Prediction of left ventricular ejection fraction using simple : Quantitative clinical information

The left ventricular ejection fraction is useful in characterizing cardiac performance and evaluating prognosis in patients with known or suspected cardiac disease. The purpose of this study was to determine if simple, quantitative clinical information generated as part of a routine patient evaluation could be used to predict ejection fraction determined by radionuclide ventriculography. Multiple regression analysis was used to study a group of 64 patients selected to represent the full range of ejection fraction values. All patients had undergone cardiac catheterization and standard chest radiography in addition to resting and exercise radionuclide ventriculography. Using easily determined clinical variables, a regression formula was developed that predicted the radionuclide ventriculographic ejection fraction (r = 0.73). Plain film heart volume, heart rate, pulse pressure, and thoracic width were highly significant terms in the optimal regression equation. For validation, the formula was applied to a second, independent verification data set composed of 41 cases and revealed similar correlation (r = 0.78). A radionuclide ventriculographic ejection fraction below 40 was identified in the verification data set with a sensitivity of 87 percent and specificity of 83 percent. Use of this method, requiring only direct heart rate, blood pressure, and chest radiographic measurements and simple calculations, may assist physicians in patient management and facilitate the optimal use of more invasive and expensive studies.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/26416/1/0000503.pd

Timing and intensity of changes in FDG uptake with symptomatic esophagitis during radiotherapy or chemo-radiotherapy

PURPOSE: To study whether esophageal FDG activity changes by time of mid-course of fractionated radiotherapy (RT), and whether these changes are associated with radiation esophagitis in patients with non-small cell lung cancer (NSCLC). METHODS: Fifty patients with stage I-III NSCLC were enrolled prospectively and, all received ≥60 Gy RT. FDG-PET/CT scans were acquired prior to, and during-RT after delivery of 45 Gy. Normalized standardized uptake values (NSUV), defined by the esophageal maximum SUV relative to intravascular background level in the aortic arch, were sampled in the esophagus at the level of the primary tumor, sternal notch, aortic arch, carina, and gastro-esophageal junction. Symptomatic radiation esophagitis was defined as an event. RESULTS: Compared to baseline, esophageal NSUV increased significantly during-RT at the level of the primary tumor (1.09 ± 0.05 vs.1.28 ± 0.06, p = 0.001), but did not change at other levels in the esophagus. 16 patients had radiation esophagitis events and these patients had significantly higher during-RT to baseline NSUV ratios than those without esophagitis (1.46 ± 0.12, 95% CI 1.20-1.71; vs. 1.11 ± 0.05, 95% CI 1.01-1.21, p = 0.002). Maximum esophageal dose (p = 0.029), concurrent chemotherapy (p = 0.022) and esophageal FDG PET NSUV ratio (during-RT to baseline, p = 0.007), were independent factors associated with esophagitis and area under curves (AUC) were 0.76, 0.70 and 0.78, respectively. Combining esophageal maximum dose and FDG PET NSUV Ratio at the tumor level increased AUC to 0.85 (p = 0.016). CONCLUSION: FDG uptake increased in esophagus during-RT and this increase may predict radiation esphagitis during later course of treatment

Effect of Midtreatment PET/CT-Adapted Radiation Therapy With Concurrent Chemotherapy in Patients With Locally Advanced Non–Small-Cell Lung Cancer

IMPORTANCE Our previous studies demonstrated that tumors significantly decrease in size and metabolic activity after delivery of 45 Gy of fractionated radiatiotherapy (RT), and that metabolic shrinkage is greater than anatomic shrinkage. This study aimed to determine whether 18F-fludeoxyglucose–positron emission tomography/computed tomography (FDG-PET/CT) acquired during the course of treatment provides an opportunity to deliver higher-dose radiation to the more aggressive areas of the tumor to improve local tumor control without increasing RT-induced lung toxicity (RILT), and possibly improve survival. OBJECTIVE To determine whether adaptive RT can target high-dose radiation to the FDG-avid tumor on midtreatment FDG-PET to improve local tumor control of locally advanced non–small-cell lung cancer (NSCLC). DESIGN, SETTING, AND PARTICIPANTS A phase 2 clinical trial conducted at 2 academic medical centers with 42 patients who had inoperable or unresectable stage II to stage III NSCLC enrolled from November 2008, to May 2012. Patients with poor performance, more than 10% weight loss, poor lung function, and/or oxygen dependence were included, providing that the patients could tolerate the procedures of PET scanning and RT. INTERVENTION Conformal RT was individualized to a fixed risk of RILT (grade >2) and adaptively escalated to the residual tumor defined on midtreatment FDG-PET up to a total dose of 86 Gy in 30 daily fractions. Medically fit patients received concurrent weekly carboplatin plus paclitaxel followed by 3 cycles of consolidation. MAIN OUTCOMES AND MEASURES The primary end point was local tumor control. The trial was designed to achieve a 20% improvement in 2-year control from 34% of our prior clinical trial experience with 63 to 69 Gy in a similar patient population. RESULTS The trial reached its accrual goal of 42 patients: median age, 63 years (range, 45–83 years); male, 28 (67%); smoker or former smoker, 39 (93%); stage III, 38 (90%). Median tumor dose delivered was 83 Gy (range, 63–86 Gy) in 30 daily fractions. Median follow-up for surviving patients was 47 months. The 2-year rates of infield and overall local regional tumor controls (ie, including isolated nodal failure) were 82% (95% CI, 62%–92%) and 62% (95% CI, 43%–77%), respectively. Median overall survival was 25 months (95% CI, 12–32 months). The 2-year and 5-year overall survival rates were 52% (95% CI, 36%–66%) and 30% (95% CI, 16%–45%), respectively. CONCLUSIONS AND RELEVANCE Adapting RT-escalated radiation dose to the FDG-avid tumor detected by midtreatment PET provided a favorable local-regional tumor control. The RTOG 1106 trial is an ongoing clinical trial to validate this finding in a randomized fashion. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT0119052

Cancer Carepartners: Improving patients' symptom management by engaging informal caregivers

<p>Abstract</p> <p>Background</p> <p>Previous studies have found that cancer patients undergoing chemotherapy can effectively manage their own symptoms when given tailored advice. This approach, however, may challenge patients with poor performance status and/or emotional distress. Our goal is to test an automated intervention that engages a friend or family member to support a patient through chemotherapy.</p> <p>Methods/Design</p> <p>We describe the design and rationale of a randomized, controlled trial to assess the efficacy of 10 weeks of web-based caregiver alerts and tailored advice for helping a patient manage symptoms related to chemotherapy. The study aims to test the primary hypothesis that patients whose caregivers receive alerts and tailored advice will report less frequent and less severe symptoms at 10 and 14 weeks when compared to patients in the control arm; similarly, they will report better physical function, fewer outpatient visits and hospitalizations related to symptoms, and greater adherence to chemotherapy. 300 patients with solid tumors undergoing chemotherapy at two Veteran Administration oncology clinics reporting any symptom at a severity of ≥4 and a willing informal caregiver will be assigned to either 10 weeks of automated telephonic symptom assessment (ATSA) alone, or 10 weeks of ATSA plus web-based notification of symptom severity and problem solving advice to their chosen caregiver. Patients and caregivers will be surveyed at intake, 10 weeks and 14 weeks. Both groups will receive standard oncology, hospice, and palliative care.</p> <p>Discussion</p> <p>Patients undergoing chemotherapy experience many symptoms that they may be able to manage with the support of an activated caregiver. This intervention uses readily available technology to improve patient caregiver communication about symptoms and caregiver knowledge of symptom management. If successful, it could substantially improve the quality of life of veterans and their families during the stresses of chemotherapy without substantially increasing the cost of care.</p> <p>Trial Registration</p> <p><a href="http://www.clinicaltrials.gov/ct2/show/NCT00983892">NCT00983892</a></p

Identification and validation of a linear protective neutralizing epitope in the β-pore domain of alpha toxin.

The plethora of virulence factors associated with Staphylococcus aureus make this bacterium an attractive candidate for a molecularly-designed epitope-focused vaccine. This approach, which necessitates the identification of neutralizing epitopes for incorporation into a vaccine construct, is being evaluated for pathogens where conventional approaches have failed to elicit protective humoral responses, like HIV-1 and malaria, but may also hold promise for pathogens like S. aureus, where the elicitation of humoral immunity against multiple virulence factors may be required for development of an effective vaccine. Among the virulence factors employed by S. aureus, animal model and epidemiological data suggest that alpha toxin, a multimeric β-pore forming toxin like protective antigen from Bacillus anthracis, is particularly critical, yet no candidate neutralizing epitopes have been delineated in alpha toxin to date. We have previously shown that a linear determinant in the 2β2-2β3 loop of the pore forming domain of B. anthracis protective antigen is a linear neutralizing epitope. Antibody against this site is highly potent for neutralizing anthrax lethal toxin in vitro and for protection of rabbits in vivo from virulent B. anthracis. We hypothesized that sequences in the β-pore of S. aureus alpha toxin that share structural and functional homology to β-pore sequences in protective antigen would contain a similarly critical neutralizing epitope. Using an in vivo mapping strategy employing peptide immunogens, an optimized in vitro toxin neutralization assay, and an in vivo dermonecrosis model, we have now confirmed the presence of this epitope in alpha toxin, termed the pore neutralizing determinant. Antibody specific for this determinant neutralizes alpha toxin in vitro, and is highly effective for mitigating dermonecrosis and bacterial growth in a mouse model of S. aureus USA300 skin infection. The delineation of this linear neutralizing determinant in alpha toxin could facilitate the development of an epitope-focused vaccine against S. aureus

Passive immunization of mice with AT-neutralizing antisera specific for a.a. 122–137 protects mice from dermonecrosis.

<p>Five C57BL/6 mice/group were passive immunized i.p. with 0.5 mls of rabbit serum specific for a.a. 122–137 of AT, or irrelevant control rabbit serum. One day later, all mice were challenged i.d. with 20 x 10⁶ CFUs of <i>S</i>. <i>aureus</i> 8325–4 and were followed for 48 hours. After 48 hours, all mice were euthanized and dermonecrotic lesion areas were photographed (A) and lesion areas were determined as described in <i>Material and Methods</i> and displayed graphically (B). Horizontal bars are geometric means. * <i>p</i> = 0.0037, Mann-Whitney U test, one-tailed.</p

Alpha toxin and protective antigen share structural and functional homology but only limited sequence identity.

<p>Comparison of protein structural models of the heptameric AT (PDB7AHL) (A) and PA (PDB1V36) (B). Sequences in red represent aligned sequence shown in (C). Amino acid alignment of PA and AT in the region of the LND of PA demonstrates 37% sequence identity. Asterisks denote positions of amino acid identity, while periods and colons denote semi-conservative and conservative substitutions, respectively.</p

PND-specific Ab does not block binding of AT to RBC ghosts.

<p>RBC ghosts were immobilized on polystyrene 96 well plates and were blocked with 4% BSA in PBS. Soluble AT was incubated at RT with AT alone, or with AT mixed with identical concentrations of either PND-Ig or Control-Ig, or with rabbit anti-AT or sheep anti-AT at concentrations mediating neutralization equal to that of the PND-Ig. Binding of AT was detected using a mouse mAb specific for the N-terminus of AT as described in methods. *<i>p</i>< 0.0001 by ANOVA; <i>p</i>< 0.05, Tukey’s multiple comparisons test: Rabbit anti-AT and Sheep anti-AT vs both Rabbit anti-PND and Rabbit Control. Bars represent arithmetic means from quadruplicate samples and error bars indicate +/- 1 SEM. % Control AT binding = (OD₆₀₀ with Ab/OD₆₀₀ no Ab) x 100. The results are representative of 2 separate assays.</p

Rabbit-IgG specific for the 119–139 sequence from AT protects mice from LAC/USA300-mediated dermonecrosis.

<p>Groups of BALB/c mice (n = 5 except control IgG, n = 7) were passively immunized s.c. with normalized volumes of the respective affinity purified rabbit sera to establish approximately equivalent serum antibody titers in recipient mice. Approximately 48 hours later, all mice were bled and individual mouse sera were evaluated by ELISA for reactivity with immobilized AT (A) and in the TNA (B). All groups were then challenged i.d. with 38 x 10⁶ LAC/USA300. Forty-eight hours later, all mice were euthanized, lesions were photographed (C) and lesion areas determined (D). Mice passively immunized with rabbit IgG specific for the 119–139 sequence had significantly smaller lesions than mice receiving Control IgG (*<i>p</i> = 0.008, Kruskal Wallis; <i>p</i>< 0.05, Dunn’s multiple comparison test: 119–139 vs Control IgG). Lesion areas from groups of mice receiving the 114–131 and 130–147 IgG were not significantly different from the lesion areas of mice receiving the irrelevant Control-IgG, nor were they significantly different from the lesion sizes of mice administered 119–139 IgG, as assessed using the Dunn’s post-hoc analysis. Horizontal lines in (A), (B) and (D) represent geometric means.</p

Dose-Response Titration of PND Ab for protection of mice from LAC/USA300 Dermonecrosis.

<p>Groups of BALB/c mice (n = 4 except neg. controls, n = 3) were passively immunized s.c. with two-fold dilutions of PND Ab starting with a dose of 300 μl (panel A) or 24 μl (Panel B). 48 hours later, mice were challenged i.d. with 32 x 10⁶ (panel A) or 28 x 10⁶ (panel B) CFUs LAC/USA300. Two days later, all mice were euthanized and photographed and lesion areas determined (C). Group-specific lesion area data were plotted against dose and four parameter non-linear regression was used to determine the EC₅₀ of 14 μl (9.66 μg) (R² = 0.55) which represents the dose of PND-Ig which prevented 50% of the maximal lesion area. Antibody and neutralization titers from the sera of mice passively immunized with PND-Ig were determined by ELISA (D) and in the TNA (E) from serum obtained from individual mice on the day of challenge. Each circle represents an individual mouse data point and horizontal lines represent geometric means. Regression lines derived from the serum antibody and TNA data vs. dose were then used to interpolate the PA₅₀ and PN₅₀ which are expressed as reciprocal titers. The regression equation for PA₅₀ determination was log ELISA EC₅₀ = 0.9504 x log Dose + 1.75, and for PN₅₀ determination was log TNA ED₅₀ = 0.858 x log Dose + 0.3589.</p