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.

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.

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.

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.

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.

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."

Clinical outcomes of helical conformal versus nonconformal palliative radiation therapy for axial skeletal metastases.

PURPOSE: Palliative radiation therapy (RT) for bone metastases has traditionally been delivered with conventional, nonconformal RT (NCRT). Conformal RT (CRT) is potentially more complex and expensive than NCRT, but may reduce normal tissue dose and subsequently toxicity. In this retrospective analysis, we compared CRT with NCRT to investigate the association between conformality and toxicity. METHODS AND MATERIALS: A retrospective analysis of patients receiving palliative RT for axial skeletal bone metastases from 2012 to 2014 was conducted. Patient and treatment characteristics were obtained including dosimetric variables, acute toxicity, and subjective pain during treatment and in the acute posttreatment period (≤60 days after completion). Statistical analyses included t tests, χ2 tests, and multivariate logistic regression. RESULTS: A total of 179 patients and 254 bone metastases were identified (142 CRT, 112 NCRT). The CRT and NCRT groups were well matched for baseline characteristics (number of fractions, field size, treatment sites, and concurrent chemotherapy). In multivariate logistic regression models, technique (CRT vs NCRT) was not associated with development of acute toxicity. Regarding toxicity, Eastern Cooperative Oncology Group performance status and total dose were significantly associated with a higher rate of acute toxicity during RT (odds ratios, 0.649 and 1.129 and P = .027 and .044, respectively), and only a higher number of vertebral bodies in the treatment field was significantly associated with acute toxicity post-treatment (odds ratios, 1.219, P = .028). CRT was associated with improvement in bone pain during and posttreatment (P = .049 and .045, respectively). CONCLUSIONS: Our results demonstrate no difference in acute toxicity following palliative RT with CRT compared with NCRT for painful bone metastases; however, treatment volume did predict for increased toxicity. Larger studies may further elucidate the value of CRT including the impact of dose escalation for bone metastases and differences in patient reported outcomes between RT techniques.

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.

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.

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.

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.

Safety and feasibility of STAT RAD: Improvement of a novel rapid tomotherapy-based radiation therapy workflow by failure mode and effects analysis.

PURPOSE: The clinical challenge of radiation therapy (RT) for painful bone metastases requires clinicians to consider both treatment efficacy and patient prognosis when selecting a radiation therapy regimen. The traditional RT workflow requires several weeks for common palliative RT schedules of 30 Gy in 10 fractions or 20 Gy in 5 fractions. At our institution, we have created a new RT workflow termed "STAT RAD" that allows clinicians to perform computed tomographic (CT) simulation, planning, and highly conformal single fraction treatment delivery within 2 hours. In this study, we evaluate the safety and feasibility of the STAT RAD workflow. METHODS AND MATERIALS: A failure mode and effects analysis (FMEA) was performed on the STAT RAD workflow, including development of a process map, identification of potential failure modes, description of the cause and effect, temporal occurrence, and team member involvement in each failure mode, and examination of existing safety controls. A risk probability number (RPN) was calculated for each failure mode. As necessary, workflow adjustments were then made to safeguard failure modes of significant RPN values. After workflow alterations, RPN numbers were again recomputed. RESULTS: A total of 72 potential failure modes were identified in the pre-FMEA STAT RAD workflow, of which 22 met the RPN threshold for clinical significance. Workflow adjustments included the addition of a team member checklist, changing simulation from megavoltage CT to kilovoltage CT, alteration of patient-specific quality assurance testing, and allocating increased time for critical workflow steps. After these modifications, only 1 failure mode maintained RPN significance; patient motion after alignment or during treatment. CONCLUSIONS: Performing the FMEA for the STAT RAD workflow before clinical implementation has significantly strengthened the safety and feasibility of STAT RAD. The FMEA proved a valuable evaluation tool, identifying potential problem areas so that we could create a safer workflow.

Phantomless patient-specific TomoTherapy QA via delivery performance monitoring and a secondary Monte Carlo dose calculation.

PURPOSE: To describe the validation and implementation of a novel quality assurance (QA) system for TomoTherapy using a Monte Carlo (MC)-based secondary dose calculation and CT detector-based multileaf collimator (MLC) leaf opening time measurement QA verification. This system is capable of detecting plan transfer and delivery errors and evaluating the dosimetric impact of those errors. METHODS: The authors' QA process, MCLogQA, utilizes an independent pretreatment MC secondary dose calculation and postdelivery TomoTherapy exit detector-based MLC sinogram comparison and log file examination to confirm accurate dose calculation, accurate dose delivery, and to verify machine performance. MC radiation transport simulations are performed to estimate patient dose utilizing prestored treatment machine-specific phase-space information, the patient's planning CT, and MLC sinogram data. Sinogram data are generated from both the treatment planning system (MC_TPS) and from beam delivery log files (MC_Log). TomoTherapy treatment planning dose (DTPS) is compared with DMC_TPS and DMC_Log via dose-volume metrics and mean region of interest dose statistics. For validation, in-phantom ionization chamber dose measurements (DIC) for ten sample patient plans are compared with the computed values. RESULTS: Dose comparisons to in-phantom ion chamber measurements validate the capability of the MCLogQA method to detect delivery errors. DMC_Log agreed with DIC within 1%, while DTPS values varied by 2%-5% compared to DIC. The authors demonstrated that TomoTherapy treatments can be vulnerable to MLC deviations and interfraction output variations during treatment delivery. Interfractional Linac output variations for each patient were approximately 2% and average output was 1%-1.5% below the gold standard. While average MLC leaf opening time error from patient to patient varied from -0.6% to 1.6%, the MLC leaf errors varied little between fractions for the same patient plan, excluding one patient. CONCLUSIONS: MCLogQA is a new TomoTherapy QA process that validates the planned dose before delivery and analyzes the delivered dose using the treatment exit detector and log file data. The MCLogQA procedure is an effective and efficient alternative to traditional phantom-based TomoTherapy plan-specific QA because it allows for comprehensive 3D dose verification, accounts for tissue heterogeneity, uses patient CT density tables, reduces total QA time, and provides for a comprehensive QA methodology for each treatment fraction.

Prognostic significance of p16 and its relationship with human papillomavirus in pharyngeal squamous cell carcinomas.

IMPORTANCE: The prognostic significance of p16 in squamous cell carcinoma (SCC) of the hypopharynx (HP) and nasopharynx (NP) and relationship between human papillomavirus (HPV) and p16 is unclear. OBJECTIVES: To evaluate the prognostic significance of p16 in pharyngeal subsites (oropharynx [OP], HP, and NP) and assess the relationship between HPV and p16 in the HP and NP. DESIGN, SETTING, AND PARTICIPANTS: Retrospective medical record review of 172 patients with SCC of the pharynx treated with definitive radiation therapy from 2002 to 2013 at a university tertiary referral center, with tissue available for immunohistochemical analysis. The median follow-up was 30.1 months. INTERVENTIONS: A total of 118 patients were treated with chemoradiation, and 54 patients were treated with radiation alone. Immunohistochemical analysis for p16 was performed for all tumors. Hypopharynx and NP tumors were tested for HPV using in situ hybridization, and NP tumors were tested for Epstein-Barr virus. MAIN OUTCOMES AND MEASURES: Overall survival, locoregional control, and disease-free survival were analyzed according to p16, HPV, and Epstein-Barr virus status. RESULTS: Thirty-two patients had HP SCC, 127 had OP SCC, and 13 had NP SCC. p16 Was positive in the HP (34%), OP (66%), and NP (46%). Prevalence of HPV was 14% in the HP and 50% in the NP. As a test for HPV, p16 had a positive predictive value of 38% (HP) and 67% (NP) and a negative predictive value of 100% in HP and NP tumors. p16 Status was a significant predictor of all clinical outcomes for patients with OP SCC (P<.001), but not for patients with HP or NP SCC. Patients with Epstein-Barr virus- or HPV-associated NP SCC had improved clinical outcomes. CONCLUSIONS AND RELEVANCE: p16 Was not associated with improved outcomes in patients with HP or NP SCC. The positive predictive value of p16 as a test for HPV is too low for p16 testing alone in the HP and NP. However, p16 negativity is sufficient to rule out HPV. As a research approach, we recommend p16 immunohistochemistry as a screening test for HPV in NP SCC and HP SCC followed by confirmatory HPV in situ hybridization when p16 positive.

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.

A comparative analysis of 3D conformal deep inspiratory-breath hold and free-breathing intensity-modulated radiation therapy for left-sided breast cancer.

Patients undergoing radiation for left-sided breast cancer have increased rates of coronary artery disease. Free-breathing intensity-modulated radiation therapy (FB-IMRT) and 3-dimensional conformal deep inspiratory-breath hold (3D-DIBH) reduce cardiac irradiation. The purpose of this study is to compare the dose to organs at risk in FB-IMRT vs 3D-DIBH for patients with left-sided breast cancer. Ten patients with left-sided breast cancer had 2 computed tomography scans: free breathing and voluntary DIBH. Optimization of the IMRT plan was performed on the free-breathing scan using 6 noncoplanar tangential beams. The 3D-DIBH plan was optimized on the DIBH scan and used standard tangents. Mean volumes of the heart, the left anterior descending coronary artery (LAD), the total lung, and the right breast receiving 5% to 95% (5% increments) of the prescription dose were calculated. Mean volumes of the heart and the LAD were lower (p<0.05) in 3D-DIBH for volumes receiving 5% to 80% of the prescription dose for the heart and 5% for the LAD. Mean dose to the LAD and heart were lower in 3D-DIBH (p≤0.01). Mean volumes of the total lung were lower in FB-IMRT for dose levels 20% to 75% (p<0.05), but mean dose was not different. Mean volumes of the right breast were not different for any dose; however, mean dose was lower for 3D-DIBH (p = 0.04). 3D-DIBH is an alternative approach to FB-IMRT that provides a clinically equivalent treatment for patients with left-sided breast cancer while sparing organs at risk with increased ease of implementation.

Pilot Study of iPad Incorporation Into Graduate Medical Education.

BACKGROUND: Increased documentation and charting requirements are challenging for residents, given duty hour limits. Use of mobile electronic devices may help residents complete these tasks efficiently. OBJECTIVE: To collect initial data on usage rates, information technology (IT) support requirements, and resident use of iPads during training. METHODS: In this pilot study, we provided 12 residents/fellows from various specialties at the University of Virginia with an iPad with IT support. The system used a virtual private network with access to the institution's electronic health record. Participants were allowed to develop their own methods and systems for personalized iPad use, and after 9 months they provided data on the utility of the iPad. Feedback from the IT team also was obtained. RESULTS: Average iPad use was 2.1 h/d (range, 0.5-6 h/d). The average self-reported reduction in administrative work due to the iPad was 2.7 h/wk (range, 0-9 h/wk). A total of 75% (9 of 12) of the users would recommend universal adoption among residents and fellows. More than 90% (11 of 12) of users reported the iPad would improve communication for coordination of care. A total of 68% (8 of 12) of users reported that an iPad facilitated their activities as educators of medical students and junior residents. Residents cited slow data entry into the electronic health record and hospital areas lacking Wi-Fi connectivity as potential drawbacks to iPad use. The IT team reported minimal support time for device setup, maintenance, and upgrades, and limited security risks. CONCLUSIONS: The iPad may contribute to increased clinical efficiency, reduced hours spent on administrative tasks, and enhanced educational opportunities for residents, with minimal IT support.

p16, Cyclin D1, and HIF-1α Predict Outcomes of Patients with Oropharyngeal Squamous Cell Carcinoma Treated with Definitive Intensity-Modulated Radiation Therapy.

We evaluated a panel of 8 immunohistochemical biomarkers as predictors of clinical response to definitive intensity-modulated radiotherapy in patients with oropharyngeal squamous cell carcinoma (OPSCC). 106 patients with OPSCC were treated to a total dose of 66-70 Gy and retrospectively analyzed for locoregional control (LRC), disease-free survival (DFS), and overall survival (OS). All tumors had p16 immunohistochemical staining, and 101 tumors also had epidermal growth factor receptor (EGFR) staining. 53% of the patients had sufficient archived pathologic specimens for incorporation into a tissue microarray for immunohistochemical analysis for cyclophilin B, cyclin D1, p21, hypoxia-inducible factor-1α (HIF-1α), carbonic anhydrase, and major vault protein. Median followup was 27.2 months. 66% of the tumors were p16 positive, and 34% were p16 negative. On univariate analysis, the following correlations were statistically significant: p16 positive staining with higher LRC (P = 0.005) and longer DFS (P < 0.001); cyclin D1 positive staining with lower LRC (P = 0.033) and shorter DFS (P = 0.002); HIF-1α positive staining with shorter DFS (P = 0.039). On multivariate analysis, p16 was the only significant independent predictor of DFS (P = 0.023). After immunohistochemical examination of a panel of 8 biomarkers, our study could only verify p16 as an independent prognostic factor in OPSCC.