Effects of Multileaf Collimator Design and Function When Using an Optimized Dynamic Conformal Arc Approach for Stereotactic Radiosurgery Treatment of Multiple Brain Metastases With a Single Isocenter: A Planning Study.

Background Stereotactic radiosurgery (SRS) or fractionated SRS (fSRS) are effective options for the treatment of brain metastases. When treating multiple metastases with a linear accelerator-based approach, a single isocenter allows for efficient treatment delivery. In this study, we present our findings comparing dosimetric parameters of Brainlab (Munich, Germany) Elements™ Multiple Brain Mets SRS (MME) software (version 1.5 versus version 2.0) for a variety of scenarios and patients. The impact of multileaf collimator design and function on plan quality within the software was also evaluated. Materials and methods Twenty previously treated patients with a total of 58 lesions (from one to seven lesions each) were replanned with an updated version of the multiple brain Mets software solution. For each plan, the mean conformity index (CI), mean gradient index (GI), the volume of normal brain receiving 12 Gy (V12), and mean brain dose were evaluated. Additionally, all v2.0 plans were further evaluated with jaw tracking for by Elekta (Stockholm, Sweden) and HD120™ multileaf collimator by Varian Medical Systems (Palo Alto, USA). Results The new software version demonstrated improvements for CI, GI and V12 (p <0.01). For the Elekta Agility™ multileaf collimator, jaw tracking improved all dosimetric parameters except for CI (p =0.178) and mean brain dose (p =0.93). For the Varian with HD120 multileaf collimator, all parameters improved. Conclusions The software enhancements in v2.0 of the software provided improvements in planning efficiency and dosimetric parameters. Differences in multileaf collimator design may provide an additional incremental benefit in a subset of clinical scenarios.

Using low-dose radiation to potentiate the effect of induction chemotherapy in head and neck cancer: Results of a prospective phase 2 trial.

PURPOSE: Low-dose fractionated radiation therapy (LDFRT) induces effective cell killing through hyperradiation sensitivity and potentiates effects of chemotherapy. We report our second investigation of LDFRT as a potentiator of the chemotherapeutic effect of induction carboplatin and paclitaxel in locally advanced squamous cell cancer of the head and neck (SCCHN). EXPERIMENTAL DESIGN: Two cycles of induction therapy were given every 21 days: paclitaxel (75 mg/m2) on days 1, 8, and 15; carboplatin (area under the curve 6) day 1; and LDFRT 50 cGy fractions (2 each on days 1, 2, 8, and 15). Objectives included primary site complete response rate; secondary included overall survival, progression-free survival (PFS), disease-specific survival, and toxicity. RESULTS: A total of 24 evaluable patients were enrolled. Primary sites included oropharynx (62.5%), larynx (20.8%), oral cavity (8.3%), and hypopharynx (8.3%). Grade 3/4 toxicities included neutropenia (20%), leukopenia (32%), dehydration/hypotension (8%), anemia (4%), infection (4%), pulmonary/allergic rhinitis (4%), and diarrhea (4%). Primary site response rate was 23/24 (95.8%): 15/24 (62.5%) complete response, 8/24 (33.3%) partial response, and 1/24 (4.2%) stable disease. With median follow-up of 7.75 years, 9-year rates for overall survival were 49.4% (95% confidence interval [CI], 30.5-79.9), PFS was 72.2% (CI, 55.3-94.3), and disease-specific survival was 65.4% (44.3-96.4). CONCLUSION: Chemopotentiating LDFRT combined with paclitaxel and carboplatin is effective in SCCHN and provided an excellent median overall survival of 107.2 months, with median PFS not yet reached in this locally advanced SCCHN cohort. This compares favorably to prior investigations and caused fewer grade 3 and 4 toxicities than more intensive, 3-drug induction regimens. This trial demonstrates the innovative use of LDFRT as a potentiator of chemotherapy.

Importance of Statistical Evidence in Estimating Valid DEA Scores.

Data Envelopment Analysis (DEA) allows healthcare scholars to measure productivity in a holistic manner. It combines a production unit's multiple outputs and multiple inputs into a single measure of its overall performance relative to other units in the sample being analyzed. It accomplishes this task by aggregating a unit's weighted outputs and dividing the output sum by the unit's aggregated weighted inputs, choosing output and input weights that maximize its output/input ratio when the same weights are applied to other units in the sample. Conventional DEA assumes that inputs and outputs are used in different proportions by the units in the sample. So, for the sample as a whole, inputs have been substituted for each other and outputs have been transformed into each other. Variables are assigned different weights based on their marginal rates of substitution and marginal rates of transformation. If in truth inputs have not been substituted nor outputs transformed, then there will be no marginal rates and therefore no valid basis for differential weights. This paper explains how to statistically test for the presence of substitutions among inputs and transformations among outputs. Then, it applies these tests to the input and output data from three healthcare DEA articles, in order to identify the effects on DEA scores when input substitutions and output transformations are absent in the sample data. It finds that DEA scores are badly biased when substitution and transformation are absent and conventional DEA models are used.

p16INK4a Status and Response to Induction Low-Dose Fractionated Radiation in Advanced Head and Neck Cancer.

OBJECTIVE: To evaluate the impact of p16INK4a (p16) expression on clinical efficacy of induction low-dose fractionated radiation therapy (LDFRT) with concurrent chemotherapy in patients with locally advanced squamous cell carcinoma of the head and neck (SCCHN). STUDY DESIGN: Historical cohort study. SETTING: Tertiary medical center. METHODS: A total of 66 Patients with locally advanced SCCHN were enrolled in 2 clinical trials using paclitaxel, carboplatin, and concurrent LDFRT induction therapy. Patients were evaluated for response to induction by a multidisciplinary team and then were given definitive treatment. Adequate tissue samples from the pretreatment biopsies of 42 individuals were identified and analyzed for p16 expression. Expression was correlated with clinical outcomes. RESULTS: Of 42 tumors, 15 (35.7%) were positive for p16. Patients with p16-positive tumors had improved response to induction, but this was not statistically significant (P = .06). Five-year overall survival was 80% in p16-positive patients and 58% in p16-negative patients (P = .025). CONCLUSIONS: p16 Expression affects treatment response in patients treated with induction LDFRT with concurrent chemotherapy. This is similar to results reported for standard induction chemotherapy.

A feasibility study using TomoDirect for craniospinal irradiation.

The feasibility of delivering craniospinal irradiation (CSI) with TomoDirect is investigated. A method is proposed to generate TomoDirect plans using standard three-dimensional (3D) beam arrangements on Tomotherapy with junctioning of these fields to minimize hot or cold spots at the cranial/spinal junction. These plans are evaluated and compared to a helical Tomotherapy and a three-dimensional conformal therapy (3D CRT) plan delivered on a conventional linear accelerator (linac) for CSI. The comparison shows that a TomoDirect plan with an overlap between the cranial and spinal fields might be preferable over Tomotherapy plans because of decreased low dose to large volumes of normal tissues outside of the planning target volume (PTV). Although the TomoDirect plans were not dosimetrically superior to a 3D CRT linac plan, the patient can be easily treated in the supine position, which is often more comfortable and efficient from an anesthesia standpoint. TomoDirect plans also have only one setup position which obviates the need for matching of fields and feathering of junctions, two issues encountered with conventional 3D CRT plans. TomoDirect plans can be delivered with comparable treatment times to conventional 3D plans and in shorter times than a Tomotherapy plan. In this paper, a method is proposed for creating TomoDirect craniospinal plans, and the dosimetric consequences for choosing different planning parameters are discussed.

A professional spiritual care knowledge base: boon or bane?

An Ideal Intervention Paper was initiated in 2005 to consolidate the learnings of clinical pastoral education students. As papers from students, practitioners, and educators were collected over a period of seven years, it became evident that a knowledge base comprised of this work would expedite the professionalization of clinical chaplaincy via provision of second opinions in difficult cases, education of administrators and the public about the nature of chaplaincy work, and baseline data for effectiveness research-to include replication of effective interventions toward designation of evidence based spiritual care best practices. An online 395-sample knowledge base hosted by the Association for Clinical Pastoral Education Research Network was amassed, nearly 40 percent of which is the work of experienced practitioners and educators. A pilot effectiveness study of samples failed to produce meaningful results. As an interim measure a content analysis has provided tentative effectiveness ratings until further research can be done.

Low-dose fractionated radiation with induction chemotherapy for locally advanced head and neck cancer: 5 year results of a prospective phase II trial.

OBJECTIVE: This study aims to report the long-term outcomes of a novel treatment approach utilizing induction low-dose fractionated radiation therapy (LDFRT) and chemotherapy for locally advanced squamous cell carcinoma of head and neck (SCCHN). METHODS: We prospectively enrolled 40 patients with locally advanced SCCHN (77 % stage IV) on a phase II clinical trial and treated with induction paclitaxel (225 mg/m2), carboplatin (AUC 6), and LDFRT (80 cGy BID on days 1 and 2) every 21 days for two cycles. RESULTS: Forty patients enrolled; 39 were evaluable. The acute toxicity and response data have been previously reported; overall response rate (RR) was 82 %. After induction, definitive therapy was concurrent chemoradiation (CRT) in 51 %, XRT alone in 39 %, surgery in 5 %, and surgery and XRT in 5 %. The long-term outcomes are now reported with a median follow-up of 83 months. Locoregional control (LRC) is 80 % and distant control (DC) is 77 %. Five-year overall survival (OS), disease-specific survival, and progression-free survival (PFS) are 62 %, 66 %, and 58 %, respectively. CONCLUSION: Induction chemotherapy with LDFRT has a high initial RR, comparable toxicity to two-drug induction regimens, but adds a third novel and effective agent, LDFRT. Five-year follow-up shows favorable outcomes compared to historical controls and excellent compliance with definitive therapy. This novel treatment approach is now planned for phase 3 trial evaluation.

Employment outcomes following successful renal transplantation.

BACKGROUND: Data on employment outcomes after successful renal transplantation are few. We conducted this study to identify favorable factors for employment after transplantation. METHODS: Adult patients <65 yr of age who underwent renal transplantation between January 1, 2002 and December 31, 2007 were surveyed. Patients with graft survival <1 yr were excluded. We also tested their knowledge of Medicare coverage after transplantation. Data were analyzed using chi-squared and Fisher's exact tests. p-Value <0.05 was considered statistically significant. RESULTS: A 55% response rate was obtained where 56% of respondents were employed after transplantation. Race, marital status, previous transplant, and complicated post-operative course did not influence employment. Favorable factors include male gender (p=0.04), younger age (<40 [p=0.0003] or <50 yr [p<0.0001]), having ≥1 dependent (p=0.04), higher education (minimum high school degree [p=0.003] or some college [p=0.002]), live donor recipient (p=0.004), wait time <2 yr (p=0.03), dialysis <2 yr (p<0.0001) or pre-dialysis (p=0.04), and pre-transplantation employment (p<0.0001). Mean time for employment was 4.9±6.3 months (median three months). Common reasons for unemployment were disability (59%) and retirement (27%). Finally, 7% correctly responded that Medicare benefits end 36 months following transplantation. CONCLUSIONS: Potentially modifiable factors to improve employment are earlier referral and better education regarding Medicare eligibility.

Age-related disparities in the use of radiotherapy for treatment of localized soft tissue sarcoma.

BACKGROUND: Many elderly patients with cancer experience increased cancer-related morbidity and mortality compared with younger patients. In soft tissue sarcoma, adjuvant radiotherapy is an integral part of definitive therapy for limb preservation. The authors of this report hypothesized that age-related disparities exist in the use of radiation. METHODS: Surveillance, Epidemiology, and End Results (SEER) data were used to conduct a retrospective cohort study among patients aged ≥ 25 years who were diagnosed from 1998 to 2004 with nonmetastatic, biopsy-proven, high-grade soft tissue sarcoma of the extremities and underwent a limb-sparing procedure. Patients were stratified according to age (ages < 50 years, 50-70 years, and > 70 years). Logistic regression was used to determine the association between age and the receipt of radiotherapy adjusting for histology, tumor location, tumor size, surgery, sex, race, and marital status. A Cox proportional hazards model was used to compare disease-specific and all-cause mortality. RESULTS: Among 1354 eligible patients; 37.1% were aged > 70 years, 44.3% were women, and 84.4% were Caucasian. Although 73.8% of the cohort received radiotherapy, receipt decreased from 78.2% among patients aged < 50 years to 69.6% among patients aged >70 years (test for trend; P = .006). After adjusting for demographic and tumor factors, older patients remained less likely to receive radiotherapy (odds ratio, 0.66; 95% confidence interval, 0.47-0.92) and more likely to experience disease-specific death (hazard ratio, 2.4; 95% confidence interval, 1.4-4.1) compared with the youngest group. CONCLUSIONS: Older adults appeared to be less likely to receive definitive therapy for soft tissue sarcoma of the extremities. In the absence of clinical trials and treatment guidelines tailored to this population, under treatment may disadvantage elderly patients, who have increased cancer-related morbidity and mortality.

Symptom clusters in patients with newly-diagnosed brain tumors.

A symptom cluster comprises three or more concurrent symptoms. There is a paucity of symptom cluster research in cancer patients. Data from a previously conducted clinical trial were analyzed to search for symptom clusters. This phase III, placebo-controlled, double-blind, prospective, randomized clinical trial of 66 patients assessed the effect of prophylactic d-threo-methylphenidate (d-MPH) on quality of life (QOL) in newly diagnosed brain tumor patients receiving brain radiation therapy. Patients received 5-15 mg of d-MPH or placebo twice daily starting on week 1 of radiation therapy and continuing for 8 weeks post radiotherapy. QOL data were collected at baseline; the end of radiation therapy; and 4, 8, and 12 weeks following radiation therapy using the Functional Assessment of Cancer Therapy (FACT), the FACT-Brain subscale, and the Center for Epidemiologic Studies Depression Scale. Exploratory factor analysis, multidimensional scaling (MDS), and cluster analysis were used to search for symptom clusters. The trial failed to show a treatment effect; patients receiving d-MPH or placebo were analyzed together to search for clusters. Two symptom clusters were identified using exploratory factor analysis--a language cluster including difficulty reading, writing, and finding the right words and a mood cluster including feelings of sadness, anxiety, and depressed mood; these clusters were supported by MDS and cluster analysis. Our results suggest that interventions that target both cognitive function and mood should be considered in this patient population. Further research on symptom clusters in brain tumor patients is needed.

Nonpeptidic urotensin-II receptor antagonists I: in vitro pharmacological characterization of SB-706375.

1. SB-706375 potently inhibited [(125)I]hU-II binding to both mammalian recombinant and 'native' UT receptors (K(i) 4.7+/-1.5 to 20.7+/-3.6 nM at rodent, feline and primate recombinant UT receptors and K(i) 5.4+/-0.4 nM at the endogenous UT receptor in SJRH30 cells). 2. Prior exposure to SB-706375 (1 microM, 30 min) did not alter [(125)I]hU-II binding affinity or density in recombinant cells (K(D) 3.1+/-0.4 vs 5.8+/-0.9 nM and B(max) 3.1+/-1.0 vs 2.8+/-0.8 pmol mg(-1)) consistent with a reversible mode of action. 3. The novel, nonpeptidic radioligand [(3)H]SB-657510, a close analogue of SB-706375, bound to the monkey UT receptor (K(D) 2.6+/-0.4 nM, B(max) 0.86+/-0.12 pmol mg(-1)) in a manner that was inhibited by both U-II isopeptides and SB-706375 (K(i) 4.6+/-1.4 to 17.6+/-5.4 nM) consistent with the sulphonamides and native U-II ligands sharing a common UT receptor binding domain. 4. SB-706375 was a potent, competitive hU-II antagonist across species with pK(b) 7.29-8.00 in HEK293-UT receptor cells (inhibition of [Ca(2+)](i)-mobilization) and pK(b) 7.47 in rat isolated aorta (inhibition of contraction). SB-706375 also reversed tone established in the rat aorta by prior exposure to hU-II (K(app) approximately 20 nM). 5. SB-706375 was a selective U-II antagonist with >/=100-fold selectivity for the human UT receptor compared to 86 distinct receptors, ion channels, enzymes, transporters and nuclear hormones (K(i)/IC(50)>1 microM). Accordingly, the contractile responses induced in isolated aortae by KCl, phenylephrine, angiotensin II and endothelin-1 were unaltered by SB-706375 (1 microM). 6. In summary, SB-706375 is a high-affinity, surmountable, reversible and selective nonpeptide UT receptor antagonist with cross-species activity that will assist in delineating the pathophysiological actions of U-II in mammals.

Pastoral research: past, present, and future.

In healthcare environments of excellence, clinically trained chaplains are valued members of the medical treatment team. There are skills and values they hold in common with medicine and allied health disciplines: enhancing the health and well-being of the patient as a unity of body, mind, and spirit within a unique family and cultural system. This article examines the past, present, and future of pastoral research, including the chaplain's moral imperative to examine practice and to share what is found.

Myocardial drug distribution pattern following intrapericardial delivery: an MRI analysis.

OBJECTIVES: The main goal was to gain insights into the pharmacokinetics of intrapericardial drug delivery using magnetic resonance (MR) imaging analysis and the extracellular MR contrast agent gadopentetate dimeglumine (Gd-DTPA) as a model. BACKGROUND: Recent development of catheter-based techniques to access the intact pericardial space has increased interest in intrapericardial delivery for local cardiac therapy. Distribution and myocardial penetration of intrapericardial agents are not well characterized. METHODS: The intact pericardial space was percutaneously accessed through the right atrial appendage in ten anesthetized pigs, following which 5 mL Gd-DTPA (N = 8) or normal saline as control (N = 2) were administered. Animals were sacrificed at 1, 3, 3.5, 5, or 8 hr. The whole heart was excised, washed with normal saline, and the chambers distended with saline-filled bags. Myocardial penetration of Gd-DTPA was analyzed by a series of short-axis T1-weighted turbospin-echo MR images. RESULTS: At 1, 3, and 3.5 hr after Gd-DTPA, a uniform ring of enhancement was found along the epicardium, with a depth density related to time after administration. No contrast ring was visible at 5 or 8 hr or in control animals. Transmural myocardial T1 values obtained 5 hr after Gd-DTPA administration were reduced, suggesting that Gd-DTPA had penetrated uniformly throughout the myocardium. CONCLUSIONS: Intrapericardial administration results in relatively uniform distribution of an agent across the ventricular epicardium. The depth of penetration is consistent with functional evidence that epicardial structures can be targeted by this technique.

Inhibition of cyclin A kinase activity in E2F-1 chemogene therapy of colon cancer.

Adenoviral-mediated gene transfer of the apoptotic gene E2F-1 has been shown to induce apoptosis in a variety of tumor cells and acts in an additive or cooperative fashion with several specific chemotherapeutic agents to induce tumor cell death. The apoptotic function of E2F-1 is dependent on its ability to bind DNA; cyclin A kinase activity has been shown to negatively regulate the DNA-binding capacity of E2F-1. In the present study, we sought to determine whether cyclin A kinase activity is involved in mediating the interaction between E2F-1 and chemotherapeutic agents in colon cancer cells. Therefore, human colon adenocarcinoma (SW620) cells were treated with an adenovirus expressing E2F-1 (Ad-E2F-1, multiplicity of infection 20). Immediately following infection, a panel of conventional chemotherapeutic agents with varying modes of cytotoxic action were administered at LD(25 )doses. Three days following treatment, viability and growth inhibition were determined by trypan blue exclusion assay. Apoptosis was confirmed using cellular morphology, poly (ADP-ribose) polymerase cleavage, and flow-cytometric analysis. E2F-1 overexpression and cyclin A protein expression were monitored by immunoblot, and cyclin A kinase activity was determined by kinase assay. Vincristine (VIN), camptothecin (CPT), and actinomycin D were found to have a cooperative (>38% over the additive single therapy values) effect on E2F-1-mediated apoptosis. Etoposide, cisplatin (CIS), and 5-fluorouracil (5-FU) showed the least cooperation ( 0.1) compared to Ad-E2F-1 treatment alone. Combination of Ad-LacZ/5-FU and Ad-LacZ/actinomycin D significantly inhibited cyclin A kinase activity compared to Ad-LacZ treatment alone (p < 0.005). No other Ad-LacZ/drug combinations significantly affected cyclin A kinase activity (p > 0.05). In conclusion, combinations of E2F-1 adenovirus and VIN, CPT, or actinomycin D at LD(25 )had significant cooperative effects on colon cancer apoptotic cell death in vitro. Although inhibition of cyclin A kinase activity was observed in most Ad-E2F-1/drug combination treatments compared to Ad-E2F-1 treatment alone, there was no consistent correlation between degree of inhibition of cyclin A kinase activity and the cooperative effect. Nonetheless, inhibition of cyclin A kinase activity may be an important mechanism by which the chemogene therapy effects involving E2F-1 are modulated.

HIV Risk Behavior among Outpatients at a State Psychiatric Hospital: Prevalence and Risk Modeling.

The purpose of this archival study was to determine the prevalence and correlates of HIV-related risk behavior among adults with a severe and persistent mental illness (SPMI). Hospital records at a public psychiatric hospital were reviewed to obtain data on demographic and psychiatric characteristics, sexual behavior, and substance use. Data were available from 889 (73%) of 1214 eligible outpatients. Of these 889 patients, 49% were sexually active, 52% used alcohol, and 18% used street drugs during the past year. Eleven percent were at high risk for HIV infection: 7% reported having 3 or more sexual partners, 3% had been infected with an STD, 3% had traded sex, and fewer than 1% had shared injection equipment. HIV-risk status was modeled with logistic regression using diagnosis, type of residence, drug and alcohol use, and demographic variables; five- and six-predictor models were derived for two HIV-risk indicators. A bootstrap simulation supported the reliability of each model. We conclude that approximately one-half of adults living with a SPMI are sexually active, and a minority engages in behaviors that increase risk of HIV infection. Routine screening for HIV risk in psychiatric settings can identify patients who may benefit from risk reduction programs.