Optimization of the rounded leaf offset table in modeling the multileaf collimator leaf edge in a commercial treatment planning system.

An editable rounded leaf offset (RLO) table is provided in the Pinnacle3 treatment planning software. Default tables are provided for major linear accelerator manu- facturers, but it is not clear how the default table values should be adjusted by the user to optimize agreement between the calculated leaf tip value and the actual measured value. Since we wish for the calculated MLC-defined field edge to closely match the actual delivered field edge, optimal RLO table values are crucial. This is especially true for IMRT fields containing a large number of segments, since any errors would add together. A method based on the calculated MLC-defined field edge was developed for optimizing and modifying the default RLO table values. Modified RLO tables were developed and evaluated for both dosimetric and light field-based MLC leaf calibrations. It was shown, using a Picket Fence type test, that the optimized RLO table better modeled the calculated leaf tip than the Pinnacle3 default table. This was demonstrated for both an Elekta Synergy 80-leaf and a Varian 120-leaf MLC. 

Psychosocial assessment in liver transplantation (LT): an analysis of short-term outcomes.

BACKGROUND: Our research showed that patients with alcohol-associated liver disease (ALD) had more severe liver disease than those without a diagnosis of ALD yet were less likely to be selected for transplant listing due to their increased psychosocial vulnerability. This study aims to answer whether this vulnerability translates to worse short-term outcomes after transplant listing. METHODS: A total of 187 patients were approved for liver transplant listing and are included in the present retrospective study. We collected dates of transplantation, retransplantation, death, and pathologic data for evidence of rejection, and reviewed alcohol biomarkers and documentation for evidence of alcohol use. RESULTS: The ALD cohort had higher Stanford Integrated Psychosocial Assessment for Transplant (SIPAT) scores (39.4 vs. 22.5, p <0.001) and Model for End-Stage Liver Disease (MELD)-Na scores (25.0 vs. 18.5, p <0.001) compared with the non-ALD cohort. Forty-nine (59.7%) subjects with ALD and 60 (57.1%, p =0.71) subjects without ALD subsequently received a liver transplant. Overall mortality was similar between the 2 groups (20.7% ALD vs. 21.0% non-ALD, p =0.97). Neither the SIPAT score (HR: 0.98, 95% CI: 0.96-1.00, p =0.11) nor MELD-Na score (HR 0.99, 95% CI 0.95-1.02, p =0.40) were associated with mortality. Patients with ALD were more likely to have alcohol biomarkers tested both before (84.1% vs. 24.8% non-ALD, p <0.001) and after liver transplantation (74.0% vs. 16.7% non-ALD, p <0.001). SIPAT score was associated with alcohol use after listing (OR: 1.03, 95% CI: 1.0-1.07, p =0.04), although a return to alcohol use was not associated with mortality (HR: 1.60, 95% CI: 0.63-4.10, p =0.33). CONCLUSION: Patients with ALD had higher psychosocial risk compared with patients without a diagnosis of ALD who were placed on the waitlist, but had similar short-term outcomes including mortality, transplantation, and rejection. Although a high SIPAT score was predictive of alcohol use, in the short-term, alcohol use after transplant listing was not associated with mortality.

Preclinical efficacy and pharmacokinetics of AP5346, a novel diaminocyclohexane-platinum tumor-targeting drug delivery system.

PURPOSE: AP5346 is designed to target a diaminocyclohexane platinum (Pt) moiety to tumors through pH-sensitive linkage to a 25 kDa hydroxypropylmethacrylamide polymer. The goal of these studies was to determine the rate of release of Pt as a function of pH, the antitumor activity, and plasma and tumor pharmacokinetics of AP5346 in preclinical models. EXPERIMENTAL DESIGN: Antitumor activity was assessed in mice bearing B16F10 melanoma and M5076 and 2008 ovarian carcinomas. Pt levels in plasma, tumors, and tumor DNA were measured by atomic absorption and inductively coupled plasma mass spectrometry. RESULTS: AP5346 did not release Pt when suspended in 5% dextrose and released only 3.5% of its Pt in 24 hours in buffer at pH 7.4; the rate of release was 7-fold higher at pH 5.4. When given at their respective maximum tolerated doses, the antitumor activity of AP5346 was superior to that of oxaliplatin against both the B16 melanoma and 2008 human ovarian carcinoma. It was more effective than cisplatin in both cisplatin-sensitive and cisplatin-resistant variants of the M5076 tumor. When given at equitoxic doses, the peak plasma concentration was 25-fold higher, and AUC((0-infinity)) was 93 times higher, for AP5346 than for oxaliplatin. AP5346 delivered 16.3-fold more Pt to the tumor and 14.2-fold more Pt to tumor DNA than oxaliplatin based on AUC((1-168)). CONCLUSIONS: AP5346 has a substantially better therapeutic index than oxaliplatin. AP5346 produced a marked increase in the delivery of diaminocyclohexane Pt to the tumor and tumor DNA over and above that attainable with oxaliplatin.

Behavioral insomnia therapy for fibromyalgia patients: a randomized clinical trial.

BACKGROUND: Insomnia is common and debilitating to fibromyalgia (FM) patients. Cognitive-behavioral therapy (CBT) is effective for many types of patients with insomnia, but has yet to be tested with FM patients. This study compared CBT with an alternate behavioral therapy and usual care for improving sleep and other FM symptoms. METHODS: This randomized clinical trial enrolled 47 FM patients with chronic insomnia complaints. The study compared CBT, sleep hygiene (SH) instructions, and usual FM care alone. Outcome measures were subjective (sleep logs) and objective (actigraphy) total sleep time, sleep efficiency, total wake time, sleep latency, wake time after sleep onset, and questionnaire measures of global insomnia symptoms, pain, mood, and quality of life. RESULTS: Forty-two patients completed baseline and continued into treatment. Sleep logs showed CBT-treated patients achieved nearly a 50% reduction in their nocturnal wake time by study completion, whereas SH therapy- and usual care-treated patients achieved only 20% and 3.5% reductions on this measure, respectively. In addition, 8 (57%) of 14 CBT recipients met strict subjective sleep improvement criteria by the end of treatment compared with 2 (17%) of 12 SH therapy recipients and 0% of the usual care group. Comparable findings were noted for similar actigraphic improvement criteria. The SH therapy patients showed favorable outcomes on measures of pain and mental well-being. This finding was most notable in an SH therapy subgroup that self-elected to implement selected CBT strategies. CONCLUSIONS: Cognitive-behavioral therapy represents a promising intervention for sleep disturbance in FM patients. Larger clinical trials of this intervention with FM patients seem warranted.

Pharmaceutical quality control of the investigational polymer-conjugated platinum anticancer agent AP 5280.

AP 5280 is a novel polymer-conjugated platinum anticancer agent currently in Phase I clinical trials. In order to guarantee the quality of AP 5280 drug substance for use in the manufacture of a drug product for intravenous human use, an array of tests was utilized for its quality control. Proton nuclear magnetic resonance (1H NMR) spectroscopy and infrared (IR) spectroscopy were employed for structural identification. The molecular weight (MW) and MW distribution, which play a large role in the distribution of AP 5280 in vivo, were determined by Size Exclusion Chromatography (SEC). Platinum binding assessment was performed using platinum nuclear magnetic resonance (195Pt NMR) spectroscopy. The free platinum content and release profile of small platinum species, measured using Flameless Atomic Absorption Spectroscopy (F-AAS), were determined as a measure of molecular integrity, a very important aspect of its assumed mechanism of action. The total platinum content of the copolymer was determined employing flame Atomic Absorption Spectroscopy (AAS). The combined results of the analyses performed on AP 5280 drug substance provided a meaningful picture of its structure, size, and integrity--an excellent basis for its quality control.

Automatic quantitative analysis of morphology of apoptotic HL-60 cells.

Morphological identification is a widespread procedure to assess the presence of apoptosis by visual inspection of the morphological characteristics or the fluorescence images. The procedure is lengthy and results are observer dependent. A quantitative automatic analysis is objective and would greatly help the routine work. We developed an image processing and segmentation method which combined the Otsu thresholding and morphological operators for apoptosis study. An automatic determination method of apoptotic stages of HL-60 cells with fluorescence images was developed. Comparison was made between normal cells, early apoptotic cells and late apoptotic cells about their geometric parameters which were defined to describe the features of cell morphology. The results demonstrated that the parameters we chose are very representative of the morphological characteristics of apoptotic cells. Significant differences exist between the cells in different stages, and automatic quantification of the differences can be achieved.

The effects of written emotional disclosure and coping skills training in rheumatoid arthritis: a randomized clinical trial.

OBJECTIVE: Two psychological interventions for rheumatoid arthritis (RA) are cognitive-behavioral coping skills training (CST) and written emotional disclosure (WED). These approaches have developed independently, and their combination may be more effective than either one alone. Furthermore, most studies of each intervention have methodological limitations, and each needs further testing. METHOD: We randomized 264 adults with RA in a 2 × 2 factorial design to 1 of 2 writing conditions (WED vs. control writing) followed by 1 of 2 training conditions (CST vs. arthritis education control training). Patient-reported pain and functioning, blinded evaluations of disease activity and walking speed, and an inflammatory marker (C-reactive protein) were assessed at baseline and 1-, 4-, and 12-month follow-ups. RESULTS: Completion of each intervention was high (>90% of patients), and attrition was low (10.2% at 12-month follow-up). Hierarchical linear modeling of treatment effects over the follow-up period, and analyses of covariance at each assessment point, revealed no interactions between writing and training; however, both interventions had main effects on outcomes, with small effect sizes. Compared with control training, CST decreased pain and psychological symptoms through 12 months. The effects of WED were mixed: Compared with control writing, WED reduced disease activity and physical disability at 1 month only, but WED had more pain than control writing on 1 of 2 measures at 4 and 12 months. CONCLUSIONS: The combination of WED and CST does not improve outcomes, perhaps because each intervention has unique effects at different time points. CST improves health status in RA and is recommended for patients, whereas WED has limited benefits and needs strengthening or better targeting to appropriate patients.

Pain coping skills training and lifestyle behavioral weight management in patients with knee osteoarthritis: a randomized controlled study.

Overweight and obese patients with osteoarthritis (OA) experience more OA pain and disability than patients who are not overweight. This study examined the long-term efficacy of a combined pain coping skills training (PCST) and lifestyle behavioral weight management (BWM) intervention in overweight and obese OA patients. Patients (n=232) were randomized to a 6-month program of: 1) PCST+BWM; 2) PCST-only; 3) BWM-only; or 4) standard care control. Assessments of pain, physical disability (Arthritis Impact Measurement Scales [AIMS] physical disability, stiffness, activity, and gait), psychological disability (AIMS psychological disability, pain catastrophizing, arthritis self-efficacy, weight self-efficacy), and body weight were collected at 4 time points (pretreatment, posttreatment, and 6 months and 12 months after the completion of treatment). Patients randomized to PCST+BWM demonstrated significantly better treatment outcomes (average of all 3 posttreatment values) in terms of pain, physical disability, stiffness, activity, weight self-efficacy, and weight when compared to the other 3 conditions (Ps<0.05). PCST+BWM also did significantly better than at least one of the other conditions (ie, PCST-only, BWM-only, or standard care) in terms of psychological disability, pain catastrophizing, and arthritis self-efficacy. Interventions teaching overweight and obese OA patients pain coping skills and weight management simultaneously may provide the more comprehensive long-term benefits.

Disease severity and domain-specific arthritis self-efficacy: relationships to pain and functioning in patients with rheumatoid arthritis.

OBJECTIVE: To examine the degree to which disease severity and domains of self-efficacy (pain, function, and other symptoms) explain pain and functioning in rheumatoid arthritis (RA) patients. METHODS: Patients (n = 263) completed the Arthritis Impact Measurement Scales 2 to assess pain and functioning (physical, affective, and social), the Arthritis Self-Efficacy Scale to assess 3 self-efficacy domains (pain, physical function, and other). Disease severity was assessed with C-reactive protein level, physician's rating, and abnormal joint count. Structural equation modeling was used to examine 3 hypotheses: does disease severity have a direct relationship with pain and each area of functioning, does disease severity have a direct relationship with each arthritis self-efficacy domain, and do the self-efficacy domains mediate the relationship between disease severity and RA pain and each area of functioning. RESULTS: Disease severity was related to pain, physical functioning, and each self-efficacy domain (beta = 0.28-0.56, P < 0.001). Each self-efficacy domain was related to its respective domain of functioning (e.g., self-efficacy for pain was related to pain; beta = 0.36-0.54, P < 0.001). Self-efficacy mediated the relationship between disease severity and pain and functioning (beta = 0.12-0.19, P < 0.001). Self-efficacy for pain control and to perform functional tasks accounted for 32-42% of disease severity's total effect on their respective outcomes (e.g., self-efficacy for pain control accounted for 32% of disease severity's total effect on pain). Variance accounted for by the total model was 52% for pain, 53% for physical functioning, and 44% for affective and social functioning. CONCLUSION: Disease severity and self-efficacy both impact RA functioning, and intervening in these areas may lead to better outcomes.

Pain catastrophizing and pain-related fear in osteoarthritis patients: relationships to pain and disability.

This study examined the degree to which pain catastrophizing and pain-related fear explain pain, psychological disability, physical disability, and walking speed in patients with osteoarthritis (OA) of the knee. Participants in this study were 106 individuals diagnosed as having OA of at least one knee, who reported knee pain persisting for six months or longer. Results suggest that pain catastrophizing explained a significant proportion (all Ps < or = 0.05) of variance in measures of pain (partial r(2) [pr(2)] = 0.10), psychological disability (pr(2) = 0.20), physical disability (pr(2) = 0.11), and gait velocity at normal (pr(2) = 0.04), fast (pr(2) = 0.04), and intermediate speeds (pr(2) = 0.04). Pain-related fear explained a significant proportion of the variance in measures of psychological disability (pr(2) = 0.07) and walking at a fast speed (pr(2) = 0.05). Pain cognitions, particularly pain catastrophizing, appear to be important variables in understanding pain, disability, and walking at normal, fast, and intermediate speeds in knee OA patients. Clinicians interested in understanding variations in pain and disability in this population may benefit by expanding the focus of their inquiries beyond traditional medical and demographic variables to include an assessment of pain catastrophizing and pain-related fear.