Improved freedom from PSA failure with whole pelvic irradiation for high-risk prostate cancer

Purpose: To determine the impact of whole pelvic irradiation on the risk of PSA failure in prostate cancer patients, at high predicted risk for lymph node involvement, receiving definitive radiotherapy.

Materials and Methods: Between October 1987 and December 1995, 506 patients with clinically localized prostate cancer were treated with definitive radiotherapy at UCSF and affiliated institutions. Treatment consisted of 4-field whole pelvic irradiation followed by a prostate-only boost, or prostate-only treatment (median follow-up was 35 months and 30 months, respectively). PSA failure was defined as: 1. a PSA value ≥ 1 ng/ml; or 2. a PSA value that rose ≥ 0.5 ng/ml in ≤ 1 year posttreatment on two consecutive measurements, with the first rise defined as the time of failure. The calculated risk of lymph node positivity (%rLN+) was defined as (iPSA) + 10(GS-6), and high risk was defined as %rLN+ ≥ 15%. Univariate and multivariate analyses were performed.

Results: A total of 201 high-risk patients were identified. High-risk patients who received whole pelvic irradiation had significantly improved freedom from PSA failure compared to those who received prostate-only treatment (median PFS = 34.3 months vs. 21.0 months; p = 0.0001). Potential confounding variables, including initial PSA, Gleason score, T stage, radiation dose, year of treatment, use of three-dimensional (3D) conformal techniques, and use of hormone therapy, did not account for the observed difference in time to PSA failure. Multivariate analysis revealed type of radiation treatment to be the most significant independent predictor of outcome.

Conclusion: Whole pelvic radiotherapy significantly improves the PSA failure-free survival in patients with a high calculated risk of lymph node positivity.     

Economic choice between remifentanil and food in squirrel monkeys

Traditional approaches for evaluating if compounds are reinforcing, and thus a risk for abuse, include preclinical self-administration procedures conducted in the absence of alternative reinforcers. While the track record of this approach for determining abuse potential is good, that for predicting efficacy of addiction treatments is not. An alternate approach would be economic choice between drug and nondrug rewards, with parametrically varied options from trial to trial. This would promote goal-directed decisions between reward modalities and should provide metrics that reflect changes in internal state that influence desirability of a given option. We report herein a high throughput economic choice procedure in which squirrel monkeys choose between a short-lived opiate, remifentanil, and a palatable food reward. Stimuli on touchscreens indicate the amount of each reward type offered by varying the number of reward-specific elements. The rapid clearance of remifentanil avoids accumulation of confounding levels of drug, and permits a large number of trials with a wide range of offers of each reward modality. The use of a single metric encompassing multiple values of each reward type within a session enables estimation of indifference values using logistic regression. This indifference value is sensitive to reward devaluation within each reward domain, and is therefore a useful metric for determining shifts in reward preference, as shown with satiation and pharmacological treatment approaches.Subject terms: Addiction, Decision     

Psychosocial Correlates of Monocyte Activation and HIV Persistence in Methamphetamine Users

This cross-sectional study investigated the associations of psychosocial factors relevant to recovery from substance use disorders with monocyte activation and HIV persistence in a sample of 84 HIV-positive, methamphetamine-using sexual minority men with undetectable HIV viral load (<40 copies/mL). We examined if psychosocial factors were associated with decreased soluble CD14 (sCD14) and lower proviral HIV DNA. Multiple linear regression models adjusted for age, anti-retroviral therapy regimen, and CD4+ T-cell count. Time on ART was also included in models examining proviral HIV DNA. Greater self-efficacy for managing methamphetamine triggers and higher social support for abstinence were independently associated with lower sCD14. Greater social support for abstinence was also independently associated with lower proviral HIV DNA. Psychosocial factors relevant to recovery from substance use disorders are associated with lower monocyte activation and decreased proviral HIV DNA. Findings underscore the need for longitudinal research to identify plausible mechanisms linking psychosocial factors and substance use with biological processes relevant to HIV pathogenesis.

     

A service evaluation to examine the use of compression strapping for the management of patients with retromalleolar leg ulcers in a specialist community setting

Leg ulcers are costly to the NHS, and they have a significant impact on patients'' physical, social, and psychological well‐being. Compression therapy is traditionally the “gold‐standard” treatment for the management of venous leg ulcers and can be beneficial for those individuals with mixed ulcer aetiology. Evidence suggests that the application of standard, strong, graduated compression bandaging does not apply therapeutic compression to the retromalleolar fossa. The addition of compression strapping has been found to increase sub‐bandage pressure, promote healing, reduce pain and increase quality of life in patients with retromalleolar leg ulcers. This service evaluation aimed at evaluating the use of compression strapping with patients with retromalleolar leg ulcers. The service evaluation included 24 patients with 41 ulcers treated with compression strapping by a specialist team. Patients treated with CS had multiple comorbidities and shared common characteristics including foot and ankle oedema, previous ulceration, reduced mobility, and failure to heal despite the application of “gold‐standard” compression therapy. Following application of compression strapping, 17 patients (n = 27/41 ulcers) healed, mean pain scores decreased, and mean quality of life scores increased. The compression strapping was tolerated well, and patients reported a positive experience. This service evaluation has contributed towards a growing evidence base that supports the use of CS for the management of patients with retromalleolar leg ulcers.     

Targeted Mutations in the Fusion Peptide Region of La Crosse Virus Attenuate Neuroinvasion and Confer Protection against Encephalitis

La Crosse virus (LACV) is a major cause of pediatric encephalitis and aseptic meningitis in the Midwestern, Mid-Atlantic, and Southern United States, where it is an emerging pathogen. The LACV Gc glycoprotein plays a critical role in the neuropathogenesis of LACV encephalitis as the putative virus attachment protein. Previously, we identified and experimentally confirmed the location of the LACV fusion peptide within Gc and generated a panel of recombinant LACVs (rLACVs) containing mutations in the fusion peptide as well as the wild-type sequence. These rLACVs retained their ability to cause neuronal death in a primary embryonic rat neuronal culture system, despite decreased replication and fusion phenotypes. To test the role of the fusion peptide in vivo, we tested rLACVs in an age-dependent murine model of LACV encephalitis. When inoculated directly into the CNS of young adult mice (P28), the rLACV fusion peptide mutants were as neurovirulent as the rLACV engineered with a wild-type sequence, confirming the results obtained in tissue culture. In contrast, the fusion peptide mutant rLACVs were less neuroinvasive when suckling (P3) or weanling (P21) mice were inoculated peripherally, demonstrating that the LACV fusion peptide is a determinant of neuroinvasion, but not of neurovirulence. In a challenge experiment, we found that peripheral challenge of weanling (P21) mice with fusion peptide mutant rLACVs protected from a subsequent WT-LACV challenge, suggesting that mutations in the fusion peptide are an attractive target for generating live-attenuated virus vaccines. Importantly, the high degree of conservation of the fusion peptide amongst the Bunyavirales and, structurally, other arboviruses suggests that these findings are broadly applicable to viruses that use a class II fusion mechanism and cause neurologic disease.     

A molecularly integrated grade for meningioma

BackgroundMeningiomas are the most common primary intracranial tumor in adults. Clinical care is currently guided by the World Health Organization (WHO) grade assigned to meningiomas, a 3-tiered grading system based on histopathology features, as well as extent of surgical resection. Clinical behavior, however, often fails to conform to the WHO grade. Additional prognostic information is needed to optimize patient management.MethodsWe evaluated whether chromosomal copy-number data improved prediction of time-to-recurrence for patients with meningioma who were treated with surgery, relative to the WHO schema. The models were developed using Cox proportional hazards, random survival forest, and gradient boosting in a discovery cohort of 527 meningioma patients and validated in 2 independent cohorts of 172 meningioma patients characterized by orthogonal genomic platforms.ResultsWe developed a 3-tiered grading scheme (Integrated Grades 1-3), which incorporated mitotic count and loss of chromosome 1p, 3p, 4, 6, 10, 14q, 18, 19, or CDKN2A. 32% of meningiomas reclassified to either a lower-risk or higher-risk Integrated Grade compared to their assigned WHO grade. The Integrated Grade more accurately identified meningioma patients at risk for recurrence, relative to the WHO grade, as determined by time-dependent area under the curve, average precision, and the Brier score.ConclusionWe propose a molecularly integrated grading scheme for meningiomas that significantly improves upon the current WHO grading system in prediction of progression-free survival. This framework can be broadly adopted by clinicians with relative ease using widely available genomic technologies and presents an advance in the care of meningioma patients.     

Multisystem Inflammatory Syndrome after Breakthrough SARS-CoV-2 Infection in 2 Immunized Adolescents,United States

Eight weeks after having laboratory-confirmed SARS-CoV-2 breakthrough infections, 2 otherwise healthy, fully immunized adolescent patients in the United States who were experiencing related signs and symptoms were diagnosed with multisystem inflammatory syndrome in children. Our findings indicate that COVID-19 vaccination does not completely protect adolescents against multisystem inflammatory syndrome.