Citations

ImportanceTumor necrosis factor α (TNF) inhibitor–induced psoriasiform eruption is well recognized in adults, but few reports document this paradoxical effect in children.ObjectiveTo characterize the clinical features and the clinical time course of TNF inhibitor–induced psoriasiform eruptions in children.Design, Setting, and ParticipantsA multicenter retrospective case series of children younger than 18 years seen between January 1, 2000, and December 31, 2016, who developed a new-onset psoriasiform eruption while taking a TNF inhibitor for a nondermatologic disorder. Participating sites were members of the Pediatric Dermatology Research Alliance. Data were entered into a Research Electronic Data Capture database at the Mayo Clinic (ie, the coordinating center).ResultsPsoriasiform eruptions were identified in 103 TNF inhibitor–treated patients (median age, 13.8 years [IQR, 11.7-16.4 years]; 52 female patients [50%]; 57 White patients [55%]), with 67 patients (65%) treated with infliximab, 35 (34%) with adalimumab, and 1 (1%) with certolizumab pegol. Most patients had no personal history (101 [98%]) or family history of psoriasis (60 patients [58%]). Inflammatory bowel disease was the most common indication for treatment with TNF inhibitor (94 patients [91%]). The primary extracutaneous disease was under control in 95 patients (92%) who developed the eruption. Most patients (n = 85 [83%]) developed psoriasiform eruptions at multiple anatomic sites, with scalp involvement being most common (65 patients [63%]). Skin disease developed at a median of 14.5 months (IQR, 9-24 months) after TNF inhibitor initiation. To treat the psoriasiform eruption, topical steroidal and nonsteroidal medication was prescribed for all patients. Systemic therapy was added for 30 patients (29%): methotrexate for 24 patients (23%), oral corticosteroids for 8 patients (8%), and azathioprine for 1 patient (1%). For 26 patients (25%), suboptimal effectiveness with topical medications alone prompted discontinuation of the initial TNF inhibitor and a change to a second-line TNF inhibitor with cutaneous improvement in 23 patients (88%) by a median of 3 months (IQR, 2-4 months). Eight patients (31%) who started a second-line TNF inhibitor developed a subsequent TNF inhibitor–induced psoriasiform eruption at a median of 6 months (IQR, 4-8 months). Persistent skin disease in 18 patients (17%) prompted discontinuation of all TNF inhibitors; 11 patients changed to a non-TNF inhibitor systemic therapy, and 7 discontinued all systemic therapy.Conclusions and RelevanceIn this case series, paradoxical TNF inhibitor–induced psoriasiform eruptions were seen in children treated with TNF inhibitors for any indication, and there appears to be a class effect among the varying TNF inhibitors. The majority of these children were able to continue TNF inhibitor therapy with adequate skin-directed and other adjuvant therapies.

Objectives: Deaths from an unknown cause are difficult to adjudicate and oncologic studies of comparative effectiveness often demonstrate inconsistencies in incorporating these deaths and competing events (eg, heart disease and stroke) in their analyses. In this study, we identify cancer patients most at risk for death of an unknown cause. Methods: This retrospective, population-based study used cancer registry data from the Surveillance, Epidemiology, and End Results database (1992-2015). The absolute rate of unknown causes of death (COD) cases stratified by sex, marital status, race, treatment, and cancer site were calculated and a multivariable logistic regression model was applied to obtain adjusted odds ratios with 95% CIs. Results: Out of 7,154,779 cancer patients across 22 cancer subtypes extracted from Surveillance, Epidemiology, and End Results, 3,448,927 died during follow-up and 276,068 (7.4%) of these deaths were from unknown causes. Patients with an unknown COD had a shorter mean survival time compared with patients with known COD (36.3 vs 65.7 mo, P < 0.001). The contribution of unknown COD to total mortality was highest in patients with more indolent cancers (eg, prostate [12.7%], thyroid [12.3%], breast [10.7%]) and longer follow-up (eg, >5 to 10 y). One, 3, and 5-year cancer-specific survival (CSS) calculations including unknown COD were significantly decreased compared with CSS estimates excluding cancer patients with unknown COD. Conclusion: Of the patients, 7.4% died of unknown causes during follow-up and the proportion of death was higher with longer follow-up and among more indolent cancers. The attribution of high percentages of unknown COD to cancer or non-cancer causes could impact population-based cancer registry studies or clinical trial outcomes with respect to measures involving CSS and mortality.

ImportanceDisparities in treatment initiation may affect outcomes, but data on racially diverse populations with chronic hepatitis B virus (HBV) infection are limited.ObjectiveTo examine whether HBV treatment initiation and outcomes differ among racial groups.Design, Setting, and ParticipantsFrom January 14, 2011, to January 28, 2018, hepatitis B surface antigen—positive adults (age ≥18 years) not receiving anti-HBV therapy were enrolled and followed up at weeks 12, 24, and every 24 weeks thereafter in a multicenter longitudinal cohort study (Hepatitis B Research Network [HBRN] adult cohort study) conducted in North America. The last study visit and data collection were completed January 28, 2019. Data were analyzed from August 27, 2021, to August 25, 2022. All HBRN participants were included unless they had acute HBV, HIV, hepatitis C or D, less than 24-weeks of follow-up after enrollment, initiated treatment at or immediately after enrollment, or had unknown race.ExposuresParticipants had clinical and laboratory assessments and could receive anti-HBV treatment after enrollment.Main Outcomes and MeasuresHepatitis B virus treatment initiation and major adverse liver outcomes (hepatic decompensation, hepatocellular carcinoma, liver transplant, and death).ResultsOf 1550 participants, 193 (12%) were African American or Black, 1157 (75%) were Asian, 157 (10%) were White, and 43 (3%) were other races; 789 (51%) were women, and the median age was 41.2 (IQR, 32.9-51.6) years. Sociodemographic and virologic parameters differed between groups. During 5727 person-years of follow-up, 504 participants initiated treatment, with incidences of 4.8 per 100 person-years in African American or Black individuals, 9.9 per 100 person-years in Asian individuals, 6.6 per 100 person-years in White individuals, and 7.9 per 100 person-years in those of other races (P &amp;lt; .001). A lower proportion (14%) of African American or Black participants met treatment criteria compared with Asian (22%) and White (27%) individuals (P = .01). The cumulative probabilities of treatment initiation after meeting the criteria were not significantly different among racial groups (African American or Black, 0.45; Asian, 0.38; White, 0.40 at 48 weeks and African American or Black, 0.45; Asian, 0.51; White, 0.51 at 72 weeks; P = .68). The incidence of major adverse liver outcomes was 0.1 per 100 person-years and did not differ by race.Conclusions and RelevanceIn this observational study of chronic HBV, African American or Black participants were less likely than individuals of other races to meet treatment criteria, but among those who did, HBV treatment receipt did not differ significantly by race or socioeconomic factors. Not all eligible participants initiated treatment, but adverse liver outcomes were rare. These findings may not be generalizable to patients with chronic HBV receiving care in other settings.

Abstract Introduction/Objectives: Purines regulate DNA repair in brain tumors through uncertain mechanisms. We sought to define the mechanisms by which purines regulate DNA repair and therapy response. Methods: Crispr/Cas9, siRNA, and CDNA overexpression and immunoblot were used to modulate and confirm protein levels. γ-H2AX and Rad51 foci were enumerated using immunofluorescence. Fluorescent reporter assays were performed to detect DNA repair activity. Phosphoproteomics was used to identify GTP-dependent (de)phosphorylation events after RT and antibodies generated against novel sites. Celltiter-glo or clonogenic assay were performed to evaluate drug/RT responses. IHC was used to detect protein expression. Animal models of glioblastoma and normal tissue (irradiation of GI system) were used to assess DNA repair and treatment responses in vivo. Results: Pharmacogenomic inhibition of GTP (but not ATP) synthesis sensitized GBM cells to RT, slowed the repair of RT-induced DSBs and inhibited the activity of non-homologous end joining (NHEJ), but not homologous recombination (HR). These effects could be rescued by GTP (but not ATP) supplementation. We found a GTP-dependent RT-induced dephosphorylation event on Abl interactor 1 (Abi-1) serine 323 (S323) using phosphoproteomics. We generated a new antibody for p-Abi-1 (S323), validated its specificity, and confirmed that RT causes a GTP-dependent dephosphorylation of Abi-1 (S323). Knockout of Abi-1 slowed RT-induced DSB repair and this was rescued by re-expression of dephosphomimetic Abi-1 (S323A) but not phosphomimetic Abi-1 (S323D). Abi-1 canonically binds to the small GTP-activated protein Rac1. Expression of constitutively active Rac1 promoted the dephosphorylation of Abi-1 (S323) and DSB repair while these effects were blocked by dominant negative Rac1. Pharmacogenomic inhibition of protein phosphatase 5 reversed the GTP- and Rac1-mediated dephosphorylation of Abi-1 and DSB repair. These findings have therapeutic relevance. In GBM PDX samples, levels of p-Abi-1 (S323) negatively correlated with Rac1 activity and predicted favorable efficacy of genotoxic treatments. In orthotopic GBM mouse models, inhibition of Rac1 enhanced RT responses and suppressed Abi-1 S323 dephosphorylation. Abi-1 knockout enhanced efficacy of numerous genotoxic treatments and could be rescued by Abi-1 S323A (but not Abi-1 S323D) re-expression. This regulation is generalizable beyond brain cancer, as GTP supplementation promoted DNA repair and p-Abi1 (S323) dephosphorylation in normal astrocytes and enteroids and protected mice from RT-mediated gastrointestinal injury. Conclusions: GTP promotes DNA repair by activating Rac1 and PP5 to dephosphorylate Abi-1 and stimulate NHEJ. Disrupting this regulation could improve brain tumor treatment responses while augmenting it could help protect normal tissues from genotoxic injury. Citation Format: Weihua Zhou, Angelica Lin, Zitong Zhao, John Yang, Kari Wilder-Romans, Jie Xu, Sumeet Solanki, Jing Li, Annabel Yang, Andrew Scott, Ayesha Kothari, Erik Peterson, Navyateja Korimerla, Jessica Liang, Janna Jacobson, Sravya Palavalasa, Alexandra Obrien, Sean Ferris, Shuang Zhao, Jann N. Sarkaria, Meredith Morgan, Theodore S. Lawrence, Costas A. Lyssiotis, Yatrik Shah, Daniel R. Wahl. GTP-dependent signaling links metabolism, non-homologous end joining and treatment responses in cancer and normal tissues [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3498.

Abstract Background H3K27-altered diffuse midline glioma (DMG) is the deadliest pediatric brain tumor; despite intensive research efforts, every clinical trial to date has failed. Is this because we are choosing the wrong drugs? Or are drug delivery and other pharmacokinetic variables at play? We hypothesize that the answer is likely a combination, where optimization may result in a much needed novel therapeutic approach. Methods We used in vitro drug screening, patient samples, and shRNA knockdown models to identify an upregulated target in DMG. A single small molecule protein kinase inhibitor with translational potential was selected for systemic and direct, loco-regional delivery to patient-derived xenografts (PDX) and genetically engineered mouse models (GEMM). Pharmacokinetic studies were conducted in non-tumor bearing rats. Results Aurora kinase (AK) inhibitors demonstrated strong antitumor effects in DMG drug screens. Additional in vitro studies corroborated the importance of AK to DMG survival. Systemic delivery of alisertib showed promise in subcutaneous PDX but not intracranial GEMM and PDX models. Repeated loco-regional drug administration into the tumor through convection-enhanced delivery (CED) was equally inefficacious, and pharmacokinetic studies revealed rapid clearance of alisertib from the brain. In an effort to increase the drug to tumor residence time, continuous CED over 7 days improved drug retention in the rodent brainstem and significantly extended survival in both orthotopic PDXs and GEMMs. Conclusions These studies provide evidence for increasing drug-tumor residence time of promising targeted therapies via extended CED as a valuable treatment strategy for DMG.

BACKGROUND: There are limited data regarding outcomes for patients with gastrointestinal (GI) primaries and brain metastases treated with stereotactic radiosurgery (SRS). OBJECTIVE: To examine clinical outcomes after SRS for patients with brain metastases from GI primaries and evaluate potential prognostic factors. METHODS: The International Radiosurgery Research Foundation centers were queried for patients with brain metastases from GI primaries managed with SRS. Primary outcomes were local control (LC) and overall survival (OS). Kaplan-Meier analysis was used for univariate analysis (UVA) of prognostic factors. Factors significant on UVA were evaluated with a Cox multivariate analysis proportional hazards model. Logistic regressions were used to examine correlations with RN. RESULTS: We identified 263 eligible patients with 543 brain metastases. Common primary sites were rectal (31.2%), colon (31.2%), and esophagus (25.5%) with a median age of 61.6 years (range: 37-91.4 years) and a median Karnofsky performance status (KPS) of 90% (range: 40%-100%). One-year and 2-year LC rates were 83.5% (95% CI: 78.9%-87.1%) and 73.0% (95% CI: 66.4%-78.5%), respectively. On UVA, age >65 years ( P = .001), dose <20 Gy ( P = .006) for single-fraction plans, KPS <90% ( P < .001), and planning target volume ≥2cc ( P = .007) were associated with inferior LC. All factors other than dose were significant on multivariate analysis ( P ≤ .002). One-year and 2-year OS rates were 68.0% (95% CI: 61.5%-73.6%) and 31.2% (95% CI: 24.6%-37.9%), respectively. Age > 65 years ( P = .006), KPS <90% ( P = .005), and extracranial metastases ( P = .05) were associated with inferior OS. CONCLUSION: SRS resulted in comparable LC with common primaries. Age and KPS were associated with both LC and OS with planning target volume and extracranial metastases correlating with LC and OS, respectively. These factors should be considered in GI cancer patient selection for SRS.

TPS739 Background: The landscape for treatment of metastatic renal cell carcinoma (mRCC) has changed dramatically over the past 7 years with the approvals of tyrosine kinase inhibitors and immune-oncology (IO) agents alone or in combination for untreated mRCC. However, multiple knowledge gaps remain. While active surveillance remains an option for selected pts, prospective evidence on selection of and outcomes for pts is limited. Recent phase III trials all used a common comparator, sunitinib, so no comparative effectiveness data on the new IO-based regimens exists. There are also no routinely used predictive biomarkers in mRCC pt management. Therefore, a better understanding of the biologic determinants associated with cancer heterogeneity and clinical outcomes through blood, tumor, and radiographic based assessments is needed. Importantly, longitudinal changes in health-related quality of life (QOL) and symptom burden of patients with mRCC initiated on new IO–based regimens outside of an interventional clinical trial are poorly understood. Pt reported outcomes (PRO) are rarely captured in a systematic manner. Addressing the evidence gap for how real world pts symptomatically change with treatment combinations and sequences over time is a pressing unmet need. Methods: This is a prospective, observational cohort, phase IV study of 800 mRCC pts in the US. Pts must: be age ≥19 at informed consent; have a diagnosis of mRCC (any histology) with no prior systemic therapy for mRCC (surgery and radiation therapy, prior neoadjuvant/adjuvant therapy for non-mRCC, and pts currently not on systemic therapy and being observed are all permitted); and be able to comply with completion of PROs. Those being treated for active malignancies other than mRCC or not intending to undergo follow up care at a study site within PCORnet are excluded. Pts will undergo consent and baseline assessments, including research blood collection and processing, by the study site team. A novel aspect of this study is the use of PCORnet and Medicare data to minimize data collection burden on sites. PCORnet, the National Patient-Centered Clinical Research Network, is a network of networks that curates EHR data from multiple health systems using a common data model. This allows subsequent follow up to be centrally coordinated by the coordinating center. PRO will be collected at baseline (pre-treatment), every 3 mos for 2 yrs, and then every 6 mos until end of follow up (minimum 18 mos follow-up; maximum 36 mos follow-up). The primary objective is to determine distinct patterns of change in QOL and symptom burden of mRCC pts receiving therapy. Secondary objectives include quantifying the time to treatment discontinuation of pts, identifying patterns of clinical management in the real world setting of mRCC pts on various treatment regimens, and evaluating overall survival of mRCC pts. ClinicalTrials.gov Identifier: NCT04919122 Clinical trial information: NCT04919122 .

260 Background: NGS to identify HRR mutations (mut) is indicated in advanced prostate cancer (aPC); samples for testing may be tissue or plasma. In a large real-world (RW) database, we determined concordance between plasma ctDNA and primary tumor tissue (PT) and/or metastatic tissue (MT) for BRCA1, BRCA2, and ATM mut in PC patients (pts) who received both LB and tissue NGS any time during standard of care (SOC) management. The study objective was to assess the utility of LB to detect actionable mut in these HRR genes and demonstrate the utility of combined LB and tissue testing. Methods: We examined de-identified data from pts who had NGS using both Tempus xF (105 genes-LB) and Tempus xT (648 genes-tissue) during SOC for aPC. Analyses included 1) PT and LB and 2) MT and LB. The results from the pts’ earliest PT or MT and earliest LB were used for paired analyses. The prevalence of a pathogenic/likely pathogenic germline and/or somatic mut in BRCA1, BRCA2, or ATM was reported as N (%), 95% CI. The sensitivity of the LB to identify observed HRR mut in tissue was also reported as N (%), 95% CI. Concordance between pairs was evaluated by Cohen’s kappa statistic with 95% CI. Results: HRR results are show for 1074 PC pts who had NGS performed on PT and LB and 451 PC pts with NGS on both MT and LB. In the PT and LB analysis, HRR mut were found in 6.2% (95% CI: 4.9%-7.9%) of LB and 8.8% (95% CI: 7.2%-11%) of PT. The sensitivity of LB to detect HRR mut in the PT was 53% (95% CI: 43%-64%). Cohen’s kappa statistic was 0.59, 95% CI=0.50-0.68, between PT and LB. In the MT and LB analysis, HRR mut were found in 10% (95% CI 7.8%-14%) of LB and 10% (7.6%-13%) of MT. The sensitivity of LB to detect HRR mut in the MT was 70% (95% CI: 54%-82%). Cohen’s kappa statistic was 0.65, 95% CI=0.54-0.77, between MT and LB. Conclusions: In this large RW dataset, plasma ctDNA-based analysis of BRCA1, BRCA2, and ATM mut showed greater concordance between LB and MT than LB and PT, and may be used as an initial tool for HRR mut detection. When LB results are negative, further exploration with tissue-based testing may identify HRR mut to guide clinical decisions. [Table: see text]

Abstract Purpose: To determine the rate of rib fracture in a cohort of patients with breast cancer treated with proton therapy and enrolled on a prospective registry. In series investigating photon therapy for breast cancer, the rib fracture rate ranges from 0.3-13% Methods: From a prospective database, we identified patients treated with proton therapy for breast cancer at our institution between January 1, 2012 and December 31, 2020. Clinical and dosimetric data was extracted from the electronic medical record. The cumulative incidence method assessed rib fracture rate; the Fine-Gray test statistic assessed prognostic significance select variables. Results: 225 patients were identified, 223 women and 2 men. Median age at the time of radiation was 57.8 years (range, 25 – 87). 26% of patients were black, 69% white and 5% were other races or race not disclosed. 5% were Hispanic. 74% of patients had left-sided breast cancer, 5% bilateral, and 21% right-sided. DEXA scan was normal in 20%, showed osteopenia in 34%, osteoporosis in 6%, and not performed in 40%. 57% of patients received antiendocrine therapy with an aromatase inhibitor. For 16% of patients, the breast +/- internal mammary nodes (IMN) were treated, while 32% underwent proton therapy to treat the breast and comprehensive regional lymphatics. 1% of patients had chest wall +/- IMN treated, while 51% underwent proton therapy to treat the chest wall and comprehensive regional lymphatics. 41% of patients were treated with passive scatter proton therapy (n=92); 52% of these had mastectomy. 58% of patients received treatment with pencil beam scanning (PBS) proton therapy (n=131); 53% of these had mastectomy. A combination of passive scatter and PBS was used for 2 patients (1%). 85% of patients received a boost. Median follow-up was 3.1 years (range, 0.2 – 9.1). 97% of patients had &gt; 12 months of follow-up. The 3 year cumulative incidence of in-field rib fracture was 3.7% (95%CI: 1.6%-7.1%). In total, 8 patients developed in-field rib fractures, one symptomatic and 7 identified incidentally on surveillance imaging, for a 0.4% rate of symptomatic rib fracture. Median time from completion of radiation to identification of rib fracture was 1.8 years (range, 0.4-7.4 years). Rib fractures occurred within 2.2 years from radiotherapy completion for seven of the eight patients who experienced this side effect. Three patients developed rib fractures outside of the radiation field, for a cumulative incidence of out-of-field rib fracture of 0.9% (95%CI: 0.2-3.0%). No variables were associated with rib fracture on univariate analysis. Of those with in-field rib fractures, 3 had low and 3 had normal bone density while 2 had not undergone testing; of those with out-of-field rib fractures, 2 had osteopenia and 1 did not have testing. Conclusions: Although a proton beam has higher biological dose deposition at end-of-range than the assumed constant RBE=1.1, the 3 year rate of any in-field rib fractures in our series remains low at 3.7%, with a 0.4% rate of symptomatic rib fracture. Contouring ribs as an OAR and establishing a dose constraint warrants further investigation as a means to maintaining a low rate of rib fracture with proton therapy. Citation Format: Julie Bradley, Xiaoying Liang, Raymond Mailhot Vega, Chunbo Liu, Eric Brooks, Teena Burchianti, Emma Viviers, Roi Dagan, Oluwadamilola Oladeru, Christopher Morris, Nancy Mendenhall. Incidence of rib fracture following treatment with proton therapy for breast cancer [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 P1-10-08.

Abstract The Mayo Clinic Florida Integrated Oncology Building will be the home of the first spot-scanning only carbon/proton hybrid therapy system by Hitachi, Ltd. It will provide proton beams up to kinetic energies of 230 MeV and carbon beams up to 430 MeV n −1 for clinical deployment. To provide adequate radiation protection, the Geant4 (v10.6) Monte Carlo toolkit was utilized to quantify the ambient dose equivalent at a 10 mm depth ( H *(10)) for photons and neutrons. To perform accurate calculations of the ambient dose equivalent, three-dimensional computer-aided design files of the entire planned facility were imported into Geant4, as well as certain particle system components such as the bending magnets, fast Faraday cup, and gantry. Particle fluence was scored using 60 cm diameter spheres, which were strategically placed throughout areas of interests. Analytical calculations were performed as first-pass design checks. Major shielding slabs were optimized using Geant4 simulations iteratively, with more than 20 alternative designs evaluated within Geant4. The 430 MeV n −1 carbon beams played the most significant role in concrete thickness Requirements. The primary wall thickness for the carbon fixed beam room is 4 meters. The presence of the proton gantry structure in the simulation caused the ambient dose equivalent to increase by around 67% at the maze entrance, but a decrease in the high energy beam transport corridor. All shielding primary and secondary goals for clinical operations were met per state regulation and national guidelines.