Rates of progression of carotid in-stent stenosis and clinical outcomes.

BACKGROUND: We previously reported the incidence of ≥50% and ≥80% carotid in-stent stenosis. In the present study, we analyzed the rate of progression of in-stent stenosis and clinical outcomes with longer follow-up. METHODS: We performed a retrospective analysis of prospectively collected data for 450 patients who had undergone transfemoral carotid artery stenting with longer follow-up (mean, 70 months). The progression of in-stent stenosis was defined as stenosis advancing to a higher severity of disease (ie, from <50% to ≥50% and from ≥50% to ≥80%). Kaplan-Meier analysis was used to estimate the rate of progression from <50% to ≥50% and ≥50% to ≥80%, the overall rates of ≥50% and ≥80% in-stent stenosis, and survival at 1, 3, 5, and 10 years. RESULTS: At a mean follow-up of 70.3 months (range, 1-222 months), 121 of 446 patients (27%) had had progression to ≥50% and 39 (8.7%) to ≥80% in-stent stenosis. Of the 406 patients whose first duplex ultrasound findings were normal or showed in-stent stenosis of <50%, 82 had had progression from normal or <50% to ≥50% in-stent stenosis at a mean of 51.7 months (range, 1-213 months). Of the 121 patients with ≥50% stenosis, 14 (11.6%) had experienced progression to ≥80% at a mean of 33.6 months (range, 6-89 months). Of the 82 patients with progression from <50 to ≥50%, 10 (12%) had experienced a neurologic event (eight transient ischemic attacks [TIAs] and two strokes). Of the 14 with progression from ≥50% to ≥80%, 2 (14.3%) had experienced a TIA, and the remaining patients were asymptomatic. Of the 39 patients with ≥80% in-stent stenosis, 9 (23%) had experienced a neurologic event (eight TIAs and one contralateral stroke). Overall, 13 of the 121 patients with late ≥50% restenosis (10.7%) had experienced a neurologic event (10 ipsilateral TIA, 2 ipsilateral stroke, and 1 contralateral stroke. Thus, 12 of 446 patients (2.7%) had experienced an ipsilateral TIA or stroke at a mean follow-up of 70 months. The rates of freedom from <50% to ≥50% in-stent stenosis progression were 93%, 85%, 78%, and 66% at 1, 3, 5, and 10 years. The rates of freedom from progression from ≥50% to ≥80% in-stent stenosis were 89%, 81%, and 77% at 1, 3, and 5 years, respectively. The overall rates of freedom from ≥50% in-stent stenosis and ≥80% in-stent stenosis were 86%, 77%, 71%, and 59% and 96%, 93%, 91%, and 84% at 1, 3, 5, and 10 years, respectively. Finally, the stroke survival rates were 95%, 80%, 63%, and 31% at 1, 3, 5, and 10 years, respectively. CONCLUSIONS: The rate of progression of carotid in-stent stenosis was modest, with a low incidence of stroke events. Therefore, the use of duplex ultrasound surveillance after carotid artery stenting should be selective and its benefits and utility perhaps reevaluated.

Novel roles of apoptotic caspases in tumor repopulation, epigenetic reprogramming, carcinogenesis, and beyond.

Apoptotic caspases have long been studied for their roles in programmed cell death and tumor suppression. With recent discoveries, however, it is becoming apparent these cell death executioners are involved in additional biological pathways beyond killing cells. In some cases, apoptotic cells secrete growth signals to stimulate proliferation of neighboring cells. This pathway functions to regenerate tissues in multiple organisms, but it also poses problems in tumor resistance to chemo- and radiotherapy. Additionally, it was found that activation of caspases does not irreversibly lead to cell death, contrary to the established paradigm. Sub-lethal activation of caspases is evident in cell differentiation and epigenetic reprogramming. Furthermore, evidence indicates spontaneous, unprovoked activation of caspases in many cancer cells, which plays pivotal roles in maintaining their tumorigenicity and metastasis. These unexpected findings challenge current cancer therapy approaches aimed at activation of the apoptotic pathway. At the same time, the newly discovered functions of caspases suggest new treatment approaches for cancer and other pathological conditions in the future.

Moringa oleifera functionalised sand - reuse with non-ionic surfactant dodecyl glucoside.

Moringa oleifera seeds are well known for their ability to cause flocculation in turbid water and facilitate bacterial inhibition. These effects are due to the cationic polypeptide MO2.1, which affects the surface charge of suspended particles and causes lysis of bacterial cells. However, the attachment of bacteria to MO2.1 prevents further bacterial attachment, reducing the effectiveness of the seeds. This research investigated the effect of surfactants on functionality and reuse of Moringa seeds to develop a sustainable water treatment technique. The seed extracts (MO2.1) were used with a functionalised sand system, and the sands were exposed to commercially available (ionic and non-ionic) surfactants, dodecyl glucoside and sodium dodecyl sulfate. Artificially polluted water contaminated with Escherichia coli was used to evaluate the efficiency of the system. The non-ionic surfactant was found to be effective at separating E. coli from the functionalised sand without the detachment of the MO2.1 and subsequent loss of the system efficiency. This was successfully repeated four times. The results demonstrated a sustainable, reusable technique to inhibit bacterial contamination in water.

Relationship between illness uncertainty, anxiety, fear of progression and quality of life in men with favourable-risk prostate cancer undergoing active surveillance.

OBJECTIVES: To evaluate prospectively the associations between illness uncertainty, anxiety, fear of progression and general and disease-specific quality of life (QoL) in men with favourable-risk prostate cancer undergoing active surveillance (AS). PATIENTS AND METHODS: After meeting stringent enrollment criteria for an AS cohort study at a single tertiary care cancer centre, 180 men with favourable-risk prostate cancer completed questionnaires at the time of enrollment and every 6 months for up to 30 months. Questionnaires assessed illness uncertainty, anxiety, prostate-specific QoL (using the Expanded Prostate Cancer Index Composite [EPIC] scale) and general QoL (using the 12-time short-form health survey [SF-12]) and fear of progression. We used linear mixed-model analyses and multilevel mediation analyses. RESULTS: Sexual scores on the EPIC scale significantly declined over time (P < 0.05). Illness uncertainty was a significant predictor of all EPIC summary scores, SF-12 physical component summary (PCS) scores, mental component summary (MCS) scores and fear of progression scores (all P < 0.05), after controlling for demographic and clinicopathological factors. Anxiety predicted all EPIC summary, MCS and fear of progression scores (all P < 0.05) but not PCS scores (P = 0.08). Scores on PCS, MCS, EPIC summary scales (except sexual scale), and fear of progression did not change significantly over the study period (all P > 0.10). CONCLUSION: Over the 2.5-year follow-up, QoL remained stable; only sexual function scores significantly declined. Illness uncertainty and anxiety were significant predictors of general and prostate-specific QoL and fear of progression. Interventions to reduce uncertainty and anxiety may enhance QoL for men with prostate cancer on AS.

Disease reclassification risk with stringent criteria and frequent monitoring in men with favourable-risk prostate cancer undergoing active surveillance.

OBJECTIVES: To determine the frequency of disease reclassification and to identify clinicopathological variables associated with it in patients with favourable-risk prostate cancer undergoing active surveillance (AS). PATIENTS AND METHODS: We assessed 191 men, selected by what may be the most stringent criteria used in AS studies yet conducted, who were enrolled in a prospective cohort AS trial. Clinicopathological characteristics were analysed in a multivariate Cox proportional hazards regression model. Key features were an extended biopsy with a single core positive for Gleason score (GS) 3 + 3 (<3 mm) or 3 + 4 (<2 mm) and a prostate-specific antigen (PSA) level <4 ng/mL (adjusted for prostate volume). Biopsies were repeated every 1-2 years and clinical evaluations every 6 months. Disease was reclassified when PSA level increased by 30% from baseline, or when biopsy tumour length increased beyond the enrolment criteria, more than one positive core was detected or any grade increased to a dominant 4 pattern or any 5 pattern. RESULTS: Disease was reclassified in 32 patients (16.8%) including upgrading to GS 4 + 3 in five patients (2.6%). The median (interquartile range) follow-up time among survivors was 3 (1.9-4.6) years. Overall, 13 of the 32 (40.6%) had incremental increases in GS. Tumour length (hazard ratio 2.95, 95% confidence interval [CI] 1.34-6.46; P = 0.007) and older age (hazard ratio 1.05, 95% CI 1.00-1.09; P = 0.05) were identified as significant and marginally significant predictors of disease reclassification, respectively. Disease remained stable in 83.2% of patients. CONCLUSION: The need persists for improvements in risk stratification and predictive indicators of cancer progression.

Quantitative phosphoproteomics of Alzheimer's disease reveals cross-talk between kinases and small heat shock proteins.

Abnormal phosphorylation contributes to the formation of neurofibrillary tangles in Alzheimer's disease (AD), but may play other signaling roles during AD pathogenesis. In this study, we employed IMAC followed by LC-MS/MS to identify phosphopeptides from eight individual AD and eight age-matched control postmortem human brain tissues. Using this approach, we identified 5569 phosphopeptides in frontal cortex across all 16 cases in which phosphopeptides represented 80% of all peptide spectral counts collected following IMAC enrichment. Marker selection identified 253 significantly altered phosphopeptides by precursor intensity, changed by at least 1.75-fold relative to controls, with an empirical false discovery rate below 7%. Approximately 21% of all significantly altered phosphopeptides in AD tissue were derived from tau. Of the other 142 proteins hyperphosphorylated in AD, membrane, synapse, cell junction, and alternatively spliced proteins were overrepresented. Of these, we validated differential phosphorylation of HSP 27 (HSPB1) and crystallin-alpha-B (CRYAB) as hyperphosphorylated by Western blotting. We further identified a network of phosphorylated kinases, which coenriched with phosphorylated small HSPs. This supports a hypothesis that a number of kinases are regulating and/or regulated by the small HSP folding network.

Proton therapy for prostate cancer: why and what orthopaedic surgeons need to know about it.

Most orthopaedic surgeons are unfamiliar with proton therapy or the difference between proton radiation and photon (X-ray) radiation. After they perform a total hip replacement or metallic hip implant, their patient cannot have proton therapy for prostate cancer because the protons must pass exclusively through the hips and are blocked by metal. Proton therapy is a sophisticated and expensive technology with growing demand and limited supply. In proton therapy, heavy protons are accelerated to almost the speed of light in a synchrotron (particle accelerator) down a magnetic beam the length of a football field to radiate cancers. Proton therapy is a remarkably safe and effective treatment for prostate cancer, the most common cancer in men, although treatment superiority has yet to be proved in randomized studies. There are currently only 10 proton centers in the United States.

Current clinical presentation and treatment of localized prostate cancer in the United States.

PURPOSE: SEER recently released patient Gleason scores at biopsy/transurethral resection of the prostate. For the first time this permits accurate assessment of prostate cancer presentation and treatment according to clinical factors at diagnosis. MATERIALS AND METHODS: We used the SEER database to identify men diagnosed with localized prostate cancer in 2010 who were assigned NCCN(®) risk based on clinical factors. We identified sociodemographic factors associated with high risk disease and analyzed the impact of these factors along with NCCN risk on local treatment. RESULTS: Of the 42,403 men identified disease was high, intermediate and low risk in 38%, 40% and 22%, respectively. On multivariate analysis patients who were older, nonwhite, unmarried or living in a county with a higher poverty rate were more likely to be diagnosed with high risk disease (each p <0.05). Of the 38,634 men in whom prostate cancer was the first malignancy 23% underwent no local treatment, 40% were treated with prostatectomy, 36% received radiation therapy and 1% underwent local tumor destruction, predominantly cryotherapy. On multivariate analysis patients who were older, black, unmarried or living in a county with a higher poverty rate, or who had low risk disease were less likely to receive local treatment (each p <0.05). CONCLUSIONS: Our analysis provides information on the current clinical presentation and treatment of localized prostate cancer in the United States. Nonwhite and older men living in a county with a higher poverty rate were more likely to be diagnosed with high risk disease and less likely to receive local treatment.

Impact of a clinical trial initiative on clinical trial enrollment in a multidisciplinary prostate cancer clinic.

Clinical oncology trials are hampered by low accrual rates, with fewer than 5% of adult patients with cancer treated on study. Clinical trial enrollment was evaluated at The University of Texas MD Anderson Cancer Center's Multidisciplinary Prostate Cancer Clinic (MPCC) to assess whether a clinical trial initiative, introduced in 2006, impacted enrollment. The trial initiative included posting trial-specific information in clinic, educating patients about appropriate clinical trial options during the treatment recommendation discussion, and providing patients with trial-specific educational information. The investigators evaluated the frequency of clinical trial enrollment for men with newly diagnosed prostate cancer seen in the MPCC from 2004 to 2008. Logistic regression evaluated the impact of patient characteristics and the clinical trial initiative on trial enrollment. The median age of the 1370 men was 64 years; 32% had low-risk, 49% had intermediate-risk, and 19% had high-risk disease. Overall, 74% enrolled in at least one trial and 29% enrolled in more than one trial. Trial enrollment increased from 39% before the initiative (127/326) to 84% (880/1044) after the trial initiative. Patient enrollment increased in laboratory studies (from 25% to 80%), quality-of-life studies (from 10% to 26%), and studies evaluating investigational treatments and systemic agents (from 6% to 15%) after the trial initiative. In multivariate analysis, younger men (P<.001) and men seen after implementation of the clinical trial initiative (P<.001) were more likely to enroll in trials. Clinical trial enrollment in the MPCC was substantially higher than that seen nationally in adult patients with cancer, and enrollment rates increased after the introduction of a clinical trial initiative.

Proton therapy toxicity outcomes for localized prostate cancer: Long-term results at a comprehensive cancer center.

Background: Proton therapy (PT) has unique biologic properties with excellent clinical outcomes for the management of localized prostate cancer. Here, we aim to characterize the toxicity of PT for patients with localized prostate cancer and propose mitigation strategies using a large institutional database. Methods: We reviewed medical records of 2772 patients with localized prostate cancer treated with definitive PT between May 2006 through January 2020. Disease risk was stratified according to National Comprehensive Cancer Network guidelines as low [LR, n = 640]; favorable-intermediate [F-IR, n = 849]; unfavorable-intermediate [U-IR, n = 851]; high [HR, n = 315]; or very high [VHR, n = 117]. Descriptive statistics and Kaplan-Meier estimates assessed toxicity and freedom from biochemical relapse (FFBR). Results: Median follow-up was 7.0 years. The median dose was 78 Gy(RBE)(range: 72-79.2 Gy) in 2.0 Gy(RBE) fractions; 63 % of patients received 78 Gy(RBE) in 39 fractions, and 29 % received 76 Gy(RBE) in 38 fractions. Overall rates of late grade ≥3 GU and GI toxicity were 0.87 % and 1.01 %, respectively. Two patients developed grade 4 late GU toxicity and seven patients with grade 4 late GI toxicity. All patients experiencing severe late grade 4 toxicities were treated to 78 Gy(RBE) in 39 fractions with 80 Gy(RBE) dose to the anterior rectal wall and/or bladder neck. The 10-year FFBR rates for patients with LR to U-IR disease were compared between those treated with 76 and 78 Gy(RBE); the rates were 94.5 % (95 % confidence interval [CI] 92.4-96.0 %) and 93.2 % (95 % CI 91.3-95.7 %), respectively (log-rank p = 0.22). Conclusions: Proton therapy is associated with low rates of late grade ≥3 GU and GI toxicity. While rare, late grade 4 toxicities occurred in nine (0.3 %) patients. De-escalation to a total dose of 76 Gy(RBE) yields excellent clinical outcomes for patients with LR to U-IR disease with the potential for significant reductions in grade ≥3 late toxicity.

Tissue-type plasminogen activator regulates the neuronal uptake of glucose in the ischemic brain.

The ability to sense and adapt to hypoxic conditions plays a pivotal role in neuronal survival. Hypoxia induces the release of tissue-type plasminogen activator (tPA) from cerebral cortical neurons. We found that the release of neuronal tPA or treatment with recombinant tPA promotes cell survival in cerebral cortical neurons previously exposed to hypoxic conditions in vitro or experimental cerebral ischemia in vivo. Our studies using liquid chromatography and tandem mass spectrometry revealed that tPA activates the mammalian target of rapamycin (mTOR) pathway, which adapts cellular processes to the availability of energy and metabolic resources. We found that mTOR activation leads to accumulation of the hypoxia-inducible factor-1α (HIF-1α) and induction and recruitment to the cell membrane of the HIF-1α-regulated neuronal transporter of glucose GLUT3. Accordingly, in vivo positron emission tomography studies with 18-fluorodeoxyglucose in mice overexpressing tPA in neurons show that neuronal tPA induces the uptake of glucose in the ischemic brain and that this effect is associated with a decrease in the volume of the ischemic lesion and improved neurological outcome following the induction of ischemic stroke. Our data indicate that tPA activates a cell signaling pathway that allows neurons to sense and adapt to oxygen and glucose deprivation.

Long-term outcomes for men with high-risk prostate cancer treated definitively with external beam radiotherapy with or without androgen deprivation.

BACKGROUND: Men with high-risk prostate cancer are often thought to have very poor outcomes in terms of disease control and survival even after definitive treatment. However, results after external beam radiotherapy have improved significantly through dose escalation and the use of androgen deprivation therapy (ADT). This report describes long-term findings after low-dose (< 75.6 Gy) or high-dose (≥ 75.6 Gy) external beam radiation, with or without ADT. METHODS: This analysis included 741 men with high-risk prostate cancer (clinical classification ≥ T3, Gleason score ≥ 8, or prostate-specific antigen level ≥ 20 ng/mL) treated with external beam radiotherapy at a single tertiary institution from 1987 through 2004. The radiation dose ranged from 60 to 79.3 Gy (median, 70 Gy); 295 men had received ADT for ≥ 2 years, and the median follow-up time was 8.3 years. RESULTS: The 5- and 10-year actuarial overall survival rates were significantly better for men treated with the higher radiation dose (no ADT plus ≥ 75.6 Gy, 87.3% and 72.0%, respectively; and ADT plus ≥ 75.6 Gy, 92.3% and 72%, respectively) (P = .0035). The corresponding 5- and 10-year biochemical failure-free survival rates were significantly better for patients treated with both ADT and higher radiation dose (82% and 77%, P < .0001). At 5 years, men who had not received ADT and had received radiation dose < 75.6 Gy had higher clinical local failure rates than those given ADT and radiation dose ≥ 75.6 Gy (24.2% versus 0%, P < .0001). The 10-year symptomatic local failure rate was only 2% for all patients. CONCLUSIONS: Contrary to lingering historical perceptions, treatment of high-risk prostate cancer with modern, high-dose, external beam radiotherapy and ADT can produce better biochemical, clinical, and survival outcomes over those from previous eras. Specifically, symptomatic local failure is uncommon, and few men die of prostate cancer even 10 or more years after treatment.

Proton therapy for the management of localized prostate cancer: Long-term clinical outcomes at a comprehensive cancer center.

BACKGROUND AND PURPOSE: Proton therapy (PT) has emerged as a standard-of-care treatment option for localized prostate cancer at our comprehensive cancer center. However, there are few large-scale analyses examining the long-term clinical outcomes. Therefore, this article aims to evaluate the long-term effectiveness and toxicity of PT in patients with localized prostate cancer. MATERIALS AND METHODS: Review of 2772 patients treated from May 2006 through January 2020. Disease risk was stratified according to National Comprehensive Cancer Network guidelines as low [LR, n = 640]; favorable-intermediate [F-IR, n = 850]; unfavorable-intermediate [U-IR, n = 851]; high [HR, n = 315]; or very high [VHR, n = 116]. Biochemical failure and toxicity were analyzed using Kaplan-Meier estimates and multivariate models. RESULTS: The median patient age was 66 years; the median follow-up time was 7.0 years. Pelvic lymph node irradiation was prescribed to 28 patients (1%) (2 [0.2%] U-IR, 11 [3.5%] HR, and 15 [12.9%] VHR). The median dose was 78 Gy in 1.8-2.0 Gy(RBE) fractions. Freedom from biochemical relapse (FFBR) rates at 5 years and 10 years were 98.2% and 96.8% for the LR group; 98.3% and 93.6%, F-IR; 94.2% and 90.2%, U-IR; 94.3% and 85.2%, HR; and 86.1% and 68.5%, VHR. Two patients died of prostate cancer. Overall rates of late grade ≥ 3 GU and GI toxicity were 0.87% and 1.01%. CONCLUSIONS: Proton therapy for localized prostate cancer demonstrated excellent clinical outcomes in this large cohort, even among higher-risk groups with historically poor outcomes despite aggressive therapy.

Effectiveness of a novel gas-release endorectal balloon in the removal of rectal gas for prostate proton radiation therapy.

Endorectal balloons (ERBs) are routinely used in prostate proton radiation therapy to immobilize the prostate and spare the rectal wall. Rectal gas can distend the rectum and displace the prostate even in the presence of ERBs. The purpose of this work was to quantify the effects an ERB with a passive gas release conduit had on the incidence of rectal gas. Fifteen patients who were treated with a standard ERB and 15 with a gas-release ERB were selected for this retrospective study. Location and cross-sectional area of gas pockets and the fraction of time they occurred on 1133 lateral kilovoltage (kV) images were analyzed. Gas locations were classified as trapped between the ERB and anterior rectal wall, between the ERB and posterior rectal wall, or superior to the ERB. For patients using the standard ERB, gas was found in at least one region in 45.8% of fractions. Gas was trapped in the anterior region in 37.1% of fractions, in the posterior region in 5.0% of fractions, and in the sigmoid region in 9.6% of fractions. For patients using the ERB with the gas-release conduit, gas was found in at least one region in 19.7% of fractions. Gas was trapped in the anterior region in 5.6% of fractions, in the posterior region in 8.3% of fractions, and in the sigmoid region in 7.4% of fractions. Both the number of fractions with gas in the anterior region and the number of fractions with gas in at least one region were significantly higher in the former group than in the latter. The cross-sectional area of trapped gas did not differ between the two groups. Thus gas-release balloon can effectively release gas, and may be able to improve clinical workflow by reducing the need for catheterization.

Endoscopically assisted decompression for pronator syndrome.

PURPOSE: Traditional surgical management for pronator syndrome results in a relatively long and possibly disfiguring scar across the antecubital fossa. The purposes of this study were to present an endoscopic technique that facilitates the decompression of the proximal median nerve without extensile incisions, and to evaluate whether this minimally invasive procedure could adequately and safely treat the condition to improve outcome scores. METHODS: We treated 13 patients (14 cases) with isolated pronator syndrome with endoscopically assisted decompression and retrospectively reviewed them. We excluded patients with concomitant carpal tunnel syndrome or other compression neuropathies. The average age of the patient at presentation was 41 years. Final follow-up averaged 22 months. We asked all patients to rate their preoperative and postoperative condition and functional capabilities using the validated Disabilities of the Shoulder, Arm, and Hand (DASH) scoring protocol. RESULTS: All 13 patients improved symptomatically as reflected in the DASH score assessment. The preoperative scores averaged 56 and the postoperative scores were significantly reduced and averaged 6. There were 3 minor complications, which resolved spontaneously. CONCLUSIONS: The endoscopically assisted, minimally invasive approach to treat pronator syndrome adequately and safely decompressed all anatomical points of compression and improved DASH scores. This may reduce morbidity and facilitate a quicker recovery compared with the traditional open incision techniques. TYPE OF STUDY/LEVEL OF EVIDENCE: Therapeutic IV.

Exploring Psychosocial Dynamics Underpinning Driver Identity in an Older Adult Sample.

Many older adults consider driving a crucial aspect of their daily routine and the prospect of driving cessation to be disruptive to their current lifestyle. Driving cessation is associated with multiple adverse consequences, including poorer health trajectories, and increased depressive symptoms. Research suggests that driving cessation may be disruptive to identity. This study aimed to explore the characteristics that are associated with driver identity and whether identity impacted people's readiness for mobility changes. Of interest was whether stopping driving was perceived as either a positive or negative event. Participants, (N = 410) older adults recruited via Prolific survey panel between July and November 2021, responded to questions about transport and travel behaviors, driver identity, and perceptions of mobility changes. Driving cessation was generally perceived as a negative change. However, individuals with self-reported low readiness for mobility change also had higher overall scores for Identity, and for the subscales, Centrality and Ingroup Affect. These findings suggest that people with more concerns for mobility transition may think about and have more of an emotional investment regarding driving. The findings provide novel insight into the psychosocial dynamics of driving and the factors that influence driver identity, however further research, co-designed with older drivers and retired drivers is required.

Quantitative analysis of beam delivery parameters and treatment process time for proton beam therapy.

PURPOSE: To evaluate patient census, equipment clinical availability, maximum daily treatment capacity, use factor for major beam delivery parameters, and treatment process time for actual treatments delivered by proton therapy systems. METHODS: The authors have been recording all beam delivery parameters, including delivered dose, energy, range, spread-out Bragg peak widths, gantry angles, and couch angles for every treatment field in an electronic medical record system. We analyzed delivery system downtimes that had been recorded for every equipment failure and associated incidents. These data were used to evaluate the use factor of beam delivery parameters, the size of the patient census, and the equipment clinical availability of the facility. The duration of each treatment session from patient walk-in and to patient walk-out of the treatment room was measured for 82 patients with cancers at various sites. RESULTS: The yearly average equipment clinical availability in the last 3 yrs (June 2007-August 2010) was 97%, which exceeded the target of 95%. Approximately 2200 patients had been treated as of August 2010. The major disease sites were genitourinary (49%), thoracic (25%), central nervous system (22%), and gastrointestinal (2%). Beams have been delivered in approximately 8300 treatment fields. The use factor for six beam delivery parameters was also evaluated. Analysis of the treatment process times indicated that approximately 80% of this time was spent for patient and equipment setup. The other 20% was spent waiting for beam delivery and beam on. The total treatment process time can be expressed by a quadratic polynomial of the number of fields per session. The maximum daily treatment capacity of our facility using the current treatment processes was estimated to be 133 +/- 35 patients. CONCLUSIONS: This analysis shows that the facility has operated at a high performance level and has treated a large number of patients with a variety of diseases. The use factor of beam delivery parameters varies by disease site. Further improvements in efficiency may be realized in the equipment- and patient-related processes of treatment.

Characterization of dose impact on IMRT and VMAT from couch attenuation for two Varian couches.

In intensity-modulated radiation therapy (IMRT) and volumetric-modulated arc therapy (VMAT), the use of posterior oblique beams has become common. Beam attenuation by the treatment couch is not negligible when the couch is in the beam portal. In this study, we established the relationship of relative dose vs. beam angle for two Varian 21EX linacs, one equipped with the Exact couch (standard couch) with sliding side support rails, and the other equipped with the Exact image-guided radiation therapy (IGRT) carbon fiber couch. Measurements were performed using an ion chamber placed at the center of an acrylic cylindrical phantom positioned at the linac isocenter for 6 MV and 18 MV photon beams. Measurements were performed at three different field sizes (3 × 3, 5 × 5, and 10 × 10 cm2), and were repeated with the phantom positioned at different longitudinal locations on the couches. To evaluate beam attenuation by the standard couch in a clinical setting, two test IMRT plans and two test VMAT plans on the standard couch were delivered. The plans were generated with the sliding rails at the "in" position and delivered with the rails at both "in" and "out" positions. The dose difference to the ion chamber was determined. For oblique fields with 6 MV photons, the standard couch attenuated the radiation beam by up to 26.8%, while the carbon fiber IGRT couch attenuated the beam by up to 4.1%. In the clinical evaluation, the highest dose difference between rails set at the "in" and "out" positions was 2.6% in the IMRT case and 2.1% in the VMAT case. The magnitude of potential dose difference has been quantified and could be used for a quick estimation of dose difference due to couch attenuation in IMRT and VMAT.

Beam-Specific Spot Guidance and Optimization for PBS Proton Treatment of Bilateral Head and Neck Cancers.

PURPOSE: A multi-field optimization (MFO) technique that uses beam-specific spot placement volumes (SPVs) and spot avoidance volumes (SAVs) is introduced for bilateral head and neck (H&N) cancers. These beam-specific volumes are used to guide the optimizer to consistently achieve optimal organ-at-risk (OAR) sparing with target coverage and plan robustness. MATERIALS AND METHODS: Implementation of this technique using a 4-beam, 5-beam, and variant 5-beam arrangement is discussed. The generation of beam-specific SPVs and SAVs derived from target and OARs are shown. The SPVs for select fields are further partitioned into optimization volumes for uniform dose distributions that resemble those of single-field optimization (SFO). A conventional MFO plan that does not use beam-specific spot placement guidance (MFOcon) and an MFO plan that uses only beam-specific SPV (MFOspv) are compared with current technique (MFOspv/sav), using both simulated scenarios and forward-calculated plans on weekly verification computed tomography (VFCT) scans. RESULTS: Dose distribution characteristics of the 4-beam, 5-beam, and variant 5-beam technique are demonstrated with discussion on OAR sparing. When comparing the MFOcon, MFOspv, and MFOspv/sav, the MFOspv/sav is shown to have superior OAR sparing in 9 of the 14 OARs examined. It also shows clinical plan robustness when evaluated by using both simulated uncertainty scenarios and forward-calculated weekly VFCTs throughout the 7-week treatment course. CONCLUSION: The MFOspv/sav technique is a systematic approach using SPVs and SAVs to guide the optimizer to consistently reach desired OAR dose values and plan robustness.

Endogenous Retrovirus Activation as a Key Mechanism of Anti-Tumor Immune Response in Radiotherapy.

The generation of DNA double-strand breaks has historically been taught as the mechanism through which radiotherapy kills cancer cells. Recently, radiation-induced cytosolic DNA release and activation of the cGAS/STING pathway, with ensuing induction of interferon secretion and immune activation, have been recognized as important mechanisms for radiation-mediated anti-tumor efficacy. Here we demonstrate that radiation-induced activation of endogenous retroviruses (ERVs) also plays a major role in regulating the anti-tumor immune response during irradiation. Radiation-induced ERV-associated dsRNA transcription and subsequent activation of the innate antiviral MDA5/MAVS/TBK1 pathway led to downstream transcription of interferon-stimulated genes. Additionally, genetic knockout of KAP1, a chromatin modulator responsible for suppressing ERV transcription sites within the genome, enhanced the effect of radiation-induced anti-tumor response in vivo in two different tumor models. This anti-tumor response was immune-mediated and required an intact host immune system. Our findings indicate that radiation-induced ERV-dsRNA expression and subsequent immune response play critical roles in clinical radiotherapy, and manipulation of epigenetic regulators and the dsRNA-sensing innate immunity pathway could be promising targets to enhance the efficacy of radiotherapy and cancer immunotherapy.