Differential Distribution of the DNA-PKcs Inhibitor Peposertib Selectively Radiosensitizes Patient-derived Melanoma Brain Metastasis Xenografts.

Radioresistance of melanoma brain metastases limits the clinical utility of conventionally fractionated brain radiation in this disease, and strategies to improve radiation response could have significant clinical impact. The catalytic subunit of DNA-dependent protein kinase (DNA-PKcs) is critical for repair of radiation-induced DNA damage, and inhibitors of this kinase can have potent effects on radiation sensitivity. In this study, the radiosensitizing effects of the DNA-PKcs inhibitor peposertib were evaluated in patient-derived xenografts of melanoma brain metastases (M12, M15, M27). In clonogenic survival assays, peposertib augmented radiation-induced killing of M12 cells at concentrations ≥100 nmol/L, and a minimum of 16 hours exposure allowed maximal sensitization. This information was integrated with pharmacokinetic modeling to define an optimal dosing regimen for peposertib of 125 mpk dosed just prior to and 7 hours after irradiation. Using this drug dosing regimen in combination with 2.5 Gy × 5 fractions of radiation, significant prolongation in median survival was observed in M12-eGFP (104%; P = 0.0015) and M15 (50%; P = 0.03), while more limited effects were seen in M27 (16%, P = 0.04). These data support the concept of developing peposertib as a radiosensitizer for brain metastases and provide a paradigm for integrating in vitro and pharmacokinetic data to define an optimal radiosensitizing regimen for potent DNA repair inhibitors.

Resection of a Solitary Right Ventricular Metastasis in Oligorecurrent Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC), constituting the predominant manifestation of liver cancer, stands as a formidable medical challenge. The prognosis subsequent to surgical intervention, particularly for individuals presenting with a solitary tumor, relies heavily on the degree of invasiveness. The decision-making process surrounding therapeutic modalities in such cases assumes paramount importance. This case report illuminates a rather unusual clinical scenario. Here, we encounter a patient who, following a disease-free interval, manifested an atypical presentation of HCC, specifically, a solitary cardiac metastasis. The temporal interval of remission adds an additional layer of complexity to the case. Through a multidisciplinary planning process, the decision was made for surgical removal of the metastatic tumor.

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 H2O2-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. METHODS AND MATERIALS: Clonogenic survival was assessed in human (human colon tumor [HCT]116, SW480, HT29) and murine (CT26, MC38) colorectal tumor lines and normal cells (human umbilical vein endothelial cell, FHs74) after radiation ± DNA repair inhibitors ± P-AscH-. Tumor growth delay was assessed in mice with HCT116 or MC38 tumors after fractionated radiation (5 Gy × 3) ± the ATM inhibitor KU60019 ± P-AscH-. Intestinal injury, oxidative damage, and transforming growth factor ß immunoreactivity were quantified using immunohistochemistry after whole abdominal radiation (10 Gy) ± KU60019 ± P-AscH-. Cell cycle distribution and ATM subcellular localization were assessed using flow cytometry and immunohistochemistry. The role of intracellular H2O2 fluxes was assessed using a stably expressed doxycycline-inducible catalase transgene. RESULTS: KU60019 with P-AscH- enhanced radiosensitization in colorectal cancer models in vitro and in vivo by H2O2-dependent oxidative damage to proteins and enhanced DNA damage, abrogation of the postradiation G2 cell cycle checkpoint, and inhibition of ATM nuclear localization. In contrast, concurrent P-AscH- markedly reduced intestinal toxicity and oxidative damage with KU60019. CONCLUSIONS: We provide evidence that redox modulating drugs, such as P-AscH-, may facilitate the clinical translation of ATM inhibitors by enhancing tumor radiosensitization while simultaneously protecting normal tissues.

Assessment of Gadobutrol Safety in Combination with Ionizing Radiation Using a Preclinical MRI-Guided Radiotherapy Model.

MR-linac technology enhances the precision of therapeutic radiation by clarifying the tumor-normal tissue interface and provides the potential for adaptive treatment planning. Accurate delineation of tumors on diagnostic magnetic resonance imaging (MRI) frequently requires gadolinium-based contrast agents (GBCAs). Despite generally being considered safe, previous literature suggests that GBCAs are capable of contrast-induced acute kidney injury (AKI). It is unclear if the risk for AKI is enhanced when GBCAs are administered concurrently with ionizing radiotherapy. During irradiation, gadolinium may be liberated from its chelator which may induce AKI. The goal of this work was to determine if radiation combined with GBCAs increased the incidence of AKI. Using a preclinical MRI-guided irradiation system, where MRI acquisitions and radiation delivery are performed in rapid succession, tumor-bearing mice with normal kidney function were injected with GBCA and treated with 2, 8 or 18 Gy irradiation. Renal function was assessed on days three and seven postirradiation to assess for AKI. No clinically relevant changes in blood urea nitrogen and creatinine were observed in any combination of GBCA and radiation dose. From these data, we conclude that GBCA in combination with radiation does not increase the risk for AKI in mice. Additional investigation of multiple doses of GBCA administered concurrently with irradiation is warranted to evaluate the risk of chronic kidney injury.

The Effect of Concurrent Stereotactic Body Radiation and Anti-PD-1 Therapy for Recurrent Metastatic Sarcoma.

Patients diagnosed with metastatic sarcoma have limited options for achieving both local and distant tumor control. While SBRT can achieve local control, distant response rates remain low. There is limited evidence demonstrating the safety and efficacy for combining SBRT with concurrent PD-1 checkpoint blockade in metastatic sarcoma. In this prospective case-series, we examined five patients with metastatic sarcoma on pembrolizumab treated concurrently with SBRT from July 1, 2016-October 30, 2018. Acute and chronic toxicity were recorded using Common Terminology Criteria for Adverse Events (CTCAE, version 5.0). SBRT-treated tumor control was assessed using Response Evaluation Criteria in Solid Tumors (RECIST version 1.1). With median follow-up of 14.9 months, three patients with undifferentiated pleomorphic sarcoma, one with intimal, and one with chondroblastic osteosarcoma received SBRT with concurrent pembrolizumab to 10 sites of metastatic disease. No grade 5 toxicities were observed. There was a single incidence of transient grade 4 lymphopenia which resolved without intervention. Grade 3 toxicities included anemia, thrombocytopenia, lymphopenia and colitis. One tumor demonstrated local progression after SBRT, and all others remained stable or with response. In conclusion, combining SBRT with PD-1 inhibition appeared to be safe in this patient population. Expected high rates of treated-tumor local control after SBRT were observed. Two of five patients demonstrated either enhanced local tumor regression, or possible abscopal effect.

Neoadjuvant Radiotherapy-Related Wound Morbidity in Soft Tissue Sarcoma: Perspectives for Radioprotective Agents.

Historically, patients with localized soft tissue sarcomas (STS) of the extremities would undergo limb amputation. It was subsequently determined that the addition of radiation therapy (RT) delivered prior to (neoadjuvant) or after (adjuvant) a limb-sparing surgical resection yielded equivalent survival outcomes to amputation in appropriate patients. Generally, neoadjuvant radiation offers decreased volume and dose of high-intensity radiation to normal tissue and increased chance of achieving negative surgical margins-but also increases wound healing complications when compared to adjuvant radiotherapy. This review elaborates on the current neoadjuvant/adjuvant RT approaches, wound healing complications in STS, and the potential application of novel radioprotective agents to minimize radiation-induced normal tissue toxicity.

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. METHODS AND MATERIALS: We performed a candidate drug screen and used flow cytometry to assess effects of the PARP inhibitor veliparib on IR-mediated changes in MHC-1 antigen presentation and surface localization of immune-modulating proteins including PD-L1 and calreticulin in colorectal cancer tumor models. Reverse transcription polymerase chain reaction was used to assess the effects of veliparib and radiation on the expression of proinflammatory and immunosuppressive cytokines. The ability of concurrent PARP inhibition and subablative doses of radiation therapy to enhance in vivo responsiveness to anti-PD-1 antibodies was assessed using unilateral flank-tumor models with or without T-cell depletion. RESULTS: Veliparib was a potent radiosensitizer in both cell lines. Radiation increased surface localization of MHC-1 and PD-L1 in a dose-dependent manner, and veliparib pretreatment significantly enhanced these effects with high (8 Gy) but not with lower radiation doses. Enhancement of MHC-1 and PD-L1 surface localization by IR and IR+ veliparib remained significant 1, 3, and 7 days after treatment. IR significantly increased delayed tumoral expression of proinflammatory cytokines interferon-Ƴ and CXCL10 but had no significant effect on the expression of IL-6 or TGF-ß. Concurrent administration of veliparib and subablative radiation therapy (8 Gy × 2) significantly prolonged anti-PD-1-mediated in vivo tumor growth delay and survival in both tumor models. Moreover, these effects were more pronounced in the microsatellite instability-mutated MC38 tumor model. Enhancement of anti-PD-1 mediated tumor growth delay with veliparib and IR was attenuated by CD8+ T-cell depletion. CONCLUSIONS: We provide preclinical evidence for a novel therapeutic strategy to enhance responsiveness of colorectal tumors to immune checkpoint inhibitors.

Brachytherapy Future Directions.

Brachytherapy has advanced dramatically in the last decade due largely to improvements in applicators, imaging, treatment planning, and use of clinical trials. In addition, current research in brachytherapy technology continues to change how we deliver this treatment modality. The future of brachytherapy lies in the ability of new technologies to overcome real or perceived barriers. The focus for this manuscript is on specific tools that have or are near to being introduced in the clinic. First, we explore the impact electromagnetic tracking technologies can have on brachytherapy implants and planning workflow. This is followed by an overview of the use of 3D printing and its ability to help tailor brachytherapy implants. Next, we discuss advances in self-shielded applicators and intensity-modulated brachytherapy technology. The manuscript closes out with 2 sections on treatment planning. First is a discussion of biological optimization and its potential as compared with current techniques (eg, based on physical dosimetry). And lastly, a section on optimization treatment planning efficiencies in which we explore the potential for machine learning in brachytherapy. As recent clinical evidence continues to show excellent outcomes, this is an exciting time to practice brachytherapy. With the new technologies presented here, the future is even brighter.

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. A growing number of novel cancer immunotherapies have been discovered but their clinical translation has been limited by shortcomings of conventional drug delivery. Immune signaling is tightly-regulated and often requires simultaneous or near-simultaneous activation of multiple signals in specific subpopulations of immune cells. Nucleic acid therapies, which require intact intracellular delivery, are among the most promising approaches to modulate the tumor microenvironment to a pro-immunogenic phenotype. Advanced nanomedicines can be precisely engineered to overcome many of these limitations and appear well-poised to enable the clinical translation of promising cancer immunotherapies.

Systematic Review of Intensity-Modulated Brachytherapy (IMBT): Static and Dynamic Techniques.

PURPOSE: To systematically review scientific literature on the use of intensity-modulated brachytherapy (IMBT), including static and dynamic shielding approaches, to enhance therapeutic ratio. Studies were evaluated for technique, disease site, dosimetry, applicators, dosimetric calculations, and planning algorithms. Comparisons with standard-of-care brachytherapy techniques, alternative IMBT methods, or both were performed for dose-to-target volumes, organs at risk (OARs), and treatment planning or delivery times. METHODS AND MATERIALS: Inclusion criteria were any peer-reviewed journal articles on IMBT published from January 1, 1980, to January 1, 2019, on PubMed, Google Scholar, Cochrane Library, and EBSCO databases. Two independent investigators reviewed each article for inclusion and exclusion criteria and scope. Data collected on each study included technique, source or shield material, disease site, n of study (n = number of simulated plans/treated patients), dose-to-target/OARs, and planning or delivery times. This review adhered to the Preferred Reporting Items for Systemic reviews and Meta Analyses (PRISMA). RESULTS: Database queries yielded 1734 results, which were reduced to 436 after exclusion criteria and 78 peer-reviewed journal articles after evaluation of scope. Studies per disease site were 31 for cervical; 16 for rectal; 10 for oculocutaneous; 7 for breast; 6 for prostate; and 8 for other, multiple, or no specific disease site. Eighteen studies demonstrated a significant decrease in dose to OARs (5.1%-68.2%), 11 improved treatment planning or delivery times (7.6%-99.7%), and 6 increased target coverage (18.6%-71.6%) relative to standard-of-care or alternative IMBT technique. IMBT consistently decreased dose to OAR compared with the standard of care at the cost of increased planning or delivery times. Innovations in dose calculation or planning algorithms and applicators were capable of ameliorating prolonged treatment intervals. CONCLUSIONS: IMBT techniques improved the therapeutic ratio by reducing OAR doses, facilitating dose escalation, or both. Static-shielding techniques are clinically available as a result of the advent of commercially available heterogeneity-corrected dose-calculation algorithms, whereas dynamic-shielding techniques are still preclinical.

Merkel cell carcinoma in the community setting: a case report.

Merkel cell carcinoma (MCC) is a rare neuroendocrine tumor of the skin initially believed to arise from the Merkel cells. In the community setting a general radiation oncologist may only encounter this pathology in a handful of cases over the course of their career. Due to the low incidence of this malignancy, few prospective randomized controlled trials have ever been conducted and therefore guidelines are based on relatively lower levels of evidence upon which the clinical recommendations are made. We discuss the case of a female in her 90s presenting with a classic MCC primary lesion, as well as satellite lesions proximal to both the primary and the draining regional lymph nodes with no evidence of nodal involvement. Here we discuss the presentation, management, treatment planning, underlying pathology, results and sequelae of treatment. We also review new treatment modalities, and the most current staging systems and guidelines.

Outcomes Comparison for Microsurgical Breast Reconstruction in Specialty Surgery Hospitals Versus Tertiary Care Facilities.

BACKGROUND: Postoperative monitoring is crucial in the care of free flap breast reconstruction patients. Tertiary care facilities (TCFs) provide postoperative monitoring in an ICU after surgery. Specialty surgery hospitals (SSHs) do not have ICUs, but these facilities perform free flap breast reconstruction as well. Are outcomes comparable between the 2 facilities in terms of flap reexploration times and overall success? METHODS: Retrospective study including 163 SSH and 157 TCF patients. Primary predictor was facility in which the procedure was performed. Secondary predictors included operative, demographic, and comorbidity data. Primary outcomes were flap take back rate and flap failures. Secondary outcomes were total time from adverse event noticed in the flap to returning to the operating room (OR) and total time from decision made to return to the OR to returning to the OR (decision made). Tertiary outcomes were length of stay, operative times, and blood loss. RESULTS: Patients at the TCF were generally less healthy than SSH patients. Salvage rates and failure rates were similar between the 2 institutions. Adverse event noticed and decision made times did not differ between the 2 facilities. Overall flap success rate was 98.22% at SSH and 98.81% at TCF. No primary or secondary predictors had a significant correlation with increased odds for flap failure. CONCLUSION: SSHs can offer similar outcomes in free flap breast reconstruction with just as effective clinical response times to endangered flaps as found in a TCF. However, surgery at an SSH may best be reserved for healthier patients.

Low-dose-rate prostate brachytherapy: 4-8 week postimplant prostate-specific antigen a novel predictor of biochemical failure-free survival.

PURPOSE: The purpose of this study was to determine the relationship between patient, disease, and treatment variables and biochemical failure-free survival (bFFS) following low-dose-rate prostate brachytherapy (LDR-BT). METHODS AND MATERIALS: Data from 624 consecutive patients who received LDR-BT for localized prostate cancer between 2002 and 2012 at a single institution were collected for various patient, disease, and treatment characteristics including a 4-8 week postimplant PSA (4-8wkPSA). Subgroup analysis was stratified by risk category and treatment regimen. Analysis was performed using Kaplan-Meier survival curves, Cox proportional hazard ratios (HRs), and receiver-operator characteristic curves. RESULTS: A total of 624 consecutive patients were included with followup time of 4.0 ± 3.1 years. Predictors of bFFS included PSA nadir and 4-8wkPSA (HR = 2.48, p = 0.000 and HR = 1.24, p = 0.000, respectively) for total population. Diabetes mellitus (p = 0.026), chronic obstructive pulmonary disease (p = 0.000), alcohol use (p = 0.024), and age (p = 0.002) were predictors for specific subgroups. Receiver-operator characteristic curves 4-8wkPSA were found to be significant (p = 0.036). CONCLUSION: 4-8wkPSA is a novel predictor of bFFS for patients receiving LDR-BT across several risk categories and treatment regimens with potential clinical utility as a prognostic indicator. Certain comorbidities and exposure histories also demonstrated significant relationships with bFFS including chronic obstructive pulmonary disease, diabetes mellitus, age, alcohol history, proton pump inhibitor use, PSA nadir, and PSA density.

Nanotechnology combined therapy: tyrosine kinase-bound gold nanorod and laser thermal ablation produce a synergistic higher treatment response of renal cell carcinoma in a murine model.

OBJECTIVE: To investigate tyrosine kinase inhibitors (TKI) and gold nanorods (AuNRs) paired with photothermal ablation in a human metastatic clear cell renal cell carcinoma (RCC) mouse model. Nanoparticles have been successful as a platform for targeted drug delivery in the treatment of urological cancers. Likewise, the use of nanoparticles in photothermal tumour ablation, although early in its development, has provided promising results. Our previous in vitro studies of nanoparticles loaded with both TKI and AuNRs and activated with photothermal ablation have shown significant synergistic cell kill greater than each individual arm alone. This study is a translation of our initial findings to an in vivo model. MATERIALS AND METHODS: Immunologically naïve nude mice (athymic nude-Foxn1nu ) were injected subcutaneously bilaterally in both flanks (n = 36) with 2.5 × 106 cells of a human metastatic renal cell carcinoma cell line (RCC 786-O). Subcutaneous xenograft tumours developed into 1-cm palpable nodules. AuNRs encapsulated in human serum albumin protein (HSA) nanoparticles were synthesised with or without a TKI and injected directly into the tumour nodule. Irradiation was administered with an 808-nm light-emitting diode laser for 6 min. Mice were humanely killed 14 days after irradiation; tumours were excised, formalin fixed, paraffin embedded, and evaluated for size and the percentage of necrosis by a genitourinary pathologist. The untreated contralateral flank tumours were used as controls. RESULTS: In mice that did not receive irradiation, TKI alone yielded 4.2% tumour necrosis on the injected side and administration of HSA-AuNR-TKI alone yielded 11.1% necrosis. In the laser-ablation models, laser ablation alone yielded 62% necrosis and when paired with HSA-AuNR there was 63.4% necrosis. The combination of laser irradiation and HSA-AuNR-TKI had cell kill rate of 100%. CONCLUSIONS: In the absence of laser irradiation, TKI treatment alone or when delivered via nanoparticles produced moderate necrosis. Irradiation with and without gold particles alone also improves tumour necrosis. However, when irradiation is paired with gold particles and drug-loaded nanoparticles, the combined therapy showed the most significant and synergistic complete tumour necrosis of 100% (P < 0.05). This study illustrates the potential of combination nanotechnology as a new approach in the treatment of urological cancers.

Combined Treatment of Tyrosine Kinase Inhibitor-Labeled Gold Nanorod Encapsulated Albumin With Laser Thermal Ablation in a Renal Cell Carcinoma Model.

To characterize and evaluate human serum albumin-encapsulated nanoparticles for drug delivery of a tyrosine kinase inhibitor combined with induction of photothermal ablation combination therapy of renal cell carcinoma (RCC), nanoparticles of varying preparations and concentrations were characterized via zeta potential, drug loading, and release profile. Cytotoxicity and uptake trials were also studied using clear cell RCC cell line RCC 786-0, a human metastatic carcinoma. Target temperatures of >50°C were consistently attained by 0.1 and 0.05 µM concentrations of irradiated human serum albumin nanoparticle-gold nanorods (HSAP-AuNRs). Irradiated trials of HSAP-AuNRs demonstrated significantly decreased cell viabilities compared with nonirradiated "dark" controls (p < 0.01). Increasing loaded masses of sorafenib (SRF) also significantly decreased relative cell viability of RCC (p < 0.05). Photothermal ablation using HSAP-AuNRs is capable of inducing significant hyperthermia while the loading of SRF further enhances cytotoxicity relative to treatment with HSAP-AuNRs alone. HSAP-AuNR-SRFs have the potential to be an effective, novel combination treatment for advanced RCC.

Comparison of sorafenib-loaded poly (lactic/glycolic) acid and DPPC liposome nanoparticles in the in vitro treatment of renal cell carcinoma.

The objective of this study is to develop and compare several Sorafenib-loaded biocompatible nanoparticle models in order to optimize drug delivery and tumor cellular kill thereby improving the quality of Sorafenib-regimented chemotherapy. Sorafenib-loaded poly (lactic-co-glycolic) acid (PLGA), 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC) liposomes, and hydrophobically modified chitosan (HMC)-coated DPPC liposomes were evaluated for several characteristics including zeta potential, drug loading, and release profile. Cytotoxicity and uptake trials were also studied using cell line RCC 786-0, a human metastatic clear cell histology renal cell carcinoma cell line. Sorafenib-loaded PLGA particles and HMC-coated DPPC liposomes exhibited significantly improved cell kill compared to Sorafenib alone at lower concentrations, namely 10-15 and 5-15 µM from 24 to 96 h, respectively. At maximum dosage and time (15 µM and 96 h), Sorafenib-loaded PLGA and HMC-coated liposomes killed 88.3 ± 1.8% and 98 ± 1.1% of all tumor cells, significant values compared with Sorafenib 81.8 ± 1.7% (p < 0.01). Likewise, HMC coating substantially improved cell kill for liposome model for all concentrations (5-15 µM) and at time points (24-96 h) (p < 0.01). PLGA and HMC-coated liposomes are promising platforms for drug delivery of Sorafenib. Because of different particle characteristics of PLGA and liposomes, each model can be further developed for unique clinical modalities.

Nanotechnology applications in urology: a review.

The objectives of this review are to discuss the current literature and summarise some of the promising areas with which nanotechnology may improve urological care. A Medline literature search was performed to elucidate all relevant studies of nanotechnology with specific attention to its application in urology. Urological applications of nanotechnology include its use in medical imaging, gene therapy, drug delivery, and photothermal ablation of tumours. In vitro and animal studies have shown initial encouraging results. Further study of nanotechnology for urological applications is warranted to bridge the gap between preclinical studies and translation into clinical practice, but nanomedicine has shown significant potential to improve urological patient care.