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Active surveillance (AS) is recommended as a management option for men with favorable-risk (low risk and favorable intermediate risk) prostate cancer; however, national rates remain low. The Michigan Urological Surgery Improvement Collaborative (MUSIC) established a quality improvement (QI) initiative in June 2014 to increase AS utilization. In this report, we analyze the rates of AS utilization over time in the state of Michigan (MUSIC) for men with favorable-risk prostate cancer and compare these to rates for other men diagnosed with favorable-risk prostate cancer in the USA outside the state of Michigan. While the variables that influence AS utilization were the same in both cohorts, we found that the AS utilization rates and the rate of increase were significantly higher in MUSIC. We conclude that the QI initiative started in MUSIC should serve as a roadmap to increasing AS use nationwide. PATIENT SUMMARY: Active surveillance (AS), which involves close monitoring with blood tests and scans, is recommended for management of favorable-risk prostate cancer to avoid or delay unnecessary treatment. Our results show that a quality improvement program in Michigan increased AS use for prostate cancer patients in the state. This program should be used to increase AS uptake throughout the USA.

Our purpose was to evaluate the accuracy of LI-RADS Treatment Response Algorithm (LR-TRA) for assessing the viability of hepatocellular carcinoma (HCC) treated with stereotactic body radiation therapy (SBRT), using explant pathology as the gold standard.This retrospective study included patients who underwent SBRT for locoregional treatment of HCC between 2008 and 2019 with subsequent liver transplantation. Five radiologists independently assessed all treated lesions by using the LR-TRA. Imaging and posttransplant histopathology were compared. Lesions were categorized as either completely (100%) or incompletely (100%) necrotic, and performance characteristics and predictive values for the LR-TR viable and nonviable categories were calculated for each reader. Interreader reliability was calculated using the Fleiss kappa test.A total of 40 treated lesions in 26 patients (median age, 63 years [interquartile range, 59.4-65.5]; 23 men) were included. For lesions treated with SBRT, sensitivity for incomplete tumor necrosis across readers ranged between 71% and 86%, specificity between 85% and 96%, and positive predictive value between 86% and 92%, when the LR-TR equivocal category was treated as nonviable, accounting for subject clustering. When the LR-TR equivocal category was treated as viable, sensitivity of complete tumor necrosis for lesions treated with SBRT ranged from 88% to 96%, specificity from 71% to 93%, and negative predictive value from 85% to 96%. Interreader reliability was fair (k = 0.22; 95% confidence interval, 0.13-0.33). Although a loss of arterial phase hyperenhancement (APHE) was highly correlated with pathologically nonviable tumor on explant, almost half of the patients with APHE had pathologically nonviable tumor on explant.LR-TRA v2018 performs well for predicting complete and incomplete necrosis in HCC treated with SBRT. In contrast to other locoregional therapies, the presence of APHE after SBRT does not always indicate viable tumor and suggests that observation may be an appropriate strategy for these patients.

Background: Randomised trials have investigated various androgen deprivation therapy (ADT) intensification strategies in men receiving radiotherapy for the treatment of prostate cancer. This individual patient data meta-analysis of relevant randomised trials aimed to quantify the benefit of these interventions in aggregate and in clinically relevant subgroups. Methods: For this meta-analysis, we performed a systematic literature search in MEDLINE, Embase, trial registries, the Web of Science, Scopus, and conference proceedings to identify trials with results published in English between Jan 1, 1962, and Dec 30, 2020. Multicentre randomised trials were eligible if they evaluated the use or prolongation of ADT (or both) in men with localised prostate cancer receiving definitive radiotherapy, reported or collected distant metastasis and survival data, and used ADT for a protocol-defined finite duration. The Meta-Analysis of Randomized trials in Cancer of the Prostate (MARCAP) Consortium was accessed to obtain individual patient data from randomised trials. The primary outcome was metastasis-free survival. Hazard ratios (HRs) were obtained through stratified Cox models for ADT use (radiotherapy alone vs radiotherapy plus ADT), neoadjuvant ADT extension (ie, extension of total ADT duration in the neoadjuvant setting from 3–4 months to 6–9 months), and adjuvant ADT prolongation (ie, prolongation of total ADT duration in the adjuvant setting from 4–6 months to 18–36 months). Formal interaction tests between interventions and metastasis-free survival were done for prespecified subgroups defined by age, National Comprehensive Cancer Network (NCCN) risk group, and radiotherapy dose. This meta-analysis is registered with PROSPERO, CRD42021236855. Findings: Our search returned 12 eligible trials that provided individual patient data (10 853 patients) with a median follow-up of 11·4 years (IQR 9·0–15·0). The addition of ADT to radiotherapy significantly improved metastasis-free survival (HR 0·83 [95% CI 0·77–0·89], p

Purpose We hypothesized that dose-intensified chemoradiation therapy targeting adversely prognostic hypercellular (TVHCV) and hyperperfused (TVCBV) tumor volumes would improve outcomes in patients with glioblastoma. Methods and Materials This single-arm, phase 2 trial enrolled adult patients with newly diagnosed glioblastoma. Patients with a TVHCV/TVCBV >1 cm3, identified using high b-value diffusion-weighted magnetic resonance imaging (MRI) and dynamic contrast-enhanced perfusion MRI, were treated over 30 fractions to 75 Gy to the TVHCV/TVCBV with temozolomide. The primary objective was to estimate improvement in 12-month overall survival (OS) versus historical control. Secondary objectives included evaluating the effect of 3-month TVHCV/TVCBV reduction on OS using Cox proportional-hazard regression and characterizing coverage (95% isodose line) of metabolic tumor volumes identified using correlative 11C-methionine positron emission tomography. Clinically meaningful change was assessed for quality of life by the European Organisation for the Research and Treatment of Cancer Quality of Life Questionnaire C30, for symptom burden by the MD Anderson Symptom Inventory for brain tumor, and for neurocognitive function (NCF) by the Controlled Oral Word Association Test, the Trail Making Test, parts A and B, and the Hopkins Verbal Learning Test–Revised. Results Between 2016 and 2018, 26 patients were enrolled. Initial patients were boosted to TVHCV alone, and 13 patients were boosted to both TVHCV/TVCBV. Gross or subtotal resection was performed in 87% of patients; 22% were O6-methylguanine-DNA methyltransferase (MGMT) methylated. With 26-month follow-up (95% CI, 19-not reached), the 12-month OS rate among patients boosted to the combined TVHCV/TVCBV was 92% (95% CI, 78%-100%; P = .03) and the median OS was 20 months (95% CI, 18-not reached); the median OS for the whole study cohort was 20 months (95% CI, 14-29 months). Patients whose 3-month TVHCV/TVCBV decreased to less than the median volume (3 cm3) had superior OS (29 vs 12 months; P = .02). Only 5 patients had central or in-field failures, and 93% (interquartile range, 59%-100%) of the 11C-methionine metabolic tumor volumes received high-dose coverage. Late grade 3 neurologic toxicity occurred in 2 patients. Among non-progressing patients, 1-month and 7-month deterioration in quality of life, symptoms, and NCF were similar in incidence to standard therapy. Conclusions Dose intensification against hypercellular/hyperperfused tumor regions in glioblastoma yields promising OS with favorable outcomes for NCF, symptom burden, and quality of life, particularly among patients with greater tumor reduction 3 months after radiation therapy.

To assess associations between imaging biomarkers from standard of care pre-treatment CT and FDG-PET scans and locoregional (LR) and distant metastatic (DM) recurrences in patients with p16+ oropharyngeal squamous cell carcinoma (OPSCC) treated with definitive chemoradiotherapy (CRT).An institutional database from a single NCI-designated cancer center identified 266 patients with p16+ OPSCC treated with definitive CRT in our department from 2005 to 2016 with evaluable pre-treatment FDG-PET scans. Quantitative SUV metrics and qualitative imaging metrics were determined from FDG-PET and CT scans, while clinical characteristics were abstracted from the medical record. Associations between clinical/imaging features and time to LR (TTLRF) or DM (TTDMF) failure and overall survival (OS) were assessed using univariable Cox regression and penalized stepwise regression for multivariable analyses (MVA).There were 27 LR and 32 DM recurrences as incident failures. Imaging biomarkers were significantly associated with TTLRF, TTDMF and OS. FDG-PET metrics outperformed CT and clinical metrics for TTLRF, with metabolic tumor volume being the only significant feature selected on MVA: C-index = 0.68 (p = 0.01). Radiographic extranodal extension (rENE), positive retropharyngeal nodes (RPN+), and clinical stage were significant on MVA for TTDMF: C-index = 0.84 (p 0.001). rENE, group stage, and RPN+ were significant on MVA for OS: C-index = 0.77 (p 0.001).In the largest study to date of uniformly treated patients with CRT to evaluate both pretreatment CT and FDG-PET, radiographic biomarkers were significantly associated with TTLRF, TTDMF and OS among patients with p16+ OPSCC treated with CRT. CT metrics performed best to predict TTDMF, while FDG-PET metrics showed improved prediction for LRRFS. These metrics may help identify candidates for treatment intensification or de-escalation of therapy.Pre-treatment imaging features from standard-of-care PET/CT imaging show promise for predicting long-term outcomes following HPV-associated oropharynx cancer (HPV-OPC) therapy. This study comprehensively characterizes qualitative and quantitative pre-treatment imaging metrics associated with time to pattern-specific failure in a cohort of 266 patients treated uniformly with definitive chemoradiation. Multivariate analysis (MVA) for time to locoregional failure (TTLRF), time to distant metastatic failure (TTDMF), and overall survival (OS) was performed. FDG-PET metrics outperformed CT and clinical metrics for TTLRF. CT radiographic extranodal extension, positive retropharyngeal nodes, and stage strongly predicted TTDMF (combined C-index = 0.84, log rank p 0.001). Number of smoking pack-years complemented clinical and imaging features only in patients without radiographic extranodal extension or positive retropharyngeal nodes. Time to pattern-specific failure is important for guiding treatment de-escalation strategies, which intend to reduce treatment-related toxicity in patients with relatively long expected survival times. This study suggests that PET/CT features should play a crucial role in future de-escalation trials and management of HPV-OPC patients.

Purpose To identify and define the incidence, risk factors, clinical characteristics, and treatment approaches to pelvic insufficiency fractures (PIFs) that develop as a consequence of pelvic radiation therapy for gynecologic malignancies. Materials and Methods A systematic literature review (PubMed and Embase indexed from January 1, 1980, to May 1, 2020) of studies describing PIFs that result from radiation therapy for gynecologic malignancies. A random-effects model weighted by the inverse variance was used to calculate the pooled crude incidence, actuarial incidence, and proportion of symptomatic PIFs, and to evaluate the relationship between PIF incidence and various risk factors. Results Thirty-eight studies describing PIFs following radiation therapy for gynecologic malignancies were reviewed. A meta-analysis of 6488 patients (37 studies) identified the crude incidence of PIF as 9.4% (95% confidence interval [CI] 6.8%-12.4%), and a meta-analysis of 2131 patients (9 studies) identified the 5-year actuarial incidence of PIF as 15.3% (95% CI 7.5%-25.0%). Factors that significantly correlated with increased risk of PIF development included evidence of osteoporosis (P Conclusions PIFs cause significant morbidity in gynecologic cancer patients after radiation therapy. In this systematic review, we discuss the incidence and risk factors associated with PIF development as it relates to the different detection methods, radiation techniques, doses, and gynecologic cancers treated. Additional studies are needed to further define prevention and treatment approaches for insufficiency fractures.

BACKGROUND: Declining liver function is a concerning side effect associated with radiation therapy. Biomarkers of liver toxicity would be useful in personalizing therapy. METHODS: As part of two prospective clinical trials examining adaptive radiation therapy, we collected serum samples from patients receiving liver radiation. We performed a screen of 22 cytokines using a multiplex assay then used ELISA to quantify the cytokines of greatest interest. Subjects were split into screening and validation cohorts. Toxicity was defined as an increase in Child-Pugh score of 2 points or greater within 6 months. Logistic regression models were used to estimate the relationship between our toxicity endpoint and serum cytokine concentrations. RESULTS: Our initial screen (46 subjects, 11 events) identified hepatocyte growth factor (HGF), CD40L (CD154), and eotaxin (CCL11) as potentially predictive of toxicity. We then tested these markers in an expanded patient cohort (104 subjects, 18 events) with a batch correction due to varying age of the samples which confirmed that high HGF and low CD40L were associated with a subsequent decline in liver function following radiation therapy. Multivariate analysis factoring in baseline Child-Pugh score and mean liver radiation dose demonstrated that HGF and CD40L were potentially predictive of toxicity (HGF OR 4.3, P = .009; CD40L OR 0.5 P = .06). Additionally, higher than median baseline HGF levels (1.4 ng/ml) were significantly associated with decreased survival following liver radiation (27.1 vs 14.5 months, P = .03). CONCLUSIONS: Our study identifies high HGF and low CD40L as potential markers of liver toxicity following radiation therapy.

Grade 2 and higher radiation pneumonitis (RP2) is a potentially fatal toxicity that limits efficacy of radiation therapy (RT). We wished to identify a combined biomarker signature of circulating miRNAs and cytokines which, along with radiobiological and clinical parameters, may better predict a targetable RP2 pathway. In a prospective clinical trial of response-adapted RT for patients (n = 39) with locally advanced non-small cell lung cancer, we analyzed patients' plasma, collected pre- and during RT, for microRNAs (miRNAs) and cytokines using array and multiplex enzyme linked immunosorbent assay (ELISA), respectively. Interactions between candidate biomarkers, radiobiological, and clinical parameters were analyzed using data-driven Bayesian network (DD-BN) analysis. We identified alterations in specific miRNAs (miR-532, -99b and -495, let-7c, -451 and -139-3p) correlating with lung toxicity. High levels of soluble tumor necrosis factor alpha receptor 1 (sTNFR1) were detected in a majority of lung cancer patients. However, among RP patients, within 2 weeks of RT initiation, we noted a trend of temporary decline in sTNFR1 (a physiological scavenger of TNFα) and ADAM17 (a shedding protease that cleaves both membrane-bound TNFα and TNFR1) levels. Cytokine signature identified activation of inflammatory pathway. Using DD-BN we combined miRNA and cytokine data along with generalized equivalent uniform dose (gEUD) to identify pathways with better accuracy of predicting RP2 as compared to either miRNA or cytokines alone. This signature suggests that activation of the TNFα-NFκB inflammatory pathway plays a key role in RP which could be specifically ameliorated by etanercept rather than current therapy of non-specific leukotoxic corticosteroids.

The present study demonstrates how TOP3B is involved in resolving R-loops. We observed elevated R-loops in TOP3B knockout cells (TOP3BKO), which are suppressed by TOP3B transfection. R-loop-inducing agents, the topoisomerase I inhibitor camptothecin, and the splicing inhibitor pladienolide-B also induce higher R-loops in TOP3BKO cells. Camptothecin- and pladienolide-B-induced R-loops are concurrent with the induction of TOP3B cleavage complexes (TOP3Bccs). RNA/DNA hybrid IP-western blotting show that TOP3B is physically associated with R-loops. Biochemical assays using recombinant TOP3B and oligonucleotides mimicking R-loops show that TOP3B cleaves the single-stranded DNA displaced by the R-loop RNA-DNA duplex. IP-mass spectrometry and IP-western experiments reveal that TOP3B interacts with the R-loop helicase DDX5 independently of TDRD3. Finally, we demonstrate that DDX5 and TOP3B are epistatic in resolving R-loops in a pathway parallel with senataxin. We propose a decatenation model for R-loop resolution by TOP3B-DDX5 protecting cells from R-loop-induced damage.

Purpose/Objective(s) Head and neck cancer (HNC) RT typically results in high doses to organs-at-risk (OARs), contributing to decreased quality-of-life (QOL) seen in patient reported outcomes (PRO). Current RT planning methods are driven by singular dosimetric trade-offs that may be inconsistent with improving a patient's overall predicted total toxicity burden (TTB). We developed an aggregate toxicity assessment over time including PROs that represents a paradigm shift over informal summary of individual toxicity. Here we introduce a treatment planning approach to directly optimize and reduce the predicted TTB-PRO of a patient's RT plan. Materials/Methods We implemented a prioritized approach to TTB optimization using an in-house optimization plugin linked to a commercial treatment planning system. Prioritized TTB (P-TTB) plans were optimized using a two-stage hierarchal method for inverse IMRT planning. In the first stage, TTB, defined as the weighted-sum of NTCPs, is minimized subject to high-priority OAR dose limits, target prescription, and target coverage requirements. Weights for the toxicities directly represent the relative undesirability of toxicities. In the second stage, a weighted-sum dose-metric objective is minimized, similar to current clinical practice. This stage is subject to the same constraints as the first stage, but an additional constraint for TTB is incorporated based on the optimal solution of the first stage. Using this approach, we retrospectively generated plans for 5 HNC patients and compared the resulting plans to IMRT plans generated without the added TTB constraint. Both plans consisted of 9 equally spaced beams with the same OAR dose limits and dose-metric objective. Target dose requirements were based on simultaneous integrated boost prescriptions of 70 and 56 Gy delivered in 35 fractions. TTB was calculated using previously published NTCP models for dysphagia and xerostomia. Dysphagia was based on increase in aspiration or HNQOL score > 81 as a function of pharyngeal constrictor (PC) mean dose. Xerostomia was based on parotid flow ratio 73 as a function of parotid gland (PG) mean dose. Results Our optimization engine successfully generated P-TTB plans for all five patients while maintaining similar target coverage to the standard dosimetrically optimized plans. P-TTB plans resulted in average absolute NTCP reductions of 15.5% (range: 0.2 - 53.4) for dysphagia and 20.5% (1.9 - 68.5) for xerostomia. These changes correlate to average mean dose decreases of 6.9 Gy (0.2 - 22.7) for PC and 10.2 Gy (1.2 - 33.5) for PGs. P-TTB planning resulted in greater fluence modulation and higher doses to OARs not included in the calculation of TTB. Conclusion The P-TTB planning method offers an intuitive optimization approach to balancing trade-offs between various treatment outcomes and has the ability to directly reduce and redistribute predicted toxicity which may aid in improving QOL for HNC patients receiving RT.

SUMMARYGenetic inactivation of TOP3B is linked with schizophrenia, autism, intellectual disability and cancer. The present study demonstrates that in vivo TOP3B forms both RNA and DNA cleavage complexes (TOP3Bccs) and reveals a pathway for repairing TOP3Bccs. For detecting cellular TOP3Bccs, we engineered a “self-trapping” mutant of TOP3B (R338W TOP3B) and to determine how human cells repair TOP3Bccs, we depleted tyrosyl-DNA phosphodiesterases (TDP1 and TDP2). TDP2-deficient cells produced elevated TOP3Bccs both in DNA and RNA. Conversely, overexpression of TDP2 lowered cellular TOP3Bccs. Using recombinant human TDP2, we demonstrate that TDP2 cannot excise the native form of TOP3Bccs. Hypothesizing that TDP2 cannot access phosphotyrosyl linkage unless TOP3B is either proteolyzed or denatured, we found that cellular TOP3Bccs are ubiquitinated by the E3 Ubiquitin Ligase TRIM41 before undergoing proteasomal degradation and excision by TDP2.HIGHLIGHTSMethod for in vivo detection of TOP3B cleavage complexes (TOP3Bccs) formed both in DNA and RNA, using a religation defective “self-trapping” R338W TOP3B mutant.First evidence that TDP2 excises TOPccs produced by a type IA topoisomerase.TDP2 processes both RNA and DNA TOP3Bccs following their ubiquitylation and proteasomal degradation inside cell.TRIM41 is the first reported E3 ubiquitin ligase for TOP3Bcc ubiquitylation and proteasomal degradation.

APC/C is a well characterized E3 ligase that couples with UBE2C and UBE2S E2s for ubiquitylation of the targeted substrates via the K11 linkage. Our recent data showed that SAG/RBX2/ROC2, a RING component of Cullin-RING E3 ligase (CRL), also complexes with these two E2s (UBE2C/2S) for K11-linked substrate polyubiquitylation. Whether these two E3s cross-talk with each other and the associated biological consequence are previously unknown. Here we report that these two E3s inhibit each other during cell cycle progression, which could lead to drug resistance. Specifically, SAG competes with APC2 for UBE2C/UBE2S binding to act as an endogenous inhibitor of APC/C, thereby regulating the G2/M progression. SAG inactivation triggers premature activation of APC/C, leading to mitotic slippage, as well as the resistance of cancer cells to anti-microtubule drugs both in vitro and in vivo models. On the other hand, SAG itself is a substrate of APC/CCDH1 for targeted degradation at the G1 phase. The degradation-resistant mutant of SAG-R82A/L85A accelerates the G1 to S progression, thereby promoting proliferation/survival of lung cancer cells. Our study reveals that the negative crosstalk between SAG and APC/C is likely a mechanism to ensure the fidelity of cell cycle progression, and manipulations to abrogate this fine balance would lead to enhanced proliferation and drug resistance.

The coke in the coils has a serious impact on the long-term and stable operation of the ethylene plant. Inhibiting coking of the cracking furnace is an important issue. In this paper, the Cr/CeO2 coatings were prepared on the surface of 310S stainless steel by high-velocity oxygen-fuel (HVOF) spraying. The anti-coking performances of the bare 310S specimen and the Cr/CeO2 coatings were tested by using the pyrolysis of naphtha. The results show that the coating with the thickness of 10–15 μm and a very small number of pores was built up by the obviously deformed splats and the coating/substrate interface is jagged bond. The white area on the surface of Cr/CeO2 coatings mainly includes CeO2. However, the gray area is made of Cr or Cr2O3. Compared with the bare 310S specimen, the coking inhibition rates of coatings are 48.7%, 58.9%, 76.1% and 88.9% when the ratio of Cr and CeO2 powder is 19:1, 9:1, 4:1 and 3:2, respectively. With increasing the relative ratio of CeO2, more white areas without coke are exposed. The CeO2 surface can not only inhibit catalytic coking, but also promote the reaction of water vapor and coke.

SARS-CoV-2 infection causes diverse outcomes ranging from asymptomatic infection to respiratory distress and death. A major unresolved question is whether prior immunity to endemic, human common cold coronaviruses (hCCCoV) impacts susceptibility to SARS-CoV-2 infection or immunity following infection and vaccination. Therefore, we analyzed samples from the same individuals before and after SARS-CoV-2 infection or vaccination. We found hCCCoV antibody levels increase after SARS-CoV-2 exposure, demonstrating cross-reactivity. However, a case-control study indicates baseline hCCCoV antibody levels are not associated with protection against SARS-CoV-2 infection. Rather, higher magnitudes of pre-existing betacoronavirus antibodies correlate with more SARS-CoV-2 antibodies following infection, an indicator of greater disease severity. Additionally, immunization with hCCCoV spike proteins before SARS-CoV-2 immunization impedes generation of SARS-CoV-2 neutralizing antibodies in mice. Together, these data suggest pre-existing hCCCoV antibodies hinder SARS-CoV-2 antibody-based immunity following infection and provide insight on how pre-existing coronavirus immunity impacts SARS-CoV-2 infection, which is critical considering emerging variants., Graphical Abstract, A major unresolved question is whether prior immunity to endemic, human common cold coronaviruses (hCCCoV) impacts susceptibility to SARS-CoV-2 infection. Lin et al. analyze hCCCoV antibodies in the same individuals before and after SARS-CoV-2 infection, finding pre-existing betacoronavirus antibodies may hinder SARS-CoV-2 effective immunity following infection.

Commissioning a new treatment planning system (TPS) involves many time-consuming tasks. We investigated the role that knowledge-based planning (KBP) can play in aiding a clinic's transition to a new TPS. Sixty clinically treated prostate/prostate bed intensity-modulated radiation therapy (IMRT) plans were exported from an in-house TPS and were used to create a KBP model in a newly implemented commercial application. To determine the benefit that KBP may have in a TPS transition, the model was tested on 2 groups of patients. Group 1 consisted of the first 10 prostate/prostate bed patients treated in the commercial TPS after the transition from the in-house TPS. Group 2 consisted of 10 patients planned in the commercial TPS after 8 months of clinical use. The KBP-generated plan was compared with the clinically used plan in terms of plan quality (ability to meet planning objectives and overall dose metrics) and planning efficiency (time required to generate clinically acceptable plans). The KBP-generated plans provided a significantly improved target coverage (p = 0.01) compared with the clinically used plans for Group 1, but yielded plans of comparable target coverage to the clinically used plans for Group 2. For the organs at risk, the KBP-generated plans produced lower doses, on average, for every normal-tissue objective except for the maximum dose to 0.1 cc of rectum. The time needed for the KBP-generated plans ranged from 6 to 15 minutes compared to 30 to 150 and 15 to 60 minutes for manual planning in Groups 1 and 2, respectively. KBP is a promising tool to aid in the transition to a new TPS. Our study indicates that high-quality treatment plans could have been generated in the newly implemented TPS more efficiently compared with not using KBP. Even after 8 months of the clinical use, KBP still showed an increase in plan quality and planning efficiency compared with manual planning.

PURPOSE/OBJECTIVE(S) To compare acute toxicity and quality of life (QOL) outcomes up to 3 months post chemoradiotherapy (CRT) versus CRT with nivolumab (iCRT) in locally advanced p16+ oropharyngeal cancer (OPC). MATERIALS/METHODS Matched cohorts with AJCC 8 stage III p16+ OPC patients treated at a single institution on two prospective protocols were compared: 1) CRT (Carboplatin + Paclitaxel) to 70 Gy with concurrent and 3 months of adjuvant nivolumab (iCRT) 2) CRT (Carboplatin or Cisplatin) to 70-80 Gy. 30 CRT patients were matched 2:1 to 15 iCRT patients according to primary site and tumor volume. In both groups, we compared the following clinical variables during and within 3 months of RT: physician graded mucositis, ED visits/hospitalizations, treatment interruptions, opioids requirements, and need for IV hydration or feeding tube (FT). The iCRT patients reported weekly Common Terminology Criteria for Adverse Events (CTCAE) during RT. Videofluoroscopy (VFSS) and validated QOL patient reported outcomes (PROs) were completed at baseline and 3 months. PROs were scored for minimal clinically important difference (MCID) changes. Student t-tests and chi-square were used to compare groups. RESULTS Clinical characteristics were balanced in mean age (P = 0.065), tumor volume (P = .74), base of tongue vs tonsil site (P = .88). Current smoking and pack year history were higher in the CRT patients (P = 0.003). iCRT patients had significantly higher rates of grade 3+ mucositis (87 vs 17%, P < 0.001), persistent opioid use at 3mo post-RT (69 vs 17%, P = 0.002), and missed chemotherapy doses (47 vs 13%, P = 0.04). No patient had any RT interruption. Non-significantly increased endpoints in iCRT patients included ED visits (53 vs 23%, P = 0.09), hospitalizations (40 vs 20%, P = .28), FT use (53 vs 33%, P = .33) and need for IV hydration during therapy (80% vs 47%, P = 0.07). From the 10 iCRT and 30 CRT patients who had complete PROs, iCRT patients reported significant MCID changes at 3 months in global QOL (80% vs 20%, P = 0.002), pain (90 vs 40%, P = 0.02) and sticky saliva (100% vs 57, P = 0.03), while changes in taste (90% vs 60%, P = .17) and swallow function (90% vs 50%, P = 0.06) were non-significantly worse in iCRT patients. In addition, from the 8 iCRT and 27 CRT who had complete VFSS scored by SLP at the time of this interim evaluation, there were increased aspiration events in the iCRT from baseline to 3 months (63 vs 44%, P = 0.06). Finally, weekly PROs during RT in iCRT patients revealed severe taste changes (78%), severe mouth sores (54%), and severe dry mouth (62%) by week 3. CONCLUSION Despite increased smoking history and RT boost, CRT patients exhibited fewer acute toxicities compared to iCRT patients. iCRT patients reported severe taste changes, mucositis, and xerostomia early in treatment. As many trials are currently ongoing to establish the oncologic benefit of concurrent immunotherapy, attention must be paid to acute and late toxicities as well as their impact on QOL in order to define their therapeutic utility.

Purpose/Objective(s) Standard clinicopathologic variables including T-category, Gleason grade, and prostate-specific antigen (PSA) guide the management of localized prostate cancer. The prognostic and predictive performance of these variables has been assessed primarily in retrospective cohorts without standardized quality assurance. Given the substantial heterogeneity in oncologic outcomes for men with localized prostate cancer, we hypothesized that standard clinicopathologic variables have inherent limitations. We therefore sought to assess their performance in a meta-analysis of 10 phase III randomized trials. Materials/Methods Individual patient data was obtained from 10 radiotherapy-related RCTs (NRG/RTOG 9202, 9408, 9413, 9910, 0126; EORTC 22863, 22961, 22991; DART 01/05 GICOR, and Ottawa 0101). The cohort was split 2:1 into training and validation cohorts. In the training set, multivariable cox regression and random forest models were developed. Concordance indices (c-indices) and bootstrapped 95% confidence intervals were calculated for models based on age, performance status, T-category, Gleason score, and PSA. Interactions with androgen deprivation therapy (ADT) treatment effects were also tested. Endpoints included distant metastasis (DM), metastasis-free survival (MFS), and overall survival (OS). Results A total of 10,535 patients were included. The training cohort (n = 7382) was used to develop an optimized clinicopathologic model. Using the locked-model in the validation cohort (n = 3153), the 10-year c-index was 0.70 (95% CI: 0.66-0.74), 0.61 (0.59-0.63), and 0.61 (0.59 – 0.63), for 10-year DM, MFS, and OS, respectively. Similar results were obtained using random forest models. In trials testing the addition of short-term (ST) ADT, or those testing the addition of long-term (LT) ADT, there was no evidence of treatment effect modification by any variable for any endpoint (all P-interaction > 0.05). There was, however, significant heterogeneity in the absolute benefit derived from ADT intensification; the empirical 10-year absolute DM risk reduction with LT ADT over ST ADT ranged from 4.1% to 18.0% depending on modelled baseline risk. Conclusion In this large cohort with long-term follow-up and trial-level quality assurance, models based on standard clinicopathologic variables had limitations in accurately estimating prognosis. The proportional benefit of ADT use was consistent, but the absolute magnitude of benefit varied greatly by predicted baseline risk of DM. Incorporation of genomic prognostic information into risk stratification to better estimate absolute ADT benefit are needed and ongoing (NCT04513717).

Purpose Planning for spine stereotactic body radiation therapy (SBRT) is time consuming, and differences in planner experience and technique result in discrepancies in plan quality between facilities. Here, knowledge-based planning is analyzed to determine if it may be effective in improving the quality and efficiency of spine SBRT planning. Materials and methods Thirty-eight spine SBRT cases were collected from the University of Michigan database and inverse planned to deliver 3 10-Gy fractions to the planning target volume (PTV). These plans were used to train a knowledge-based model (model A) using RapidPlan (Varian Medical Systems). The model was evaluated for outliers and validated in 10 independent cases. Each of these cases was manually planned to compare the quality of the model-generated plans with the manual plans. To further test the robustness of the software, 2 additional models (models B and C) were created with intentional outliers resulting from inconsistent contouring. Results Using models A, B, and C, all 10 generated plans met all dose objectives for modeled organs at risk (OARs) (spinal cord, cord planning risk volume, and esophagus) without user intervention. The target coverage and OAR dose sparing was improved or equivalent to manual planning by an expert dosimetrist; however, manually created plans typically required 1 to 1.5 hours to produce and model-generated plans required only 10 to 15 minutes with minimal human intervention to meet all dose objectives. Conclusions The clinical quality of plans produced by RapidPlan were found to improve on or be similar to the manually created plans in terms of normal tissue objectives and PTV dose coverage and could be produced in a fraction of the time. RapidPlan is a robust technique that can improve planning efficiency in spine SBRT while maintaining or potentially improving plan quality and standardization across planners and centers.

Retinol binding protein and vitamin D were measured in children aged

Purpose Dose to normal lung has commonly been linked with radiation-induced lung toxicity (RILT) risk, but incorporating functional lung metrics in treatment planning may help further optimize dose delivery and reduce RILT incidence. The purpose of this study was to investigate the impact of the dose delivered to functional lung regions by analyzing perfusion (Q), ventilation (V), and combined V/Q single-photon-emission computed tomography (SPECT) dose-function metrics with regard to RILT risk in patients with non-small cell lung cancer (NSCLC) patients who received radiation therapy (RT). Methods and Materials SPECT images acquired from 88 patients with locally advanced NSCLC before undergoing conventionally fractionated RT were retrospectively analyzed. Dose was converted to the nominal dose equivalent per 2 Gy fraction, and SPECT intensities were normalized. Regional lung segments were defined, and the average dose delivered to each lung region was quantified. Three functional categorizations were defined to represent low-, normal-, and high-functioning lungs. The percent of functional lung category receiving ≥20 Gy and mean functional intensity receiving ≥20 Gy (iV20) were calculated. RILT was defined as grade 2+ radiation pneumonitis and/or clinical radiation fibrosis. A logistic regression was used to evaluate the association between dose-function metrics and risk of RILT. Results By analyzing V/Q normalized intensities and functional distributions across the population, a wide range in functional capability (especially in the ipsilateral lung) was observed in patients with NSCLC before RT. Through multivariable regression models, global lung average dose to the lower lung was found to be significantly associated with RILT, and Q and V iV20 were correlated with RILT when using ipsilateral lung metrics. Through a receiver operating characteristic analysis, combined V/Q low-function receiving ≥20 Gy (low-functioning V/Q20) in the ipsilateral lung was found to be the best predictor (area under the curce: 0.79) of RILT risk. Conclusions Irradiation of the inferior lung appears to be a locational sensitivity for RILT risk. The multivariable correlation between ipsilateral lung iV20 and RILT, as well as the association of low-functioning V/Q20 and RILT, suggest that irradiating low-functioning regions in the lung may lead to higher toxicity rates.

Small cell neuroendocrine cancers (SCNCs) are recalcitrant cancers arising from diverse primary sites that lack effective treatments. Using chemical genetic screens, we identified inhibition of ataxia telangiectasia and rad3 related (ATR), the primary activator of the replication stress response, and topoisomerase I (TOP1), nuclear enzyme that suppresses genomic instability, as synergistically cytotoxic in small cell lung cancer (SCLC). In a proof-of-concept study, we combined M6620 (berzosertib), first-in-class ATR inhibitor, and TOP1 inhibitor topotecan in patients with relapsed SCNCs. Objective response rate among patients with SCLC was 36% (9/25), achieving the primary efficacy endpoint. Durable tumor regressions were observed in patients with platinum-resistant SCNCs, typically fatal within weeks of recurrence. SCNCs with high neuroendocrine differentiation, characterized by enhanced replication stress, were more likely to respond. These findings highlight replication stress as a potentially transformative vulnerability of SCNCs, paving the way for rational patient selection in these cancers, now treated as a single disease.

Background Optimal management of oral cancer relies upon accurate and individualized risk prediction of relevant clinical outcomes. Individualized prognostic calculators have been developed to guide patient–physician communication and treatment-related decision-making. However it is critical to scrutinize their accuracy prior to integrating into clinical care. Aim To compare and evaluate oral cavity cancer prognostic calculators using an independent dataset. Methods Five prognostic calculators incorporating patient and tumor characteristics were identified that evaluated five-year overall survival. A total of 505 patients with previously untreated oral cancer diagnosed between 2003 and 2014 were analyzed. Calculators were applied to each patient to generate individual predicted survival probabilities. Predictions were compared among prognostic tools and with observed outcomes using Kaplan-Meier plots, ROC curves and calibration plots. Results Correlation between the five calculators varied from 0.59 to 0.86. There were considerable differences between individual predictions from pairs of calculators, with as many as 64% of patients having predictions that differed by more than 10%. Four of five calculators were well calibrated. For all calculators the predictions were associated with survival outcomes. The area under the ROC curve ranged from 0.65 to 0.71, with C-indices ranging from 0.63 to 0.67. An average of the 5 predictions had slightly better performance than any individual calculator. Conclusion Five prognostic calculators designed to predict individual outcomes of oral cancer differed significantly in their assessments of risk. Most were well calibrated and had modest discriminatory ability. Given the increasing importance of individualized risk prediction, more robust models are needed.

Background Approaches to improve the immune response of immunocompromised patients to influenza vaccination are needed. Methods Children and young adults (3–21 years) with cancer or HIV infection were randomized to receive 2 doses of high-dose (HD) trivalent influenza vaccine (TIV) or of standard-dose (SD) TIV. Hemagglutination inhibition (HAI) antibody titers were measured against H1, H3, and B antigens after each dose and 9 months later. Seroconversion was defined as ≥4-fold rise in HAI titer comparing pre- and post-vaccine sera. Seroprotection was defined as a post-vaccine HAI titer ≥1:40. Reactogenicity events (RE) were solicited using a structured questionnaire 7 and 14 days after each dose of vaccine, and adverse events by medical record review for 21 days after each dose of vaccine. Results Eighty-five participants were enrolled in the study; 27 with leukemia, 17 with solid tumor (ST), and 41 with HIV. Recipients of HD TIV had significantly greater fold increase in HAI titers to B antigen in leukemia group and to H1 antigen in ST group compared to SD TIV recipients. This increase was not documented in HIV group. There were no differences in seroconversion or seroprotection between HD TIV and SD TIV in all groups. There was no difference in the percentage of solicited RE in recipients of HD TIV (54% after dose 1 and 38% after dose 2) compared to SD TIV (40% after dose 1 and 20% after dose 2, p = 0.27 and 0.09 after dose 1 and 2, respectively). Conclusion HD TIV was more immunogenic than SD TIV in children and young adults with leukemia or ST, but not with HIV. HD TIV was safe and well-tolerated in children and young adults with leukemia, ST, or HIV.

Microbial fuel cell (MFC) technology is widely used to remediate heavy metal pollution of soil, and the applicability of soils with different physical and chemical properties under micro-electric field has not been studied. In this study, copper was effectively removed in four typical soil-filled MFCs. The removal efficiencies of copper from closed-circuit MFCs filled with paddy, red, black and alluvial soils were 2.9, 1.50, 3.48 and 3.40 times higher than those in the open-circuit control group, respectively. However, the contributions of electromigration and diffusion mechanisms were different under different soil types. The greatest copper removal (19.3 ± 0.8%) was achieved based on electromigration of the electric field inside the paddy soil MFC in 63 days, while the greatest copper removal (25 ± 2%) was achieved under the action of diffusion mechanism inside the red soil MFC. According to redundancy analysis, the removal of copper by electromigration was positively correlated with electricity generation performance and acid extractable Cu content, whereas copper removal based on diffusion was positively related to soil pore volume and acid extractable Cu content. The cation exchange capacity and total organic carbon of soil were negatively correlated with the acid extractable Cu content, and electrical conductivity of soil was positively correlated with the MFC electricity generation performance. Furthermore, the directional movement of protons under an electric field alleviated the issue of soil acidification caused by citric acid.

SUMMARY Anaphase-promoting complex/cyclosome (APC/C) is a well-characterized E3 ligase that couples with UBE2C and UBE2S E2s for substrate ubiquitylation by the K11 linkage. Our recent data show that SAG/RBX2/ROC2, a RING component of Cullin-RING E3 ligase, also complexes with these E2s for K11-linked substrate polyubiquitylation. Whether these two E3s cross-talk with each other was previously unknown. Here, we report that SAG competes with APC2 for UBE2C/UBE2S binding to act as a potential endogenous inhibitor of APC/C, thereby regulating the G2-to-M progression. As such, SAG knockdown triggers premature activation of APC/C, leading to mitotic slippage and resistance to anti-microtubule drugs. On the other hand, SAG itself is a substrate of APC/CCDH1 for targeted degradation at the G1 phase. The degradation-resistant mutant of SAG-R98A/L101A accelerates the G1-to-S progression. Our study reveals that the negative cross-talk between SAG and APC/C is likely a mechanism to ensure the fidelity of cell cycle progression., Graphical Abstract, In Brief Zhang et al. provide a mechanistic insight of how negative cross-talk between E3 ligases SAG and APC/C ensures proper cell cycle progression. SAG knockdown prematurely activates APC/C to promote mitotic progression and trigger anti-microtubule drugs resistance, whereas SAG degradation by APC/CCDH1 mainly occurs in G1 phase for proper G1-to-S transition.

Topoisomerases are essential enzymes solving DNA topological problems such as supercoils, knots and catenanes that arise from replication, transcription, chromatin remodeling and other nucleic acid metabolic processes. They are also the targets of widely used anticancer drugs (e.g. topotecan, irinotecan, enhertu, etoposide, doxorubicin, mitoxantrone) and fluoroquinolone antibiotics (e.g. ciprofloxacin and levofloxacin). Topoisomerases manipulate DNA topology by cleaving one DNA strand (TOP1 and TOP3 enzymes) or both in concert (TOP2 enzymes) through the formation of transient enzyme-DNA cleavage complexes (TOPcc) with phosphotyrosyl linkages between DNA ends and the catalytic tyrosyl residue of the enzymes. Failure in the self-resealing of TOPcc results in persistent TOPcc (which we refer it to as topoisomerase DNA-protein crosslinks (TOP-DPC)) that threaten genome integrity and lead to cancers and neurodegenerative diseases. The cell prevents the accumulation of topoisomerase-mediated DNA damage by excising TOP-DPC and ligating the associated breaks using multiple pathways conserved in eukaryotes. Tyrosyl-DNA phosphodiesterases (TDP1 and TDP2) cleave the tyrosyl-DNA bonds whereas structure-specific endonucleases such as Mre11 and XPF (Rad1) incise the DNA phosphodiester backbone to remove the TOP-DPC along with the adjacent DNA segment. The proteasome and metalloproteases of the WSS1/Spartan family typify proteolytic repair pathways that debulk TOP-DPC to make the peptide-DNA bonds accessible to the TDPs and endonucleases. The purpose of this review is to summarize our current understanding of how the cell excises TOP-DPC and why, when and where the cell recruits one specific mechanism for repairing topoisomerase-mediated DNA damage, acquiring resistance to therapeutic topoisomerase inhibitors and avoiding genomic instability, cancers and neurodegenerative diseases.