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Abstract Background Ionizing radiation (IR) accelerates atherosclerosis through induction of cellular senescence, DNA damage, defective efferocytosis, and dysregulation of clonal hematopoiesis (CH) drivers. Although low-dose colchicine reduces ischemic cardiovascular events in coronary artery disease, the precise molecular mechanisms underlying its vasculoprotective effects remain incompletely defined, and whether it mitigates radiation-associated vascular injury is unknown. Methods Bone marrow–derived macrophages (BMDMs) were pretreated with low-dose colchicine and exposed to 2 Gy IR. Molecular effects were assessed by RNA-seq, immunoblotting, and molecular docking. In vivo effects were tested in a partial carotid ligation (PLCL) model using spatial proteomics. Human monocyte-derived macrophages (HMDMs) from thoracic malignancy patients were analyzed before and after radiation therapy (RT). Results Low-dose colchicine suppressed IR-induced macrophage senescence signaling while preserving NRF2 activity. In a cell-free assay, colchicine directly activated aldehyde dehydrogenase 2 (ALDH2) in a dose-dependent manner (EC 50 1–5 nM), identifying ALDH2 as a direct molecular target of colchicine. Following irradiation, colchicine restored ALDH2, reduced mitochondrial (mt)ROS - dependent p90 ribosomal S6 kinase ( p90RSK ) activation and lipid peroxidation, preserved TET2 and DNMT3A expression, and rescued impaired efferocytosis while preventing nicotinamide adenine dinucleotide (NAD⁺) and adenosine triphosphate (ATP) depletion. These protective effects were ALDH2-dependent, as they were lost with ALDH2 inhibition or depletion and were mimicked by pharmacologic ALDH2 activation. In vivo, colchicine attenuated radiation-induced atherosclerosis and macrophage senescence-associated stemness (SAS). Consistently, macrophages from patients after RT showed reduced ALDH2 with increased mtROS, lipid peroxidation, and senescence. Conclusion These findings identify ALDH2 as a previously unrecognized molecular target of colchicine that links mitochondrial redox control to suppression of radiation-induced macrophage senescence and atherosclerosis and may contribute to the efficacy of low-dose colchicine in cardiovascular disease.

PURPOSE Most oncology trials define superiority according to dichotomized P value thresholds, which are frequently misinterpreted. Posterior probability, however, directly estimates the probability of the hypothesis at hand. Here, we reanalyze a large collection of modern phase III trials and benchmark posterior probability versus the standard trial interpretation based on statistical significance. METHODS Outcomes from 194,129 patients were manually reconstructed from the primary end points of 230 phase III, superiority-design oncology trials. Posterior probabilities of treatment effect were then calculated across multiple priors and several effect sizes of clinical relevance, including minimum clinically important difference (MCID) defined as hazard ratio (HR) < 0.8 per ASCO criteria or HR < 0.64 per European Society of Medical Oncology (ESMO) criteria. RESULTS All trials interpreted as superior using P value thresholds had probabilities >90% for achieving at least marginal benefits (HR < 1). However, only 62% of positive trials (74/120) had >90% probabilities of achieving the ASCO MCID (HR < 0.8), even under an enthusiastic prior, including 70% of trials (57/82) leading to regulatory approval. Only 30% of positive trials (36/120) had >90% probability of achieving the ESMO MCID (HR < 0.64). Conversely, 24% of trials (26/110) interpreted as not superior had >90% probability of achieving marginal benefits (HR < 1), even under a skeptical prior. CONCLUSION Bayesian models, although often in agreement with statistical significance thresholds, add considerable unique interpretative value for a subset of phase III oncology trials. Posterior probability may provide a solution for overcoming the discrepancies between refuting the null hypothesis and detecting clinically relevant effects.

Background: Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) is a functional imaging modality that can quantify tissue permeability and blood flow. Due to vasculature changes resulting from radiation therapy (RT), DCE-MRI quantitative parameters should be significantly different in regions receiving a high radiation dose compared to regions receiving a low radiation dose. This study sought to determine whether a significant difference exists in post-head-and-neck-cancer (HNC)-RT DCE-MRI quantitative parameters (Ktrans and ve) between regions of the mandible receiving a high radiation dose and regions of the mandible receiving a low radiation dose. Methods: DCE-MRI was acquired from HNC subjects post-RT. The DCE-MRI quantitative parameters Ktrans and ve were obtained through Tofts model fitting. Four mandible sections (left ramus, left body, right ramus, and right body) were delineated on subject mandible contours. Two Friedman tests comparing the mean Ktrans and ve in low-dose (≤60 Gy) areas of the four mandible regions were computed. If the Friedman test determined that a significant difference for a parameter between mandible regions exists, post hoc Wilcoxon signed-rank tests were completed comparing the four mandible regions. If the Friedman test determined that there was no significant difference between mandible regions, a Wilcoxon signed-rank test was used to determine whether a significant difference exists in the parameter between high-dose (>60 Gy) and low-dose (≤60 Gy) mandible regions. Results: 48 HNC subjects were included in the analysis. The Friedman tests showed no significant difference in ve means between mandible regions (χ(3)2 = 1.63, p = 0.44) and a significant difference in Ktrans means between mandible regions (χ(3)2 = 10.29, p = 0.005). Post hoc testing between Ktrans mandible regions found that the left body and right body differed significantly from the left ramus and right ramus. The Wilcoxon signed-rank test comparing the mean ve between high- and low-dose mandible regions found a significant difference (W = 214, p = 0.00013). Conclusions: no inherent difference in the DCE-MRI quantitative parameter ve was observed within subject mandibles, but a significant difference was observed between ve means in high- and low-radiation-dose mandible regions. These results provide evidence of the utility of DCE-MRI to monitor mandible vasculature changes resulting from head and neck cancer radiation therapy. Monitoring post-HNC-RT mandible vasculature changes is important to initiate earlier toxicity management and ultimately improve HNC survivors’ quality of life.

It is an exciting time for big data efforts in radiation oncology. The use of big data to help aid both outcomes and decision‐making research is becoming a reality. However, there are true challenges that exist in the space of gathering and utilizing performance and outcomes data. Here, we summarize the current state of big data in radiation oncology with respect to outcomes and discuss some of the efforts and challenges in radiation oncology big data.

OBJECTIVEThe objective of this study was to assess outcomes after Gamma Knife radiosurgery (GKRS) re-irradiation for palliation of patients with trigeminal pain secondary to recurrent malignant skull base tumors.METHODSFrom 2009 to 2016, 26 patients who had previously undergone radiation treatment to the head and neck received GKRS for palliation of trigeminal neuropathic pain secondary to recurrence of malignant skull base tumors. Twenty-two patients received single-fraction GKRS to a median dose of 17 Gy (range 15–20 Gy) prescribed to the 50% isodose line (range 43%–55%). Four patients received fractionated Gamma Knife Extend therapy to a median dose of 24 Gy in 3 fractions (range 21–27 Gy) prescribed to the 50% isodose line (range 45%–50%). Those with at least a 3-month follow-up were assessed for symptom palliation. Self-reported pain was evaluated by the numeric rating scale (NRS) and MD Anderson Symptom Inventory–Head and Neck (MDASI-HN) pain score. Frequency of as-needed (PRN) analgesic use and opioid requirement were also assessed. Baseline opioid dose was reported as a fentanyl-equivalent dose (FED) and PRN for breakthrough pain use as oral morphine-equivalent dose (OMED). The chi-square and Student t-tests were used to determine differences before and after GKRS.RESULTSSeven patients (29%) were excluded due to local disease progression. Two experienced progression at the first follow-up, and 5 had local recurrence from disease outside the GKRS volume. Nineteen patients were assessed for symptom palliation with a median follow-up duration of 10.4 months (range 3.0–34.4 months). At 3 months after GKRS, the NRS scores (n = 19) decreased from 4.65 ± 3.45 to 1.47 ± 2.11 (p < 0.001); MDASI-HN pain scores (n = 13) decreased from 5.02 ± 1.68 to 2.02 ± 1.54 (p < 0.01); scheduled FED (n = 19) decreased from 62.4 ± 102.1 to 27.9 ± 45.5 mcg/hr (p < 0.01); PRN OMED (n = 19) decreased from 43.9 ± 77.5 to 10.9 ± 20.8 mg/day (p = 0.02); and frequency of any PRN analgesic use (n = 19) decreased from 0.49 ± 0.55 to 1.33 ± 0.90 per day (p = 0.08). At 6 months after GKRS, 9 (56%) of 16 patients reported being pain free (NRS score 0), with 6 (67%) of the 9 being both pain free and not requiring analgesic medications. One patient treated early in our experience developed a temporary increase in trigeminal pain 3–4 days after GKRS requiring hospitalization. All subsequently treated patients were given a single dose of intravenous steroids immediately after GKRS followed by a 2–3-week oral steroid taper. No further cases of increased or new pain after treatment were observed after this intervention.CONCLUSIONSGKRS for palliation of trigeminal pain secondary to recurrent malignant skull base tumors demonstrated a significant decrease in patient-reported pain and opioid requirement. Additional patients and a longer follow-up duration are needed to assess durability of symptom relief and local control.

AbstractBackgroundOverexpression of p16 is associated with improved outcomes among patients with oropharyngeal carcinoma. However, its role in the outcomes of patients with nasopharyngeal cancer (NPC) remains unclear.MethodsEighty‐six patients with NPC treated at MD Anderson Cancer Center from 2000 to 2014 were identified. Epstein‐Barr virus (EBV) and human papillomavirus (HPV) status were determined by in situ hybridization (ISH) and p16 by immunohistochemical staining.ResultsEBV positivity was associated with extended overall survival (OS; median, 95.0 vs 44.9 months; p < .004), progression‐free survival (PFS; median, 80.4 vs 28.1 months; p < .013), and locoregional control (median, 104.4 vs 65.5 months; p < .043). In patients with EBV‐positive tumors, p16 overexpression correlated with improved PFS (median, 106.3 vs 27.1 months; p < .02) and locoregional control (median, 93.6 vs 64.5 months; p < .02).ConclusionP16 overexpression is associated with improved PFS and locoregional control in patients with EBV‐positive NPC. P16 expression may complement EBV status in predicting treatment outcomes for patients with NPC. © 2015 Wiley Periodicals, Inc. Head Neck 38: E1459–E1466, 2016

Severely comminuted fractures of the metatarsal bones with significant bone and soft-tissue loss have commonly subjected patients to proximal amputation procedures. We describe two patients who experienced high-energy traumatic injuries to their limbs that resulted in significant destruction of their first and second metatarsal bones with overlying soft-tissue trauma not amenable to local coverage. In both cases, a vascularized free fibular osteocutaneous flap was used to reconstruct the metatarsal bone defect and traumatized soft tissues so that a proximal amputation was avoided. At an average of 14 months of follow-up, both patients had recovered well and regained independent ambulation, with one patient being able to play soccer. We show that the free fibular osteoseptocutaneous flap is useful in reconstructing significant metatarsal bone defects and in avoiding amputations in this patient population. The skin component of the flap may be used to fill soft-tissue losses, and the fibula bone may be osteotomized so that more than one ray may be reconstructed. (J Am Podiatr Med Assoc 101(6): 531–536, 2011)