Implementation and Efficacy of a Large-Scale Radiation Oncology Case-Based Peer-Review Quality Program across a Multinational Cancer Network.

PURPOSE: With expansion of academic cancer center networks across geographically-dispersed sites, ensuring high-quality delivery of care across all network affiliates is essential. We report on the characteristics and efficacy of a radiation oncology peer-review quality assurance (QA) system implemented across a large-scale multinational cancer network. METHODS AND MATERIALS: Since 2014, weekly case-based peer-review QA meetings have been standard for network radiation oncologists with radiation oncology faculty at a major academic center. This radiotherapy (RT) QA program involves pre-treatment peer-review of cases by disease site, with disease-site subspecialized main campus faculty members. This virtual QA platform involves direct review of the proposed RT plan as well as supporting data, including relevant pathology and imaging studies for each patient. Network RT plans were scored as being concordant or nonconcordant based on national guidelines, institutional recommendations, and/or expert judgment when considering individual patient-specific factors for a given case. Data from January 1, 2014, through December 31, 2019, were aggregated for analysis. RESULTS: Between 2014 and 2019, across 8 network centers, a total of 16,601 RT plans underwent peer-review. The network-based peer-review case volume increased over the study period, from 958 cases in 2014 to 4,487 in 2019. A combined global nonconcordance rate of 4.5% was noted, with the highest nonconcordance rates among head-and-neck cases (11.0%). For centers that joined the network during the study period, we observed a significant decrease in the nonconcordance rate over time (3.1% average annual decrease in nonconcordance, P = 0.01); among centers that joined the network prior to the study period, nonconcordance rates remained stable over time. CONCLUSIONS: Through a standardized QA platform, network-based multinational peer-review of RT plans can be achieved. Improved concordance rates among newly added network affiliates over time are noted, suggesting a positive impact of network membership on the quality of delivered cancer care.

Long-Term Results of NRG Oncology RTOG 0617: Standard- Versus High-Dose Chemoradiotherapy With or Without Cetuximab for Unresectable Stage III Non-Small-Cell Lung Cancer.

PURPOSE: RTOG 0617 compared standard-dose (SD; 60 Gy) versus high-dose (HD; 74 Gy) radiation with concurrent chemotherapy and determined the efficacy of cetuximab for stage III non-small-cell lung cancer (NSCLC). METHODS: The study used a 2 × 2 factorial design with radiation dose as 1 factor and cetuximab as the other, with a primary end point of overall survival (OS). RESULTS: Median follow-up was 5.1 years. There were 3 grade 5 adverse events (AEs) in the SD arm and 9 in the HD arm. Treatment-related grade ≥3 dysphagia and esophagitis occurred in 3.2% and 5.0% of patients in the SD arm v 12.1% and 17.4% in the HD arm, respectively (P = .0005 and < .0001). There was no difference in pulmonary toxicity, with grade ≥3 AEs in 20.6% and 19.3%. Median OS was 28.7 v 20.3 months (P = .0072) in the SD and HD arms, respectively, 5-year OS and progression-free survival (PFS) rates were 32.1% and 23% and 18.3% and 13% (P = .055), respectively. Factors associated with improved OS on multivariable analysis were standard radiation dose, tumor location, institution accrual volume, esophagitis/dysphagia, planning target volume and heart V5. The use of cetuximab conferred no survival benefit at the expense of increased toxicity. The prior signal of benefit in patients with higher H scores was no longer apparent. The progression rate within 1 month of treatment completion in the SD arm was 4.6%. For comparison purposes, the resultant 2-year OS and PFS rates allowing for that dropout rate were 59.6% and 30.7%, respectively, in the SD arms. CONCLUSION: A 60-Gy radiation dose with concurrent chemotherapy should remain the standard of care, with the OS rate being among the highest reported in the literature for stage III NSCLC. Cetuximab had no effect on OS. The 2-year OS rates in the control arm are similar to the PACIFIC trial.

Mid-radiotherapy PET/CT for prognostication and detection of early progression in patients with stage III non-small cell lung cancer.

BACKGROUND AND PURPOSE: Pre- and mid-radiotherapy FDG-PET metrics have been proposed as biomarkers of recurrence and survival in patients treated for stage III non-small cell lung cancer. We evaluated these metrics in patients treated with definitive radiation therapy (RT). We also evaluated outcomes after progression on mid-radiotherapy PET/CT. MATERIAL AND METHODS: Seventy-seven patients treated with RT with or without chemotherapy were included in this retrospective study. Primary tumor and involved nodes were delineated. PET metrics included metabolic tumor volume (MTV), total lesion glycolysis (TLG), and SUVmax. For mid-radiotherapy PET, both absolute value of these metrics and percentage decrease were analyzed. The influence of PET metrics on time to death, local recurrence, and regional/distant recurrence was assessed using Cox regression. RESULTS: 91% of patients had concurrent chemotherapy. Median follow-up was 14months. None of the PET metrics were associated with overall survival. Several were positively associated with local recurrence: pre-radiotherapy MTV, and mid-radiotherapy MTV and TLG (p=0.03-0.05). Ratio of mid- to pre-treatment SUVmax was associated with regional/distant recurrence (p=0.02). 5/77 mid-radiotherapy scans showed early out-of-field progression. All of these patients died. CONCLUSIONS: Several PET metrics were associated with risk of recurrence. Progression on mid-radiotherapy PET/CT was a poor prognostic factor.

Impacts of regional transport on black carbon in Huairou, Beijing, China.

The 22nd Asia-Pacific Economic Cooperation (APEC) Conference was held near Yanqi Lake, Huairou, in Beijing, China during November 10-11, 2014. To guarantee haze-free days during the APEC Conference, the Beijing government and the governments of the surrounding provinces implemented a series of controls. Three months of Aethalometer 880 nm black carbon (BC) measurements were examined to understand the hourly fluctuations in BC concentrations that resulted from emission controls and meteorology changes. Measurements were collected at the University of Chinese Academy of Sciences near the APEC Conference site and in Central Beijing at the Institute of Remote Sensing and Digital Earth of the Chinese Academy of Sciences. Synoptic conditions are successfully represented through analysis of backward trajectories in six cluster groups. The clusters are identified based on air mass transport from various areas such as Inner Mongolia, Russia, three northeastern provinces, and Hebei industrial areas, to the measurement sites. Air pollution control measures during the APEC Conference significantly reduced BC at the conference site (Huairou) and in Central Beijing, with greater reductions in BC concentrations at the conference site than in Central Beijing. The highest BC concentrations in Huairou were associated with air masses originating from Central Beijing rather than from the Hebei industrial region. The success of the control measures implemented in Beijing and the surrounding regions demonstrates that BC concentrations can be effectively reduced to protect human health and mitigate regional climate forcing. This study also demonstrates the need for regional strategies to reduce BC concentrations, since urban areas like Beijing are sources as well as downwind receptors of emissions.

Temporal variations of black carbon during haze and non-haze days in Beijing.

Black carbon (BC) aerosol has been identified as one of key factors responsible for air quality in Beijing. BC emissions abatement could help slow regional climate change while providing benefits for public health. In order to quantify its variations and contribution to air pollution, we systematically studied real-time measurements of equivalent black carbon (eBC) in PM2.5 aerosols at an urban site in Beijing from 2010 to 2014. Equivalent black carbon (eBC) is used instead of black carbon (BC) for data derived from Aethalometer-31 measurement. Equivalent BC concentrations showed significant temporal variations with seasonal mean concentration varying between 2.13 and 5.97 µg m(-3). The highest concentrations of eBC were found during autumn and winter, and the lowest concentrations occurred in spring. We assessed the temporal variations of eBC concentration during haze days versus non-haze days and found significantly lower eBC fractions in PM2.5 on haze days compared to those on non-haze days. Finally, we observed a clear inverse relationship between eBC and wind speed. Our results show that wind disperses PM2.5 more efficiently than eBC; so, secondary aerosols are not formed to the same degree as primary aerosols over the same transport distance during windy conditions.

Atmospheric impacts of black carbon emission reductions through the strategic use of biodiesel in California.

The use of biodiesel as a replacement for petroleum-based diesel fuel has gained interest as a strategy for greenhouse gas emission reductions, energy security, and economic advantage. Biodiesel adoption may also reduce particulate elemental carbon (EC) emissions from conventional diesel engines that are not equipped with after-treatment devices. This study examines the impact of biodiesel blends on EC emissions from a commercial off-road diesel engine and simulates the potential public health benefits and climate benefits. EC emissions from the commercial off-road engine decreased by 76% when ultra-low sulfur commercial diesel (ULSD) fuel was replaced by biodiesel. Model calculations predict that reduced EC emissions translate directly into reduced EC concentrations in the atmosphere, but the concentration of secondary particulate matter was not directly affected by this fuel change. Redistribution of secondary particulate matter components to particles emitted from other sources did change the size distribution and therefore deposition rates of those components. Modification of meteorological variables such as water content and temperature influenced secondary particulate matter formation. Simulations with a source-oriented WRF/Chem model (SOWC) for a severe air pollution episode in California that adopted 75% biodiesel blended with ULSD in all non-road diesel engines reduced surface EC concentrations by up to 50% but changed nitrate and total PM2.5 mass concentrations by less than ±5%. These changes in concentrations will have public health benefits but did not significantly affect radiative forcing at the top of the atmosphere. The removal of EC due to the adoption of biodiesel produced larger coatings of secondary particulate matter on other atmospheric particles containing residual EC leading to enhanced absorption associated with those particles. The net effect was a minor change in atmospheric optical properties despite a large change in atmospheric EC concentrations. These results emphasize the importance of considering EC mixing state in climate research.

The effects of emission control strategies on light-absorbing carbon emissions from a modern heavy-duty diesel engine.

UNLABELLED: Control of atmospheric black carbon (BC) and brown carbon (BrC) has been proposed as an important pathway to climate change mitigation, but sources of BC and BrC are still not well understood. In order to better identify the role of modern heavy-duty diesel engines on the production of BC and BrC, emissions from a heavy-duty diesel engine operating with different emission control strategies were examined using a source dilution sampling system. The effect of a diesel oxidation catalyst (DOC) and diesel particulate filter (DPF) on light-absorbing carbon (LAC) was evaluated at three steady-state engine operation modes: idle, 50% speed and load, and 100% speed and load. LAC was measured with four different engine configurations: engine out, DOC out, DPF out, and engine out with an altered combustion calibration. BC and BrC emission rates were measured with the Aethalometer (AE-31). EC and BC emission rates normalized to the mass of CO2emitted increased with increasing engine speed and load. Emission rates normalized to brake-specific work did not exhibit similar trends with speed and load, but rather the highest emission rate was measured at idle. EC and OC emissions were reduced by 99% when the DOC and DPF architecture was applied. The application of a DPF was equally effective at removing 99% of the BC fraction of PM, proving to be an important control strategy for both LAC and PM. BC emissions were unexpectedly increased across the DOC, seemingly due to a change aerosol optical properties. Removal of exhaust gas recirculation (EGR) flow due to simulated EGR cooler failure caused a large increase in OC and BrC emission rates at idle, but had limited influence during high load operation. LAC emissions proved to be sensitive to the same control strategies effective at controlling the total mass of diesel PM. IMPLICATIONS: In the context of black carbon emissions, very small emission rates of brown carbon were measured over a range of control technologies and engine operating conditions. During specific idle engine operation without EGR and adjusted fueling conditions, brown carbon can be formed in significant amounts, requiring careful management tactics. Control technologies for particulate matter are very effective for light-absorbing carbon, reducing black carbon emissions to near zero for modern engines equipped with a DPF. Efforts to control atmospheric brown carbon need to focus on other sources other than modern diesel engines, such as biomass burning.

Treatment of pediatric hodgkin lymphoma.

OPINION STATEMENT: We are increasingly successful in the treatment of Hodgkin lymphoma. Current risk adapted trials seek to maintain the excellent efficacy of older therapies, while simultaneously limiting their late toxicities. Current management of early stage/favorable disease involves the use of two to four cycles of tailored chemotherapy, often followed by low-dose, involved field radiation. Those with intermediate and advanced stage disease require more intense chemotherapy and radiation regimens. Functional imaging using [(18)F]-2 fluoro-D-2-deoxyglucose is increasingly used to determine complete vs. partial response and to detect relapse. Given the success of primary therapy, retrieval of patients remains a highly individualized challenge. The majority of children failing combined-modality treatment undergo high-dose chemotherapy followed by autologous hematopoietic stem cell rescue, oftentimes with consolidative radiotherapy.

Mitochondrial localization of Reaper to promote inhibitors of apoptosis protein degradation conferred by GH3 domain-lipid interactions.

Morphological hallmarks of apoptosis result from activation of the caspase family of cysteine proteases, which are opposed by a pro-survival family of inhibitors of apoptosis proteins (IAPs). In Drosophila, disruption of IAP function by Reaper, HID, and Grim (RHG) proteins is sufficient to induce cell death. RHG proteins have been reported to localize to mitochondria, which, in the case of both Reaper and Grim proteins, is mediated by an amphipathic helical domain known as the GH3. Through direct binding, Reaper can bring the Drosophila IAP (DIAP1) to mitochondria, concomitantly promoting IAP auto-ubiquitination and destruction. Whether this localization is sufficient to induce DIAP1 auto-ubiquitination has not been reported. In this study we characterize the interaction between Reaper and the mitochondria using both Xenopus and Drosophila systems. We find that Reaper concentrates on the outer surface of mitochondria in a nonperipheral manner largely mediated by GH3-lipid interactions. Importantly, we show that mitochondrial targeting of DIAP1 alone is not sufficient for degradation and requires Reaper binding. Conversely, Reaper able to bind IAPs, but lacking a mitochondrial targeting GH3 domain (DeltaGH3 Reaper), can induce DIAP1 turnover only if DIAP1 is otherwise targeted to membranes. Surprisingly, targeting DIAP1 to the endoplasmic reticulum instead of mitochondria is partially effective in allowing DeltaGH3 Reaper to promote DIAP1 degradation, suggesting that co-localization of DIAP and Reaper at a membrane surface is critical for the induction of DIAP degradation. Collectively, these data provide a specific function for the GH3 domain in conferring protein-lipid interactions, demonstrate that both Reaper binding and mitochondrial localization are required for accelerated IAP degradation, and suggest that membrane localization per se contributes to DIAP1 auto-ubiquitination and degradation.

A GH3-like domain in reaper is required for mitochondrial localization and induction of IAP degradation.

Reaper is a potent pro-apoptotic protein originally identified in a screen for Drosophila mutants defective in apoptotic induction. Multiple functions have been ascribed to this protein, including inhibition of IAPs (inhibitors of apoptosis); induction of IAP degradation; inhibition of protein translation; and when expressed in vertebrate cells, induction of mitochondrial cytochrome c release. Structure/function analysis of Reaper has identified an extreme N-terminal motif that appears to be sufficient for inhibition of IAP function. We report here that this domain, although required for IAP destabilization, is not sufficient. Moreover, we have identified a small region of Reaper, similar to the GH3 domain of Grim, that is required for localization of Reaper to mitochondria, induction of IAP degradation, and potent cell killing. Although a mutant Reaper protein lacking the GH3 domain was deficient in these properties, these defects could be fully rectified by appending either the C-terminal mitochondrial targeting sequence from Bcl-xL or a homologous region from the pro-apoptotic protein HID. Together, these data strongly suggest that IAP destabilization by Reaper in intact cells requires Reaper localization to mitochondria and that induction of IAP instability by Reaper is important for the potent induction of apoptosis in Drosophila cells.

Reaper is regulated by IAP-mediated ubiquitination.

In most cases, apoptotic cell death culminates in the activation of the caspase family of cysteine proteases, leading to the orderly dismantling and elimination of the cell. The IAPs (inhibitors of apoptosis) comprise a family of proteins that oppose caspases and thus act to raise the apoptotic threshold. Disruption of IAP-mediated caspase inhibition has been shown to be an important activity for pro-apoptotic proteins in Drosophila (Reaper, HID, and Grim) and in mammalian cells (Smac/DIABLO and Omi/HtrA2). In addition, in the case of the fly, these proteins are able to stimulate the ubiquitination and degradation of IAPs by a mechanism involving the ubiquitin ligase activity of the IAP itself. In this report, we show that the Drosophila RHG proteins (Reaper, HID, and Grim) are themselves substrates for IAP-mediated ubiquitination. This ubiquitination of Reaper requires IAP ubiquitin-ligase activity and a stable interaction between Reaper and the IAP. Additionally, degradation of Reaper can be blocked by mutating its potential ubiquitination sites. Most importantly, we also show that regulation of Reaper by ubiquitination is a significant factor in determining its biological activity. These data demonstrate a novel function for IAPs and suggest that IAPs and Reaper-like proteins mutually control each other's abundance.

Drosophila Bruce can potently suppress Rpr- and Grim-dependent but not Hid-dependent cell death.

Bruce is a large protein (530 kDa) that contains an N-terminal baculovirus IAP repeat (BIR) and a C-terminal ubiquitin conjugation domain (E2). BRUCE upregulation occurs in some cancers and contributes to the resistance of these cells to DNA-damaging chemotherapeutic drugs. However, it is still unknown whether Bruce inhibits apoptosis directly or instead plays some other more indirect role in mediating chemoresistance, perhaps by promoting drug export, decreasing the efficacy of DNA damage-dependent cell death signaling, or by promoting DNA repair. Here, we demonstrate, using gain-of-function and deletion alleles, that Drosophila Bruce (dBruce) can potently inhibit cell death induced by the essential Drosophila cell death activators Reaper (Rpr) and Grim but not Head involution defective (Hid). The dBruce BIR domain is not sufficient for this activity, and the E2 domain is likely required. dBruce does not promote Rpr or Grim degradation directly, but its antiapoptotic actions do require that their N termini, required for interaction with DIAP1 BIR2, be intact. dBruce does not block the activity of the apical cell death caspase Dronc or the proapoptotic Bcl-2 family member Debcl/Drob-1/dBorg-1/Dbok. Together, these results argue that dBruce can regulate cell death at a novel point.

Reaper eliminates IAP proteins through stimulated IAP degradation and generalized translational inhibition.

Inhibitors of apoptosis (IAPs) inhibit caspases, thereby preventing proteolysis of apoptotic substrates. IAPs occlude the active sites of caspases to which they are bound and can function as ubiquitin ligases. IAPs are also reported to ubiquitinate themselves and caspases. Several proteins induce apoptosis, at least in part, by binding and inhibiting IAPs. Among these are the Drosophila melanogaster proteins Reaper (Rpr), Grim, and HID, and the mammalian proteins Smac/Diablo and Omi/HtrA2, all of which share a conserved amino-terminal IAP-binding motif. We report here that Rpr not only inhibits IAP function, but also greatly decreases IAP abundance. This decrease in IAP levels results from a combination of increased IAP degradation and a previously unrecognized ability of Rpr to repress total protein translation. Rpr-stimulated IAP degradation required both IAP ubiquitin ligase activity and an unblocked Rpr N terminus. In contrast, Rpr lacking a free N terminus still inhibited protein translation. As the abundance of short-lived proteins are severely affected after translational inhibition, the coordinated dampening of protein synthesis and the ubiquitin-mediated destruction of IAPs can effectively reduce IAP levels to lower the threshold for apoptosis.