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Background: About 15–20% of breast cancers are HER2 positive. Approximately 15–24% of individuals with localized HER2-positive cancer develop metastatic disease after curative treatment, while 3–10% present with de novo metastasis. Survival has significantly improved with various anti-HER2 agents, but there is considerable heterogeneity at the individual level. Our study aims to identify factors influencing survival in de novo metastatic HER2-positive breast cancer using a large sample from the National Cancer Database (NCDB). Methods: Women with metastatic HER2-positive breast cancer diagnosed from 2010 to 2020 in the NCDB were included. Demographic, clinicopathological, treatment data, and overall survival (OS) were collected. Kaplan–Meier curves estimated OS. The log-rank test identified OS differences between groups in univariate analysis. The Cox proportional hazard model with backward elimination identified factors affecting OS in multivariate analysis. The 12-month, 36-month, and 60-month survival estimates, 95% confidence intervals (CIs), and adjusted hazard ratios were reported. Results: Among 5376 women with metastatic HER2-positive breast cancer from 2010 to 2020, the median OS was 55.95 months (95% CI 53.55-NE). Multivariate analysis identified age, Charlson–Deyo comorbidity score, histology, HER2 IHC expression, hormone receptor status, the number of metastatic sites, metastasis location, first-line chemotherapy, anti-HER2 therapy, hormone-blocking therapy, surgery at primary/non-primary sites, and palliative treatment as significant factors affecting OS. Race and radiation receipt were not significant. Conclusions: This is the largest analysis of overall survival estimates in de novo metastatic HER2-positive breast cancer to date in the real-world setting. We identified several independent prognostic factors influencing OS in this population. These findings will help individualize prognostication at diagnosis, optimize treatment strategies, and facilitate patient stratification in future trials.

Abstract Introduction: Myeloid sarcoma (MS) is also known as chloroma, extramedullary acute myeloid leukemia (AML), or granulocytic sarcoma. MS is a rare extramedullary infiltration of myeloid cells, most commonly collecting in the skin and causing a small number of localized lesions. It is strongly associated with AML; however, MS more commonly occurs after diagnosis of AML is previously established or after previous treatment of AML. Case Presentation: This case describes a patient with an atypical presentation of MS with no known history of AML and up to 18 lesions identified on CT scan that were previously being monitored for months by her primary care physician. She presented with sepsis attributed to choledocholithiasis versus bacteremia from scattered abscesses versus osteomyelitis of her left knee; nonetheless, lactic acid failed to improve after common bile duct stent with biliary sphincterotomy/dilation or with incision and drainage and empiric antibiotics. Core needle biopsy of her left abdominal sidewall was eventually positive for MS, but she unfortunately developed multiorgan failure with symptomatic hypercalcemia refractory to treatment and ultimately decided to go to comfort care rather than pursue further workup and treatment. Although bone marrow biopsy was ultimately not performed to rule out synchronous AML, this is likely a case of isolated MS due to her scattered skin lesions being present for months prior to hospitalization and acute illness. Conclusion: This case highlights the importance of maintaining MS in the differential diagnosis and the importance of early diagnostic core needle biopsy for patients with persistent skin lesions of unknown origin.

Current strategies to suppress graft-versus-host disease (GVHD) also compromise graft-versus-tumor (GVT) responses. Furthermore, most experimental strategies to separate GVHD and GVT responses merely spare GVT function without actually enhancing it. We have previously shown that endogenously expressed TNF-related apoptosis-inducing ligand (TRAIL) is required for optimal GVT activity against certain malignancies in recipients of allogeneic hematopoietic stem cell transplantation (allo-HSCT). In order to model a donor-derived cellular therapy, we genetically engineered T cells to overexpress TRAIL and adoptively transferred donor-type unsorted TRAIL+ T cells into mouse models of allo-HSCT. We found that murine TRAIL+ T cells induced apoptosis of alloreactive T cells, thereby reducing GVHD in a DR5-dependent manner. Furthermore, murine TRAIL+ T cells mediated enhanced in vitro and in vivo antilymphoma GVT response. Moreover, human TRAIL+ T cells mediated enhanced in vitro cytotoxicity against both human leukemia cell lines and against freshly isolated chronic lymphocytic leukemia (CLL) cells. Finally, as a model of off-the-shelf, donor-unrestricted antitumor cellular therapy, in vitro-generated TRAIL+ precursor T cells from third-party donors also mediated enhanced GVT response in the absence of GVHD. These data indicate that TRAIL-overexpressing donor T cells could potentially enhance the curative potential of allo-HSCT by increasing GVT response and suppressing GVHD.

Current strategies to suppress graft-versus-host disease (GVHD) also compromise graft-versus-tumor (GVT) responses. Furthermore, most experimental strategies to separate GVHD and GVT responses merely spare GVT function without actually enhancing it. We have previously shown that endogenously expressed TNF-related apoptosis-inducing ligand (TRAIL) is required for optimal GVT activity against certain malignancies in recipients of allogeneic hematopoietic stem cell transplantation (allo-HSCT). In order to model a donor-derived cellular therapy, we genetically engineered T cells to overexpress TRAIL and adoptively transferred donor-type unsorted TRAIL^sup +^ T cells into mouse models of allo-HSCT. We found that murine TRAIL^sup +^ T cells induced apoptosis of alloreactive T cells, thereby reducing GVHD in a DR5-dependent manner. Furthermore, murine TRAIL^sup +^ T cells mediated enhanced in vitro and in vivo antilymphoma GVT response. Moreover, human TRAIL^sup +^ T cells mediated enhanced in vitro cytotoxicity against both human leukemia cell lines and against freshly isolated chronic lymphocytic leukemia (CLL) cells. Finally, as a model of off-the-shelf, donor-unrestricted antitumor cellular therapy, in vitro-generated TRAIL^sup +^ precursor T cells from third-party donors also mediated enhanced GVT response in the absence of GVHD. These data indicate that TRAIL-over-expressing donor T cells could potentially enhance the curative potential of allo-HSCT by increasing GVT response and suppressing GVHD. [PUBLICATION ABSTRACT]

Current strategies to suppress graft-versus-host disease (GVHD) also compromise graft-versus-tumor (GVT) responses. Furthermore, most experimental strategies to separate GVHD and GVT responses merely spare GVT function without actually enhancing it. We have previously shown that endogenously expressed TNF-related apoptosis-inducing ligand (TRAIL) is required for optimal GVT activity against certain malignancies in recipients of allogeneic hematopoietic stem cell transplantation (allo-HSCT). In order to model a donor-derived cellular therapy, we genetically engineered T cells to overexpress TRAIL and adoptively transferred donor-type unsorted TRAIL super( +) T cells into mouse models of allo-HSCT. We found that murine TRAIL super( +) T cells induced apoptosis of alloreactive T cells, thereby reducing GVHD in a DR5-dependent manner. Furthermore, murine TRAIL super( +) T cells mediated enhanced in vitro and in vivo antilymphoma GVT response. Moreover, human TRAIL super( +) T cells mediated enhanced in vitro cytotoxicity against both human leukemia cell lines and against freshly isolated chronic lymphocytic leukemia (CLL) cells. Finally, as a model of off-the-shelf, donor-unrestricted antitumor cellular therapy, in vitro-generated TRAIL super( +) precursor T cells from third-party donors also mediated enhanced GVT response in the absence of GVHD. These data indicate that TRAIL-over-expressing donor T cells could potentially enhance the curative potential of allo-HSCT by increasing GVT response and suppressing GVHD.