Next-Generation Boron Drugs and Rational Translational Studies Driving the Revival of BNCT.

BNCT is a high-linear-energy transfer therapy that facilitates tumor-directed radiation delivery while largely sparing adjacent normal tissues through the biological targeting of boron compounds to tumor cells. Tumor-specific accumulation of boron with limited accretion in normal cells is the crux of successful BNCT delivery. Given this, developing novel boronated compounds with high selectivity, ease of delivery, and large boron payloads remains an area of active investigation. Furthermore, there is growing interest in exploring the immunogenic potential of BNCT. In this review, we discuss the basic radiobiological and physical aspects of BNCT, traditional and next-generation boron compounds, as well as translational studies exploring the clinical applicability of BNCT. Additionally, we delve into the immunomodulatory potential of BNCT in the era of novel boron agents and examine innovative avenues for exploiting the immunogenicity of BNCT to improve outcomes in difficult-to-treat malignancies.

Dosimetric Analysis of Axillary Lymph Node Coverage Using High Tangents in the Prone Position for Left-Sided Breast Cancers.

AIM/OBJECTIVE: Prone positioning is often used to reduce the dose to organs at risk during adjuvant breast irradiation. High tangents are used with supine treatments in patients with the low-volume nodal disease to increase nodal coverage while minimizing toxicities. Our study aims to evaluate nodal coverage for patients treated in the prone position with high tangents. MATERIALS AND METHODS: Our study analyzed the plans for 20 patients with early-stage, left-sided breast cancers treated at our institution from 2018 to 2019. All patients were treated in the prone position. Axillary nodal levels I-III were contoured, and treatment plans were generated using high tangents. The heart, bilateral lungs, and breast tissue were retrospectively contoured. All plans were evaluated to a dose of 42.4 Gy in 16 fractions. RESULTS: Level I lymph node levels had a mean coverage of 99% of the prescription dose (range: 98-100%). Similarly, level II coverage was approximately 88% (range: 65-100%). The mean coverage for level III was approximately 25% (range: 0-52%). The mean heart dose, mean lung volume receiving ≥20 Gy (V20) for the bilateral lungs, and ipsilateral V20 were 1.69 Gy, 1.64%, and 3.56%, respectively. CONCLUSION: Treating patients in the prone position with high tangents provides excellent coverage of axillary levels I and II, although there is minimal coverage of axillary level III. Prospective trials are needed to evaluate the clinical outcomes when treating patients with high tangents in the prone position.

Novel Strategies for Nanoparticle-Based Radiosensitization in Glioblastoma.

Radiotherapy (RT) is one of the cornerstones in the current treatment paradigm for glioblastoma (GBM). However, little has changed in the management of GBM since the establishment of the current protocol in 2005, and the prognosis remains grim. Radioresistance is one of the hallmarks for treatment failure, and different therapeutic strategies are aimed at overcoming it. Among these strategies, nanomedicine has advantages over conventional tumor therapeutics, including improvements in drug delivery and enhanced antitumor properties. Radiosensitizing strategies using nanoparticles (NP) are actively under study and hold promise to improve the treatment response. We aim to describe the basis of nanomedicine for GBM treatment, current evidence in radiosensitization efforts using nanoparticles, and novel strategies, such as preoperative radiation, that could be synergized with nanoradiosensitizers.

Boron Neutron Capture Therapy: A Review of Clinical Applications.

Boron neutron capture therapy (BNCT) is an emerging treatment modality aimed at improving the therapeutic ratio for traditionally difficult to treat tumors. BNCT utilizes boronated agents to preferentially deliver boron-10 to tumors, which, after undergoing irradiation with neutrons, yields litihium-7 and an alpha particle. The alpha particle has a short range, therefore preferentially affecting tumor tissues while sparing more distal normal tissues. To date, BNCT has been studied clinically in a variety of disease sites, including glioblastoma multiforme, meningioma, head and neck cancers, lung cancers, breast cancers, hepatocellular carcinoma, sarcomas, cutaneous malignancies, extramammary Paget's disease, recurrent cancers, pediatric cancers, and metastatic disease. We aim to provide an up-to-date and comprehensive review of the studies of each of these disease sites, as well as a review on the challenges facing adoption of BNCT.

Assessment of unintended shifts during frame-based stereotactic radiosurgery using cone beam computed tomography image guidance.

PURPOSE: To investigate the frequency, magnitude and possible causes of frame-shifts that may occur between treatment planning and treatment delivery when performing Gamma Knife radiosurgery with rigid frame-based immobilization. METHODS: Differences between computed tomography (CT) framed fiducial stereotactic coordinate reference and cone beam computed tomography stereotactic coordinates after image registration were recorded for 49 frame-based GK radiosurgery cases performed using the Gamma Knife Icon. Parameters recorded include rotational shifts, translational shifts, and the GK-computed Maximum Shot Displacement (MSD) between the two stereotactic coordinate spaces. Other patient-specific parameters were collected and linear regression analysis was performed to evaluate predictors of increased displacement. RESULTS: The median values of rotational shifts were: pitch 0.14°, yaw 0.17°, and roll 0.13°. The median absolute values of translational shifts were: left-right 0.39 mm, anteroposterior 0.14 mm, and superior-inferior 0. 22 mm. The median value of MSD was 0.71 mm. Twelve cases (24.5%) had a MSD of greater than 1.0 mm. Male gender was associated with increased MSD (p = 0.013) and translational shifts (root-mean-squared value, p = 0.017). Cases with large differences between right and left sided pin lengths were also associated with increased MSD (p = 0.011). CONCLUSIONS: The use of CBCT image guidance in frame-based GK radiosurgery allows unintended frame shifts to be identified and corrected. A significant fraction (24.5%) of patients had large enough shifts to result in a MSD of greater than 1.0 mm. Male gender and eccentrically placed frames were associated with increased MSD, and particular care should be taken in these cases.

Intracranial motion during frameless Gamma-Knife stereotactic radiosurgery.

PURPOSE/OBJECTIVES: The Gamma-Knife radiosurgery (GKRS) (Elekta AB, Stockholm) platform delivers highly conformal and precise radiation; however, intracranial displacement during treatment allows for the potential of a marginal target-miss. Frameless (mask-based) GKRS using the Gamma Knife Icon system monitors nasal tip motion as a surrogate for intracranial motion by tracking an infrared marker using a high-definition motion management (HDMM) system. To date, there is limited data available regarding the incidence and severity of motion and factors that impact intrafraction motion when treating with frameless GKRS. MATERIALS/METHODS: A retrospective study was performed to evaluate patients with brain tumors who were treated with frameless GKRS using the Gamma Knife Icon between May and December 2018. All patients underwent mask-based immobilization using a thermoplastic mask. Data on patient demographics, mask type, use of bite block, and number of treatments received, use of anxiolytics, treatment time, and whether a physics clearance check was performed prior to treatment were collected. For each treatment session, average displacement (mm), maximum displacement (mm) and total treatment time (min) were recorded and logistic regression analyses were performed. RESULTS: Data was collected for 89 consecutive treatments (38 patients). Of these, an anxiolytic was used in 61 treatments and a physics clearance check was performed for 45 treatments. The median average and maximum displacement was 0.60 mm and 1.22 mm, respectively. An average displacement greater than 0.60 mm was seen with Eastern Cooperative Oncology Group performance status (ECOG) > 1, male gender, and malignant tumors (p < 0.05). Anxiolytic use prior to treatment was associated with a significant reduction in average displacement (p < 0.05). Significantly greater odds of observing a maximum displacement over 1.22 mm was seen with patients with ECOG > 1, male gender, and increased treatment time (p < 0.05). Age > 65 and anxiolytic use were associated with a significant reduction in maximum displacement (p < 0.05). Performance of clearance checks and use of bite block use did not impact average or maximum patient displacement. CONCLUSIONS: This is the first study to evaluate patient and treatment-related factors that influence intrafraction motion during GKRS with mask-based immobilization through HDMM tracking. Increased intracranial displacement during frameless GKRS was associated with higher ECOG, male gender, increased treatment time and malignant tumors, while anxiolytics were shown to mitigate excessive motion. Radiosurgery teams should consider these patient factors when treating patients with mask immobilization.

Carbon Ion Therapy: A Modern Review of an Emerging Technology.

Radiation therapy is one of the most widely used therapies for malignancies. The therapeutic use of heavy ions, such as carbon, has gained significant interest due to advantageous physical and radiobiologic properties compared to photon based therapy. By taking advantage of these unique properties, carbon ion radiotherapy may allow dose escalation to tumors while reducing radiation dose to adjacent normal tissues. There are currently 13 centers treating with carbon ion radiotherapy, with many of these centers publishing promising safety and efficacy data from the first cohorts of patients treated. To date, carbon ion radiotherapy has been studied for almost every type of malignancy, including intracranial malignancies, head and neck malignancies, primary and metastatic lung cancers, tumors of the gastrointestinal tract, prostate and genitourinary cancers, sarcomas, cutaneous malignancies, breast cancer, gynecologic malignancies, and pediatric cancers. Additionally, carbon ion radiotherapy has been studied extensively in the setting of recurrent disease. We aim to provide a comprehensive review of the studies of each of these disease sites, with a focus on the current trials using carbon ion radiotherapy.

Current use of stereotactic body radiation therapy for low and intermediate risk prostate cancer: A National Cancer Database Analysis.

BACKGROUND: Recent studies have demonstrated both safety and efficacy of stereotactic body radiation therapy (SBRT) as monotherapy in the treatment of low and intermediate risk prostate cancer. Our study aims to provide an update analyzing the use of SBRT compared with conventional and hypofractionated regimens in the United States from 2004 to 2015. METHODS: This retrospective review was conducted using the National Cancer Database. We identified 114,931 patients with sufficient diagnostic and treatment information treated with definitive radiation therapy in the United States from 2004 to 2015. The relative utilization of conventional fractionation (defined as 180-200 cGy per fraction and >5 fractions), moderate hypofractionation (defined as >200 cGy per fraction and >5 fractions), and SBRT (defined as >200 cGy per fraction and 5 fractions or less) were compared over the same time period. Logistic regression models were used to estimate trends. Demographic factors were collected and analyzed using chi-squared tests and independent t-tests. RESULTS: The proportion of prostate cancer patients receiving SBRT increased substantially from 0.9% in 2004 to 19.5% in 2015. Moderate hypofractionation exhibited some growth, increasing from 2.7% of patients to 4.7% in 2015. Conventional fractionation use declined significantly from 96.3% in 2004 to 75.8% in 2015. Notably, there was a sharp decline in the absolute number of patients receiving conventional fractionation in 2011, from 14,699 patients treated in 2009 to 1492 in 2011. Patients treated with SBRT were more likely to be treated in academic centers, younger, and have higher income than other fractionation groups. The most frequently used fractionation schedule was 3625 cGy in five fractions. CONCLUSIONS: The use of SBRT for low and intermediate risk prostate cancer has increased significantly from 2004 to 2015, coinciding with recently published data supporting the efficacy and favorable toxicity profile of this technique.

Unbiased compound screening identifies unexpected drug sensitivities and novel treatment options for gastrointestinal stromal tumors.

Most gastrointestinal stromal tumors (GIST) are caused by oncogenic KIT or platelet-derived growth factor receptor activation, and the small molecule kinase inhibitor imatinib mesylate is an effective first-line therapy for metastatic or unresectable GIST. However, complete remissions are rare and most patients ultimately develop resistance, mostly because of secondary mutations in the driver oncogenic kinase. Hence, there is a need for novel treatment options to delay failure of primary treatment and restore tumor control in patients who progress under therapy with targeted agents. Historic data suggest that GISTs do not respond to classical chemotherapy, but systematic unbiased screening has not been performed. In screening a compound library enriched for U.S. Food and Drug Administration (FDA)-approved chemotherapeutic agents (NCI Approved Oncology Drugs Set II), we discovered that GIST cells display high sensitivity to transcriptional inhibitors and topoisomerase II inhibitors. Mechanistically, these compounds exploited the cells' dependency on continuous KIT expression and/or intrinsic DNA damage response defects, explaining their activity in GIST. Mithramycin A, an indirect inhibitor of the SP1 transcription factor, and mitoxantrone, a topoisomerase II inhibitor, exerted significant antitumor effects in mouse xenograft models of human GIST. Moreover, these compounds were active in patient-derived imatinib-resistant primary GIST cells, achieving efficacy at clinically relevant concentrations. Taken together, our findings reveal that GIST cells have an unexpectedly high and specific sensitivity to certain types of FDA-approved chemotherapeutic agents, with immediate implications for encouraging their clinical exploration.

Novel Death Defying Domain in Met entraps the active site of caspase-3 and blocks apoptosis in hepatocytes.

UNLABELLED: Met, the transmembrane tyrosine kinase receptor for hepatocyte growth factor (HGF), is known to function as a potent antiapoptotic mediator in normal and neoplastic cells. Herein we report that the intracellular cytoplasmic tail of Met has evolved to harbor a tandem pair of caspase-3 cleavage sites, which bait, trap, and disable the active site of caspase-3, thereby blocking the execution of apoptosis. We call this caspase-3 cleavage motif the Death Defying Domain (DDD). This site consists of the following sequence: DNAD-DEVD-T (where the hyphens denote caspase cleavage sites). Through functional and mechanistic studies, we show that upon DDD cleavage by caspase-3 the resulting DEVD-T peptide acts as a competitive inhibitor and entraps the active site of caspase-3 akin to DEVD-CHO, which is a potent, synthetic inhibitor of caspase-3 activity. By gain- and loss-of-function studies using restoration of DDD expression in DDD-deficient hepatocytic cells, we found that both caspase-3 sites in DDD are necessary for inhibition of caspase-3 and promotion of cell survival. Employing mutagenesis studies, we show that DDD could operate independently of Met's enzymatic activity as determined by using kinase-dead human Met mutant constructs. Studies of both human liver cancer tissues and cell lines uncovered that DDD cleavage and entrapment of caspase-3 by DDD occur in vivo, further proving that this site has physiological and pathophysiological relevance. CONCLUSION: Met can directly inhibit caspase-3 by way of a novel mechanism and promote hepatocyte survival. The results presented here will further our understanding of the mechanisms that control not only normal tissue homeostasis but also abnormal tissue growth such as cancer and degenerative diseases in which apoptotic caspases are at play.

The DREAM complex mediates GIST cell quiescence and is a novel therapeutic target to enhance imatinib-induced apoptosis.

Gastrointestinal stromal tumors (GIST) can be successfully treated with imatinib mesylate (Gleevec); however, complete remissions are rare and patients frequently achieve disease stabilization in the presence of residual tumor masses. The clinical observation that discontinuation of treatment can lead to tumor progression suggests that residual tumor cells are, in fact, quiescent and, therefore, able to re-enter the cell-division cycle. In line with this notion, we have previously shown that imatinib induces GIST cell quiescence in vitro through the APC(CDH1)-SKP2-p27(Kip1) signaling axis. Here, we provide evidence that imatinib induces GIST cell quiescence in vivo and that this process also involves the DREAM complex, a multisubunit complex that has recently been identified as an additional key regulator of quiescence. Importantly, inhibition of DREAM complex formation by depletion of the DREAM regulatory kinase DYRK1A or its target LIN52 was found to enhance imatinib-induced cell death. Our results show that imatinib induces apoptosis in a fraction of GIST cells while, at the same time, a subset of cells undergoes quiescence involving the DREAM complex. Inhibition of this process enhances imatinib-induced apoptosis, which opens the opportunity for future therapeutic interventions to target the DREAM complex for more efficient imatinib responses.