Early Palliative Care Reduces End-of-Life Intensive Care Unit (ICU) Use but Not ICU Course in Patients with Advanced Cancer.

BACKGROUND: Early palliative care for advanced cancer patients improves quality of life and survival, but less is known about its effect on intensive care unit (ICU) use at the end of life. This analysis assessed the effect of a comprehensive early palliative care program on ICU use and other outcomes among patients with advanced cancer. PATIENTS AND METHODS: A retrospective cohort of patients with advanced cancer enrolled in an early palliative care program (n = 275) was compared with a concurrent control group of patients receiving standard care (n = 195) during the same time period by using multivariable logistic regression analysis. The multidisciplinary outpatient palliative care program used early end-of-life care planning, weekly interdisciplinary meetings to discuss patient status, and patient-reported outcomes assessment integrated within the electronic health record. RESULTS: Patients in the control group had statistically significantly higher likelihood of ICU admission at the end of life (odds ratios [ORs]: last 6 months, 3.07; last month, 3.59; terminal admission, 4.69), higher likelihood of death in the hospital (OR, 4.14) or ICU (OR, 5.57), and lower likelihood of hospice enrollment (OR, 0.13). Use of chemotherapy or radiation did not significantly differ between groups, nor did length of ICU stay, code status, ICU procedures (other than cardiopulmonary resuscitation), disposition location, and outcomes after ICU admission. CONCLUSION: Early palliative care significantly reduced ICU use at the end of life but did not change ICU events. This study supports early initiation of palliative care for advanced cancer patients before hospitalizations and intensive care. The Oncologist 2017;22:318-323 IMPLICATIONS FOR PRACTICE: Palliative care has shown clear benefit in quality of life and survival in advanced cancer patients, but less is known about its effect on intensive care. This retrospective cohort study at a university hospital showed that in the last 6 months of life, palliative care significantly reduced intensive care unit (ICU) and hospital admissions, reduced deaths in the hospital, and increased hospice enrollment. It did not, however, change patients' experiences within the ICU, such as number of procedures, code status, length of stay, or disposition. The findings further support that palliative care exerts its benefit before, rather than during, the ICU setting.

Longitudinal patterns of cancer patient reported outcomes in end of life care predict survival.

PURPOSE: Patients with advanced cancer typically demonstrate sharp deterioration in physical function and psychological status during the last months of life. This study evaluates the relationship between survival in patients with advanced cancer and longitudinal assessment of anxiety, depression, fatigue, pain interference, and/or physical function using the US National Institute of Health Patient Reported Outcomes Information System. METHODS: Mixed-effects models were used to evaluate patient-reported outcome trajectories over time among patients with advanced loco-regional or metastatic cancer receiving care in a hospital-based palliative care clinic. Cox regression analysis was used to assess the statistical significance of differences in the probability of survival associated with patient-reported outcome scores. RESULTS: A total of 472 patients completed 1992 assessments during the 18-month study period. Longitudinal scores for fatigue, pain interference, and physical function demonstrated statistically significant non-linear trajectories. Scores for depression, fatigue, pain interference, and physical function were highly statistically significant predictors of survival (p < 0.01). Clinically meaningful differences in the probability of survival were demonstrated between patients with scores at the 25th vs. 75th percentiles, with absolute differences in survival at 6 and 12 months after assessment from 10 to 18 percentage points. CONCLUSIONS: Patient-reported outcomes can be used to reliably estimate where patients are along the trajectory of deteriorating health status leading toward the end of life, and for identifying patients with declining symptoms in need of referral to palliative care or more aggressive symptom management.

How dose sparing of cardiac structures correlates with in-field heart volume and sternal displacement.

Cardiac irradiation increases the risk of coronary artery disease in patients with left-sided breast cancer. Techniques exist to reduce cardiac irradiation, but the optimum technique depends on individual patient anatomy and physiology. We investigated the correlation of delta heart volume in field (dHVIF) and sternal excursion with dose sparing in heart and left anterior descending artery (LAD) to develop quantitative predictive models for expected dose to heart and LAD. A treatment planning study was performed on 97 left-breast cancer patients who underwent whole breast radiotherapy (prescription dose = 50 Gy) under deep inspiratory breath hold (DIBH). Two CT datasets, free breathing (FB) and DIBH, were utilized for treatment planning and for determination of the internal anatomy-based DIBH amplitude. The mean heart and LAD dose were compared between FB and DIBH plans and dose to the heart and LAD as a function of dHVIF and sternal excursion were determined. The [Average (STD); Range] mean heart doses from free breathing and DIBH are [120.5(65.2); 28.9 ~ 393.8] cGy and [67.5(25.1); 19.7 ~ 145.6] cGy, respectively. The mean LAD doses from free breathing and DIBH are [571.0(582.2); 42.2 ~ 2332.2] cGy and [185.9(127.0); 41.2 ~ 898.4] cGy, respectively. The mean dose reductions with DIBH are [53.1(50.6); -15.4 ~ 295.1] cGy for the heart and [385.1(513.4); -0.6 ~ 2105.8] cGy for LAD. Percent mean dose reductions to the heart and LAD with DIBH are 44% (p < 0.0001) and 67% (p < 0.0001), respectively, compared to FB. The dHVIF mean dose reduction correlation is 8.1 cGy/cc for the heart and 81.6 cGy/cc for LAD (with linear trend and y intercept: 26.0 cGy for the heart, 109.1 cGy for LAD). DIBH amplitude using sternal position was [1.3(.48); .38 ~ 2.5] cm. The DIBH amplitude mean dose reduction correlation is 14 cGy/cm for the heart and 212cGy/cm for LAD (with linear trend with y intercept: 35.6 cGy for the heart, 102.4 cGy for LAD). The strong correlation of dose sparing to the heart and LAD with dHVIF and sternal excursion suggests that mean dose sparing to heart and LAD can be predicted with either dHVIF or sternal excursion equally well. The metrics proposed could be utilized to allow providers to determine the relative dosimetric benefits of different heart-sparing techniques as early as time of consultation.

A Phase I/II adaptive design for heterogeneous groups with application to a stereotactic body radiation therapy trial.

Dose-finding studies that aim to evaluate the safety of single agents are becoming less common, and advances in clinical research have complicated the paradigm of dose finding in oncology. A class of more complex problems, such as targeted agents, combination therapies and stratification of patients by clinical or genetic characteristics, has created the need to adapt early-phase trial design to the specific type of drug being investigated and the corresponding endpoints. In this article, we describe the implementation of an adaptive design based on a continual reassessment method for heterogeneous groups, modified to coincide with the objectives of a Phase I/II trial of stereotactic body radiation therapy in patients with painful osseous metastatic disease. Operating characteristics of the Institutional Review Board approved design are demonstrated under various possible true scenarios via simulation studies.

Agonist-induced Ca2+ sensitization in smooth muscle: redundancy of Rho guanine nucleotide exchange factors (RhoGEFs) and response kinetics, a caged compound study.

Many agonists, acting through G-protein-coupled receptors and Gα subunits of the heterotrimeric G-proteins, induce contraction of smooth muscle through an increase of [Ca(2+)]i as well as activation of the RhoA/RhoA-activated kinase pathway that amplifies the contractile force, a phenomenon known as Ca(2+) sensitization. Gα12/13 subunits are known to activate the regulator of G-protein signaling-like family of guanine nucleotide exchange factors (RhoGEFs), which includes PDZ-RhoGEF (PRG) and leukemia-associated RhoGEF (LARG). However, their contributions to Ca(2+)-sensitized force are not well understood. Using permeabilized blood vessels from PRG(-/-) mice and a new method to silence LARG in organ-cultured blood vessels, we show that both RhoGEFs are activated by the physiologically and pathophysiologically important thromboxane A2 and endothelin-1 receptors. The co-activation is the result of direct and independent activation of both RhoGEFs as well as their co-recruitment due to heterodimerization. The isolated recombinant C-terminal domain of PRG, which is responsible for heterodimerization with LARG, strongly inhibited Ca(2+)-sensitized force. We used photolysis of caged phenylephrine, caged guanosine 5'-O-(thiotriphosphate) (GTPγS) in solution, and caged GTPγS or caged GTP loaded on the RhoA·RhoGDI complex to show that the recruitment and activation of RhoGEFs is the cause of a significant time lag between the initial Ca(2+) transient and phasic force components and the onset of Ca(2+)-sensitized force.

Diagnostic Delay in HPV-Related Oropharyngeal Squamous Cell Carcinoma.

Introduction Human papillomavirus-related (HPV + ) oropharyngeal squamous cell carcinoma (OPSCC) is increasing in incidence and presents diagnostic challenges given its unique clinical presentation. Objective The purpose of the present study is to characterize the impact of the unique clinical presentation of HPV-related OPSCC on delays in diagnosis. Methods Retrospective review of presenting symptoms and clinical characteristics of 284 patients with OPSCC treated from 2002-2014. Delay in diagnosis was defined as the presence of any of the following: multiple non-diagnostic fine needle aspirate (FNA) biopsies; two or more courses of antibiotic therapy; surgery with incorrect preoperative diagnosis; evaluation by an otolaryngologist without further workup; or surgery without definitive postoperative diagnosis. Results p16+ tumors demonstrated a distinct clinical presentation that more commonly involved a neck mass (85.1% versus 57.3% of p16-; p < 0.001) and less frequently included odynophagia (24.6% versus 51.7% of p16-; p < 0.001). Patients who experienced diagnostic delay were more likely to have p16+ tumors (77.7% delayed versus 62.8% not delayed; p = 0.006). p16+ primary tumors were more likely to be undetectable by physical examination of the head and neck including flexible laryngoscopy (19.0% versus 6.7% of p16-; p = 0.007) and more frequently associated with nondiagnostic FNA biopsies of a cervical nodal mass (11.8% versus 3.4% of p16-, p = 0.03). Conclusions Compared with non-HPV related OPSCC, the unique clinical presentation and characteristics of HPV+ OPSCC are associated with an increased incidence of diagnostic delay. Targeted education of appropriate care providers may improve time to diagnosis and treatment.

Novel HPV Associated Oropharyngeal Squamous Cell Carcinoma Surveillance DNA Assay Cost Analysis.

OBJECTIVES: We aim to propose a modified surveillance strategy using a novel blood assay that detects plasma circulating tumor-specific HPV DNA with reported 100% NPV and 94% PPV as the main method of detection to understand the cost implications of potentially avoiding routine imaging and surveillance visits at our institution. METHODS: We performed a retrospective chart review focusing on recurrences in p16+ patients with OPSCC and defined two surveillance strategies: "Strategy A", follow-up visits with flexible laryngoscopy (FL) plus regular imaging studies; "Strategy B", follow-up visits with FL plus regular NavDx assays and imaging used at the discretion of the physician(s) in cases of high clinical suspicion. RESULTS: Of the p16+ OPSCC patients (n = 214), 23 had confirmed recurrence (11%). Standard work-flow model determined 72 imaging studies and 2198 physical examinations with FL were needed to detect one recurrence. Potential individual patient cost reduction during surveillance was 42%. CONCLUSION: Implementing NavDx for HPV + OPSCC surveillance would benefit patients by reducing costs and unnecessary diagnostic testing. LEVEL OF EVIDENCE: Step/Level 3 Laryngoscope, 133:3006-3012, 2023.

Cisplatin and fluorouracil alone or with docetaxel in head and neck cancer.

BACKGROUND: A randomized phase 3 trial of the treatment of squamous-cell carcinoma of the head and neck compared induction chemotherapy with docetaxel plus cisplatin and fluorouracil (TPF) with cisplatin and fluorouracil (PF), followed by chemoradiotherapy. METHODS: We randomly assigned 501 patients (all of whom had stage III or IV disease with no distant metastases and tumors considered to be unresectable or were candidates for organ preservation) to receive either TPF or PF induction chemotherapy, followed by chemoradiotherapy with weekly carboplatin therapy and radiotherapy for 5 days per week. The primary end point was overall survival. RESULTS: With a minimum of 2 years of follow-up (> or =3 years for 69% of patients), significantly more patients survived in the TPF group than in the PF group (hazard ratio for death, 0.70; P=0.006). Estimates of overall survival at 3 years were 62% in the TPF group and 48% in the PF group; the median overall survival was 71 months and 30 months, respectively (P=0.006). There was better locoregional control in the TPF group than in the PF group (P=0.04), but the incidence of distant metastases in the two groups did not differ significantly (P=0.14). Rates of neutropenia and febrile neutropenia were higher in the TPF group; chemotherapy was more frequently delayed because of hematologic adverse events in the PF group. CONCLUSIONS: Patients with squamous-cell carcinoma of the head and neck who received docetaxel plus cisplatin and fluorouracil induction chemotherapy plus chemoradiotherapy had a significantly longer survival than did patients who received cisplatin and fluorouracil induction chemotherapy plus chemoradiotherapy. (ClinicalTrials.gov number, NCT00273546 [ClinicalTrials.gov].).

Effects of breathing variation on gating window internal target volume in respiratory gated radiation therapy.

PURPOSE: To investigate the effects of breathing variation on gating window internal target volume (ITVGW) in respiratory gated radiation therapy. METHOD AND MATERIALS: Two-dimensional dynamic MRI (dMRI) of lung motion was acquired in ten volunteers and eight lung cancer patients. Resorted dMRI using 4DCT acquisition method (RedCAM) was generated for selected subjects by simulating the image rebinning process. A dynamic software generated phantom (dSGP) was created by moving a solid circle (to mimic the "tumor") with dMRI-determined motion trajectories. The gating window internal target area (ITAGw, 2D counterpart of ITVGW) was determined from both RedCAM and dSGP/dMRI. Its area (A), major axis (L1), minor axis (L2), and similarity (S) were calculated and compared. RESULTS: In the phantom study of 3 cm tumor, measurements of the ITAGW from dSGP (A =10.0 +/- 1.3 cm2, L1=3.8 +/- 0.4 cm, and L2=3.3 +/- 0.1 cm) are significantly (p <0.001) greater than those from RedCAM (A=8.5 +/- 0.7 cm(2), L1 =3.5 +/- 0.2 cm, and L2=3.1 +/- 0.1 cm). Similarly, the differences are significantly greater (p <0.001) for the 1 cm tumor (A=1.9 +/- 0.5 cm(2), L1 =1.9 +/- 0.4 cm, and L2=1.3 +/- 0.1 cm in dSGP; A=l1.3 +/- 0.1 cm(2), L1=1.5 +/- 0.2 cm, and L2 = 1.1 +/- 0.1 cm in RedCAM). In patient studies, measurements of the ITAGW from dMRI (A =15.5 +/- 8.2 cm(2), Ll=5.0 +/- 1.1 cm, and L2=3.8 +/- 1.2 cm) are also significantly greater (p <0.05) than those from RedCAM (A=13.2 +/- 8.5 cm(2), L1=4.3 +/- 1.4 cm, and L2=3.7 +/- 1.2 cm). Similarities were 0.9 +/- 0.1, 0.8 +/- 0.1, and 0.8 +/- 0.1 in the 3 cm tumor phantom, 1 cm tumor phantom, and patient studies, respectively. CONCLUSION: ITVGW can be underestimated by 4DCT due to breathing variations. An additional margin may be needed to account for this potential error in generating a PTVGW. Cautions need to be taken when generating ITVGW from 4DCT in respiratory gated radiation therapy, especially for small tumors (<3 cm) with a large motion range (>1 cm).

STAT RAD: Prospective Dose Escalation Clinical Trial of Single Fraction Scan-Plan-QA-Treat Stereotactic Body Radiation Therapy for Painful Osseous Metastases.

PURPOSE: Radiation therapy is a well-established treatment for symptomatic bone metastases. Despite continued advances in both planning techniques and treatment delivery, the standard workflow has remained relatively unchanged, often requiring 1 to 3 weeks and resulting in patient inconvenience and delayed palliation. We developed an expedited method wherein computed tomography simulation, treatment planning, quality assurance, and treatment delivery are performed in 1 day. This prospective pilot clinical trial evaluates the safety, efficacy, and patient satisfaction of this rapid workflow. METHODS AND MATERIALS: Patients with 1 to 3 painful bone metastases were prospectively enrolled and treated with 1 fraction of stereotactic body radiation therapy, using a same-day Scan-Plan-QA-Treat workflow, termed STAT RAD, in a phase 1/2 dose escalation trial from 8 Gy to 15 Gy per fraction. Bone pain, opioid use, patient satisfaction, performance status, and quality of life were evaluated before and at 1, 4, 8, 12, 26, and 52 weeks after treatment. Outcomes and treatment-related toxicity were analyzed. RESULTS: A total of 49 patients were enrolled, and 46 patients with 60 bone metastases were treated per the protocol. Partial or greater pain response occurred in 50% of patients at 1 week, 75% of patients at 8 weeks, 68.7% of patients at 6 months, and 33.3% of patients at 12 months. There were 2 grade-3 toxicities, including 1 spinal fracture associated with disease progression and hyperbilirubinemia. Reirradiation was required in 16.7% of treated lesions at a median time to retreatment of 4.9 months. Most patient responses (78.6%) indicated that patients would choose this workflow again. CONCLUSIONS: The results demonstrate that treating bone metastases with palliative stereotactic body radiation therapy via a single-fraction, patient-centric workflow is feasible and safe with doses up to 15 Gy. However, pain response decreased at 12 months and was associated with a 16.7% retreatment rate, which suggests that further dose escalation is warranted.

Tracking brain motion during the cardiac cycle using spiral cine-DENSE MRI.

Cardiac-synchronized brain motion is well documented, but the accurate measurement of such motion on the pixel-by-pixel basis has been hampered by the lack of proper imaging technique. In this article, the authors present the implementation of an autotracking spiral cine displacement-encoded stimulation echo (DENSE) magnetic resonance imaging (MRI) technique for the measurement of pulsatile brain motion during the cardiac cycle. Displacement-encoded dynamic MR images of three healthy volunteers were acquired throughout the cardiac cycle using the spiral cine-DENSE pulse sequence gated to the R wave of an electrocardiogram. Pixelwise Lagrangian displacement maps were computed, and 2D displacement as a function of time was determined for selected regions of interests. Different intracranial structures exhibited characteristic motion amplitude, direction, and pattern throughout the cardiac cycle. Time-resolved displacement curves revealed the pathway of pulsatile motion from brain stem to peripheral brain lobes. These preliminary results demonstrated that the spiral cine-DENSE MRI technique can be used to measure cardiac-synchronized pulsatile brain motion on the pixel-by-pixel basis with high temporal/spatial resolution and sensitivity.

STAT RT: a prospective pilot clinical trial of Scan-Plan-QA-Treat stereotactic body radiation therapy for painful osseous metastases.

BACKGROUND: Planning and treatment of bone metastases with palliative radiotherapy often requires 1-3 weeks, resulting in patient inconvenience and delayed palliation. We developed an expedited workflow that delivers palliative stereotactic body radiation therapy (SBRT) to painful bone metastases in which CT, planning, quality assurance (QA), and initial treatment are performed one day. This prospective pilot clinical trial evaluates the feasibility, safety, efficacy, and patient satisfaction of this workflow. METHODS: Patients with 1-3 painful bone metastases were prospectively enrolled and treated with 2-5 fractions of 5-10 Gy per fraction. Bone pain, opioid use, patient satisfaction, performance status, and quality of life were evaluated prior to and at 1, 4, 8, 12, 26, and 52 weeks post treatment. Outcomes and treatment-related toxicity were analyzed. RESULTS: Twenty-eight patients were enrolled and 37 metastases treated, receiving an average of 21.6 Gy in 3.1 fractions. Median time from CT simulation to 1st treatment was 6.6 hours. Average worst pain scores were significantly lower at all post-treatment time points with maximal response noted at 3 months. Opioid use was not significantly different from baseline at any follow up. Performance status was significantly increased only at week 12. Bone pain quality of life was significantly increased at all time points except at 52 weeks while general quality of life was significantly increased at only weeks 8 and 26. Ninety-two percent of patients reported being mostly or completely satisfied with the treatment results from week 8 until the end of follow-up. There was no grade 3 or higher toxicities. CONCLUSIONS: Results demonstrate that treating bone metastases with palliative SBRT via a multi-fraction Scan-Plan-QA-Treat patient centric workflow is feasible and safe. Although performance status, general quality of life, and opioid use were not significantly altered, patient satisfaction was high with this same-day treatment workflow.

Diagnostic Delay in HPV-Related Oropharyngeal Squamous Cell Carcinoma

Abstract Introduction Human papillomavirus-related (HPV +) oropharyngeal squamous cell carcinoma (OPSCC) is increasing in incidence and presents diagnostic challenges given its unique clinical presentation. Objective The purpose of the present study is to characterize the impact of the unique clinical presentation of HPV-related OPSCC on delays in diagnosis. Methods Retrospective review of presenting symptoms and clinical characteristics of 284 patients with OPSCC treated from 2002-2014. Delay in diagnosis was defined as the presence of any of the following: multiple non-diagnostic fine needle aspirate (FNA) biopsies; two or more courses of antibiotic therapy; surgery with incorrect preoperative diagnosis; evaluation by an otolaryngologist without further workup; or surgery without definitive postoperative diagnosis. Results p16+ tumors demonstrated a distinct clinical presentation that more commonly involved a neck mass (85.1% versus 57.3% of p16-; p < 0.001) and less frequently included odynophagia (24.6% versus 51.7% of p16-; p < 0.001). Patients who experienced diagnostic delay were more likely to have p16+ tumors (77.7% delayed versus 62.8% not delayed; p = 0.006). p16+ primary tumors were more likely to be undetectable by physical examination of the head and neck including flexible laryngoscopy (19.0% versus 6.7% of p16-; p = 0.007) and more frequently associated with nondiagnostic FNA biopsies of a cervical nodal mass (11.8% versus 3.4% of p16-, p = 0.03). Conclusions Compared with non-HPV related OPSCC, the unique clinical presentation and characteristics of HPV+ OPSCC are associated with an increased incidence of diagnostic delay. Targeted education of appropriate care providers may improve time to diagnosis and treatment.

Evaluation of coplanar partial left breast irradiation using tomotherapy-based topotherapy.

PURPOSE: To investigate the use of topotherapy for accelerated partial breast irradiation through field-design optimization and dosimetric comparison to linear accelerator-based three-dimensional conformal radiotherapy (3D-CRT) and intensity-modulated radiation therapy (IMRT). METHODS AND MATERIALS: Hypothetical 3-cm lumpectomy sites were contoured in each quadrant of a left breast by using dosimetric guidelines from the National Surgical Adjuvant Breast and Bowel Project B-39/Radiation Therapy Oncology Group 0413 protocol. Coplanar intensity-modulated topotherapy treatment plans were optimized by using two-, three-, four-, five-, and seven-field arrangements for delivery by the tomotherapy unit with fixed gantry angles. Optimized noncoplanar five-field 3D-CRT and IMRT were compared with corresponding topotherapy plans. RESULTS: On average, 99.5% +/- 0.5% of the target received 100% of the prescribed dose for all topotherapy plans. Average equivalent uniform doses ranged from 1.20-2.06, 0.79-1.76, and 0.10-0.29 Gy for heart, ipsilateral lung, and contralateral lung, respectively. Average volume of normal breast exceeding 90% of the prescription and average area of skin exceeding 35 Gy were lowest for five-field plans. Average uniformity indexes for five-field plans using 3D-CRT, IMRT, and topotherapy were 1.047, 1.050, and 1.040, respectively. Dose-volume histograms and calculated equivalent uniform doses of all three techniques illustrate clinically equivalent doses to ipsilateral breast, lung, and heart. CONCLUSIONS: This dosimetric evaluation for a single patient shows that coplanar partial breast topotherapy provides good target coverage with exceptionally low dose to organs at risk. Use of more than five fields provided no additional dosimetric advantage. A comparison of five-field topotherapy to 3D-CRT and IMRT for accelerated partial breast irradiation illustrates equivalent target conformality and uniformity.

The effect of respiratory motion variability and tumor size on the accuracy of average intensity projection from four-dimensional computed tomography: an investigation based on dynamic MRI.

Composite images such as average intensity projection (AIP) and maximum intensity projection (MIP) derived from four-dimensional computed tomography (4D-CT) images are commonly used in radiation therapy for treating lung and abdominal tumors. It has been reported that the quality of 4D-CT images is influenced by the patient respiratory variability, which can be assessed by the standard deviation of the peak and valley of the respiratory trajectory. Subsequently, the resultant MIP underestimates the actual tumor motion extent. As a more general application, AIP comprises not only the tumor motion extent but also the probability that the tumor is present. AIP generated from 4D-CT can also be affected by the respiratory variability. To quantitate the accuracy of AIP and develop clinically relevant parameters for determining suitability of the 4D-CT study for AIP-based treatment planning, real time sagittal dynamic magnetic resonance imaging (dMRI) was used as the basis for generating simulated 4D-CT. Five-minute MRI scans were performed on seven healthy volunteers and eight lung tumor patients. In addition, images of circular phantoms with diameter 1, 3, or 5 cm were generated by software to simulate lung tumors. Motion patterns determined by dMRI images were reproduced by the software generated phantoms. Resorted dMRI using a 4D-CT acquisition method (RedCAM) based on phantom or patient images was reconstructed by simulating the imaging rebinning processes. AIP images and the corresponding color intensity projection (CIP) images were reconstructed from RedCAM and the full set of dMRI for comparison. AIP similarity indicated by the Dice index between RedCAM and dMRI was calculated and correlated with respiratory variability (v) and tumor size (s). The similarity of percentile intrafractional motion target area (IMTA), defined by the area that the tumor presented for a given percentage of time, and MIP-to-percentile IMTA similarity as a function of percentile were also determined. As a result, AIP similarity depends on both respiratory variability and tumor sizes. The AIP similarity correlated linearly with the respiratory variability normalized by tumor sizes (R2 equal to 0.82 and 0.91 for the phantom study and the patient study, respectively). For both studies, MIP derived from RedCAM was close to the area that the tumor presented 90% or more of the time and missed the region where the tumor appeared less than 10% of the time. In conclusion, the accuracy of composite images such as AIP and MIP derived from 4D-CT to define the tumor motion and position is affected by patient-specific respiratory variability and tumor sizes. Based on our study, normalized respiratory variability appears to be a pertinent parameter to assess the suitability of a 4D-CT image set for ALP-based treatment planning.

The Neddylation Inhibitor Pevonedistat (MLN4924) Suppresses and Radiosensitizes Head and Neck Squamous Carcinoma Cells and Tumors.

The cullin RING E3 ubiquitin ligase 4 (CRL4) with its substrate receptor CDT2 (CRL4-CDT2) is emerging as a critical regulator of DNA replication through targeting CDT1, SET8, and p21 for ubiquitin-dependent proteolysis. The aberrant increased stability of these proteins in cells with inactivated CRL4-CDT2 results in DNA rereplication, which is deleterious to cells due to the accumulation of replication intermediates and stalled replication forks. Here, we demonstrate that CDT2 is overexpressed in head and neck squamous cell carcinoma (HNSCC), and its depletion by siRNA inhibits the proliferation of human papilloma virus-negative (HPV-ve) HNSCC cells primarily through the induction of rereplication. Treatment of HNSCC with the NEDD8-activating enzyme inhibitor pevonedistat (MLN4924), which inhibits all cullin-based ligases, induces significant rereplication and inhibits HNSCC cell proliferation in culture and HNSCC xenografts in mice. Pevonedistat additionally sensitizes HNSCC cells to ionizing radiation (IR) and enhances IR-induced suppression of xenografts in mice. Induction of rereplication via CDT2 depletion, or via the stabilization or activation of CDT1, also radiosensitizes HNSCC cells. Collectively, these results demonstrate that induction of rereplication represents a novel approach to treating radioresistant HNSCC tumors and suggest that pevonedistat may be considered as an adjuvant for IR-based treatments. Mol Cancer Ther; 17(2); 368-80. ©2017 AACRSee all articles in this MCT Focus section, "Developmental Therapeutics in Radiation Oncology."

Estimation of error in maximal intensity projection-based internal target volume of lung tumors: a simulation and comparison study using dynamic magnetic resonance imaging.

PURPOSE: To evaluate the error in four-dimensional computed tomography (4D-CT) maximal intensity projection (MIP)-based lung tumor internal target volume determination using a simulation method based on dynamic magnetic resonance imaging (dMRI). METHODS AND MATERIALS: Eight healthy volunteers and six lung tumor patients underwent a 5-min MRI scan in the sagittal plane to acquire dynamic images of lung motion. A MATLAB program was written to generate re-sorted dMRI using 4D-CT acquisition methods (RedCAM) by segmenting and rebinning the MRI scans. The maximal intensity projection images were generated from RedCAM and dMRI, and the errors in the MIP-based internal target area (ITA) from RedCAM (epsilon), compared with those from dMRI, were determined and correlated with the subjects' respiratory variability (nu). RESULTS: Maximal intensity projection-based ITAs from RedCAM were comparatively smaller than those from dMRI in both phantom studies (epsilon = -21.64% +/- 8.23%) and lung tumor patient studies (epsilon = -20.31% +/- 11.36%). The errors in MIP-based ITA from RedCAM correlated linearly (epsilon = -5.13nu - 6.71, r(2) = 0.76) with the subjects' respiratory variability. CONCLUSIONS: Because of the low temporal resolution and retrospective re-sorting, 4D-CT might not accurately depict the excursion of a moving tumor. Using a 4D-CT MIP image to define the internal target volume might therefore cause underdosing and an increased risk of subsequent treatment failure. Patient-specific respiratory variability might also be a useful predictor of the 4D-CT-induced error in MIP-based internal target volume determination.

Direct measurement of lung motion using hyperpolarized helium-3 MR tagging.

PURPOSE: To measure lung motion between end-inhalation and end-exhalation using a hyperpolarized helium-3 (HP (3)He) magnetic resonance (MR) tagging technique. METHODS AND MATERIALS: Three healthy volunteers underwent MR tagging studies after inhalation of 1 L HP (3)He gas diluted with nitrogen. Multiple-slice two-dimensional and volumetric three-dimensional MR tagged images of the lungs were obtained at end-inhalation and end-exhalation, and displacement vector maps were computed. RESULTS: The grids of tag lines in the HP (3)He MR images were well defined at end-inhalation and remained evident at end-exhalation. Displacement vector maps clearly demonstrated the regional lung motion and deformation that occurred during exhalation. Discontinuity and differences in motion pattern between two adjacent lung lobes were readily resolved. CONCLUSIONS: Hyperpolarized helium-3 MR tagging technique can be used for direct in vivo measurement of respiratory lung motion on a regional basis. This technique may lend new insights into the regional pulmonary biomechanics and thus provide valuable information for the deformable registration of lung.