Citations

Abstract Task Group (TG) 314 of the American Association of Physicists in Medicine (AAPM) was charged to develop guidance for recovering from fault states in radiation therapy, specifically regarding the delivery of photon or electron beams using a linear accelerator (linac) including ancillary systems. The fault conditions addressed may involve software, hardware, or a combination of causes. The report provides detailed recommendations for the proactive steps to be taken before a fault, the actions to be taken at the time of a fault, and the safety steps before returning a linac to clinical service, as well as the activities that device manufacturers and standard organizations can do to prevent and resolve the faults. A user‐maintained log of prior faults; establishment of remote access by the vendor; and user training in emergency gantry, couch, and door motions are all useful proactive steps. At the moment of downtime and after ensuring the safety of the patient, the report stresses the importance of capturing fault information, prompt contact with the service engineer after the initial assessment, and considerations for communicating the estimated duration before the linac is returned to service. The medical physicist has a critical responsibility to assess the impact of the fault on patient care. Before resuming clinical use, the medical physicist must both determine the level of testing required to ensure safe operation of the linac and ensure any partially or totally delivered treatments have been correctly saved for accurate completion of the treatment fraction. The report stresses the roles of the radiation therapist, medical physicist, and service engineer to efficiently and safely address linac downtime. The appendices contain a description of the efforts of several organizations regarding linac safety: Integrating the Healthcare Enterprise—Radiation Oncology, International Standards Organization/International Electrotechnical Commission, Radiation Oncology Safety Stakeholder Initiative, and the AAPM Vendor Relations and Product Usability Subcommittee. Disclaimer: The recommendations of this TG should not be used to establish regulations. These recommendations are guidelines for Qualified Medical Physicists and others to use and appropriately interpret for their institution and clinical setting. Each institution may have site‐specific or state‐mandated needs and requirements which may modify their usage of these recommendations.

BACKGROUND: Studies in the past have demonstrated an association between sarcoidosis and pulmonary embolism but little is known about its impact, especially in young adults. We aim to determine the burden and impact of pulmonary embolism (PE) in young adults hospitalized with sarcoidosis. METHOD: The study investigates the prevalence and consequences of PE in young adults aged 18-44 years hospitalized with sarcoidosis using data from the National Inpatient Sample (2016-2020) with relevant ICD-10 codes. This study aims to address the primary outcomes of the burden and trends of PE and its associated impact on in-hospital mortality. Additionally, it explores secondary outcomes such as healthcare resource utilization and discharge patterns. RESULT: Among 50,385 young adults (median age 37 years) hospitalized with sarcoidosis, 1120 had PE, showing a linear increase from 2% in 2016 to 2.9% (p<0.001) in 2020. Sarcoidosis-PE+ group, predominantly in young blacks, exhibited a higher prevalence of comorbidities such as obesity, smoking, drug use, peripheral vascular disease, hypothyroidism, and prior history of VTE. In contrast, the sarcoidosis-PE- group had a higher prevalence of diabetes (with/without chronic complication), hyperlipidemia, and chronic pulmonary disease. Multivariable regression analysis adjusted for all potential sociodemographic and comorbid variables showed higher odds of all-cause mortality (OR: 2.92, 95% CI: 1.18-7.24, p <0.02) in the sarcoidosis-PE+ group as compared to sarcoidosis-PE- group. The sarcoidosis-PE+ group also had higher hospital costs and length of stay. CONCLUSION: The higher odds of in-hospital mortality with an increased length of stay and hospital cost observed in the sarcoidosis-PE+ group highlight the often underreported complications of sarcoidosis, particularly in a younger demographic. The relevance of this study stems from its potential to uncover trends that could lead to improved diagnostic and therapeutic strategies.

IMPORTANCEYoung adults aged 18 to 39 years represent the minority of breast cancer diagnoses but are particularly vulnerable to financial hardship. Factors contributing to sustained financial hardship are unknown.OBJECTIVESTo identify financial hardship patterns over time and characterize factors associated with discrete trajectories; it was hypothesized that treatment-related arm morbidity, a key source of expense, would be associated with long-term financial difficulty.DESIGN, SETTING, AND PARTICIPANTSThis cohort study included US young adults aged 40 years or younger treated between 2006 and 2016. Eligible patients were treated for stage 0 to stage III breast cancer at institutions participating in the Young Women’s Breast Cancer Study, which included a specialized cancer institute and 12 other academic and community hospitals. Patients who responded at baseline and returned a 1-year survey were included in analysis. Data were analyzed in March 2024.MAIN OUTCOMES AND MEASURESTrajectory modeling classified patterns of financial difficulty from baseline through 10 years postdiagnosis using the Cancer Rehabilitation Evaluation System (CARES) scale. Multinomial regression examined characteristics, including treatment-related arm morbidity, associated with each trajectory.RESULTSA total 1008 patients were included (median [IQR] age at diagnosis, 36 [33-39] years; 60 Asian [6.0%], 35 Black [3.5%], 47 Hispanic [4.7%], 884 White [87.7%]); 840 patients were college graduates (83.3%), 764 were partnered at baseline (75.8%), 649 were nulliparous (64.4%), and 908 were without comorbidities at enrollment (90.1%). Patients’ tumors were primarily stage I-II (778 [77.2%]), estrogen receptor/progesterone receptor–positive (754 [74.8%]), and ERBB2-negative (formerly HER2) (686 [68.1%]). Patients were more frequently treated with mastectomy than breast conservation (771 [76.5%] vs 297 [29.5%]; P &amp;lt; .001). A majority of patients received radiation therapy (627 [62.2%]), chemotherapy (760 [75.4%]), and endocrine therapy (610 [60.6%]). A total of 727 patients (72.1%) reported arm symptoms within 2 years of surgery. Three distinct trajectories of experiences with finances emerged: 551 patients (54.7%) had low financial difficulty (trajectory 1), 293 (29.1%) had mild difficulty that improved (trajectory 2), and 164 (16.3%) had moderate to severe difficulty peaking several years after diagnosis before improving (trajectory 3). Hispanic ethnicity (OR, 3.71; 95% CI, 1.47-9.36), unemployment at baseline and 1 year (OR, 2.66; 95% CI, 1.63-4.33), and arm symptoms (OR, 1.77; 95% CI, 1.06-2.96) were associated with increased odds of experiencing trajectory 3. Having a college degree (OR, 0.20; 95% CI, 0.12-0.34) or being partnered (OR, 0.24; 95% CI, 0.15-0.38) were associated with increased odds of experiencing trajectory 1.CONCLUSIONIn this cohort study of young adults with breast cancer, we identified a subset of patients who experienced a high degree of financial difficulty persisting into early survivorship. Targeted interventions to mitigate financial toxicity—modifiable factors that include support for the employability or return to work support for those experiencing arm symptoms after treatment—are needed.

Introduction: Cardiac sarcoidosis (CS) often results in systolic heart failure (HF) and responds favorably to guideline directed medical therapy (GDMT). A multidisciplinary team approach to HF care is recommended but few published examples exist in CS patients. Methods: We queried an institutional registry of 599 CS patients (2000-2023) for patients with index LVEF < 50% (within 90 d of index CS evaluation) and follow-up TTE within 11-36 months. In our CS medication therapy management (MTM) program (started 1/8/2019), pharmacists conduct independent visits with CS patients (in person or remote), discuss GDMT tolerance and symptoms, review monitoring laboratory studies, and adjust GDMT (ACEi/ARB/ARNi, beta-blocker, MRA, and/or SGLT2i) via collaborative practice agreement with the CS cardiologists. Patients were classified as MTM (≥1 MTM encounter) or NMTM patients (0 encounters). We compared (1) GDMT, (2) cardiac remodeling, and (3) clinical outcomes (event free survival to first heart failure hospitalization, LVAD, heart transplant, or death). Results: Nineteen percent (113/599) CS patients met inclusion criteria (34% female, 92% white, median age 57 y, 19% definite CS, 58% probable CS, 31% presumed CS), with 44 MTM (median 11.5 encounters, IQR 11) and 69 NMTM patients. Both MTM and NMTM patients were on a median 2 GDMT agents at index evaluation (p=0.21). At follow-up (median 19 mo MTM, 15 mo NMTM, p=0.05), MTM patients were on more GDMT agents than NMTM (median 3.0 vs 2.0, p<0.001), with higher % target dose of ACEi/ARB/ARNi (98% vs 71%, p=0.009), beta-blocker (87% vs 57%, p=0.004), and SGLT2i use (30% vs 9%, p=0.004), but similar MRA use (48% vs 32%, p=0.09). Immunosuppressive therapy was used in 88% patients (89% MTM vs 87% NMTM, p=0.79). Index LVEF was similar (MTM 36%, NMTM 32%, p=0.07). Mean change in LVEF (excluding LVAD/transplant patients) demonstrated a non-significant trend towards improved remodeling in MTM (+8.6%) vs NMTM patients (+5.5%; p=0.39). MTM patients exhibited lower risk of the clinical outcome (1/44 MTM vs 16/69 MTM patients; univariable HR 0.08 [95%CI 0.01 - 0.63], log-rank p=0.016). Conclusions: A pharmacist MTM program for CS patients with HF is associated with improved GDMT uptitration and clinical outcomes, emphasizing the value of collaborative multidisciplinary CS care.

Abstract Genomic alterations and molecular subgroups between extracranial disease sites and brain metastases often differ, yet the prevalence and clinical significance of divergent evolution in brain metastases is not fully understood. This study examined genomic alterations and molecular subgroup divergence rates between matched brain metastases and extracranial disease sites. A retrospective, two-center study was conducted on patients who underwent resection of brain metastases between 2014-2022 with clinical and matched genomic data and/or molecular markers available. The overall cohort comprised 256 patients with matched tumors from multiple cancer types, most commonly from breast (n=108, 42.2%), melanoma (n=83, 32.4%), and NSCLC (n=43, 16.8%). Targeted next-generation sequencing of over 500 oncogenes was performed on resected tumors as part of clinical care (n=41 patients with matched specimens). Molecular subgroups for breast, melanoma, and non-small cell lung cancer were also assessed by immunohistochemistry to evaluate rates of molecular subgroup discordance between sites. Subgroup discordance by immunohistochemistry was observed most frequently across breast cancer (22.2%, n=24/108) with loss of the estrogen receptor (ER) and progesterone receptor (PR) and gain of HER2 most frequently observed within brain metastases. Molecular subgroup discordance was rare within melanoma (7.3%, n=6/82) and NSCLC (14.0%, n=6/43) patients. When evaluating oncogenomic alterations from targeted DNA sequencing in 41 patients with matched specimens, 80.5% (33/41) of brain metastases demonstrated a unique oncogene alteration profile compared to an extracranial disease site. Fourteen patients (34.1%) had a gain of at least 1 targetable alteration within a brain metastasis that was not observed in an extracranial disease site. Brain metastases demonstrated high rates of genomic divergence compared to primary and extracranial metastatic disease sites. This data supports obtaining brain metastasis tissue and conducting molecular profiling of this tissue to help select optimal CNS penetrant systemic therapies for each patient.

Abstract Current standard of care for IDH-wildtype glioblastoma (GBM) includes maximal safe resection, adjuvant radiation, and chemotherapy with the alkylating agent temozolomide. A subset of gliomas treated with temozolomide develop somatic hypermutation with a predominance of C&gt;T transitions due to the alkylation effects on DNA. However, the frequency of occurrence, clinical ramifications, and predictive biomarkers for developing temozolomide-induced hypermutation (TMZ-HM) in GBM are unknown. Here we performed comprehensive histopathologic, genomic, and epigenomic evaluation of paired initial and recurrent GBM from 106 patients. Seven patients (7%) developed hypermutation at time of first recurrence, while an additional five patients (5%) developed hypermutation at a subsequent recurrence. Patients who developed TMZ-HM had a significantly longer interval between initial surgery and first recurrence (27.8 vs. 9.9 months, p&lt;0.001). In contrast to IDH-mutant gliomas where TMZ-HM is associated with poor prognosis, those patients with IDH-wildtype GBM who developed TMZ-HM had significantly longer overall survival from both initial surgery (67.9 vs. 20.3 months, p&lt;0.001) and from time of recurrence after development of hypermutation (30.9 vs. 9.5 months, p=0.001). There was no difference in oncogenic alteration frequency in initial GBM that subsequently developed TMZ-HM. However, 4 specific CpG sites out of 12 total interrogated sites in the promoter region of MGMT (a DNA repair enzyme) and 5 specific CpG sites in the promoter region of KCNQ1DN (a negative regulator of c-Myc) were significantly more hypermethylated in those GBM that developed TMZ-HM. We then generated a weighted risk score across these CpG sites that can be used to prospectively identify GBM likely to develop TMZ-HM associated with favorable survival. In summary, patients with GBM that develop TMZ-HM follow a more favorable clinical course, and specific MGMT and KCNQ1DN promoter hypermethylation patterns could serve as a biomarker to identify these patients who may potentially benefit from extended alkylating chemotherapy treatment.