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The article discusses a case report of a 60-year-old Hispanic woman who underwent heart transplantation and later developed therapy-related acute myeloid leukemia (t-AML) with TP53 mutation. She achieved remission through stem cell transplantation from her sister, with successful engraftment and no measurable residual disease. The article highlights the challenges and outcomes of hematopoietic cell transplantation (HCT) following solid organ transplantation, specifically heart transplants, emphasizing the importance of careful patient selection and monitoring to prevent organ rejection and improve survival rates. [Extracted from the article]

Purpose: To evaluate the dosimetric impact of daily positioning variations measured with cone‐beam computed tomography (CBCT) on whole‐breast radiotherapy patients treated in the prone position. Methods: Daily CBCT was prospectively acquired for 30 consecutive patients positioned prone. Treatment for early‐stage (≤II) breast cancer was prescribed with standard dose (50 Gy/25 fractions) or hypofractionation (42.56 Gy/16 fractions) for 13 and 17 patients, respectively. Systematic and random errors were calculated from the translational CBCT shifts and used to determine population‐based setup margins. Mean translations (±one standard deviation) for each patient were used to simulate the dosimetric impact on targets (PTV_eval and lumpectomy cavity), heart, and lung. Paired Student's t tests at α = 0.01 were used to compare dose metrics after correction for multiple testing (P < 0.002). Significant correlation coefficients were used to identify associations (P < 0.01). Results: Of 597 total fractions, 20 ± 13% required patient rotation. Mean translations were 0.29 ± 0.27 cm, 0.41 ± 0.34 cm, and 0.48 ± 0.33 cm in the anterior–posterior, superior–inferior, and lateral directions leading to calculated setup margins of 0.63, 0.88, and 1.10 cm, respectively. Average three‐dimensional (3D) shifts correlated with the maximum distance of breast tissue from the sternum (r = 0.62) but not with body‐mass index. Simulated shifts showed significant, but minor, changes in dose metrics for PTV_eval, lung, and heart. For left‐sided treatments (n = 18), mean heart dose increased from 109 ± 75 cGy to 148 ± 115 cGy. Shifts from the original plan caused PTV_eval hotspots (V105%) to increase by 5.2% ± 3.8%, which correlated with the total MU of wedged fields (r = 0.59). No significant change in V95% to the cavity was found. Conclusions: Large translational variations that occur when positioning prone breast patients had small but significant dosimetric effects on 3DCRT plans. Daily CBCT may still be necessary to correct for rotational variations that occur in 20% of treatments. To maintain planned dose metrics, unintended beam shifts toward the heart and the contribution of wedged fields should be minimized. [ABSTRACT FROM AUTHOR]

BETting against brain metastases: Brain metastases are a dreaded complication of many cancer types. Even for malignancies that are relatively treatable, such as breast cancer, brain metastases are difficult to reach and often are not susceptible to the same therapies as peripheral tumors. By comparing primary and metastatic breast cancers, Kanojia et al. identified differences in the expression of cytoskeletal protein βIII-tubulin, which was increased in tumors that metastasized to the brain and sensitized them to vinorelbine, a chemotherapy drug. Another drug type, called a BET inhibitor, promoted βIII-tubulin expression and further sensitized breast cancer metastases to vinorelbine in mouse models, demonstrating a promising therapeutic combination. Metastases from primary breast cancer result in poor survival. βIII-tubulin (TUBB3) has been established as a therapeutic target for breast cancer metastases specifically to the brain. In this study, we conducted a systematic analysis to determine the regulation of TUBB3 expression in breast cancer metastases to the brain and strategically target these metastases using vinorelbine (VRB), a drug approved by the U.S. Food and Drug Administration (FDA). We found that human epidermal growth factor receptor 2 (HER2) signaling regulates TUBB3 expression in both trastuzumab-sensitive and trastuzumab-resistant neoplastic cells. We further discovered that bromodomain and extra-terminal domain (BET) inhibition increases TUBB3 expression, rendering neoplastic cells more susceptible to apoptosis by VRB. Orthotopic xenograft assays using two different breast cancer cell models revealed a reduction in tumor volume with BET inhibition and VRB treatment. In addition, in vivo studies using a model of multiple brain metastasis (BM) showed improved survival with the combination of radiation + BET inhibitor (iBET-762) + VRB (75% long-term survivors, P < 0.05). Using in silico analysis and BET inhibition, we found that the transcription factor myeloid zinc finger-1 (MZF-1) protein binds to the TUBB3 promoter. BET inhibition decreases MZF-1 expression and subsequently increases TUBB3 expression. Overexpression of MZF-1 decreases TUBB3 expression and reduces BM in vivo, whereas its knockdown increases TUBB3 expression in breast cancer cells. In summary, this study demonstrates a regulatory mechanism of TUBB3 and provides support for an application of BET inhibition to sensitize breast cancer metastases to VRB-mediated therapy. [ABSTRACT FROM AUTHOR]

Abstract: Purpose: We calculated setup margins for whole breast radiotherapy during voluntary deep‐inspiration breath‐hold (vDIBH) using real‐time surface imaging (SI). Methods and Materials: Patients (n = 58) with a 27‐to‐31 split between right‐ and left‐sided cancers were analyzed. Treatment beams were gated using AlignRT by registering the whole breast region‐of‐interest to the surface generated from the simulation CT scan. AlignRT recorded (three‐dimensional) 3D displacements and the beam‐on‐state every 0.3 s. Means and standard deviations of the displacements during vDIBH for each fraction were used to calculate setup margins. Intra‐DIBH stability and the intrafraction reproducibility were estimated from the medians of the 5th to 95th percentile range of the translations in each breath‐hold and fraction, respectively. Results: A total of 7269 breath‐holds were detected over 1305 fractions in which a median dose of 200 cGy was delivered. Each fraction was monitored for 5.95 ± 2.44 min. Calculated setup margins were 4.8 mm (A/P), 4.9 mm (S/I), and 6.4 mm (L/R). The intra‐DIBH stability and the intrafraction reproducibility were ≤0.7 mm and ≤2.2 mm, respectively. The isotropic margin according to SI (9.2 mm) was comparable to other institutions’ calculations that relied on x‐ray imaging and/or spirometry for patients with left‐sided cancer (9.8–11.0 mm). Likewise, intra‐DIBH variability and intrafraction reproducibility of breast surface measured with SI agreed with spirometry‐based positioning to within 1.2 and 0.36 mm, respectively. Conclusions: We demonstrated that intra‐DIBH variability, intrafraction reproducibility, and setup margins are similar to those reported by peer studies who utilized spirometry‐based positioning. [ABSTRACT FROM AUTHOR]

Background: Glomus tumors are typically benign soft tissue neoplasms that arise in peripheral cutaneous structures. Visceral organ involvement is exceedingly rare., Case Description: Here we present a case of malignant glomus tumor of the esophagus with pulmonary metastases in a 57-year-old woman presenting with three weeks of progressive dysphagia, epigastric pain, and 35-pound weight loss. Upper endoscopy revealed a 5×3.5×2.5 cm vascular esophageal mass. Contrast-enhanced CT showed multiple, scattered sub-centimeter pulmonary nodules bilaterally. Diagnosis of metastatic glomus tumor was confirmed immunohistochemically on primary tumor and lung biopsies. Localized resection was not feasible due to the patient's poor condition. A trial of gemcitabine and docetaxel was planned, but the patient experienced rapid clinical deterioration after a single dose of gemcitabine before electing for hospice care., Conclusions: We have reviewed the 11 other published cases of esophageal glomus tumors, only one of which was similarly metastatic at time of presentation. Of those patients with localized disease treated with surgical excision, all were alive and had no evidence of recurrence (NER) at their times of publication. In contrast, disease ultimately progressed despite surgery and chemoradiotherapy in the sole other case of metastatic glomus tumor of the esophagus. Although glomus tumors are largely benign entities, this case highlights their rare and aggressive malignant potential., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://acr.amegroups.com/article/view/10.21037/acr-21-72/coif). The authors have no conflicts of interest to declare., (2022 AME Case Reports. All rights reserved.)

Isolation of tumor-initiating cells currently relies on markers that do not reflect essential biologic functions of these cells. We proposed to overcome this limitation by isolating tumor-initiating cells based on enhanced migration, a function tightly linked to tumor-initiating potential through epithelial-to-mesenchymal transition (EMT). We developed a high-throughput microfluidic migration platform with automated cell tracking software and facile recovery of cells for downstream functional and genetic analyses. Using this device, we isolated a small subpopulation of migratory cells with significantly greater tumor formation and metastasis in mouse models. Whole transcriptome sequencing of migratory versus non-migratory cells from two metastatic breast cancer cell lines revealed a unique set of genes as key regulators of tumor-initiating cells. We focused on phosphatidylserine decarboxylase (PISD), a gene downregulated by 8-fold in migratory cells. Breast cancer cells overexpressing PISD exhibited reduced tumor-initiating potential in a high-throughput microfluidic mammosphere device and mouse xenograft model. PISD regulated multiple aspects of mitochondria, highlighting mitochondrial functions as therapeutic targets against cancer stem cells. This research establishes not only a novel microfluidic technology for functional isolation of tumor-initiating cells regardless of cancer type, but also a new approach to identify essential regulators of these cells as targets for drug development.

Malignant cells from breast cancer and other common cancers such as prostate and melanoma may persist in bone marrow as quiescent, non-dividing cells that remain viable for years or even decades before resuming proliferation to cause recurrent disease. This phenomenon, referred to clinically as tumor dormancy, poses tremendous challenges to curing patients with breast cancer. Quiescent tumor cells resist chemotherapy drugs that predominantly target proliferating cells, limiting success of neo-adjuvant and adjuvant therapies. We recently developed a 3D spheroid model of quiescent breast cancer cells in bone marrow for mechanistic and drug testing studies. We combined this model with optical imaging methods for label-free detection of cells preferentially utilizing glycolysis versus oxidative metabolism to investigate the metabolic state of co-culture spheroids with different bone marrow stromal and breast cancer cells. Through imaging and biochemical assays, we identified different metabolic states of bone marrow stromal cells that control metabolic status and flexibilities of co-cultured breast cancer cells. We tested metabolic stresses and targeted inhibition of specific metabolic pathways to identify approaches to preferentially eliminate quiescent breast cancer cells from bone marrow environments. These studies establish an integrated imaging approach to analyze metabolism in complex tissue environments to identify new metabolically-targeted cancer therapies.

Genetically-encoded fluorescence resonance energy transfer (FRET) reporters are powerful tools to analyze cell signaling and function at single cell resolution in standard two-dimensional cell cultures, but these reporters rarely have been applied to three-dimensional environments. FRET interactions between donor and acceptor molecules typically are determined by changes in relative fluorescence intensities, but wavelength-dependent differences in absorption of light complicate this analysis method in three-dimensional settings. Here we report fluorescence lifetime imaging microscopy (FLIM) with phasor analysis, a method that displays fluorescence lifetimes on a pixel-wise basis in real time, to quantify apoptosis in breast cancer cells stably expressing a genetically encoded FRET reporter. This microscopic imaging technology allowed us to identify treatment-induced apoptosis in single breast cancer cells in environments ranging from two-dimensional cell culture, spheroids with cancer and bone marrow stromal cells, and living mice with orthotopic human breast cancer xenografts. Using this imaging strategy, we showed that combined metabolic therapy targeting glycolysis and glutamine pathways significantly reduced overall breast cancer metabolism and induced apoptosis. We also determined that distinct subpopulations of bone marrow stromal cells control resistance of breast cancer cells to chemotherapy, suggesting heterogeneity of treatment responses of malignant cells in different bone marrow niches. Overall, this study establishes FLIM with phasor analysis as an imaging tool for apoptosis in cell-based assays and living mice, enabling real-time, cellular-level assessment of treatment efficacy and heterogeneity.