Several reports of second malignant neoplasm (SMN) in patients with relapsed neuroblastoma after treatment with (131)I-MIBG suggest the possibility of increased risk. Incidence of and risk factors for SMN after (131)I-MIBG have not been defined. This is a multi-institutional retrospective review of patients with neuroblastoma treated with (131)I-MIBG therapy. A competing risk approach was used to calculate the cumulative incidence of SMN from time of first exposure to (131)I-MIBG. A competing risk regression was used to identify potential risk factors for SMN. The analytical cohort included 644 patients treated with (131)I-MIBG. The cumulative incidence of SMN was 7.6% (95% confidence interval [CI], 4.4-13.0%) and 14.3% (95% CI, 8.3-23.9%) at 5 and 10 years from first (131)I-MIBG, respectively. No increase in SMN risk was found with increased number of (131)I-MIBG treatments or higher cumulative activity per kilogram of (131)I-MIBG received (p = 0.72 and p = 0.84, respectively). Thirteen of the 19 reported SMN were haematologic. In a multivariate analysis controlling for variables with p< 0.1 (stage, age at first (131)I-MIBG, bone disease, disease status at time of first (131)I-MIBG), patients with relapsed/progressive disease had significantly lower risk of SMN (subdistribution hazard ratio 0.3, 95% CI, 0.1-0.8, p = 0.023) compared to patients with persistent/refractory neuroblastoma. The cumulative risk of SMN after (131)I-MIBG therapy for patients with relapsed or refractory neuroblastoma is similar to the greatest published incidence for high-risk neuroblastoma after myeloablative therapy, with no dose-dependent increase. As the number of patients treated and length of follow-up time increase, it will be important to reassess this risk.

Background: We investigated whether surveillance imaging had an impact on post-relapse survival in patients with rhabdomyosarcoma (RMS). We hypothesized that relapse detected by imaging (group IM) would be associated with longer survival compared with relapse detected with a clinical sign or symptom (group SS). Materials and Methods: We performed an observational multi-institutional study in 127 patients with relapsed RMS comparing overall survival (OS) after relapse using Kaplan-Meier and Cox proportional hazards analyses. Results: Relapse was detected in 60 (47%) group IM and 67 (53%) SS patients. Median follow-up in survivors was 4 years (range 1.0 to 16.7 y). Four-year OS rates were similar between group IM (28%, 95% confidence interval [CI]: 14%-40%) and SS (21%, 95% CI: 11%-31%) (P=0.14). In multivariable analyses accounting for institution, age at diagnosis, time to relapse, risk group at diagnosis, and primary site, not receiving chemotherapy (hazard ratio [HR]: 6.8, 95% CI: 2.8-16.6), radiation (HR: 3, 95% CI: 1.7-5.3), or surgery (HR: 2.8, 95% CI: 1.6-4.8) after relapse were independently associated with poor OS. Conclusion: These results on whether surveillance imaging provides survival benefit in patients with relapsed RMS are inconclusive. Larger studies are needed to justify current surveillance recommendations. Chemotherapy, radiotherapy and surgery to treat recurrence prolong OS.

Sarcomas with BCOR alteration are a heterogenous group characterized by changes including internal tandem duplications (ITDs) and recurring fusions with CCNB3, ZC3H7B, and other rare partners. With widespread genomic testing, these alterations are now associated with histologies such as Ewing-like sarcoma (BCOR:: CCNB3), high-grade endometrial stromal sarcoma (ZC3H7B:: BCOR), and clear cell sarcoma of kidney (BCOR-ITD). BCOR altered sarcomas of soft tissues and organs were identified through PubMed using keywords "Sarcoma (AND) BCOR" from 2005 through October 2021. Summary statistics and outcome data were calculated using STATA v12.1. Forty-one publications described 190 patients with BCOR altered soft tissue or organ sarcomas. BCOR-ITD was most common, followed by BCOR::CCNB3, ZC3H7B:: BCOR. BCOR-ITD tumors occurred mainly in infants, BCOR:: CCNB3 commonly occurred in adolescent young adults, and ZC3H7B::BCOR only in adults. The most common site for BCOR:: CCNB3 fused tumors was extremity, BCOR-ITD kidney and ZC3H7B::BCOR uterus. Metastasis was rare in patients with BCOR::CCNB3. While most underwent resection and chemotherapy, few received radiation. Median follow-up of survivors was 24 months. Five year overall survival for patients with BCOR::CCNB3 fusions was 68% (95% confidence interval [CI]: 46%-83%). Patients with BCOR-ITD and ZC3H7B::BCOR had worse prognoses with 5 years overall survival of 35% (95% CI: 15%-56%) and 41% (95% CI: 11%-71%), respectively, demonstrating need for collaborative efforts identifying optimal treatments to improve outcomes.

Key Clinical MessageAn isolated IgA-mediated autoimmune hemolytic anemia can present a diagnostic challenge. When a routine direct antiglobulin test (DAT) is negative but clinical suspicion remains high, further testing with monospecific antisera should be performed. As with IgG-mediated WAIHA, steroids are first-line treatment, though splenectomy is often required to achieve a durable treatment response.

Methods We generated MUC18-cytotoxic and csCARs with 4-1BB, OX40, 2B4, and DNAM-1 endodomains and confirmed specificity and functionality using MUC18 overexpressing and knockout targets and a long-term TME co-culture comprised of alveolar rhabdomyosarcoma, Rh4, and inhibitory macrophages (M2s). Safety of MUC18-csCARs was tested against the MUC18+ liver sinusoidal endothelial cell (LSEC) line. Anti-tumor activity of dual-targeted NK cells compared to unmodified and singly-modified NK cells was assessed in vivo using a novel TME xenograft model with Rh4 and MDSCs. Results MUC18 cytotoxic CAR-NK cells killed MUC+ high targets, while exhibiting low killing against an Rh4-MUC18 KO cell line, confirming CAR specificity and function. MUC18-OX40csCAR NK cells expanded without additional killing in the TME compared to NK cells with other co-stimulatory endodomains. MUC18-OX40csCAR NK cells did not exhibit killing of LSECs. Dual-targeted NK cells demonstrated enhanced tumor control in TME co-cultures (2.4-fold change in tumor vs. 4.6 by unmodified NK, 10.6 by NKG2D.z, and 6.8 by cs.MUC18) compared to either singly-modified NK population (figure 1). Dual-targeted NK cells demonstrated superior tumor control in the in vivo TME xenograft model compared to controls (p=0.007 versus NKG2D.z) and prolonged survival (p= <0.0001) (figure 2). Conclusions Dual-targeted NK cells demonstrate enhanced anti-tumor activity without toxicity against normal tissue. Use of co-stimulation-only CARs in NK cells may allow exploitation of previously non-targetable sarcoma antigens. Abstract 394 Figure 1 The dual-targeted CAR NK cells were compared to unmodified NK cells, NKG2D.? CAR NK cells, and csMUC18 CAR NK cells in a TME co-culture system. A) Rh4 fold expansion in the tumor alone conditions and B) in the TME conditions was determined for each time point. C) Fold change in NK cells in the tumor alone conditions. D) Fold change in NK cells in the TME conditions. Abstract 394 Figure 2 (A) Mice (n=5 per treatment group) received two NK cells doses at 31 and 38 days post tumor inoculation and three times per week IL-2 and IL-15 to promote NK cell survival. (B) Survival probability of each treatment cohort.

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A 16-month-old, previously healthy male is hospitalized for new onset seizures. Initial investigation is significant for enterovirus/rhinovirus respiratory infection, abnormal T2 signal predominantly in the white matter and scattered microhemorrhages on brain MRI, transaminitis, and thrombocytopenia. His symptoms initially improve on steroid therapy and he is discharged from the hospital. During the ensuing month with the tapering of the steroids, he develops new motor deficits for which he is rehospitalized. His laboratory investigation on readmission is unremarkable. However, there is significant progression of white matter lesions and microhemorrhages on repeat MRI. While in the hospital, he becomes febrile and has seizure recurrence and worsening neurologic symptoms, including cerebral salt wasting and encephalopathy. Subsequent neuroimaging demonstrates cerebral edema and diffuse brain injury. A high index of suspicion for a rare condition ultimately leads us to perform the specialized testing that confirms the diagnosis. We will discuss the diagnostic challenges that arise from an atypical presentation of an uncommon condition, and from the disease progression that is modified by previous interventions.