Short report: Plasma based biomarkers detect radiation induced brain injury in cancer patients treated for brain metastasis: A pilot study.

BACKGROUND: Radiotherapy has an important role in the treatment of brain metastases but carries risk of short and/or long-term toxicity, termed radiation-induced brain injury (RBI). As the diagnosis of RBI is crucial for correct patient management, there is an unmet need for reliable biomarkers for RBI. The aim of this proof-of concept study is to determine the utility of brain-derived circulating free DNA (BncfDNA), identified by specific methylation patterns for neurons, astrocytes, and oligodendrocytes, as biomarkers brain injury induced by radiotherapy. METHODS: Twenty-four patients with brain metastases were monitored clinically and radiologically before, during and after brain radiotherapy, and blood for BncfDNA analysis (98 samples) was concurrently collected. Sixteen patients were treated with whole brain radiotherapy and eight patients with stereotactic radiosurgery. RESULTS: During follow-up nine RBI events were detected, and all correlated with significant increase in BncfDNA levels compared to baseline. Additionally, resolution of RBI correlated with a decrease in BncfDNA. Changes in BncfDNA were independent of tumor response. CONCLUSIONS: Elevated BncfDNA levels reflects brain cell injury incurred by radiotherapy. further research is needed to establish BncfDNA as a novel plasma-based biomarker for brain injury induced by radiotherapy.

Computational quantification and characterization of independently evolving cellular subpopulations within tumors is critical to inhibit anti-cancer therapy resistance.

BACKGROUND: Drug resistance continues to be a major limiting factor across diverse anti-cancer therapies. Contributing to the complexity of this challenge is cancer plasticity, in which one cancer subtype switches to another in response to treatment, for example, triple-negative breast cancer (TNBC) to Her2-positive breast cancer. For optimal treatment outcomes, accurate tumor diagnosis and subsequent therapeutic decisions are vital. This study assessed a novel approach to characterize treatment-induced evolutionary changes of distinct tumor cell subpopulations to identify and therapeutically exploit anticancer drug resistance. METHODS: In this research, an information-theoretic single-cell quantification strategy was developed to provide a high-resolution and individualized assessment of tumor composition for a customized treatment approach. Briefly, this single-cell quantification strategy computes cell barcodes based on at least 100,000 tumor cells from each experiment and reveals a cell-specific signaling signature (CSSS) composed of a set of ongoing processes in each cell. RESULTS: Using these CSSS-based barcodes, distinct subpopulations evolving within the tumor in response to an outside influence, like anticancer treatments, were revealed and mapped. Barcodes were further applied to assign targeted drug combinations to each individual tumor to optimize tumor response to therapy. The strategy was validated using TNBC models and patient-derived tumors known to switch phenotypes in response to radiotherapy (RT). CONCLUSIONS: We show that a barcode-guided targeted drug cocktail significantly enhances tumor response to RT and prevents regrowth of once-resistant tumors. The strategy presented herein shows promise in preventing cancer treatment resistance, with significant applicability in clinical use.

Endovascular brachytherapy for extensive right-heart and pulmonary artery sarcoma - a case report.

PURPOSE: Primary sarcoma of the heart is a rare but devastating tumor. Median survival with conventional treatment is 8-12 months. When resection is not feasible, patients often succumb to heart failure secondary to obstruction of blood flow, valve dysfunction, chamber compression or conduction abnormalities. Palliative treatment options include systemic chemotherapy and external beam irradiation. We herein describe a novel technique using endovascular brachytherapy, aiming at reducing tumor mass, alleviating right ventricular pressure overload and at the same time keeping the option of R0 resection viable. MATERIAL AND METHODS: A 35-year-old man was diagnosed with a non-resectable high-grade intimal sarcoma of the right ventricle (RV), main pulmonary artery (PA) and right PA. After three cycles of doxorubicin and ifosfamide, the patient's symptoms of right heart failure worsened. Imaging documented tumor progression and supra-systemic pulmonary artery pressure. Through a trans-femoral venous access, a brachytherapy sleeve was placed in the RV and main and right PA. A dose of 20 Gy was delivered over a period of ten minutes. RESULTS: The patient had an uneventful course and was discharged home 24 hours after the procedure. Ten months after brachytherapy, repeat imaging demonstrated a significant reduction in tumor volume and an increase in pulmonary artery cross-sectional area with a marked reduction of pulmonary artery pressure, leading to a complete resolution of heart failure symptoms. CONCLUSIONS: Endovascular brachytherapy is a novel, safe and effective therapeutic modality for non-resectable primary cardiac sarcomas either for palliation of obstruction, or tumor mass reduction to allow complete resection.

Novel high dose rate lip brachytherapy technique to improve dose homogeneity and reduce toxicity by customized mold.

PURPOSE/OBJECTIVES: The purpose of this study is to describe a novel brachytherapy technique for lip Squamous Cell Carcinoma, utilizing a customized mold with embedded brachytherapy sleeves, which separates the lip from the mandible, and improves dose homogeneity. MATERIALS AND METHODS: Seven patients with T2 lip cancer treated with a "sandwich" technique of High Dose Rate (HDR) brachytherapy to the lip, consisting of interstitial catheters and a customized mold with embedded catheters, were reviewed for dosimetry and outcome using 3D planning. Dosimetric comparison was made between the "sandwich" technique to "classic" - interstitial catheters only plan. We compared dose volume histograms for Clinical Tumor Volume (CTV), normal tissue "hot spots" and mandible dose. We are reporting according to the ICRU 58 and calculated the Conformal Index (COIN) to show the advantage of our technique. RESULTS: The seven patients (ages 36-81 years, male) had median follow-up of 47 months. Four patients received Brachytherapy and External Beam Radiation Therapy, 3 patients received brachytherapy alone. All achieved local control, with excellent esthetic and functional results. All patients are disease free. The Customized Mold Sandwich technique (CMS) reduced the high dose region receiving 150% (V150) by an average of 20% (range 1-47%), The low dose region (les then 90% of the prescribed dose) improved by 73% in average by using the CMS technique. The COIN value for the CMS was in average 0.92 as opposed to 0.88 for the interstitial catheter only. All differences (excluding the low dose region) were statistically significant. CONCLUSION: The CMS technique significantly reduces the high dose volume and increases treatment homogeneity. This may reduce the potential toxicity to the lip and adjacent mandible, and results in excellent tumor control, cosmetic and functionality.

Photon activation therapy and brachytherapy.

PURPOSE: In photon activation therapy (PAT), energy deposition at critical sites within a tumor can be increased by complexing the DNA with higher Z atoms, and provoking the emission of Auger electrons after inducing a photoelectric effect. This in vivo study evaluates the hypothesis using X-rays from palladium-103 seeds to excite the L-edge of platinum (Pt) atoms bound to the DNA of cancerous cells. METHODS AND MATERIALS: Pt (II) tetrakis(N-methyl-4-pyridyl) porphyrin chloride was used to locate Pt atoms adjacent to the DNA of the KHJJ murine mammary carcinoma; a 2.3-mCi palladium-103 seed was implanted in the tumor. RESULTS: The tumor periphery received subtherapeutic doses. The rate of tumor growth in mice treated with PAT was slower than in mice treated with brachytherapy only. CONCLUSIONS: The tumor growth delay for PAT-treated mice is attributed to Auger emission from Pt atoms that produced substantial local damage. However, other co-existing mechanisms cannot be ruled out.