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Pioneering technologies such as proteomics have helped fuel the biotechnology and pharmaceutical industry with the discovery of novel targets and an intricate understanding of the activity of therapeutics and their various activities in vitro and in vivo. The field of proteomics is undergoing an inflection point, where new sensitive technologies are allowing intricate biological pathways to be better understood, and novel biochemical tools are pivoting us into a new era of chemical proteomics and biomarker discovery. In this review, we describe these areas of innovation, and discuss where the fields are headed in terms of fueling biotechnological and pharmacological research and discuss current gaps in the proteomic technology landscape.Single cell sequencing and single molecule sequencing. Chemoproteomics. Biological matrices and clinical samples including biomarkers. Computational tools including instrument control software, data analysis.Proteomics will likely remain a key technology in the coming decade, but will have to evolve with respect to type and granularity of data, cost and throughput of data generation as well as integration with other technologies to fulfill its promise in drug discovery.

The NASA Double Asteroid Redirection Test (DART) is a technology demonstration mission to test the kinetic impactor technique on a binary near-Earth asteroid system, Didymos. Internal to the DART spacecraft is the Single Board Computer (SBC) card, - the main computing element of the spacecraft. The SBC contains the LEON3FT UT700 processor and the DART Single Board Computer FPGA. The DART SBC FPGA is a System on a Chip (SoC) design, supporting payload and bus-side functionality in a single chip. 10+ designers split into three teams worked on the FPGA: the avionics design team for the bus-side functionality, the image processing design team for the payload, and the FPGA System team for overseeing the FPGA top-level integration and verification. The DART SBC FPGA performs routing of the spacecraft communication and forwarding of timecodes, handles critical commands used to help recover the spacecraft, provides interrupts to the UT700 processor, provides boot management to the UT700, and provides a watchdog timer. The DART SBC FPGA is a key component of the spacecraft avionics and provides required functionality to flight software (FSW) running on the UT700. The DART SBC FPGA also receives image data from the instrument, performs image processing, transmits post-processed images back to Earth, and supports recording images to NAND Flash for later retrieval. More specifically, the FPGA consists of three key parts: SpaceWire modules for data communication and execution, support infrastructure for FSW, and onboard image processing. The FPGA contains the spacecraft's central Space Wire router with 9 SpaceWire ports that receives and transmits data traffic to their designated destinations. The FPGA also controls the boot loading of FSW and additionally provides FSW registers, a watchdog timer, general purpose timers, reads /writes to flash, reads/writes to MRAM, reads/writes to SRAM, GPIOs, test functions, and interrupts. The FPGA receives image data sent through a SERDES interface, performs image processing to support autonomous navigation, and finally sends the processed image out to the radio. The FPGA also executes ground-initiated commands independent of the FSW to support key configuration and critical recovery functions. The DART SBC FPGA was challenging to integrate and verify due to its complexity and large design. To guarantee the correctness of the SoC design, the team created new roles and a new methodology with multiple verification checks including an ©2021 IEEEautomated regression test in simulation. This paper describes 1) the requirements and architecture of the DART SBC FPGA design, 2) the design and verification methodology employed, 3) the challenges faced in designing the large and complex design on the Microsemi RTG4 FPGA, and 4) the results and lessons learned.

Since the beginning of space exploration, one of the most ambitious goals has been to explore beyond the boundaries of our solar system. Ground and Earth-orbit based systems have given a deep understanding of the overall characteristics of the heliosphere in the local interstellar medium and how the characteristics of our solar system are similar to and different from other systems. Viewing the heliosphere from outside will allow, for the first time, a more complete understanding of how a star system evolves and interacts with the Universe. Interstellar missions have been studied for decades. The primary reasons we have not yet explored this region are critical limitations in technology. These include a lack of propulsion that can achieve the high speeds needed to get to the heliospheric boundary in reasonable time, reliable systems that can function for the long lifetime needed, reasonable communications capabilities at interstellar range, and constraints on mission resources such as power when more than 100 AU from the Earth. Recent developments in launch systems, execution of long-lived missions such as New Horizons, new radioisotope power systems, and advanced communications systems have for the first time allowed for a practical, feasible near-term mission that can achieve the goal of exploring outside the solar system. We present recent results of a concept study that examined possible missions that could be launched as early as 2030 using existing, or near-existing, technology. These possible missions support significant payloads for heliospheric science, with the potential for additions to the payload for planetary investigations or astrophysics. The concept study includes a detailed look at possible trajectories in launch years from 2030 to 2040 with flyout speeds at least twice that of Voyager 1 and 2, and significant opportunities for tuning the flyout direction to maximize the heliophysics return as well as allow encounters with outer planets or Kuiper Belt Objects. We present a summary of trade studies performed to investigate the constraints and design space for an interstellar probe. These trades include a comparison of trajectories that include gravity assists at Jupiter and at the Sun to increase speed, optimization of the telecommunications architecture to balance data downlink rate with power usage, and spacecraft control methods to allow precise pointing for telecommnications while minimizing propellant usage for an extremely long-lived mission. We present a spacecraft design that can support the potential payloads designed to operate reliably for 50 years, while allowing for communications from 1000 AU.

INTRODUCTION: The proposed Radiation Oncology Alternative Payment Model (RO-APM) aims to test prospective episode-based payments for radiotherapy episodes. Practices will need a tool that can calculate historical episode reimbursements to succeed in this new model. An automated software-based technology was created to calculate historical episode reimbursements within a large Network of community oncology practices. MATERIALS AND METHODS: Claims data between January 1, 2017, and July 31, 2019, were cleaned, organized into episodes, and analyzed with a series of Python computer programs per proposed RO-APM methodology. Averaged Winsorized historical episode reimbursements were first calculated over the entire Network, then over 24 of the largest Practices, and then rerun after application of Clinical Rules to remove misattributed episodes. RESULTS: A total of 79,418 RO-APM–defined episodes were generated from 6,512,375 claims lines. A total of 7,086 episodes (8.9%) were removed because of no treatment delivery code within 28 days of treatment planning. The Network of practices had more bone metastases, and breast, cervical, and uterine cancers but less lung and prostate cancer than the RO-APM dataset. Combination-modality episodes were more costly and required more providers than single-modality episodes. Clinical Rules reattributed 2,495 episodes (3.4%) and increased episode reimbursement by +5.8% over all disease sites (+3.7% using volume weighting; P = .001). CONCLUSION: As payment models continue to shift from volume to value, practices will need an automated analytics technology to measure historical costs and prepare for operational and financial transformation. This automated approach can be adapted to future versions of the RO-APM. Our analysis suggests that future iterations of the RO-APM could incorporate Clinical Rules to remove misattributed palliative care episodes and could implement a separate payment for episodes with multiple radiation therapy modalities.

Lupus nephritis (LN) is a severe clinical manifestation of systemic lupus erythematosus (SLE) associated with significant morbidity and mortality. Assessment of severity and activity of renal involvement in SLE requires a kidney biopsy, an invasive procedure with limited prognostic value. Noninvasive biomarkers are needed to inform treatment decisions and to monitor disease activity. Proteinuria is associated with disease progression in LN; however, the composition of the LN urinary proteome remains incompletely characterized. To address this, we profiled LN urine samples using complementary mass spectrometry-based methods: protein gel fractionation, chemical labeling using tandem mass tags, and data-independent acquisition. Combining results from these approaches yielded quantitative information on 2573 unique proteins in urine from LN patients. A multiple-reaction monitoring (MRM) method was established to confirm eight proteins in an independent cohort of LN patients, and seven proteins (transferrin, α-2-macroglobulin, haptoglobin, afamin, α-1-antitrypsin, vimentin, and ceruloplasmin) were confirmed to be elevated in LN urine compared to healthy controls. In this study, we demonstrate that deep mass spectrometry profiling of a small number of patient samples can identify high-quality biomarkers that replicate in an independent LN disease cohort. These biomarkers are being used to inform clinical biomarker strategies to support longitudinal and interventional studies focused on evaluating disease progression and treatment efficacy of novel LN therapeutics.

Purpose: Treatment of patients with relapsed or refractory lymphoid neoplasms represents a significant clinical challenge, largely due to the genetic heterogeneity of these malignancies. Our study goal was to design a rational treatment strategy that simultaneously targets multiple disease drivers to provide safe, efficacious, and durable responses in patients with relapsed or refractory non-Hodgkin lymphoma (NHL). Experimental procedures and data summary: Venetoclax is a selective BCL-2 inhibitor that induces apoptosis and is efficacious in chronic lymphocytic leukemia; however, single-agent efficacy in other lymphoid neoplasms is limited. Using pharmacologic and genetic studies, we identified the pro-survival BCL-2 protein family member MCL-1 as a venetoclax resistance factor in NHL cell lines. We found that the monomethyl auristatin E (MMAE) payload of the antibody-drug conjugate polatuzumab vedotin promotes MCL-1 degradation via the ubiquitin/proteasome system, thus providing a strong rationale for combination with venetoclax. Mechanistically, polatuzumab vedotin combined with venetoclax promoted apoptotic NHL cell death. In NHL animal models, venetoclax, polatuzumab vedotin, and the anti-CD20 antibody obinutuzumab, that activates targeted antibody- and complement-dependent cell cytotoxicity, produced durable tumor regressions. In a phase 1b clinical trial, 33 patients with relapsed or refractory follicular lymphoma were evaluable for response over 6 dose levels with 19 complete responses and 6 partial responses (overall response rate 76%). All patients (8 of 8) treated with the recommended phase 2 regimen (venetoclax 800mg + polatuzumab vedotin 1.8mg/kg + obinutuzumab 1000mg) achieved complete responses at end of induction. The median duration of follow-up for all dose levels was 17.7 months. This triplet combination was well-tolerated by most patients and had an expected and acceptable safety profile. Conclusions: Our studies implicate MCL-1 as a key venetoclax resistance factor in NHL that can be overcome by polatuzumab vedotin, which promotes MCL-1 degradation. Pre-clinical NHL animal models and early clinical data confirmed that the combination of venetoclax, polatuzumab vedotin, and obinutuzumab is safe and promotes durable responses. Because MMAE and other anti-tubulin agents are likely not the only therapeutics that antagonize MCL-1, our study provides scientific rationale to pursue the broader strategy of identifying other therapeutics that similarly neutralize MCL-1 function. Such agents could be used in combination with venetoclax in other malignancies where MCL-1 is a venetoclax resistance factor. Our mechanism-based treatment regimen that directly targets oncogenic drivers in NHL patients may serve as a framework for treating other malignancies with complex etiologies. Citation Format: Dhara N. Amin, Rajat Bannerji, Raghuveer Singh Mali, Jason Oeh, Eva Lin, Anuradha Zindal, MaryAnn Go, Shang-Fan Yu, Maxwell Krem, Chris Arthur, Uwe Hahn, Anna M. Johnston, Vinit G. Karur, Nadia Khan, Paula Marlton, Tycel Phillips, Giuseppe Gritti, John F. Seymour, Monica Tani, Sam Yuen Yuen, Scott Martin, Matthew T. Chang, Christopher M. Rose, Victoria C. Pham, Elizabeth A. Lasater, Andrew G. Polson, YiMeng Chang, Jamie Hirata, Lisa Musick, Deepak Sampath, Christopher R. Flowers, Ingrid E. Wertz. Targeting BCL-2 and MCL-1 overcomes treatment resistance in relapsed and refractory non-Hodgkin lymphoma: Pre-clinical rationale and results from an open-label phase 1b study [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr CT133.

Electron transfer dissociation (ETD) has been broadly adopted and is now available on a variety of commercial mass spectrometers. Unlike collisional activation techniques, optimal performance of ETD requires considerable user knowledge and input. ETD reaction duration is one key parameter that can greatly influence spectral quality and overall experiment outcome. We describe a calibration routine that determines the correct number of reagent anions necessary to reach a defined ETD reaction rate. Implementation of this automated calibration routine on two hybrid Orbitrap platforms illustrate considerable advantages, namely, increased product ion yield with concomitant reduction in scan rates netting up to 75% more unique peptide identifications in a shotgun experiment. Graphical Abstract ᅟ.

We have developed and implemented a sequence identification algorithm ( inSeq ) that processes tandem mass spectra in real-time using the mass spectrometer’s (MS) onboard processors. The inSeq algorithm relies on accurate mass tandem MS data for swift spectral matching with high accuracy. The instant spectral processing technology takes ∼16 ms to execute and provides information to enable autonomous, real-time decision making by the MS system. Using inSeq and its advanced decision tree logic, we demonstrate ( i ) real-time prediction of peptide elution windows en masse (∼3 min width, 3,000 targets), ( ii ) significant improvement of quantitative precision and accuracy (~3x boost in detected protein differences), and ( iii ) boosted rates of posttranslation modification site localization (90% agreement in real-time vs. offline localization rate and an approximate 25% gain in localized sites). The decision tree logic enabled by inSeq promises to circumvent problems with the conventional data-dependent acquisition paradigm and provides a direct route to streamlined and expedient targeted protein analysis.

Purpose The National Radiation Oncology Registry (NROR) is a collaborative initiative of the Radiation Oncology Institute and the American Society of Radiation Oncology, with input and guidance from other major stakeholders in oncology. The overarching mission of the NROR is to improve the care of cancer patients by capturing reliable information on treatment delivery and health outcomes. Methods The NROR will collect patient-specific radiotherapy data electronically to allow for rapid comparison of the many competing treatment modalities and account for effectiveness, outcome, utilization, quality, safety, and cost. It will provide benchmark data and quality improvement tools for individual practitioners. The NROR steering committee has determined that prostate cancer provides an appropriate model to test the concept and the data capturing software in a limited number of sites. The NROR pilot project will begin with this disease-gathering treatment and outcomes data from a limited number of treatment sites across the range of practice; once feasibility is proven, it will scale up to more sites and diseases. Results When the NROR is fully implemented, all radiotherapy facilities, along with their radiation oncologists, will be solicited to participate in it. With the broader participation of the radiation oncology community, NROR has the potential to serve as a resource for determining national patterns of care, gaps in treatment quality, comparative effectiveness, and hypothesis generation to identify new linkages between therapeutic processes and outcomes. Conclusions The NROR will benefit radiation oncologists and other care providers, payors, vendors, policy-makers, and, most importantly, cancer patients by capturing reliable information on population-based radiation treatment delivery.

Purpose Despite growth of palliative care programs and evidence on the effectiveness of radiotherapy in palliating cancer symptoms, radiotherapy is probably underused in this setting. Radiation and medical oncologists and palliative medicine specialists were surveyed regarding the perceived role of palliative radiotherapy and barriers to its use. Methods The survey was sent electronically to all physician members of the American Society for Therapeutic Radiology and Oncology (ASTRO) and the American Academy of Hospice and Palliative Medicine (AAHPM) and a random sample of American Society of Clinical Oncology (ASCO) members, with known e-mail addresses. Results Response rates were 27%, 14% and 26% for ASTRO, ASCO, and AAHPM respondents, respectively. Although most felt radiotherapy is an effective and important option for palliation of some common cancer symptoms, referrals for such therapy may be declining. Most agreed that radiation oncologists should be more involved in palliative care; however, multiple barriers were identified, such as poor reimbursement, emotional burden of care, insufficient training/knowledge, and the sense of unwillingness of others to share delivery of such services. Conclusions Although multiple barriers limit optimal integration, most agree that there should be greater national and professional society efforts to promote the advancement of radiation oncology in the area of palliative care.

OVERVIEW:Companies and their shareholders stand to benefit from consistently developing and promoting their intellectual property portfolios with a structured IP story. An IP story shows how a company developed IP that supports important products and technologies, with clear linkages from the market opportunities to patents. Companies that follow this approach stand to 1) support higher stock prices, given the incredibly high value placed on intangibles in today's market, 2) maximize return on investment in their IP by supporting strategic technologies that are linked to market needs, and 3) lead the corporate world with best-in-class IP management.

We, as a large community practice, retrospectively reviewed our experience in treating early stage breast cancer to determine rates of breast-conserving therapy (BCT), disease outcomes after such treatment, and risk factors for local recurrence. A hospital tumor registry was used to identify breast cancer cases diagnosed between 1987 and 2003. Rates of BCT and radiotherapy were examined using primary treatment data. For subsequent disease outcomes analyses, cases were limited to only those treated between 1987 and 1994 to allow for adequate follow-up. For the subset of 521 T1–2N0 patients treated with BCT, we calculated crude rates of first failure at 8 years, with outcomes classified as local failure (LF), distant or regional node failure (DNF), dead without failure (DWF), or alive without failure (AWF). Polychotomous logistic regression was done to assess the influence of age at diagnosis, tumor grade, total radiation dose to the tumor bed, and use of systemic therapy. From 1987 to 2003, rates of BCT went from 69% to 89% and the rate of radiation after breast-conserving surgery was 90%. For the subset of 521 T1–2N0 patients treated with BCT who had at least 8 years of follow-up, median age was 58 years, 15% had grade 1 tumors, 83% had T1 tumors, 4.6% had positive margins, 83% got a total radiation dose ≥60 Gy to the tumor bed, and 51% had systemic therapy. At 8 years, 7% of patients had LF, 8% DNF, 10% were DWF, and 75% were AWF. Patient age (p = 0.076), tumor grade (p = 0.056), use of systemic therapy (p = 0.077), and radiation dose (p = 0.127) had borderline significant effects on the risk of LF versus AWF. The majority of patients in this community were treated with BCT and most received radiotherapy. Local control was excellent and comparable to that seen in large academic centers.

The current study documented the implementation of three-dimensional conformal radiotherapy and assessed the tumor control and toxicity of such treatment in a large, multisite community practice.The authors retrospectively reviewed their first 222 consecutive patients with clinically localized (N0) prostate carcinoma treated with a 6-field conformal technique from October 1993 through March 2000. Standardized target definitions, dose planning constraints, and gantry angles were utilized to develop the treatment plan. Patients were categorized by low, intermediate, and high risk. Low risk was defined as T1a-T2a disease, a Gleason score7, and prostate-specific antigen (PSA) level/= 10.0 ng/mL (n = 47 [21%]). Intermediate risk was defined as T2b disease, a Gleason score6, or PSA level10.01 ng/mL (n = 60 [27%]). High risk was defined as 2 of the above risk factors or as T3 disease, a Gleason score7, or a PSA level20 (n = 115 [52%]). Biochemical disease recurrence was defined in accordance with the American Society for Therapeutic Radiology and Oncology definition. Urinary and bowel toxicity were graded using the Radiation Therapy Oncology Group morbidity scoring system.The median follow-up after radiotherapy for surviving patients was 47 months (range, 0-99 months). The 2 and 5-year actuarial biochemical control rates for all patients were 84% and 78%, respectively. Using logistic regression analysis, lower dose (75.6 gray [Gy] vs. 75.6 Gy; P = 0.006), higher risk group (P = 0.033), higher stage (P = 0.045), and higher PSA level (P = 0.001) were significantly associated with biochemical disease recurrence. Toxicity was not significantly correlated with a higher radiotherapy dose.Dose escalation to 75.6 Gy using a 6-field conformal technique was feasible in the authors' community practice and resulted in acceptable toxicity and early biochemical outcomes.

The National Radiation Oncology Registry (NROR), sponsored by the Radiation Oncology Institute and the American Society for Radiation Oncology, is designed to collect standardized information on cancer care delivery among patients treated with radiotherapy in the United States and will focus on patients with prostate cancer. Stakeholders were engaged through a forum that emphasized the need for patient-centered outcomes, minimal data burden, and maximal connectivity to existing registries and databases. An electronic infrastructure is under development to provide connectivity across radiation oncology and hospital information systems. The NROR Gateway features automatic abstraction as well as aggregation of treatment and outcome data. The prostate cancer data dictionary provides standardized elements in four domains: facility, physician, patient, and treatment. The pilot phase will consist of clinical centers chosen to provide a representative mix of radiation treatment modalities, facility types, population-based settings, and regional locations. The initial set of radiation practice metrics includes physician board certification and maintenance, ordering of staging scans, active surveillance discussion, dose prescriptions for low-risk/high-risk disease, radiation fields for low-risk/high-risk disease, image-guided radiation therapy use, androgen deprivation therapy use, post-brachytherapy implant computed tomography dosimetry, collection of toxicity assessments, and longitudinal patient follow-up. The NROR pilot study will provide the framework for expansion to a nationwide electronic registry for radiation oncology.

In summary, the ASTRO Committee on Human Resources believes that there is ample evidence for the existence of an oversupply of radiation oncologists in the United States at the present time. It believes that this oversupply has already affected the specialty in a variety of ways that are difficult to measure, for example, increased competition, conflicts between radiation oncology groups, conflicts between the private sector and academics, and increased costs, and that it is beginning to have a significant effect on the job market. This oversupply came about because of the rapid expansion in medical school enrollment in the 1970s. This led to an increased number of graduates available for enrollment into specialty residencies, one of which was radiation oncology. The actual number of radiation oncology residency positions offered has not changed significantly since 1972. However, only about half of the residency positions were filled in the early years. Since 1986, virtually all radiation oncology training positions in the United States have been filled, and this has led to a significantly greater number of radiation oncologists entering the field than have left the field through death or retirement. Preliminary data suggest that a shift to a managed care system would result in decreased demand for radiation oncology services, and that would increase the manpower problem for our specialty.

Purpose: Health care delivery in the United States is in the midst of a structural revolution called managed care. Demands for cost control within the managed care environment force radiation oncologists to defend the need and obligation to follow their patients. Methods and Materials: We have analyzed this follow-up requirement from six potential justifications: patient care, medical-legal, quality assurance, outcome measurement, cost, and improvement of care. Results: Practical recommendations for discussing the need for follow-up with the medical directors and primary care physicians of managed care entities are given. Follow-up without valid documentation of benefit is hard to justify in this era of managed care. Conclusions: Collaborative follow-up between the referring physician, the treating radiation oncologist, and the other oncologic specialists will allow for outcome measurement and improvement in practice without driving up cost or exposing the patient to undue risk.

Rose, C. M. Radiation Scientists and Homeland Security. Radiat. Res. 157, 607–609 (2002). Radiation scientists represent an important resource in homeland defense. Security analysts worry that a crude but deadly radiological bomb might be fashioned from stolen nuclear material and a few sticks of dynamite. Such a device could kill dozens, hundreds, and possibly thousands and could contaminate a square mile or more. Emergency workers may call upon radiation scientists to aid the injured. Educational materials are available on the ACR, ASTRO, and RRS websites, linked to the Armed Forces Radiobiology Research Institute and the Oak Ridge National Laboratory, to provide radiation workers material that they can use to help emergency room and civil defense personnel after a terrorist attack. Radiation scientists are urged to obtain these materials and contact their local hospital and public health authorities to volunteer their services and expertise.

The modulation architecture in the Frontier Software Defined Radio platform supports a wide variety of modulation formats with a single low-power hardware/firmware circuit: PSK, QAM, subcarrier BPSK and ranging. The wideband hardware supports downlink data rates from 1 sps to 150 Msps, yet the firmware circuitry can generate tightly controlled narrow-band modulation. This flexibility is achieved with oversampled waveform generation, including sine-wave subcarriers and interpolated turnaround ranging. For phase modulation, a composite modulation signal is converted to parallel I/Q signals that modulate the RF carrier. Due to imperfections in the analog I/Q modulator, harmonic upcon-verter and DACs, calibration of the digital phase-to-I/Q conversion is necessary to accurately generate the desired RF signal. The calibration procedure optimizes a discrete PSK constellation, and then interpolates the constellation for applications that require continuous phase modulation, such as sine-wave subcarrier or turnaround ranging. For S-band and Ka-band exciters, the modulation is applied at the RF frequency, and the I/Q conversion subtends 360°. In contrast, for X-band exciters, the modulation is applied at 1/4th the RF frequency, and the I/Q conversion subtends only 90°. In summary, this architecture can generate wide-band high-rate downlink when sufficient link margin and bandwidth are available, and can also generate tightly controlled narrow-band signals when only low-rate links are available or limited bandwidth can be allocated.

Radiation treatment is generally safe. The reported adverse event rate requiring follow-up care is low: (e.g., z1.2/ 10,000 treated patients; NY State Department of Health estimates [J. Krishnamoorthy, personal communication, August 6, 2010]). Recently however, there is increased interest in patient safety within radiation oncology, prompted, at least in part, by articles in the New York Times (1–4). These articles complement other articles in the lay press (5, 6) and several reports within the radiation oncology literature (7). Taken in concert, these reports implicate the increasing complexity of radiation oncology as a potential source of increased risks for patients (8). Even though radiation therapy is generally safe and efficacious, the potentially devastating effects of misadministrations remind us that we need to be continually vigilant. Subsequent to the NY Times articles, patient safety concerns have been the topic of recent congressional hearings, and meetings sponsored by the Food and Drug Administration (May 2010) and ASTRO/AAPM (June 2010). ASTRO has committed itself to a six-point ‘‘Target Safely’’ action plan (9). The device manufacturers have committed themselves to their own response to the challenge (10). These activities will change the way we practice. There will likely be new standards for clinical practice and training, certification, and recertification of personnel. Quality assurance procedures may be redefined with mandatory time-outs and checklists, and human–computer interfaces will be reengineered to facilitate correct use (11). These initiatives should be applauded and may improve patient safety. Improvements in patient safety will also require us to broaden the scope of our concern. Radiation oncology is a component of an increasingly complicated health care system: We routinely evaluate, treat, and follow patients with

PURPOSE: Radical prostatectomy and external-beam radiation are the most common treatments for localized prostate cancer. Given the absence of clinical consensus in favor of one treatment or the other, relative costs may be a significant factor. This study compares the direct medical costs during the month before and 9 months after diagnosis for patients treated primarily with external-beam radiation or radical prostatectomy for early-stage prostate cancer. METHODS: Patients age 65 or older and coded by the Surveillance, Epidemiology, and End Results (SEER) registry as having been diagnosed with adenocarcinoma of the prostate treated primarily with external-beam radiation or radical prostatectomy during 1992 and 1993 were identified. The initial treatment costs, as measured by Medicare-approved payment amounts, for each strategy were analyzed using linked SEER-Medicare claims data after adjusting for differences in comorbidity and age. An intent-to-treat analysis was also performed to adjust for differences in staging between the two groups. RESULTS: For patients in the treatment-received analysis, the average costs were significantly different; $14,048 (95% confidence interval [CI], $13,765 to $14,330) for radiation therapy and $17,226 (95% CI, $16,891 to $17,560) for radical prostatectomy (P < .001). The average costs for patients in the intent-to-treat analysis were also significantly less for radiation therapy patients ($14,048; 95% CI, $13,765 to $14,330) than for those who underwent radical prostatectomy ($17,516; 95% CI, $17,195 to $17,837; P < .001). CONCLUSION: For patients with early-stage prostate cancer, average costs during the initial treatment interval were at least 23% greater for radical prostatectomy than for external-beam radiation. Major limitations of the research include not studying costs after the initial treatment interval and questionable current applicability, given changes in management of early prostate cancer.

observational cohort study since October 2010. Information on diagnosis, stage, risk factors for cancer, and treatment plan are collected at the initial visit. During subsequent phone calls and follow-up visits, treatment response and survival are assessed. We report on patients enrolled through February 2012. Results: One hundred forty-four participants were enrolled; median age at cancer diagnosis was 45.4 years and 64% were female. Of the 136 patients with known HIV status, 85 (63%) were HIV-infected and 67 (49%) were on antiretroviral therapy. For 90 (66%), the diagnosis of HIV preceded the diagnosis of cancer, and median time from HIV diagnosis to cancer diagnosis was 3.7 years. Forty patients (30%) had a smoking history but only 14 (10%) were active smokers. The most common cancer types for women were breast (24% of all women), cervix (20%), and Kaposi’s sarcoma (KS, 14%), and for men were KS (33% of all men), head and neck (19%), and non-Hodgkin lymphoma (15%). Nearly all patients (96%) presented due to symptoms, the most common being palpable lump/mass, pain, or bleeding. Of patients who had staging studies (n Z 124), 68% had advanced stage cancers (III/IV). Pathologic confirmation of cancer diagnosis was obtained in 81% of patients. The treatment plan involved surgery in 77 patients, chemotherapy in 81, and radiation therapy (RT) in 39. Of the 38 patients who started RT (one died prior to starting), the most common conditions were cervical cancer, breast cancer, and KS. Median dose prescribed was 60 Gy (range, 8-78 Gy). Thirty-four patients completed RT with the average course duration of 53.7 days (range, 1-113 days). RT was delivered at Gaborone Private Hospital on a linear accelerator with photon, electron, or combined modality therapy. With median follow-up of 14.2 months, the median survival was 22.5 months for early stage disease and 16.5 months for advanced disease. Conclusions: In this limited sample of patients, the majority of cancers were HIV-associated and diagnosed at advanced stage after presentation with symptoms, even for preventable/detectable cancers such as cervix and breast. A greater understanding of cancer in Botswana will inform decisions of resource allocation and infrastructure development, including cancer prevention/screening and RT availability. Author Disclosure: G. Suneja: None. S. Dryden-Peterson: None. M. Boyer: None. Z. Musimar: None. M. Nsingo-Bvochora: None. D. RamogolaMasire: None. H. Medhin: None. J. Bekelman: None. S. Lockman: None. T. Rebbeck: None.

267 Background: The National Radiation Oncology Registry (NROR), sponsored by the Radiation Oncology Institute and the American Society for Radiation Oncology, is building a nationwide electronic infrastructure to collect standardized information on cancer care delivery among patients treated with radiotherapy in the United States. The NROR pilot registry will focus on patients with prostate cancer (PCa). Methods: Since October 2010 the NROR has undertaken four main efforts (1) stakeholder engagement, including hosting a forum with ongoing opportunities for feedback from patients, clinicians, payers, vendors, and federal agencies; (2) electronic infrastructure development to facilitate transfer of information from disparate clinical systems to a database model designed for efficient aggregate analysis; (3) data dictionary development with guidance from PCa and technical experts, and health services researchers; and (4) pilot site engagement, in which over 80 clinical centers indicated willingness to participate in the pilot registry by filling out an online survey. Results: The stakeholder forum revealed enthusiasm for the NROR and emphasized the need for patient-centered outcomes, minimal data burden, and maximal connectivity to existing registries and databases. In partnership with Healthcare IT, Inc, the NROR is building an electronic infrastructure to provide connectivity across radiation oncology and hospital information systems. The data dictionary provides standardized data elements in seven domains: facility characteristics, physician demographics, patient demographics and comorbidity status, radiotherapy technical data for external beam and brachytherapy, hormone therapy details, clinician- and patient-reported outcomes. Up to 30 clinical centers will be selected to serve as pilot sites through an objective, blinded, and transparent process. Pilot registry endpoints include percentage of eligible patients enrolled, percentage of data elements captured for each participant, determination of barriers to participation, and patterns of care delivery. Conclusions: The NROR pilot study will provide the framework for expansion to a nationwide electronic registry for radiation oncology.

The purpose of this study was to determine whether daily use of a rotary electric toothbrush (Rota-dent, Prodentec Corp., Batesville, Ark.) and a 0.05% sodium fluoride (NaF) rinse would significantly reduce decalcification when compared with manual toothbrushing only (control group) or manual toothbrushing and daily use of a NaF rinse (rinse group). All three groups used a standard fluoride toothpaste. Ninety consecutive adolescent patients who were to receive orthodontic treatment were placed into one of three groups according to age and sex criteria. Decalcification was evaluated single blind by two calibrated examiners on the facial surfaces of all permanent teeth before appliances were placed (baseline) and 3 months after appliances were removed (posttreatment). Data were analyzed by analysis of covariance with the dependent variable derived by subtracting the baseline decalcification scores from the posttreatment scores and using the baseline scores as the covariate. The results showed that although there were no significant differences between the three groups at baseline, the Rota-dent group showed significantly (p < 0.05) less posttreatment decalcification than either the control or rinse groups. In a separate analysis of first molars, the Rota-dent group again showed the least decalcification and the control group showed the most. These data suggest that twice daily use of the Rota-dent electric toothbrush with a standard fluoride toothpaste and once daily use of a 0.05% NaF rinse is more effective for preventing decalcification in adolescents during orthodontic treatment with fixed appliances than either conventional toothbrushing with a fluoride toothpaste, or similar toothbrushing and toothpaste with a once daily NaF rinse.

laudable, and the results are encouraging. That the indicators largely improved between the two survey rounds was encouraging, especially given that the project is in its infancy. What was disheartening, however, was that the capability for collecting quality indicators using EHR systems was neither entertained in the conception of the study nor in the associated article discussions. While this is understandable given the limited penetration of EHR systems, it neglects considerations for scaling and evolving the QOPI program. Oncology-specific EHR systems are currently available, and are capable of providing a robust infrastructure for support of such projects. These systems will likely render manual data abstraction and collection methods obsolete, and help reduce the $1,000 per practice cost for the QOPI assessment, a cost that scales dramatically when one considers a nationwide system. Further, the market penetration and use of EHR systems in oncology will undoubtedly increase over time, with their costs offset by their proclivity for promoting efficiency, reducing medical errors, and enhancing quality care. Incentives launched by the Office of the National Coordinator for Health Information Technology, the promotion of the Oncology Demonstration Programs by the Centers for Medicare and Medicaid Services, and proposed legislation to incentivize pay for performance, as well as potential patient demands, all suggest that widespread adoption of EHR systems by oncologists is imminent. Advantages of embedding quality measures into the core of an EHR system abound. Indicators can be calculated based on data entered in the course of routine care, and reports of quality could become routine. Quality for all patients, not just a random few, could be tracked and quantified in real time. Using EHR systems, aggregation across practices along with centralized collection, comparison, and analysis is more readily supported as may be methods for abstracting, reviewing, auditing, and identifying other leading and lagging quality indicators. By promoting and standardizing QOPI measures, data from disparate EHR systems could be compared, and otherwise leveraged in support of quality management. Perhaps most importantly, an EHR can help promote the very quality it is tasked with measuring by enforcing rules such as "no chemotherapy administration unless a consent is present."

We read with great interest the article by Neuss et al (“A Process for Measuring the Quality of Cancer Care: The Quality Oncology Practice Initiative”) in the September 1, 2005, Journal of Clinical Oncology, and the Quality Oncology Practice Initiative (QOPI) article from the January 2006 JOP. From the perspectives of an electronic health record (EHR) vendor and a practicing oncologist, we found the reports on the QOPI system timely and laudable, and the results are encouraging. That the indicators largely improved between the two survey rounds was encouraging, especially given that the project is in its infancy. What was disheartening, however, was that the capability for collecting quality indicators using EHR systems was entertained neither in the conception of the study nor in the associated article discussions. While this is understandable given the limited penetration of EHR systems, it neglects considerations for scaling and evolving the QOPI program. Oncology-specific EHR systems are currently available and are capable of providing a robust infrastructure for support of quality-improvement projects. These systems will likely render manual data abstraction and collection methods obsolete, and help reduce the $1,000 per-practice cost for the QOPI assessment—a cost that increases dramatically when applied to a nationwide system. Furthermore, the use of EHR systems in oncology will undoubtedly increase over time, and their costs can be offset by their potential for promoting efficiency, reducing medical errors, and enhancing quality care. Initiatives launched by the Office of the National Coordinator for Health Information Technology, the promotion of the Oncology Demonstration Programs by Centers for Medicare and Medicaid Services, and proposed legislation encouraging Pay for Performance, as well as patient demands, all suggest that widespread adoption of EHR systems by oncologists is imminent. Advantages of embedding quality measures into the core of an EHR system abound. Indicators can be “calculated” based on data entered during the course of routine care, and reports of quality could become routine. Quality for all patients, not just a random few, could be tracked and quantified in real time. Using EHR systems, aggregation across practices along with centralized collection, comparison, and analysis is more readily supported. The same may be true for methods of abstracting, reviewing, auditing, and identifying other leading and lagging quality indicators. By promoting and standardizing QOPI measures, data from disparate EHR systems could be compared, and otherwise leveraged in support of quality management. Perhaps most importantly, an EHR can help promote the very quality it is responsible for measuring, by enforcing rules such as “no chemotherapy administration unless a consent is present.” We believe that quantification of most of the 11 QOPI indicators is already possible using commercially available oncology-specific EHR systems. However, as the QOPI project evolves, the following EHR-specific criteria would add significantly to the “ideal and practical” criteria introduced by the authors: Coordination and standardization of indicators among all the stakeholders, including professional societies, insurers, payers, patient advocacy groups, governmental organizations, accreditation bodies, and the practices themselves Consideration for ease of “calculating” the indicator from measures already present in an EHR. For example, whether an explicit statement of the patient's staging has been entered is far easier to “calculate” and validate than whether there was appropriate use of chemotherapy and hormonal therapy for a subset of breast cancer patients It is vital that all stakeholders agree upon a standardized nomenclature, lest the field degenerate into a “Tower of Babel.” We agree with the authors that a process for gathering data concerning the quality of oncology care in individual practices needs to be expeditiously designed and implemented. The QOPI system may indeed allow rapid feedback of performance data for each of the selected indicators, but probably not as efficiently and rapidly as a QOPI-equipped EHR system. In an era where EHRs are coming of age, the time to incorporate indicators into the core of such systems is now. EHR vendors have an interest in collaborating in the development and adaptation of current indicators, but the responsibility of equipping EHRs to measure, track, and enhance quality in the oncology practice belongs to all of us.

Parasternal lymphoscintigraphy is an easily performed technique for visualizing and accurately determining thethree dimensional location of internal mammary lymph nodes. Sixty-eight women with primary or locally recurrent breast cancer underwent parasternal lymphoscintigraphy before treatment planning. The mean depth and lateral position of the internal mammary nodes were 1.8. ± 0.9 cm and 2.4 ± 0.9 cm respectively. Thirteen per cent of the nodes would have been undertreated by the standard tangential technique used at our institution. Six of 15 patients whose treatment plans were examined retrospectively had at least 1 lymph node undertreated by the standard tangential tec hnique. Thus, although standard tangential portals provide adequate coverage for the internal mammary lymph nodes in a majority of patients, parasternal lymphoscintigraphy can insure complete coverage of this lymph node group.

Between January, 1967 and July, 1980, 176 women who were referred to the Joint Center for Radiation Therapy (JCRT) for definitive breast irradiation underwent low axillary dissection. A typical operative technique is described. The dissection stops short of the axillary vein although the vein is usually visualized. One hundred thirty-two axillae were thought to be N 0 or N 1a . Forty-six axillae were felt to be N. Seventeen percent of the T 1 N 0 patients had pathologically positive nodes. Twenty-seven percent of the T 2 N 0 patients had positive nodes. When 5 or less nodes were removed at axillary sampling the incidence of nodal involvement was very low. There were no differences in nodal positivity when comparing upper quadrant to lower or central lesions. Lateral lesions appeared to have higher positivity rates compared with either medial or central lesions. Ninety-four percent of axillae with N 1b lesions were pathologically confirmed. The complication rate for this procedure was low. There were 5 transient non-surgical complications and 1 cellulitis resulting in a frozen shoulder, which required corrective surgery. There were no cases of moderat or severe arm edema. Axillary sampling is compared to axillary dissection as a diagnostic procedure. Axillary sampling may underestimate the true pathologic positive rate, but diagnostic accuracy appears excellent if level 1 and 2 nodes are sampled.

The addition of Fluosol-DA carbogen breathing to melphalan treatment of the FSa-IIC fibrosarcoma was assessed by tumor growth delay and cell survival assays. Melphalan (10 mg/kg) administered intraperitoneally (i.p.) was preceded by Fluosol-DA (0.3 ml) administered intravenously (i.v.) and followed by 1 hr of carbogen breathing; this resulted in a tumor growth delay of 9.5 +/- 1.4 days or an approximately 3-fold increase compared to melphalan alone. Melphalan produced about 1.7 logs of cell killing; neither carbogen breathing nor Fluosol-DA pretreatment altered the cell killing observed. There was a 10-fold increase in tumor-cell killing when Fluosol-DA was administered immediately prior to melphalan administration followed by carbogen breathing for 1 hr. Density gradient separation identified a population of denser FSa-IIC cells which showed increased sensitivity to melphalan after Fluosol-DA administration. There was no additional toxicity to bone marrow as measured by CFU-GM with the combination of melphalan/Fluosol-DA/O2 compared to melphalan alone.

Daily rhythms in concentrations of various amino acids in human blood plasma from males on diets containing various amounts of proteins

Treatment with a perfluorochemical emulsion combined with breathing a 95% or 100% oxygen atmosphere has been shown to be an effective adjuvant to radiation therapy in several animal tumor systems. Similarly, the addition of treatment with a perfluorochemical emulsion combined with breathing a high oxygen atmosphere has been shown to improve the response of several animal tumor systems to treatment with BCNU. We now report results of the use of the perfluorochemical emulsion, Fluosol-DA, and carbogen breathing with single dose radiation treatment, BCNU and combined drug and radiation treatment in intracranially implanted 9L gliosarcoma. The median enhancement in life span produced by Fluosol-DA and carbogen breathing in addition to radiation was 2 days at 10 Gy and 6 days at 20 Gy compared to radiation treatment alone. In the group receiving 20 Gy with Fluosol-DA and carbogen breathing, 2 of 20 lived 120 days. Treatment with a single intraperitoneal injection of BCNU (10 mg/kg) on day 7 post tumor cell implantation produced an increase in life span of 2 days compared to untreated control animals. The combination of drug treatment with Fluosol-DA and carbogen breathing produced an increase in life span of 26 days, which was significantly different from BCNU treatment with air breathing (p less than 0.001). Finally, when BCNU and Fluosol-DA and carbogen were combined with radiation treatment (20 Gy), an increase in life span of nearly 85 days compared to untreated controls was produced, with 47% (9 or 19) surviving 120 days. These results suggest that this combination might be effective in the treatment of malignant brain tumors.

The perfluorochemical emulsion, Fluosol-DA, combined with breathing a 95% oxygen/5% carbon dioxide atmosphere enhances the response of several rodent tumors. B6D2F1/J mice bearing Lewis lung tumors, measuring 50-100 mm3 were treated with 4, 8 and 12 ml/kg of Fluosol-DA intravenously each morning. Three Gy fractions twice per day were employed and carbogen breathing was maintained 1 hr prior to and during each X ray treatment. The dose modifying factors were 1.42 +/- 0.16 at 4 ml/kg, 1.85 +/- 0.23 at 8 ml/kg, and 2.17 +/- 0.34 at 12 ml/kg. In a second experiment, a single dose of Fluosol-DA (12 ml/kg) was administered on day 1 to B6D2F1/J male mice, bearing established subcutaneous Lewis lung tumors, as described above. X rays were delivered in 2, 3, or 4 Gy fractions once per day for five days. The dose modifying effect was 2.60 +/- 0.54. The effect of this treatment program was the same as that seen with single dose radiation. These experiments demonstrate that Fluosol-DA need not be administered with every fraction to produce an improved treatment outcome with fractionated X rays.

• Hypoxic cell sensitizers, particle therapy, hyperthermia, and combinations of chemotherapy and radiotherapy have potential to increase the therapeutic ratio in future clinical radiotherapy treatment regimens. The biologic bases of these investigations are beginning to appear as avenues of clinical investigation. ( Arch Otolaryngol 1983;109:792-796)