Hirst, Rita Mukhtar, Karthik V. Giridhar, Olufunmilayo I. Olopade, Kevin Kalinsky, Cheryl A. Ewing, Jasmine M. Wong, Michael D. Alvarado, Laura Van’t Veer, Laura J. Esserman, Jo Chien. Characterization of residual disease after neoadjuvant selective estrogen receptor degrader (SERD) therapy using tumor organoids in the I-SPY Endocrine Optimization Protocol (EOP) [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P3-09-01.

BACKGROUND: Adult traumatic brachial plexus injuries (TBPIs) are life-altering events that can have detrimental effects on a patient's quality of life. OBJECTIVE: To examine how social determinants of health (SDOH) disparities influence the risk of developing new psychosocial conditions after TBPIs in previously psychiatric-naïve patients. METHODS: Between January 2010 and June 2019, a retrospective analysis was performed using PearlDiver's Mariner, an all-payer claims database, to create 3 cohorts: TBPI disparity cohort: patients with TBPI and presence of at least 1 SDOH disparity before injury, TBPI without disparity cohort: patients with TBPI and the absence of any SDOH disparity, and control cohort: patients without TBPIs. RESULTS: The matched population analyzed in this study consisted of 1176 patients who were equally represented in the TBPI disparity cohort (n = 392, 33.33%), TBPI without disparity cohort (n = 392, 33.33%), and control cohort (n = 392, 33.33%). A total of 301 patients developed any psychosocial condition with 4 years of their injury. Patients in the TBPI disparity cohort had significantly higher rates of developing any psychosocial condition (31.12%, P < .0005), depression (22.70%, P = .0032), anxiety (18.62%, P = .0203), drug abuse (7.91%, P = .0060), and alcohol abuse (4.85%, P = .03499) when compared with the other cohorts. Furthermore, the disparity cohort carried a significantly increased risk of developing any psychosocial condition (hazard ratio 1.42, 95% CI 1.09-1.86). The rates of suicide attempt, post-traumatic stress disorder, and divorce did not significantly differ between groups. CONCLUSION: TBPI patients with SDOH disparities are at increased risk of developing new-onset psychosocial conditions, such as depression, anxiety, drug abuse, and alcohol abuse. Level of Evidence: Prognostic Level III.

Background Mechanical thrombectomy (MT) has become the standard of care for stroke patients. The majority of the clinical trials and publications analyzing the outcomes related to the procedures report interventional performance by experienced practitioners. However, few of them individualize their preliminary metrics according to the operator's experience. Objective To summarize the literature and report safety and efficacy outcomes following MT procedures and correlate them with the operator's experience. Primary outcomes were successful recanalization, defined as modified thrombolysis in cerebral infarction greater or equal to 2b or 3, duration of the procedure measured in minutes, and serious adverse event. Methods This systematic review was performed according to the PRISMA guidelines. The PubMed, Embase, and Cochrane databases were utilized. Results There were six studies comprising 9348 patients (mean age 69.8 years; 51.2% males), and 9361 MT procedures were included. Each publication used for this review used a different experience definition to report their data. Higher interventionists’ experience demonstrated a positive relationship with the possibility of successful recanalization and an inverse relationship with the duration needed for the operation in almost all of the included studies. As for the complications, none of the authors reported a statistically significant risk reduction of an adverse event, except Olthuis et al. correlating increasing training with lower odds of stroke progression. Conclusions A higher experience level is associated with better recanalization rates and shorter procedural duration in MT operations. Further studies are warranted to define the minimum required level of experience for operational autonomy.

ImportanceGlaucoma can develop following cataract removal in children.ObjectiveTo assess the cumulative incidence of glaucoma-related adverse events (defined as glaucoma or glaucoma suspect) and factors associated with risk of these adverse events in the first 5 years after lensectomy prior to 13 years of age.Design, Setting, and ParticipantsThis cohort study used longitudinal registry data collected at enrollment and annually for 5 years from 45 institutional and 16 community sites. Participants were children aged 12 years or younger with at least 1 office visit after lensectomy from June 2012 to July 2015. Data were analyzed from February through December 2022.ExposuresUsual clinical care after lensectomy.Main Outcomes and MeasuresThe main outcomes were cumulative incidence of glaucoma-related adverse events and baseline factors associated with risk of these adverse events.ResultsThe study included 810 children (1049 eyes); 443 eyes of 321 children (55% female; mean [SD] age, 0.89 [1.97] years) were aphakic after lensectomy, and 606 eyes of 489 children (53% male; mean [SD] age, 5.65 [3.32] years) were pseudophakic. The 5-year cumulative incidence of glaucoma-related adverse events was 29% (95% CI, 25%-34%) in 443 eyes with aphakia and 7% (95% CI, 5%-9%) in 606 eyes with pseudophakia; 7% (95% CI, 5%-10%) of aphakic eyes and 3% (95% CI, 2%-5%) of pseudophakic eyes were diagnosed as glaucoma suspect. Among aphakic eyes, a higher risk for glaucoma-related adverse events was associated with 4 of 8 factors, including age less than 3 months (vs ≥3 months: adjusted hazard ratio [aHR], 2.88; 99% CI, 1.57-5.23), abnormal anterior segment (vs normal: aHR, 2.88; 99% CI, 1.56-5.30), intraoperative complications at time of lensectomy (vs none; aHR, 2.25; 99% CI, 1.04-4.87), and bilaterality (vs unilaterality: aHR, 1.88; 99% CI, 1.02-3.48). Neither of the 2 factors evaluated for pseudophakic eyes, laterality and anterior vitrectomy, were associated with risk of glaucoma-related adverse events.Conclusions and RelevanceIn this cohort study, glaucoma-related adverse events were common after cataract surgery in children; age less than 3 months at surgery was associated with elevated risk of the adverse events in aphakic eyes. Children with pseudophakia, who were older at surgery, less frequently developed a glaucoma-related adverse event within 5 years of lensectomy. The findings suggest that ongoing monitoring for the development of glaucoma is needed after lensectomy at any age.

Adenocarcinoma of the endometrium (also known as endometrial cancer, or more broadly as uterine cancer or carcinoma of the uterine corpus) is the most common malignancy of the female genital tract in the United States. It is estimated that 65,950 new uterine cancer cases will have occurred in 2022, with 12,550 deaths resulting from the disease. Endometrial carcinoma includes pure endometrioid cancer and carcinomas with high-risk endometrial histology (including uterine serous carcinoma, clear cell carcinoma, carcinosarcoma [also known as malignant mixed Müllerian tumor], and undifferentiated/dedifferentiated carcinoma). Stromal or mesenchymal sarcomas are uncommon subtypes accounting for approximately 3% of all uterine cancers. This selection from the NCCN Guidelines for Uterine Neoplasms focuses on the diagnosis, staging, and management of pure endometrioid carcinoma. The complete version of the NCCN Guidelines for Uterine Neoplasms is available online at NCCN.org .

Abstract Purpose: An ongoing challenge in cancer is the management of primary and metastatic brain malignancies. This is partly due to restrictions of the blood-brain barrier and their unique microenvironment. These challenges are most evident in cancers such as lymphoma and melanoma, which are typically responsive to treatment in systemic locations but resistant when established in the brain. We propose interleukin-1 receptor-associated kinase-4 (IRAK-4) as a potential target across these diseases and describe the activity and mechanism of oral IRAK-4 inhibitor CA-4948. Experimental Design: Human primary central nervous system lymphoma (PCNSL) and melanoma brain metastases (MBM) samples were analyzed for expression of IRAK-4 and downstream transcription pathways. We next determined the central nervous system (CNS) applicability of CA-4948 in naïve and tumor-bearing mice using models of PCNSL and MBM. The mechanistic effect on tumors and the tumor microenvironment was then analyzed. Results: Human PCNSL and MBM have high expression of IRAK-4, IRAK-1, and nuclear factor kappa B (NF-κB). This increase in inflammation results in reflexive inhibitory signaling. Similar profiles are observed in immunocompetent murine models. Treatment of tumor-bearing animals with CA-4948 results in the downregulation of mitogen-activated protein kinase (MAPK) signaling in addition to decreased NF-κB. These intracellular changes are associated with a survival advantage. Conclusions: IRAK-4 is an attractive target in PCNSL and MBM. The inhibition of IRAK-4 with CA-4948 downregulates the expression of important transcription factors involved in tumor growth and proliferation. CA-4948 is currently being investigated in clinical trials for relapsed and refractory lymphoma and warrants further translation into PCNSL and MBM.