Additive Effects of Cu-ATSM and Radiation on Survival of Diffuse Intrinsic Pontine Glioma Cells.

Diffuse intrinsic pontine gliomas (DIPG) are highly aggressive and treatment-resistant childhood primary brainstem tumors with a median survival of less than one year after diagnosis. The prevailing standard of care for DIPG, radiation therapy, does not prevent fatal disease progression, with most patients succumbing to this disease 3-8 months after completion of radiation therapy. This underscores the urgent need for novel combined-modality approaches for enhancing therapy responses.

Stereotactic body radiotherapy plus rucosopasem in locally advanced or borderline resectable pancreatic cancer: GRECO-2 phase II study design.

Ablative doses of stereotactic body radiotherapy (SBRT) may improve pancreatic cancer outcomes but may carry greater potential for gastrointestinal toxicity. Rucosopasem, an investigational selective dismutase mimetic that converts superoxide to hydrogen peroxide, can potentially increase tumor control of SBRT without compromising safety. GRECO-2 is a phase II, multicenter, randomized, double-blind, placebo-controlled trial of rucosopasem in combination with SBRT in locally advanced or borderline resectable pancreatic cancer.

Depletion of Labile Iron Induces Replication Stress and Enhances Responses to Chemoradiation in Non-Small-Cell Lung Cancer.

The intracellular redox-active labile iron pool (LIP) is weakly chelated and available for integration into the iron metalloproteins that are involved in diverse cellular processes, including cancer cell-specific metabolic oxidative stress. Abnormal iron metabolism and elevated LIP levels are linked to the poor survival of lung cancer patients, yet the underlying mechanisms remain unclear. Depletion of the LIP in non-small-cell lung cancer cell lines using the doxycycline-inducible overexpression of the ferritin heavy chain (Ft-H) (H1299 and H292), or treatment with deferoxamine (DFO) (H1299 and A549), inhibited cell growth and decreased clonogenic survival.

Rapid Peroxide Removal Limits the Radiosensitization of Diffuse Intrinsic Pontine Glioma (DIPG) Cells by Pharmacologic Ascorbate.

Diffuse intrinsic pontine gliomas (DIPG) are an aggressive type of pediatric brain tumor with a very high mortality rate. Surgery has a limited role given the tumor's location. Palliative radiation therapy alleviates symptoms and prolongs survival, but median survival remains less than 1 year.

Nanotechnology and machine learning enable circulating tumor cells as a reliable biomarker for radiotherapy responses of gastrointestinal cancer patients.

A highly sensitive, circulating tumor cell (CTC)-based liquid biopsy was used to monitor gastrointestinal cancer patients during treatment to determine if CTC abundance was predictive of disease recurrence. The approach used a combination of biomimetic cell rolling on recombinant E-selectin and dendrimer-mediated multivalent immunocapture at the nanoscale to purify CTCs from peripheral blood mononuclear cells. Due to the exceptionally high numbers of CTCs captured, a machine learning algorithm approach was developed to efficiently and reliably quantify abundance of immunocytochemically-labeled cells.

Manipulation of Redox Metabolism Using Pharmacologic Ascorbate Opens a Therapeutic Window for Radio-Sensitization by ATM Inhibitors in Colorectal Cancer.

Purpose: Ataxia telangiectasia mutated kinase (ATM) inhibitors are potent radiosensitizers that regulate DNA damage responses and redox metabolism, but they have not been translated clinically because of the potential for excess normal tissue toxicity. Pharmacologic ascorbate (P-AscH; intravenous administration achieving mM plasma concentrations) selectively enhances HO-induced oxidative stress and radiosensitization in tumors while acting as an antioxidant and mitigating radiation damage in normal tissues including the bowel. We hypothesized that P-AscH could enhance the therapeutic index of ATM inhibitor-based chemoradiation by simultaneously enhancing the intended effects of ATM inhibitors in tumors and mitigating off-target effects in adjacent normal tissues.

Clinical Implementational and Site-Specific Workflows for a 1.5T MR-Linac.

MR-guided adaptive radiotherapy (MRgART) provides opportunities to benefit patients through enhanced use of advanced imaging during treatment for many patients with various cancer treatment sites. This novel technology presents many new challenges which vary based on anatomic treatment location, technique, and potential changes of both tumor and normal tissue during treatment. When introducing new treatment sites, considerations regarding appropriate patient selection, treatment planning, immobilization, and plan-adaption criteria must be thoroughly explored to ensure adequate treatments are performed.

A Recursive Partitioning Analysis Demonstrating Risk Subsets for 8-Year Biochemical Relapse After Margin-Positive Radical Prostatectomy Without Adjuvant Hormone or Radiation Therapy.

Purpose: The cohort of patients with locally advanced prostate cancer (PC) and positive surgical margin(s) at radical prostatectomy (RP) who would benefit from salvage or adjuvant treatment is unclear. This study examines the risk of prostate-specific antigen (PSA) relapse in a large population of men with PC after margin-positive RP.

Methods And Materials: Using a multi-institutional database, patients with clinically localized PC who underwent RP between 2002 and 2010 with recorded follow-up PSA were retrospectively selected.

Implementation of a real-time, ultrasound-guided prostate HDR brachytherapy program.

This work presents a comprehensive commissioning and workflow development process of a real-time, ultrasound (US) image-guided treatment planning system (TPS), a stepper and a US unit. To adequately benchmark the system, commissioning tasks were separated into (1) US imaging, (2) stepper mechanical, and (3) treatment planning aspects. Quality assurance US imaging measurements were performed following the AAPM TG-128 and GEC-ESTRO recommendations and consisted of benchmarking the spatial resolution, accuracy, and low-contrast detectability.

Combination Therapy with Radiation and PARP Inhibition Enhances Responsiveness to Anti-PD-1 Therapy in Colorectal Tumor Models.

Purpose: The majority of colorectal cancers are resistant to cancer immune checkpoint inhibitors. Ionizing radiation (IR) and several radiosensitizers, including PARP inhibitors, can enhance responsiveness to immune checkpoint inhibitors by potentially complementary mechanisms of action. We assessed the ability of radiation and PARP inhibition to induce proimmunogenic changes in tumor cells and enhance their in vivo responsiveness to anti-PD-1 antibodies.

First-in-Human Phase I Clinical Trial of Pharmacologic Ascorbate Combined with Radiation and Temozolomide for Newly Diagnosed Glioblastoma.

Purpose: Standard treatment for glioblastoma (GBM) includes surgery, radiation therapy (RT), and temozolomide (TMZ), yielding a median overall survival (OS) of approximately 14 months. Preclinical models suggest that pharmacologic ascorbate (P-AscH) enhances RT/TMZ antitumor effect in GBM. We evaluated the safety of adding P-AscH to standard RT/TMZ therapy.

Optimizing Advances in Nanoparticle Delivery for Cancer Immunotherapy.

Cancer immunotherapy is one of the fastest growing and most promising fields in clinical oncology. T-cell checkpoint inhibitors are revolutionizing the management of advanced cancers including non-small cell lung cancer and melanoma. Unfortunately, many common cancers are not responsive to these drugs and resistance remains problematic.

Assessment of the Stability of Supraphysiological Ascorbate in Human Blood: Appropriate Handling of Samples from Clinical Trials for Measurements of Pharmacological Ascorbate.

Based on encouraging results from several early-phase clinical trials, there is renewed interest in the use of pharmacological ascorbate (i.e., intravenous administration resulting in >≈10 m plasma ascorbate concentrations) in combination with standard-of-care cancer treatments including radiation and/or chemotherapy.

Organ-specific metastases obtained by culturing colorectal cancer cells on tissue-specific decellularized scaffolds.

Metastatic disease remains the primary cause of mortality in cancer patients. Yet the number of available in vitro models to study metastasis is limited by challenges in the recapitulation of the metastatic microenvironment in vitro, and by difficulties in maintaining colonized-tissue specificity in the expansion and maintenance of metastatic cells. Here, we show that decellularized scaffolds that retain tissue-specific extracellular-matrix components and bound signalling molecules enable, when seeded with colorectal cancer cells, the spontaneous formation of three-dimensional cell colonies that histologically, molecularly and phenotypically resemble in vivo metastases.

Effect of internal mammary vessels radiation dose on outcomes of free flap breast reconstruction.

To assess the impact of internal mammary (IM) vessels radiation dose on autologous free-flap based breast reconstruction outcomes. We retrospectively evaluated the medical records of breast cancer patients who underwent mastectomy and free-flap breast reconstruction after postoperative radiation therapy (RT) to the breast/chest wall with (n = 9) or without (n = 11) electively including the IM lymph nodes. Twenty patients were included.

Effectiveness of Rotating Shield Brachytherapy for Prostate Cancer Dose Escalation and Urethral Sparing.

Purpose: To compare single-fraction Gd-based rotating shield brachytherapy (RSBT) for prostate cancer with conventional Ir-based high-dose-rate brachytherapy (HDR-BT) in a planning study that radiobiologically accounts for dose rate and relative biological effectiveness. RSBT was used for planning target volume (PTV) dose escalation without increasing urethral dose for monotherapy, or for urethral sparing without decreasing PTV dose as a boost to external beam radiation therapy.

Methods And Materials: Twenty-six patients were studied.

Multivalent Binding and Biomimetic Cell Rolling Improves the Sensitivity and Specificity of Circulating Tumor Cell Capture.

We aimed to examine the effects of multivalent binding and biomimetic cell rolling on the sensitivity and specificity of circulating tumor cell (CTC) capture. We also investigated the clinical significance of CTCs and their kinetic profiles in patients with cancer undergoing radiotherapy treatment. Patients with histologically confirmed primary carcinoma undergoing radiotherapy, with or without chemotherapy, were eligible for enrollment.

Applying nanotherapeutics to improve chemoradiotherapy treatment for cancer.

Chemoradiotherapy (CRT) plays a key role in the curative treatment of many human cancers. The full utility of this paradigm is often restricted by limitations of conventional drug delivery. Nanotherapeutics have demonstrated great potential to overcome many of these issues.

Antigen-capturing nanoparticles improve the abscopal effect and cancer immunotherapy.

Immunotherapy holds tremendous promise for improving cancer treatment. To administer radiotherapy with immunotherapy has been shown to improve immune responses and can elicit the 'abscopal effect'. Unfortunately, response rates for this strategy remain low.