Predictors and characteristics of Rib fracture following SBRT for lung tumors.

BACKGROUND: The utilization of stereotactic body radiation therapy (SBRT) is increasing for primary and secondary lung neoplasms. Despite encouraging results, SBRT is associated with an increased risk of osteoradionecrosis-induced rib fracture. We aimed to (1) evaluate potential clinical, demographic, and procedure-related risk factors for rib fractures and (2) describe the radiographic features of post-SBRT rib fractures. METHODS: We retrospectively identified 106 patients who received SBRT between 2015 and 2018 for a primary or metastatic lung tumor with at least 12 months of follow up. Exclusion criteria were incomplete records, previous ipsilateral thoracic radiation, or relevant prior trauma. Computed tomography (CT) images were reviewed to identify and characterize rib fractures. Multivariate logistic regression modeling was employed to determine clinical, demographic, and procedural risk factors (e.g., age, sex, race, medical comorbidities, dosage, and tumor location). RESULTS: A total of 106 patients with 111 treated tumors met the inclusion criteria, 35 (32%) of whom developed at least one fractured rib (60 total fractured ribs). The highest number of fractured ribs per patient was five. Multivariate regression identified posterolateral tumor location as the only independent risk factor for rib fracture. On CT, fractures showed discontinuity between healing edges in 77% of affected patients. CONCLUSIONS: Nearly one third of patients receiving SBRT for lung tumors experienced rib fractures, 34% of whom experienced pain. Many patients developed multiple fractures. Post-SBRT fractures demonstrated a unique discontinuity between the healing edges of the rib, a distinct feature of post-SBRT rib fractures. The only independent predictor of rib fracture was tumor location along the posterolateral chest wall. Given its increasing frequency of use, describing the risk profile of SBRT is vital to ensure patient safety and adequately inform patient expectations.

Interactive Machine Learning-Based Multi-Label Segmentation of Solid Tumors and Organs.

We seek the development and evaluation of a fast, accurate, and consistent method for general-purpose segmentation, based on interactive machine learning (IML). To validate our method, we identified retrospective cohorts of 20 brain, 50 breast, and 50 lung cancer patients, as well as 20 spleen scans, with corresponding ground truth annotations. Utilizing very brief user training annotations and the adaptive geodesic distance transform, an ensemble of SVMs is trained, providing a patient-specific model applied to the whole image. Two experts segmented each cohort twice with our method and twice manually. The IML method was faster than manual annotation by 53.1% on average. We found significant (p < 0.001) overlap difference for spleen (DiceIML/DiceManual = 0.91/0.87), breast tumors (DiceIML/DiceManual = 0.84/0.82), and lung nodules (DiceIML/DiceManual = 0.78/0.83). For intra-rater consistency, a significant (p = 0.003) difference was found for spleen (DiceIML/DiceManual = 0.91/0.89). For inter-rater consistency, significant (p < 0.045) differences were found for spleen (DiceIML/DiceManual = 0.91/0.87), breast (DiceIML/DiceManual = 0.86/0.81), lung (DiceIML/DiceManual = 0.85/0.89), the non-enhancing (DiceIML/DiceManual = 0.79/0.67) and the enhancing (DiceIML/DiceManual = 0.79/0.84) brain tumor sub-regions, which, in aggregation, favored our method. Quantitative evaluation for speed, spatial overlap, and consistency, reveals the benefits of our proposed method when compared with manual annotation, for several clinically relevant problems. We publicly release our implementation through CaPTk (Cancer Imaging Phenomics Toolkit) and as an MITK plugin.

Machine Learning Using Multiparametric Magnetic Resonance Imaging Radiomic Feature Analysis to Predict Ki-67 in World Health Organization Grade I Meningiomas.

BACKGROUND: Although World Health Organization (WHO) grade I meningiomas are considered "benign" tumors, an elevated Ki-67 is one crucial factor that has been shown to influence tumor behavior and clinical outcomes. The ability to preoperatively discern Ki-67 would confer the ability to guide surgical strategy. OBJECTIVE: In this study, we develop a machine learning (ML) algorithm using radiomic feature analysis to predict Ki-67 in WHO grade I meningiomas. METHODS: A retrospective analysis was performed for a cohort of 306 patients who underwent surgical resection of WHO grade I meningiomas. Preoperative magnetic resonance imaging was used to perform radiomic feature extraction followed by ML modeling using least absolute shrinkage and selection operator wrapped with support vector machine through nested cross-validation on a discovery cohort (n = 230), to stratify tumors based on Ki-67 <5% and ≥5%. The final model was independently tested on a replication cohort (n = 76). RESULTS: An area under the receiver operating curve (AUC) of 0.84 (95% CI: 0.78-0.90) with a sensitivity of 84.1% and specificity of 73.3% was achieved in the discovery cohort. When this model was applied to the replication cohort, a similar high performance was achieved, with an AUC of 0.83 (95% CI: 0.73-0.94), sensitivity and specificity of 82.6% and 85.5%, respectively. The model demonstrated similar efficacy when applied to skull base and nonskull base tumors. CONCLUSION: Our proposed radiomic feature analysis can be used to stratify WHO grade I meningiomas based on Ki-67 with excellent accuracy and can be applied to skull base and nonskull base tumors with similar performance achieved.

Radiopharmaceuticals for Bone Metastases.

As a single organ distributed diffusely throughout the body, bones represent both a unique challenge and unique opportunity for the treatment of symptomatic metastatic disease. While the multifocality of bone metastases often prevents effective complete treatment with focal radiotherapy, the similar pathophysiology of these diffuse sites of disease opens the door to targeted systemic therapy. The relatively rapid dose fall-off from beta- or alpha-emitting particles, if correctly and reliably targeted to osseous metastases, might reduce tumor burden and enhance pain control or improve survival. Radioisotopes have thus been studied keenly with the first generation of primarily beta-emitting radioisotopes, strontium-89 and samarium-153, which reached early FDA approval based on successful endpoints of pain control. More recently, an alpha-emitting therapy, radium-223, has demonstrated a successful endpoint of improved overall survival in patients with a burden of symptomatic, metastatic castrate-resistant prostate cancer (mCRPC) confined to the bones. With this discovery, an additional survival-improving tool beyond systemic and hormonal agents was added to the treatment arsenal for mCRPC for suitable candidates. With an improved understanding of the optimization of hormonal and systemic therapies in the context of mCRPC, there is lingering uncertainty regarding the safety and efficacy of combinatorial use of alpha and beta-emitting therapies with the current generation of systemic agents. In this narrative review, we will highlight the current understanding of the relative utility and clinical paradigms involving alpha- and beta-emitting radioisotopes. We discuss fundamental mechanisms for antineoplastic activity, initial clinical trials validating their use, the use of concurrent antiresorptive therapies to provide bone protection, and ongoing clinical trials targeted at best utilization of these agents in the broader context of mCRPC treatment.

The Impact of Prostate Cancer Treatment on Quality of Life: A Narrative Review with a Focus on Randomized Data.

Despite excellent oncologic outcomes, the management of localized prostate cancer remains complex and is dependent on multiple factors, including patient life expectancy, medical comorbidities, tumor characteristics, and genetic risk factors. Decades of iterative clinical trials have improved the optimization and utilization of surgical and radiation-based modalities, as well as their combinatorial use with anti-androgen and systemic therapies. While cure rates are high and converging on equivalent disease control should an upfront surgical or radiotherapeutic approach be optimized, the long-term side effects of surgical and radiation-based treatments can differ significantly in nature. Decisions regarding the selection of therapy are therefore best made in an informed and shared medical decision-making process between clinician and patient with respect to cancer control as well as adverse effects. We outline in this narrative review an understanding regarding implications of surgical and radiation treatment on quality of life after treatment, and how these data may be considered in the context of advising patients regarding the selection of therapy. This narrative review largely focuses on the quality of life data obtained from prospective randomized trials of men treated for prostate cancer. We believe this provides the best assessment of the quality of life and can be used to inform patients when making treatment decisions.

The Underappreciated Role of the Humoral Immune System and B Cells in Tumorigenesis and Cancer Therapeutics: A Review.

The advent of immunotherapy has ushered in a new era in both cancer research and cancer treatment strategies. Published reviews have described potential mechanisms for therapeutic synergisms from the combination of radiation therapy and immunotherapy, largely overlooking the role of humoral immunity by only focusing on cellular immunity. Given that these 2 branches of the immune system are highly interdependent, in this review we detail both what has already been established regarding the role of humoral immunity in cancer and propose potential avenues that are ripe for further investigation and potential clinical applications.

The role of proton therapy in pediatric malignancies: Recent advances and future directions.

Proton radiotherapy has promised an advantage in safely treating pediatric malignancies with an increased capability to spare normal tissues, reducing the risk of both acute and late toxicity. The past decade has seen the proliferation of more than 30 proton facilities in the United States, with increased capacity to provide access to approximately 3,000 children per year who will require radiotherapy for their disease. We provide a review of the initial efforts to describe outcomes after proton therapy across the common pediatric disease sites. We discuss the main attempts to assess comparative efficacy between proton and photon radiotherapy concerning toxicity. We also discuss recent efforts of multi-institutional registries aimed at accelerating research to better define the optimal treatment paradigm for children requiring radiotherapy for cure.

Comparing Radiotherapy to Prostatectomy for High-Risk Prostate Cancer: A Narrative Review of Mortality and Quality-of-Life Outcomes.

There is currently a lack of level 1 evidence regarding the relative efficacy of radical prostatectomy compared with radiotherapy combined with androgen deprivation therapy for high-risk prostate cancer. There has recently been an improved optimization of treatment, achieving superior biochemical outcomes and cancer-specific mortality through the use of combined modality therapy strategies. Combined modality therapies have also increasingly incorporated brachytherapy boost. Although available observational data must be interpreted with caution because of the effects of potential residual confounding, we present here a narrative review of recent advances in understanding the relative efficacy of the principal combined modality approaches for treating high-risk prostate cancer. As the trend has demonstrated approaching equivalence between well-selected combined modality therapies, an increasing emphasis should be placed on selecting therapy tailored toward a patient's goals regarding quality of life. We present here an outline of efforts to date to understand the implications of treatment on functional outcomes and quality-of-life endpoints.

Post-mastectomy and post-breast conservation surgery pain syndrome: a review of etiologies, risk prediction, and trends in management.

Postmastectomy pain syndrome (PMPS) or breast conservation surgery (BCS) pain syndrome could be long-term and lead to disability and impairment on body and social function. The pain syndromes are not uncommon in breast cancer patients. It can affect social, psychological, physical and behavioral aspects of a patient. Surgery, radiation, chemotherapy and psychological factors can all contribute to the development of pain syndromes. Axillary dissection is a strong predictor for pain development. Pain medications, ganglion blocks are typically given to the patient for management. Integrative medicine such as acupuncture and psychological management methods are promising modalities in the management arsenal. In this study, we summarized the up-to-date literature to elucidate the etiology, risk factors and management strategies for PMPS.

Comparison of Radical Prostatectomy Versus Radiation and Androgen Deprivation Therapy Strategies as Primary Treatment for High-risk Localized Prostate Cancer: A Systematic Review and Meta-analysis.

CONTEXT: There is little level 1 evidence regarding the relative efficacy of radical prostatectomy (RP) compared with radiotherapy (RT) combined with androgen deprivation therapy (ADT) for high-risk prostate cancer. OBJECTIVE: To conduct a systematic review and meta-analysis comparing overall and prostate cancer-specific mortality (OM and PCM) among patients with high-risk prostate cancer treated with RP or RT/ADT. EVIDENCE ACQUISITION: We searched PubMed, Scopus, and the Cochrane Library through July 2019 covering a period since 2009. We report the results of our systematic search according to recommendations from the Preferred Reporting Items for Systematic Reviews and Meta-analyses statement. Adjusted hazard ratios (aHRs) were extracted for each endpoint. The risk of bias was assessed using the Newcastle-Ottawa Scale. EVIDENCE SYNTHESIS: A total of 23 studies with low to moderate risk of bias were found to meet the inclusion criteria. In keeping with prior studies, external beam radiation therapy (XRT) without specification of ADT was associated with worse OM and PCM (aHR 1.65, 95% confidence interval [CI] 1.42-1.91, p < 0.0001: I2 = 53.4%) and (aHR 1.90, 95% CI 1.61-2.23, p < 0.0001: I2 = 50.4%). These associations were weaker although not entirely eliminated when comparing RT/ADT versus RP (PCM aHR 1.54, 95% CI 1.16-2.04, p = 0.002: I2 = 61.5%). Combination of RT and brachytherapy (MaxRT), on the contrary, was associated with improved PCM compared with RP (aHR 0.48, 95% CI 0.30-0.78, p = 0.003: I2 = 23.8%), an effect that was not significant when comparing MaxRT with the combination RP/adjuvant RT (aHR 0.81, 95% CI 0.59-1.11, p = 0.197: I2 = 0%). CONCLUSIONS: Evidence demonstrating definitive superiority of either modality is lacking. Recent studies show improved consideration of ADT, radiation dose, brachytherapy boost, and utilization of postoperative adjuvant radiation. Residual confounding continues to limit the interpretation of observational data. PATIENT SUMMARY: In the treatment of high-risk prostate cancer, many observational studies reporting higher mortality for radiotherapy demonstrate potential for confounding. More recent studies with current standard of care radiation regimens using androgen deprivation therapy or brachytherapy boost demonstrate approaching equivalence of prostatectomy and radiation modalities. Prospective randomized trials are needed to confirm these findings.

Combined Modality Therapies for High-Risk Prostate Cancer: Narrative Review of Current Understanding and New Directions.

Despite the many prospective randomized trials that have been available in the past decade regarding the optimization of radiation, hormonal, and surgical therapies for high-risk prostate cancer (PCa), many questions remain. There is currently a lack of level I evidence regarding the relative efficacy of radical prostatectomy (RP) followed by adjuvant radiation compared to radiation therapy (RT) combined with androgen deprivation therapy (ADT) for high-risk PCa. Current retrospective series have also described an improvement in biochemical outcomes and PCa-specific mortality through the use of augmented radiation strategies incorporating brachytherapy. The relative efficacy of modern augmented RT compared to RP is still incompletely understood. We present a narrative review regarding recent advances in understanding regarding comparisons of overall and PCa-specific mortality measures among patients with high-risk PCa treated with either an RP/adjuvant RT or an RT/ADT approach. We give special consideration to recent trends toward the assembly of multi-institutional series targeted at providing high-quality data to minimize the effects of residual confounding. We also provide a narrative review of recent studies examining brachytherapy boost and systemic therapies, as well as an overview of currently planned and ongoing studies that will further elucidate strategies for treatment optimization over the next decade.

Clinical outcomes and late endocrine, neurocognitive, and visual profiles of proton radiation for pediatric low-grade gliomas.

PURPOSE/OBJECTIVE(S): Primary low-grade gliomas are common brain tumors of childhood, many of which require radiation therapy (RT) as definitive treatment. Increased conformality of RT could decrease the incidence and severity of late effects. We report our experience with 32 pediatric patients treated with proton RT. METHODS AND MATERIALS: Thirty-two pediatric patients with low-grade gliomas of the brain or spinal cord were treated with proton RT from 1995 to 2007. Sixteen patients received at least 1 regimen of chemotherapy before definitive RT. The median radiation dose was 52.2 GyRBE (48.6-54 GyRBE). RESULTS: The median age at treatment was 11.0 years (range, 2.7-21.5 years), with a median follow-up time of 7.6 years (range, 3.2-18.2 years). The 6-year and 8-year rates of progression-free survival were 89.7% and 82.8%, respectively, with an 8-year overall survival of 100%. For the subset of patients who received serial neurocognitive testing, there were no significant declines in Full-Scale Intelligence Quotient (P=.80), with a median neurocognitive testing interval of 4.5 years (range, 1.2-8.1 years) from baseline to follow-up, but subgroup analysis indicated some significant decline in neurocognitive outcomes for young children (<7 years) and those with significant dose to the left temporal lobe/hippocampus. The incidence of endocrinopathy correlated with a mean dose of ≥40 GyRBE to the hypothalamus, pituitary, or optic chiasm. Stabilization or improvement of visual acuity was achieved in 83.3% of patients at risk for radiation-induced injury to the optic pathways. CONCLUSIONS: This report of late effects in children with low-grade gliomas after proton RT is encouraging. Proton RT appears to be associated with good clinical outcome, especially when the tumor location allows for increased sparing of the left temporal lobe, hippocampus, and hypothalamic-pituitary axis.

The bromodomain protein Brd4 insulates chromatin from DNA damage signalling.

DNA damage activates a signalling network that blocks cell-cycle progression, recruits DNA repair factors and/or triggers senescence or programmed cell death. Alterations in chromatin structure are implicated in the initiation and propagation of the DNA damage response. Here we further investigate the role of chromatin structure in the DNA damage response by monitoring ionizing-radiation-induced signalling and response events with a high-content multiplex RNA-mediated interference screen of chromatin-modifying and -interacting genes. We discover that an isoform of Brd4, a bromodomain and extra-terminal (BET) family member, functions as an endogenous inhibitor of DNA damage response signalling by recruiting the condensin II chromatin remodelling complex to acetylated histones through bromodomain interactions. Loss of this isoform results in relaxed chromatin structure, rapid cell-cycle checkpoint recovery and enhanced survival after irradiation, whereas functional gain of this isoform compacted chromatin, attenuated DNA damage response signalling and enhanced radiation-induced lethality. These data implicate Brd4, previously known for its role in transcriptional control, as an insulator of chromatin that can modulate the signalling response to DNA damage.

Mitochondrial targeting of a catalase transgene product by plasmid liposomes increases radioresistance in vitro and in vivo.

To determine whether increased mitochondrially localized catalase was radioprotective, a human catalase transgene was cloned into a small pSVZeo plasmid and localized to the mitochondria of 32D cl 3 cells by adding the mitochondrial localization sequence of MnSOD (mt-catalase). The cell lines 32D-Cat and 32D-mt-Cat had increased catalase biochemical activity as confirmed by Western blot analysis compared to the 32D cl 3 parent cells. The MnSOD-overexpressing 32D cl 3 cell line, 2C6, had decreased baseline catalase activity that was increased in 2C6-Cat and 2C6-mt-Cat subclonal cell lines. 32D-mt-Cat cells were more radioresistant than 32D-Cat cells, but both were radioresistant relative to 32D cl 3 cells. 2C6-mt-Cat cells but not 2C6-Cat cells were radioresistant compared to 2C6 cells. Intratracheal injection of the mt-catalase-plasmid liposome complex (mt-Cat-PL) but not the catalase-plasmid liposome complex (Cat-PL) increased the resistance of C57BL/6NHsd female mice to 20 Gy thoracic irradiation compared to MnSOD-plasmid liposomes. Thus mitochondrially targeted overexpression of the catalase transgene is radioprotective in vitro and in vivo.

Radioprotection in vitro and in vivo by minicircle plasmid carrying the human manganese superoxide dismutase transgene.

Manganese superoxide dismutase plasmid liposomes (MnSOD-PL) confer organ-specific in vivo ionizing irradiation protection. To prepare for potential intravenous clinical trials of systemic MnSOD-PL for radioprotection in humans, plasmid and bacterial sequences were removed and a new minicircle construct was tested. Minicircle MnSOD was purified and then cotransfected into 32D cl 3 murine interleukin-3-dependent hematopoietic progenitor cells along with another plasmid carrying the neo gene. Cells were selected in G418 (50 microg/ml) and cloned by limiting dilution. Biochemical analysis of minicircle MnSOD-transfected cells showed an MnSOD biochemical activity level of 5.8 +/- 0.5 U/mg compared with 2.7 +/- 0.1 U/mg for control 32D cl 3 cells (p = 0.0039). 32D-mc-MnSOD cells were as radioresistant as full-length MnSOD-PL transgene-expressing 2C6 cells, relative to 32D cl 3 parent cells, with an increased shoulder on the radiation survival curve (n = 4.8 +/- 0.2 and n = 4.6 +/- 0.2, respectively, compared with 1.5 +/- 0.5 for 32D cl 3 cells; p = 0.007). C57BL/6NHsd mice received intraoral mc-MnSOD-PL, mc-DsRed-PL control, full-length MnSOD-PL, or blank-PL and then were irradiated 24 hr later with 31 Gy to the esophagus. Mice receiving mc-MnSOD-PL showed increased survival compared with control mice or mice treated with mc-DsRed-PL (p = 0.0003 and 0.039, respectively), and comparable to full-length MnSOD-PL. Intravenous, systemic administration of mc-MnSOD-PL protected mice from total body irradiation (9.75 Gy). Therefore, minicircle DNA containing the human MnSOD transgene confers undiminished radioprotection in vitro and in vivo.