Christian Fernandez

Adoptive chimeric antigen receptor (CAR)-T cell therapies have limited efficacy in solid tumors because of poor infiltration and impaired effector function, whereas radiotherapy is constrained by radioresistance and metastatic spread. Here we show that integrating the spatial precision of ionizing radiation with the biological specificity of CAR-T cells enables localized delivery of the inflammatory cytokine tumor necrosis factor (TNF). We identified radiation-responsive genes in tumor-infiltrating T cells and engineered synthetic radioinducible promoters to drive TNF expression. Human CAR-T cells carrying this construct (riTNF CAR-T cells) secreted high levels of TNF upon irradiation, independently of antigen engagement. In human xenograft and murine tumor models, the combination of riTNF CAR-T cells and local irradiation produced greater tumor regression than either treatment alone or standard CAR-T cells with irradiation. This response was associated with high intratumoral, but not systemic, TNF levels, increased tumor necrosis and apoptosis, vascular disruption and greater CAR-T cell infiltration. These findings establish a platform for spatially and temporally controlled cytokine delivery from engineered CAR-T cells.

Purpose Low-dose total skin electron beam therapy (LD-TSEBT) has recently gained popularity in treating mycosis fungoides (MF) due to its reduced toxicity and favorable response rates. Combining accelerated LD-TSEBT with the modified Stanford technique (mST), a condensed cycling approach, offers a promising and convenient option. However, in vivo dosimetry data confirming the effectiveness of this approach is limited. We retrospectively analyzed in vivo data from patients who received accelerated LD-TSEBT using the mST for MF. Methods Patients treated with accelerated LD-TSEBT using the mST for MF were identified. Optically stimulated radiation dosimeters (OSLDs) were used to measure doses at 10 anatomical sites: vertex, larynx, right shoulder, right forearm, right hip, umbilicus, left medial thigh, right knee, left dorsal foot, and left dorsal hand. Measurements were aggregated and compared to the prescribed dose, using the European Organisation For Research And Treatment Of Cancer (EORTC) homogeneity tolerance criteria, which account for the American Association of Physicians in Medicine (AAPM) TG023 setup variability: ±20% of the prescribed dose. Patient characteristics, demographics, and disease details were also collected. Descriptive statistics were performed to evaluate clinical and dosimetric characteristics. Results Thirty-six patients were identified, and 360 OSLD measurements were recorded. The median of all OSLD measurements relative to the prescribed dose at all sites was 97.4%. The highest median delivered dose was recorded at the umbilicus (106%) and the lowest at the left dorsal hand (79%). After accounting for deviation at the left dorsal hand, 85.8% of all OSLD measurements met the homogeneity criteria at the other anatomic sites. Other patient metrics, such as height and BMI, did not impact the median delivered OSLD dose or number of anatomical sites per patient meeting the EORTC tolerance criteria. Conclusion Accelerated LD-TSEBT using the mST delivers accurate doses, with most subjects meeting the EORTC tolerance criteria. This study supports the use of OSLDs for in vivo dosimetry in patients undergoing this regimen, ensuring adequate dosing despite the truncated cycling approach.

Meningeal melanocytomas are rare, benign tumours of the central nervous system arising from the melanocytes of the leptomeninges. First-line treatment consists of either gross or subtotal resection with or without radiotherapy. However, given the sensitive locations of these tumours, alternative treatment options such as definitive radiotherapy may be warranted in patients deemed high-risk or without accessible tumours. A 67-year-old male presenting with spastic gait, frequent falls, and vertical gaze palsy was diagnosed with a 2.4 cm primary meningeal melanocytoma arising from the interpeduncular fossa. Given the critical tumour position within the brainstem, definitive radiotherapy was recommended. He received fractionated stereotactic radiotherapy (FSRT) to a total dose of 54 Gy in 27 fractions, resulting in a gradual improvement in gait and ocular range of motion. Follow-up imaging over the next three years revealed largely stable disease and an increase in edema with mild upper extremity weakness that improved with steroids. He was followed for three years and expired four years after treatment due to pneumonia. For patients unable to receive surgical resection, definitive RT may provide local control with minimal morbidity.

Tumor-to-tumor metastasis describes the ability of primary tumors to metastasize to other primary tumors. These events generally occur in aggressive and widely-metastatic disease, with the appropriate management and significance of these events unknown. A 56-year-old woman with a history of bilateral, localized, invasive lobular breast carcinoma treated with surgery, systemic therapy, and adjuvant radiation presented five and two years post-treatment with progressive neurological symptoms. Imaging revealed an intracranial meningioma, and the patient underwent resection. Pathology revealed metastatic invasive lobular carcinoma cells within the resected meningioma, and the patient was treated with postoperative radiation without sequelae. Subsequent staging scans revealed a single osseous lesion suggestive of oligometastatic disease, and the patient was promptly started on systemic therapy.

Successful stereotactic radiotherapy of meningiomas in a patient with Cowden syndrome: a case report Christian Fernandez, Corey Savard, Christopher Farrell, Wenyin Shi