Common Terminology Criteria For Adverse Events Grade Research Articles

Applying the EHA/EBMT grading for ICAHT after CAR-T: comparative incidence and association with infections and mortality

AbstractCytopenias represent the most common side effect of CAR T-cell therapy (CAR-T) and can predispose for severe infectious complications. Current grading systems, such as the Common Terminology Criteria for Adverse Events (CTCAE), neither reflect the unique quality of post–CAR-T neutrophil recovery, nor do they reflect the inherent risk of infections due to protracted neutropenia. For this reason, a novel EHA/EBMT consensus grading was recently developed for Immune Effector Cell-Associated HematoToxicity (ICAHT). In this multicenter, observational study, we applied the grading system to a large real-world cohort of 549 patients treated with BCMA- or CD19-directed CAR-T for refractory B-cell malignancies (112 multiple myeloma [MM], 334 large B-cell lymphoma [LBCL], 103 mantle cell lymphoma [MCL]) and examined the clinical sequelae of severe (≥3°) ICAHT. The ICAHT grading was strongly associated with the cumulative duration of severe neutropenia (r = 0.92, P < .0001), the presence of multilineage cytopenias, and the use of platelet and red blood cell transfusions. We noted an increased rate of severe ICAHT in patients with MCL vs those with LBCL and MM (28% vs 23% vs 15%). Severe ICAHT was associated with a higher rate of severe infections (49% vs 13%, P < .0001), increased nonrelapse mortality (14% vs 4%, P < .0001), and inferior survival outcomes (1-year progression-free survival: 35% vs 51%, 1-year overall survival: 52% vs 73%, both P < .0001). Importantly, the ICAHT grading demonstrated superior capacity to predict severe infections compared with the CTCAE grading (c-index 0.73 vs 0.55, P < .0001 vs nonsignificant). Taken together, these data highlight the clinical relevance of the novel grading system and support the reporting of ICAHT severity in clinical trials evaluating CAR-T therapies.

Safety profile of methotrexate used off-label in ectopic pregnancy: an active monitoring study based on a Chinese hospital pharmacovigilance system

Objective Methotrexate (MTX) is characterized as first-line therapy although its indication of ectopic pregnancy is off-label use. We aimed to conduct a retrospective cohort study to investigate the incidence, characteristics of adverse drug reactions (ADRs) of MTX, provide valuable insights for medical workers. Methods Basing on China Hospital Pharmacovigilance System (CHPS), a retrospective analysis was performed to evaluate the safety of MTX (n = 672). An active monitoring model was set to detect ADR signals from the hospital information system. Frequency, Common Terminology Criteria for Adverse Events (CTCAE) grade proportion and association of dose exposure with ADRs were presented as outcomes. Results The total incidence of ADRs was 54.0%. Anaemia (37.6%) was the most frequent ADR, followed by hepatic function abnormal (11.3%), hyperuricemia (6.1%), neutropenia (4.6%), leukopenia (4.0%), and dyslipidaemia (2.5%). For the composition of all ADRs, CTCAE grade one, two and three dominated for 86.3%, 12.1% and 1.6%, respectively. The severity of hepatic function abnormal was more serious in the two-dose exposed group (p = .021), while other types of ADRs had no statistical or clinical differences. Logistic regression analysis showed the incidence of any ADRs (OR 1.87 [1.31–2.64]; p = .001), hepatic function abnormal (OR 2.75 [1.69–4.48]; p < .001), dyslipidaemia (OR 5.15 [1.87–14.13]; p = .001) were significantly higher in the two-dose exposed group. After adjusted, the positive associations were still maintained. Conclusions MTX is quite safe in ectopic pregnancy, despite its mild to moderate hematotoxicity, hepatotoxicity and nephrotoxicity. Taking CHPS can present the accurate denominator of the incidence of adverse drug reactions into account, our study advocates that it may have great potential to be used as an active monitoring tool for off-label drug use risk management.

Comprehensive analysis of risk factors for the severity of immune checkpoint inhibitor-associated myocarditis in cancer patients

Abstract Purpose To explore the predictive significance of patients’ clinical features and examination results, including blood laboratory tests, echocardiogram, cardiovascular magnetic resonance (CMR), and electrocardiogram (ECG), for the severity of immune checkpoint inhibitors (ICIs)-associated myocarditis. Methods Data from a real-world cohort of 81 cancer patients who developed ICI-associated myocarditis after immunotherapy were retrospectively analyzed. Myocarditis of Common Terminology Criteria for Adverse Events (CTCAE) grades 3-5 and the development of the major adverse cardiovascular event (MACE) were set as endpoints. Logistic regression was used to evaluate each parameter’s value in predicting myocarditis of grades 3-5 and MACE. Results Eventually, CTCAE grades 3-5 and MACE developed in 43/81 (53.1%) and 28/81 (34.6) cases, respectively. The occurrence of CTCAE grades 3-5 (HR, 95%CI: 4.48, 2.02-9.91, p&amp;lt;0.001) and MACE (HR, 95%CI: 16.21, 6.93-37.94, p&amp;lt;0.001) were strongly related to patients’ overall survival from ICI-associated myocarditis to death. The likelihood of CTCAE grades 3-5 and MACE increased with the accumulation of organs affected by the ICI-associated adverse events and initial clinical symptoms. Concurrent systematic therapies during ICI treatment did not raise the risk of myocarditis severity, while prior chemotherapy did. Apart from the classical cardiac markers, such as myoglobin, brain natriuretic peptide, and troponin T, a higher neutrophil ratio was also related to poorer cardiac outcomes, whereas a higher lymphocyte and monocyte ratios were predictors of favorable cardiac outcomes. Besides, the CD4+ T cell ratio and CD4/CD8 ratio were negatively related to CTCAE grades 3-5. Several cardiovascular magnetic resonance parameters were associated with myocarditis severity. In contrast, the predictive value of echocardiography and electrocardiogram was weak. Conclusions This study comprehensively evaluated the prognostic value of different patients’ clinical factors and examination results and discovered several predictors of severe ICI-associated myocarditis, which will facilitate early detection of severe ICI-associated myocarditis in patients receiving immunotherapy.

Development of a Novel Methotrexate-Related Neurotoxicity Risk Score in Pediatric Acute Leukemia: A Report from the Reducing Ethnic Disparities in Acute Leukemia (REDIAL) Consortium

Introduction: Methotrexate (MTX) chemotherapy is a critical component of contemporary pediatric acute lymphoblastic leukemia (ALL) treatment regimens. However, intrathecal (IT) and intravenous (IV) MTX can result in dose-limiting acute neurotoxicity, which has been associated with an increased risk of ALL relapse. Emerging data suggest the likelihood of MTX neurotoxicity is elevated in Latino patients and those diagnosed at older age or treated with high-dose MTX (&amp;gt; 1g/m2); however, there are no established methods for identifying those at greatest risk. Therefore, we used machine learning algorithms to develop a neurotoxicity risk prediction model in a diverse, multi-ethnic cohort of pediatric patients with ALL. Methods: The Reducing Ethnic Disparities in Acute Leukemia (REDIAL) Consortium enrolls patients diagnosed with ALL from six participating treatment centers in the Southwestern U.S. This interim analysis included pediatric patients (age &amp;lt;20 years) diagnosed and treated for ALL at Texas Children's Hospital (2005-2019). Individuals diagnosed with infant leukemia (&amp;lt;1 year of age) and/or with preexisting neurologic disease were excluded. We retrospectively reviewed medical records to identify clinical, sociodemographic, and Common Terminology Criteria for Adverse Events (CTCAE) grading of toxicities such as transaminitis and hyperbilirubinemia. Address information at the time of diagnosis was geocoded and aligned to the American Community Survey at the census-tract level to define residential social determinants of health (SDOH). Cases of MTX neurotoxicity were identified by manual review of records for any patient who underwent brain MRI imaging during ALL therapy. Cases of acute MTX neurotoxicity were defined following Ponte di Legno Delphi Consensus definitions as neurologic episodes (e.g., seizure, stroke-like symptoms, altered mental status) occurring within 21 days of IV or IT MTX with no other identifiable underlying cause. Demographic and clinical factors were compared between cases of acute MTX-related neurotoxicity and controls using logistic regression models to estimate odds ratios (OR) and 95% confidence intervals (CI). The dataset was randomly split with 80% of observations used in the training stage and 20% reserved for testing. Random forest algorithms with boosting and down sampling were grown using 5-repeat, 10-fold cross validation to optimize tuning parameters. Model performance was evaluated using test and train error rate, area under the curve of the receiver operating characteristic (AUC-ROC), sensitivity, and specificity. Results: A total of 770 patients were eligible and met inclusion criteria. Patients were a mean age of 7.0 years at diagnosis, 54% male, 55% Latino and 45% treated with high-risk protocols. Acute MTX neurotoxicity developed in 134 (17.4%) of patients. In logistic regression models, neurotoxicity odds increased with older age at diagnosis (OR = 1.20, 95% CI: 1.15-1.26), Latino ethnicity (OR = 2.14, 95% CI: 1.38-3.38), treatment on high-risk protocols (OR=4.32, 95% CI: 2.75-6.99), obesity at diagnosis (vs normal weight, OR = 2.54, 95% CI: 1.51-4.22), and CTCAE grade 3 or higher transaminitis (OR = 2.02, 95% CI: 1.03-4.47) or hyperbilirubinemia (OR = 4.71, 95% CI: 1.21-18.41) during induction therapy. Overall, the random forest machine learning algorithm resulted in an AUC-ROC of 0.79 with an error rate of 0.26 in both the training and test sets. The overall sensitivity was 0.71, with a specificity of 0.67. Recognizing ethnic disparities in MTX neurotoxicity may exist, random forest models were generated stratifying on ethnicity (Figure 1), which yielded slightly better performance in non-Latino patients (AUC-ROC = 0.77) than Latino patients (AUC-ROC = 0.73). Conclusions: This interim analysis of data from the REDIAL Consortium demonstrates the potential utility of machine learning algorithms to develop a novel risk prediction model for acute MTX-related neurotoxicity. Efforts to expand this work within the larger REDIAL cohort (n&amp;gt;2,000) and incorporate inherited genetic data are ongoing. Ultimately, this work may inform efforts to preemptively risk-stratify patients and deliver targeted interventions to vulnerable individuals.

Safe and Effective Escalation of Evidence-Based Chemotherapy for Mature B Cell Non-Hodgkin's Lymphoma in a Low Resource Setting

BACKGROUND Although high intensity chemotherapy regimens result in &amp;gt;90% long term survival of children with Mature B-cell Non-Hodgkin Lymphoma (MB-NHL), low intensity chemotherapy regimens are used in most Sub-Sahara African (SSA) setting resulting in decades of less than 20% long term survival. This is in part because dose-intense chemotherapy strategies that are standard of care in high income countries (HIC) have not been widely or effectively implemented in low- and middle income countries (LMIC). We investigated the toxicity and outcomes of children with MB-NHL who were treated with a treatment regimen that includes 1g/M2 of methotrexate per dose (mini COPADM) at Mulago National Referral Hospital in Uganda. The objective of this study was to evaluate the safety and effectiveness of an incremental chemotherapy escalation strategy to control treatment-related toxicities and increase response and survival of children treated for MB-NHL at a pediatric oncology center in the SSA setting. METHODS We prospectively collected clinical outcomes on children under 18 years with MB-NHL at Mulago National Referral Hospital (MNRH) in Uganda between January 2020 and July 2023. Overall (OS) and event-free survival (EFS) were calculated using the Kaplan-Meier method. Events in the EFS analysis were: 1) Death; 2) Relapse; or 3) Persistent or progressive disease at the end of Cycle 3. Patients were censored at the earlier of two years from presentation or their last day of follow-up. Descriptive statistics were presented. Toxicities were graded according to Common Terminology Criteria for Adverse Events (CTCAE) version 5. RESULTS We identified 77 patients, among whom 16 (21%) died prior to commencement of the first cycle of chemotherapy and 6 (8%) treated with alternative therapies. The 55 patients who were treated with mini COPADM with 1g/M 2 of methotrexate and are included in this analysis had similar demographics and clinical phenotypes to the 22 that were excluded. The median age was 9.6 years (interquartile range ((IQR) 6.6 - 11.7 years) with 38 (69%) males. Patients were Stage III (53%, 29/55), stage IV (38%, 21/55); and 55%, (30/55) were high-risk. The most common presentations were abdominal mass 43 (78%) and jaw mass 14 (25%). With a median follow-up time of 9 months (IQR 6 - 24 months), the 1-year overall survival (OS) and event free survival (EFS) were 56%; 95% CI (41 - 76) and 41%; 95%CI (27 - 61) respectively. For children with high-risk disease, 1-year OS was 44%; 95%CI (28 - 72) and EFS 25%; 95% CI (12 - 51). Toxicities included febrile neutropenia (83%) and CTCAE grade ≥3 mucositis (44%). For the 12 patients whose cause of mortality was recorded, 1 case (8.3%) was treatment-related and 11 (91.7%) were due to cancer. CONCLUSION: This study establishes baseline response rates, survival, and toxicity for patients with pediatric MB-NHL in Uganda treated with 1g/M2 of methotrexate. Toxicities were consistent with treatment received, perhaps exacerbated by synergy of anthracycline (50 mg/m2) along with intermediate dose MTX. These findings suggest that mini-COPADM with 1g/M 2 of methotrexate can be safely supported with the current clinical resources at MNRH and this low dose regimen accounts for the poor survival of children with MB-NHL in our center. We plan to escalate our therapy to mini-COAPDM with 3g/M2 and addition of Rituximab, with contingent intensification of supportive care to curb treatment-related toxicities.

Combined Photon and Carbon Ion Radiation Therapy for Sinonasal Malignancies: Results of the HIT–SNT Prospective Phase 2 Trial

Radiation treatment of sinonasal malignancies is a challenging task due to proximity to critical structures of the head and neck and skull base. Local tumor control is highly dose-dependent, but dose application is limited due to accompanying toxicity and dose constraints. To evaluate the toxicity and efficacy of combined radiation treatment with intensity-modulated radiation therapy (IMRT) and carbon ion boost, we conducted a prospective phase 2 IMRT-Heidelberg Ion-Beam Therapy Sinonasal Tumors (HIT-SNT) trial. Between 2011 and 2019, we treated 35 patients with histologically proven, incompletely resected or inoperable adeno- (51%) or squamous cell carcinoma (49%) of the paranasal sinuses with combined IMRT (50 Gy) and carbon ion boost (24 Gy relative biologic effectiveness) to a total dose of 74 Gy. Acute mucositis Common Terminology Criteria for Adverse Events (CTCAE) grade 3 occurred in 12% of patients (n = 4) and was accompanied by odynophagia CTCAE grade 3. Except for 1 case of grade 3 weight loss, no other acute high-grade toxicity (grade 3-4) was observed. In a small patient cohort of 15 patients eligible for long-term follow-up we have seen no high-grade (grade ≥3) long-term side effects 2 years after radiation therapy. None of these patients suffered from therapy-associated vision or hearing loss. Secondary endpoints were 2-year overall survival, 2-year local progression-free survival, 2-year progression-free survival, and 2-year metastases-free survival with 79.4%, 61.8%, 61.8%, and 64.8%, respectively. To our knowledge, this is the first prospective data on toxicity and outcome of bimodal radiation therapy for the rare entity of sinonasal malignancies. Our study shows a low rate of CTCAE-reported acute toxicity with reasonable tumor control and survival rates after bimodal radiation therapy, which therefore remains a therapy approach to be further evaluated.

THU513 Are Endocrinologists Using CTCAE Grading System For Endocrine Side Effects Of Cancer Treatment With Immune Checkpoint Inhibitors?

Abstract Disclosure: N. Arnouk: None. S. AbuOmar: None. A. Halik: None. A. Saif: None. P.R. Schroeder: None. Introduction: Immune checkpoint inhibitors (ICIs) have revolutionized the treatment of diverse types of cancer but can have serious endocrine system side effects. Common Terminology Criteria for Adverse Events (CTCAE) is a grading system for ICI side effects used by oncologists to aid in treatment decisions. We hypothesize that endocrinologists are not involved in managing immune-related adverse events (irAEs) and are not aware of the CTCAE grading system. Further, we hypothesize that endocrinologists in an academic setting are more likely to use CTCAE compared to endocrinologists in community setting. Methods: A retrospective review of 800 charts in our EMR from January 2018-July 2022 for patients seen in outpatient oncology and endocrinology clinics in our large Mid-Atlantic hospital system. Inclusion criteria were age ≥18 years; diagnosis of advanced melanoma, metastatic non-small cell cancer, head and neck squamous cell cancer, urothelial carcinoma, gastric adenocarcinoma, Hodgkin lymphoma, hepatocellular carcinoma, breast cancer, and renal cell carcinoma; and treatment with one or more ICIs. Patients with endocrinopathies due to chemotherapy or other classes of cancer treatment, no ICI treatment, or pre-existing endocrinopathies were excluded, thus 677 were analyzed.We also surveyed all endocrinologists practicing in our hospital network to determine whether they are involved in managing endocrinopathies associated with ICIs and whether they use the CTACE grading system. Results: Of the 677 reviewed 124 (18%) developed irAEs. In 74 (60%) of those cases, an endocrinologist was involved in management, 47 (70%) in community hospitals and 27 (47%) in academic centers. CTCAE was used in one case. Of 24 endocrinologists surveyed (14 practicing in academic centers and 10 practicing in community centers),12 (50%) responded, 3 (25%) at academic centers and 9 (75%) at community centers. Of the respondents, 9 (75%) said they sometimes are involved in managing irAEs due to ICIs, 11 (91%) had never used the CTCAE, 8 (67%) would participate in a multidisciplinary clinic to manage irAEs, and 6 (50%) preferred to see the patient in their regular clinic. Conclusion: In this study, 60% of the irAE cases resulting from ICI immunotherapy were managed by an oncologist and endocrinologist. CTCAE was used in only one case. More endocrinologists in the community were involved in management of these patients than those in academic centers. A majority of endocrinologists surveyed said they are sometimes consulted in these cases but only one had used CTCAE, thus CTCAE was not used more frequently in an academic versus community setting. More than half prefer to treat these patients in regular versus multidisciplinary clinics. More endocrinologists need to be aware of and use the CTCAE to foster a multidisciplinary team approach to treating endocrinopathies associated with ICIs. Presentation: Thursday, June 15, 2023

Cancer germline predisposing variants and late mortality from subsequent malignant neoplasms among long-term childhood cancer survivors: a report from the St Jude Lifetime Cohort and the Childhood Cancer Survivor Study

Carriers of cancer predisposing variants are at an increased risk of developing subsequent malignant neoplasms among those who have survived childhood cancer. We aimed to investigate whether cancer predisposing variants contribute to the risk of subsequent malignant neoplasm-related late mortality (5 years or more after diagnosis). In this analysis, data were included from two retrospective cohort studies, St Jude Lifetime Cohort (SJLIFE) and the Childhood Cancer Survivor Study (CCSS), with prospective follow-up of patients who were alive for at least 5 years after diagnosis with childhood cancer (ie, long-term childhood cancer survivors) with corresponding germline whole genome or whole exome sequencing data. Cancer predisposing variants affecting 60 genes associated with well-established autosomal-dominant cancer-predisposition syndromes were characterised. Subsequent malignant neoplasms were graded using the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) version 4.03 with modifications. Cause-specific late mortality was based on linkage with the US National Death Index and systematic cohort follow up. Fine-Gray subdistribution hazard models were used to estimate subsequent malignant neoplasm-related late mortality starting from the first biospecimen collection, treating non-subsequent malignant neoplasm-related deaths as a competing risk, adjusting for genetic ancestry, sex, age at diagnosis, and cancer treatment exposures. SJLIFE (NCT00760656) and CCSS (NCT01120353) are registered with ClinicalTrials.gov. 12 469 (6172 male and 6297 female) participants were included, 4402 from the SJLIFE cohort (median follow-up time since collection of the first biospecimen 7·4 years [IQR 3·1-9·4]) and 8067 from the CCSS cohort (median follow-up time since collection of the first biospecimen 12·6 years [2·2-16·6]). 641 (5·1%) of 12 469 participants carried cancer predisposing variants (294 [6·7%] in the SJLIFE cohort and 347 [4·3%] in the CCSS cohort), which were significantly associated with an increased severity of subsequent malignant neoplasms (CTCAE grade ≥4 vs grade <4: odds ratio 2·15, 95% CI 1·18-4·19, p=0·0085). 263 (2·1%) subsequent malignant neoplasm-related deaths (44 [1·0%] in the SJLIFE cohort; and 219 [2·7%] in the CCSS cohort) and 426 (3·4%) other-cause deaths (103 [2·3%] in SJLIFE; and 323 [4·0%] in CCSS) occurred. Cumulative subsequent malignant neoplasm-related mortality at 10 years after the first biospecimen collection in carriers of cancer predisposing variants was 3·7% (95% CI 1·2-8·5) in SJLIFE and 6·9% (4·1-10·7) in CCSS versus 1·5% (1·0-2·1) in SJLIFE and 2·1% (1·7-2·5) in CCSS in non-carriers. Carrying a cancer predisposing variant was associated with an increased risk of subsequent malignant neoplasm-related mortality (SJLIFE: subdistribution hazard ratio 3·40 [95% CI 1·37-8·43]; p=0·0082; CCSS: 3·58 [2·27-5·63]; p<0·0001). Identifying participants at increased risk of subsequent malignant neoplasms via genetic counselling and clinical genetic testing for cancer predisposing variants and implementing early personalised cancer surveillance and prevention strategies might reduce the substantial subsequent malignant neoplasm-related mortality burden. American Lebanese Syrian Associated Charities and US National Institutes of Health.

Frameless Fractionated Linear Accelerator-Based Stereotactic Radiotherapy for Brain Metastases: Results of a Single-Arm Phase II Multi-Institutional Clinical Trial

Stereotactic radiotherapy (SRT) yields high rates of local control for brain metastases while minimizing neurocognitive side effects. While advanced SRT platforms are widely available in urban centers, rural/suburban patients face geographic and socioeconomic barriers to access SRS. For this reason, we conducted a multi-institutional Phase 2 clinical trial to test the safety and efficacy of 3-5 fraction frameless fractionated stereotactic radiotherapy (FFSRT) for brain metastases in an integrated academic satellite network MATERIALS/METHODS: This IRB-approved Phase 2 trial was conducted for patients ≥18-years-old with 1-4 brain metastases. Brain metastases involving the optic pathway or brainstem were excluded. Gross tumor volume (GTV) was delineated with a volumetric brain MRI and planning target volume (PTV) was GTV + 2 mm margin. Radiation dose was based on GTV size: < 3.0 cm, 27 Gy in 3 fractions, and 3.0-3.9 cm, 30 Gy in 5 fractions. Toxicity was evaluated using the Common Terminology Criteria for Adverse Events (CTCAE) version 4. Of 76 evaluable patients, the median age was 67 years, 56.6% were female, 82.9% were white/Caucasian and 89.6% had an Eastern Cooperative Oncology Group performance status ≤ 2. Most brain metastases were from lung cancer (51.3%) and breast cancer (15.7%). With median follow-up of 10 months, local control was 93%, median survival was 1.8 years (95% confidence interval (CI): 1.5-2.4 years), 1-year OS was 73.8% (95% CI: 0.59-0.84), and 2-year OS was 31% (95% CI: 0.12-0.52). There were no CTCAE Grade ≥ 3 protocol-related adverse events. Outcomes of this trial compare favorably with contemporary SRT trials for brain metastases. FFSRT may provide opportunities to expand SRS access for underserved populations across the MDACC enterprise and in future clinical trials for brain metastases.

Real-World Complications of the SpaceOAR Hydrogel Spacer: A Review of the Manufacturer and User Facility Device Experience Database

To characterize adverse events related to use of the perirectal spacing agent SpaceOAR, we examined the Manufacturer and User Facility Device Experience (MAUDE) database. The MAUDE database was queried for "SpaceOAR" and "Augmenix" from June 2015 (when SpaceOAR was approved by the Food and Drug Administration) to October 2022. Reports were reviewed for adverse events (AEs), operative procedures performed because of the AE, and changes to the radiation plan. AEs were categorized using Common Terminology Criteria for Adverse Events (CTCAE), version 5.0. Six hundred fifty-four reports were reviewed. Eighty-four were excluded and 4 reports reviewed 2 separate cases of SpaceOAR administration. Five hundred seventy-four cases were ultimately included. Three deaths were reported (0.5% of all AEs). One point six percent of cases represented CTCAE grade 4 injuries (life-threatening consequences; urgent intervention indicated), 15.9% grade 3 (severe but not immediately life-threatening; hospitalization), 24.2% grade 2 (moderate; local/noninvasive intervention), and 57% of events were CTCAE grade 1 (mild; asymptomatic or mild symptoms). Bowel diversion occurred in 29 cases (9%). Both asymptomatic (n=311) and debilitating (n=12) complications of SpaceOAR hydrogel use were identified. Death, gel embolization, anaphylaxis, rectal ulcerations, and infections requiring bowel or urinary diversions were among the complications reviewed. Providers should consider these potential complications before perirectal spacer administration and during patient counseling.

Impact of reduced margin pelvic radiotherapy on gastrointestinal toxicity and outcome in gynecological cancer

PurposeTo investigate the effect of reduced margin pelvic radiotherapy on gastrointestinal toxicity and outcomes in gynecological cancer. Materials and methodsThis retrospective study analyzed data of 590 patients who underwent hysterectomy and adjuvant pelvic radiotherapy between 2010 and 2020 at two tertiary centers. The pelvic nodal region was delineated based on a reduced margin definition or the Radiation Therapy Oncology Group (RTOG) guidelines. All patients were treated with intensity-modulated radiotherapy with imaging guidance. Gastrointestinal toxicity was assessed using the Common Terminology Criteria for Adverse Events (CTCAE) and the Patient-Reported Outcome version (PRO-CTCAE). ResultsOverall, 352 (59.7%) and 238 (40.3%) patients underwent RTOG and reduced margin pelvic radiotherapy, respectively. Median follow-up was 6.4 years (IQR: 3.7–9.6). Reduced margin pelvic radiotherapy significantly lowered the radiation dose to the small bowel. For CTCAE grade ≥ 2 or 3, acute gastrointestinal toxicity was lower in the reduced margin group than in the RTOG group (16.4% vs. 33.5%, p < 0.001; 2.9% vs. 8.5%, p < 0.001). The reduced margin group reported less severe acute gastrointestinal toxicity (PRO-CTCAE score ≥ 3) than the RTOG group (12.5% vs. 28.7%, p < 0.001). Late grade 3 gastrointestinal toxicity was lower in the reduced margin group than in the RTOG group (0.8% vs. 4.8%, p = 0.006). The 5-year pelvic recurrence-free survival and disease-free survival in the RTOG and reduced margin pelvic radiotherapy groups were 97.4% and 97.9% (p = 0.55) and 80.7% and 83.5% (p = 0.18), respectively. ConclusionReduced margin pelvic radiotherapy decreased acute and late gastrointestinal toxicity and achieved favorable outcomes.

Incidence of blast phase in myelofibrosis according to anemia severity.

Myelofibrosis (MF) is a clonal malignancy frequently characterized by anemia and in 10%-20% of cases it can evolve into blast phase (BP). Anemia in MF is associated with reduced survival and -in primary MF- also with an increased probability of BP. Conventional treatments for anemia have limited effectiveness in MF. Within a dataset of 1752 MF subjects largely unexposed to ruxolitinib (RUX), BP incidence was 2.5% patients per year (p-y). This rate reached respectively 4.3% and 4.5% p-y in case of patients with common terminology criteria for adverse events (CTCAE) grade 3/4 and grade 2 anemia, respectively, that represented together 32% of the cohort. Among 273 MF cases treated with RUX, BP incidence was 2.89% p-y and it reached 4.86% p-y in subjects who started RUX with CTCAE grade 2 anemia (one third of total). Within patients with red blood cell transfusion-dependency at 6 months of RUX (21% of the exposed), BP rate was 4.2% p-y. Our study highlights a relevant incidence of BP in anemic MF patients, with a similar rate whether treated with or without RUX. These findings will help treating physicians to make decisions on the safety profile of innovative anemia treatments.

Intravascular Ultrasound Guidance for Transjugular Intrahepatic Portosystemic Shunt Creation Reduces Laboratory Markers of Acute Liver Injury

PurposeTo compare the laboratory markers of acute liver injury after transjugular intrahepatic portosystemic shunt (TIPS) creation performed using intravascular ultrasound (IVUS) guidance with those using other techniques. Materials and MethodsThis single-center, retrospective study examined 293 TIPS procedures performed between 2014 and 2022 (160 men; mean age, 57.4 years; 71.7% with ascites, 158 with IVUS). Laboratory changes on postprocedural day (PPD) 1 were classified based on Common Terminology Criteria for Adverse Events (CTCAE) grades and were compared between IVUS and non-IVUS cases. ResultsIVUS cases had a lower baseline Model for End-Stage Liver Disease (MELD) score (12.5 vs 13.7, P = .016), higher pre- (16.8 vs 15.2, P = .009), and post-TIPS (6.6 vs 5.4 mm Hg, P < .001) pressure gradient, smaller stent diameter (9.2 vs 9.9 mm, P < .001), and fewer needle passes (2.4 vs 4.2, P < .001). IVUS predicted a lower PPD 1 CTCAE grade for aspartate transaminase (8.0% vs 22.2% grade ≥ 2, P = .010), alanine transaminase (ALT) (2.2% vs 7.1%, P = .017), and bilirubin (9.4% vs 26.2%, P < .001), findings confirmed using multivariable regression and propensity score analysis. IVUS predicted fewer adverse events (1.3% vs 8.1%, P = .008) and an increased likelihood of PPD 1 discharge (81% vs 59%, P = .004). IVUS was not associated with differences in PPD 30 MELD scores or 30-day survival; however, higher PPD 1 ALT (β = 1.96, P = .008) and bilirubin levels (β = 1.38, P = .004) predicted larger PPD 30 MELD score increase. Higher increases in ALT level predicted worse 30-day survival (hazard ratio, 1.93; P = .021). ConclusionIVUS resulted in less laboratory evidence of acute liver injury immediately following TIPS creation.

A meta-analysis studying the utility of cryotherapy in the prevention of peripheral neuropathy in breast cancer patients receiving paclitaxel and nab-paclitaxel.

12025 Background: Debilitating Peripheral Neuropathy (PN) caused by paclitaxel adversely impacts the quality of life in Breast Cancer (BC) patients. Cryotherapy using cooling devices during taxane infusion is a non-invasive strategy to prevent PN, but its efficacy has not been established. We hope to answer this question through our meta-analysis. Methods: A systematic search with keywords and controlled vocabulary encompassing BC, antineoplastics, and paclitaxel was conducted in PubMed, CINHAL, Embase, Scopus, Web of Science Collections, and CENTRAL. All databases were searched on March 7, 2022. There were no search restrictions on date, language, status, or outcomes. 405 records were identified, and duplicates were removed using EndNote 20. The remaining 372 records were imported into Covidence, and the titles and abstracts were screened independently by 2 reviewers. 22 out of 63 full texts were relevant to our question of which 14 [12 Randomized control studies and 2 retrospective studies] were included for the meta-analysis using R package meta. Only studies that analyzed cryotherapy use in BC patients who received paclitaxel or nab-paclitaxel were included. Relative risk (RR) derived from random effects model with Mantel-Haenszel method was used to compare the occurrence of PN between cryotherapy vs placebo groups. Results: Pooled incidence of Common Terminology Criteria for Adverse Events (CTCAE) grade ≥ 2 PN was 24.85% (81/326) in the cryotherapy arm and 42.35% (72/170) in the placebo arm. Overall RR for CTCAE grade ≥ 2 PN with cryotherapy compared to placebo was 0.45 [0.27,0.77, p = 0.0031]. RR for sensory PN was 0.19 [0.05,0.66, p = 0.009] and for motor PN was 0.18 [0.03,0.99, p = 0.0491]. RR for Patient Neurotoxicity Questionnaire (PNQ) score ≥ D which connotes severe neuropathy was 0.24 [0.09,0.62, p = 0.0035]. Cold intolerance was the predominant adverse effect at 15% (37/247). Fingernail paronychia and skin irritation were reported at 0.8% (2/247) each. 5.1% (15/294) stopped cryotherapy use prior to completion. However, this number was driven by a single study (10/16 patients stopped using cryotherapy due to cold intolerance) and 7/11 studies had no discontinuations. Visual inspection of our funnel plots revealed no publication bias. Conclusions: Use of cryotherapy decreased the occurrence of CTCAE grade ≥ 2 PN by 55% in BC patients getting paclitaxel or nab-paclitaxel. Occurrence of both sensory and motor PN were lower. Cold intolerance was the most frequently reported issue with its use but lead to relatively low discontinuation rates in most studies. Given the lack of any severe adverse effect, cryotherapy use must be encouraged for patients receiving paclitaxel and nab-paclitaxel. Further studies are needed establish a standardized way of applying cryotherapy in terms of the device to use, timing and other logistical factors.

Ustekinumab for the treatment of immune related cutaneous adverse events (ircAEs).

e14702 Background: IrcAEs are one of the most common immune related adverse events (irAEs) associated with immune checkpoint inhibitors (ICI). Ustekinumab, a monoclonal antibody that targets IL12/IL23, is FDA approved for the treatment of autoimmune diseases including psoriasis and inflammatory bowel disease. The IL12/23 pathway may mediate a subset of ircAEs, and ustekinumab may be effective for the treatment of these events. Methods: Patients at Memorial Sloan Kettering Cancer Center who received ustekinumab for treatment of ircAEs were identified from 8/18/2017 to 2/17/2022. Common Terminology Criteria for Adverse Events (CTCAE) v 5.0 was used to grade ircAEs. Patient response to ustekinumab was subcategorized into complete resolution (CR, improvement of symptoms to baseline or grade 0), partial resolution (PR, improvement in CTCAE grade but not CR), or no response/worsening (NR, no clinical improvement or worsening of ircAEs). Results: A total of 11 patients were included in the study. The median age was 72 years (IQR 69.5-77) and 45% of patients were female. The most common ICIs were pembrolizumab (64%, n=7), nivolumab (18%, n=2), atezolizumab (9%, n=1), and avelumab (9%, n=1). Melanoma (27%, n=3) and bladder (27%, n=3) cancer were the two most common neoplasms. All patients had psoriasiform ircAEs (n=10), except one who had a pyoderma gangrenosum (PG) ircAE; most were either grade 2 (46%) or grade 3 (36%) at the time of ustekinumab initiation. The majority of patients (73%, n=8), including the one with PG, noted some improvement with ustekinumab, with 55% (n=6) and 18% (n=2) achieving CR and PR, respectively. The median duration of ustekinumab treatment was 169 days (0 – 1774), and among those with PR or CR, the median time to initial response was 27 days (21 – 39). In addition, the proportion of patients on topical and systemic steroids before and after ustekinumab decreased from 91% (n=10) to 56% (n=6) and from 64% (n=7) to 36% (n=3), respectively. Four patients (36.4%) discontinued ICIs because of severe ircAEs, with 1 (25%) successfully recontinuing their ICI following control of ircAE symptoms with ustekinumab. We noted progression of disease among 55% (n=6) of patients at any point after ustekinumab treatment. Among them, median time to next treatment was 345.5 days (70-925), with a median of 347.5 days (70-576) and 601 days (277-925 days) for patients with non-metastatic (33.3%) and metastatic tumors (66.7%), respectively. Conclusions: Ustekinumab has shown encouraging clinical activity especially for psoriasiform ircAEs and can be an effective steroid-sparing treatment for specific ircAEs. Despite the occurrence of cancer progression in some of our cohort, it was difficult to interpret the ICI anti-tumor activity post ustekinumab given the small numbers and multiple tumor types. Further prospective studies are needed to validate our findings given the significant potential of ustekinumab for the management of ircAEs.

Regional hyperthermia with cisplatin added to gemcitabine versus gemcitabine in patients with resected pancreatic ductal adenocarcinoma: The HEAT randomized clinical trial.

e16316 Background: Regional hyperthermia (RHT) with cisplatin added to gemcitabine showed efficacy in gemcitabine-pre-treated patients with advanced pancreatic ductal adeno- carcinoma. We conducted a randomised clinical trial to investigate RHT with cisplatin added to gemcitabine (GPH) compared with gemcitabine (G) in the adjuvant setting of resected pancreatic ductal adenocarcinoma. Methods: This randomised, multicentre, open-label trial randomly assigned patients to either GPH (gemcitabine 1000 mg/m2 on day 1, 15 and cisplatin 25 mg/m2 with RHT on day 2, 3 and 15,16) or to G (gemcitabine 1000 mg/m2 on day 1,8,15), four-weekly over six cycles. Disease- free survival (DFS) was the primary end-point. Secondary end-points included overall survival (OS) and safety. Results: A total of 117 eligible patients (median age, 63 years) were randomly allocated to treatment (57 GPH; 60 G). With a follow-up time of 56.6 months, the median DFS was 12.7 compared to 11.2 months for GPH and G, respectively (p= 0.39). Median post- recurrence survival was significantly prolonged in the GPH-group (15.3 versus 9.8 months; p= 0.031). Median OS reached 33.2 versus 25.2 months (p= 0.099) with 5-year survival rates of 28.4% versus 18.7%. Excluding eight patients who received additional capecitabine in the G- arm (investigators choice), median OS favored GPH (p= 0.052). Adverse events CTCAE (Common Terminology Criteria for Adverse Events) grade &gt;=3 occurred in 61.5% (GPH) versus 63.6% (G) of patients. Two patients in the G-group died because of treatment- related toxic effects. Conclusions: The randomised controlled Hyperthermia European Adjuvant Trial study failed to demonstrate a significant difference in DFS. However, it showed a difference in post- recurrence survival and a strong trend for improved OS. Regional hyperthermia (RHT) with cisplatin offers innovative treatment options in PDAC. Clinical trial information: NCT01077427 .

Dupilumab for the treatment of dermatologic adverse events associated with MEK and EGFR inhibitors.

3143 Background: Mitogen activated protein kinase kinase inhibitors (MEKi) and epidermal growth factor receptor inhibitors (EGFRi) are targeted therapies used in the treatment of various cancers. Dermatologic adverse events (dAEs) are common with these medications. Dupilumab, a human monoclonal antibody that targets IL-4, is an FDA approved therapy for the treatment of atopic dermatitis. It has also shown utility in the treatment of many other skin disorders, including toxicities associated with anticancer therapies. In our study, we aim to evaluate the efficacy and safety of dupilumab for the treatment of MEKi/EGFRi associated dAEs. Methods: Patients who received dupilumab for the treatment of a dAE attributed to MEKi or EGFRi from 3/1/2017 to 10/1/2022 were identified at Memorial Sloan Kettering Cancer Center. Severity of dAEs was graded at baseline and follow up using Common Terminology Criteria for Adverse Events (CTCAE) v5.0. Patient response to dupilumab was categorized into complete response (CR) (reduction to grade 0), partial response (PR) (reduction to grade 1), or no response (NR) (including change from grade 3/2 to grade ≥ 2). Results: A total of 17 patients (median age 62 years [5 – 87], 58.8% female) who received dupilumab for MEKi (70.6%) or EGFRi (29.4%) related dAEs were identified. Two patients on MEKi were also on concomitant BRAF inhibitors. Patients were white (88.2%), black (5.9%), and Asian (5.9%) and were all undergoing treatment for solid tumors. All dAEs had an eczematous phenotype; 16 were grade 2 (88.2%) and one (5.9%) was grade 3. The median time from dAE development to initiation of dupilumab was 121 days (5 – 1330). Following treatment, 15 patients (88.2%) experienced improvement, with 46.7% and 53.3% achieving CR and PR, respectively. Patients were on dupilumab for a median of 89 days (0-2556), with CR and PR patients exhibiting initial documented response after a median of 30 days (6 – 173). The median CTCAE grade decreased from 2 to 1, and the number of patients on topical and systemic steroids following addition of dupilumab decreased from 17 (100%) to 7 (41.2%) and 5 (29.4%) to 1 (5.9%), respectively. As a result of intolerable anti-cancer therapy-associated dAEs, 4 patients (all on MEKi) initially discontinued their antineoplastics. Three patients (75%) were successfully rechallenged with their original MEKi, while 1 (25%) was switched to another MEKi without subsequent dAE recurrence. No patients reported adverse events to dupilumab treatment. Conclusions: Patients may experience eczematous eruptions while undergoing treatment with MEKi or EGFRi. Dupilumab may be a safe and effective steroid sparing therapeutic option for the management of these dAEs.

All-oral low-dose chemotherapy TEPIP is effective and well-tolerated in patients with peripheral T-cell lymphoma.

Peripheral T-cell lymphoma (PTCL) is a rare and heterogenous hematologic malignancy with poor prognosis especially in elderly and frail patients who are not eligible for intensive treatment. The resulting palliative setting necessitates tolerable but effective schedules for outpatient treatment. TEPIP is a locally developed, all-oral low-dose regimen comprising trofosfamide, etoposide, procarbazine, idarubicin, and prednisolone. In this observational retrospective, single-center study, the safety and efficacy of TEPIP was evaluated in 12 patients (pts.) with PTCL treated at the University Medical Center Regensburg between 2010 and 2022. The endpoints were overall response rate (ORR) and overall survival (OS), and adverse events were individually reported according to the Common Terminology Criteria for Adverse Events (CTCAE) criteria. The enrolled cohort was characterized by advanced age (median 70 years), extensive disease (100% Ann Arbor ≥stage 3), and poor prognosis (75% high/high-intermediate international prognostic index). The most common subtype was angioimmunoblastic T-cell lymphoma (8/12), and 11/12 patients had relapsed or refractory disease at TEPIP onset with a median of 1.5 prior treatment regimens. After a median of 2.5 TEPIP cycles (total of 83 cycles), the ORR was 42% (complete remission 25%), and the OS reached a median of 185 days. Any grade of adverse event (AE) occurred in 8/12 patients, with four patients showing AE ≥CTCAE grade 3 (33%), and the AEs were mainly non-hematological. TEPIP demonstrated competitive efficacy with a tolerable safety profile in a highly palliative cohort of patients with difficult-to-treat PTCL. The all-oral application, which makes outpatient treatment possible, is particularly noteworthy.

Enfortumab Vedotin in Metastatic Urothelial Carcinoma: Survival and Safety in a European Multicenter Real-world Patient Cohort

BackgroundTreatment options for patients with urothelial cancer (UC) refractory to platinum and immunotherapy are limited and survival is short. Enfortumab vedotin (EV) is a monoclonal anti-NECTIN4 antibody conjugated to monomethyl auristatin. It was recently approved because of superior survival in comparison to standard-of-care (SOC) chemotherapy. Real-world patients, however, often have worse characteristics than patients included in clinical trials. ObjectiveTo analyze the efficacy and safety of EV in a cohort of real-world patients. Design, setting, and participantsRetrospective data were collected from 23 hospitals and private practices for patients with metastatic and previously treated UC who received EV either when reimbursed by their insurance company before European Medicines Agency (EMA) approval, within a compassionate use program, or as SOC treatment after EMA approval. Imaging and therapy management were in accordance with local standards. Outcome measurements and statistical analysisAdverse events (AEs) were reported according to Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 criteria. Objective responses were evaluated according to Response Evaluation Criteria in Solid Tumors version 1.1. Progression-free survival (PFS) and overall survival (OS) were estimated using the Kaplan-Meier method. Results and limitationsThe median age for the 125 eligible patients was 66 yr (range 31–89). The Eastern Cooperative Oncology Group performance status (ECOG PS) was 0–1 for 76.0%, 2–4 for 13.6%, and unknown for 10.4% of patients. EV was administered in the fourth or later line for 44.8% of patients. The overall response rate was 41.6% (partial response 39.2%, complete response 2.4%). Median OS was 10.0 months (mo) (95% confidence interval 7.20–12.80) and median PFS was 5.0 mo (95% confidence interval 4.34–5.67). For patients with ECOG PS of 0–1, median OS was 14 mo. Any-grade AEs were observed in 67.2% and CTCAE grade ≥3 AEs in 30.4%. The most common AEs were peripheral sensory neuropathy and skin toxicity. Three fatal events (pneumonia, pneumonitis) occurred. Limitations include the retrospective design and short follow-up. ConclusionsAdministration of EV for real-world patients was feasible with an acceptable toxicity profile. No new safety signals were reported. Antitumor activity in our cohort was comparable to data previously reported for trials. In summary, our results support the use of EV in patients with metastatic UC. Patient summaryEnfortumab vedotin is a medication that improved the survival of patients with bladder cancer in comparison to standard chemotherapy in clinical trials. However, patients included in clinical trials are highly selected and results for toxicities and improvements in survival do not always transfer to the real-world setting. We analyzed data for 125 patients who were treated with enfortumab vedotin. Our results are comparable to the outcomes from clinical trials regarding the safety and efficacy of this treatment.

Can Endoplasmic Reticulum Stress Responses Predict the Development of CIPN in Patients Receiving Paclitaxel-based Therapy? (P12-13.001)

<h3>Objective:</h3> To determine if XBP1s correlates with the onset and severity of chemotherapy-induced peripheral neuropathy (CIPN) in patients receiving paclitaxel (PTX) therapy for their cancer. <h3>Background:</h3> Neuroinflammation is one proposed mechanism for the development of CIPN. X-box binding protein 1 (XBP1s), a prominent molecule in the IRE1α–XBP1 signaling pathway (which regulates the production of enzymes that mediate inflammation-induced pain), shows promise as a potential biomarker to predict the onset of CIPN. <h3>Design/Methods:</h3> Patients newly diagnosed with gynecologic malignancy receiving PTX-based first-line therapy were recruited before treatment initiation. Once consented, blood samples were drawn before treatment and at each scheduled PTX infusion. Determination of serum PTX levels using mass spectrometry and XBP1s mRNA levels in peripheral blood mononuclear cells (PBMCs) by qPCR were performed. In addition, at every infusion time point, each patient’s level of peripheral neuropathy was graded by a physician or advanced provider based on CTCAE (Common Terminology Criteria for Adverse Events) grading criteria (scored 0–5, with 0 being asymptomatic and higher numbers indicating worse neuropathy). Cellular XBP1s, serum PTX, and neuropathy CTCAE scores were statistically associated. <h3>Results:</h3> The study cohort consisted of 8 patients; all female; mean age 55±17 years. All 8 received PTX/carboplatin. Of these, 7 developed symptomatic CIPN (physician assessment). Median peak neuropathy CTCAE grade was 1 (range 0–2). Mean XBP1s peak value was 0.049±0.032; mean baseline XBP1s value was 0.027±0.015. There was a significant association between rise of XBP1s from baseline to peak and neuropathy CTCAE grade (r=0.830, R₂=0.725, p=0.018). Patients with higher serum PTX also had higher PBMC XBP1s expression relative to baseline (p=0.022). Patients with longer days to peak of XBP1s also had longer days to onset of CIPN (r=0.757, R₂=0.573, p=0.049). <h3>Conclusions:</h3> A greater rise from baseline in XBP1s, a marker of ER stress, correlated with the timing and severity of PTX-induced CIPN. <b>Disclosure:</b> Mr. Limia has nothing to disclose. Dr. Foneca has nothing to disclose. Dr. Gelblung has nothing to disclose. Dr. Shalowitz has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Nimble, LLC. The institution of Dr. Shalowitz has received research support from Foundation for Women’s Cancers. The institution of Dr. Shalowitz has received research support from National Cancer Institute. Dr. Kelly has nothing to disclose. Fang-Chi Hsu has nothing to disclose. Dr. Furdui has stock in Xoder Technologies. Dr. Furdui has received intellectual property interests from a discovery or technology relating to health care. Dr. Cubillos-Ruiz has received personal compensation in the range of $50,000-$99,999 for serving as a Consultant for NextRNA Therapeutics. The institution of Dr. Cubillos-Ruiz has received research support from Department of Defense. The institution of Dr. Cubillos-Ruiz has received research support from National Institutes of Health. The institution of Dr. Cubillos-Ruiz has received research support from The Mark Foundation for Cancer Research. Edgar Alfonso Romero-Sandoval has received personal compensation in the range of $500-$4,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for Journal of Pain Research. The institution of Edgar Alfonso Romero-Sandoval has received research support from NINDS. The institution of Edgar Alfonso Romero-Sandoval has received research support from NIDA. The institution of Edgar Alfonso Romero-Sandoval has received research support from NIGMS. Dr. Strowd has received personal compensation for serving as an employee of Kaplan. Dr. Strowd has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Monteris Medical, Inc. Dr. Strowd has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Novocure. Dr. Strowd has received personal compensation in the range of $5,000-$9,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for American Academy of Neurology. The institution of Dr. Strowd has received research support from Southeastern Brain Tumor Foundation. The institution of Dr. Strowd has received research support from Jazz Pharmaceuticals. The institution of Dr. Strowd has received research support from National Institutes of Health. The institution of Dr. Strowd has received research support from Alpha Omega Alpha. The institution of Dr. Strowd has received research support from American Board of Psychiatry and Neurology. Dr. Strowd has received publishing royalties from a publication relating to health care. Dr. Strowd has received publishing royalties from a publication relating to health care.