Ocular Toxicity Profile of Targeted Cancer Therapy (TCT) at a US Tertiary Cancer Center.

PURPOSE:  Targeted cancer therapy (TCT) is a significant advancement in oncology with promising survival improvement in patients with cancer and remarkable effects on various cancers. There is evidence suggesting a connection between specific TCT classes and the occurrence of immune-related adverse events (irAEs). Our study aims to investigate the potential ocular toxicities of different classes of TCT, provide a better understanding of these toxicities, and aid in the future development of screening and management recommendations for ocular irAEs. DESIGN:  Retrospective observational case series. PARTICIPANTS:  Only ocular immune-related AEs were included in the study; patients on TCT who received a new ophthalmic diagnosis were seen at the MD Anderson Cancer Center. METHODS:  Between 2010 and 2019, we retrospectively reviewed the medical records of 6,354 patients on TCT at a large US tertiary cancer center.  Results: The criteria for data analysis were met by 1861 patients. TCT was associated with a wide range of class-specific ocular irAEs. There was a statistically significant correlation between ocular toxicity with polytherapy with a p-value of <0.001. Furthermore, there was a statistically significant correlation between toxicity and BRAF, epidermal growth factor receptor (EGFR), and ICI <0.001, <0.001, and 0.006, respectively.  Conclusion: Our cohort is the most extensive case series in English literature, demonstrating the increased risk of class-specific ocular toxicity associated with TCT, which sheds some light on the importance of developing standardized grading criteria and management guidelines.

Highlights on Ocular Toxicity of Immune Checkpoint Inhibitors at a US Tertiary Cancer Center.

Introduction: Immune checkpoint inhibitors (ICIs) have improved prognosis in advanced malignancies; however, they may be associated with extensive ocular immune-related adverse events (irAEs) that are sight threatening. Our study aimed to identify the presentation, characteristics, management, and clinical outcomes of ocular irAEs. Methods: In this retrospective, observational case series, we reviewed the medical records of 1280 patients at a large US tertiary cancer center between 2010 and 2020. Results: We identified 130 patients who presented with ocular irAEs (10%) with 69 males (53%) and 61 females (47%). The mean time to toxicity was 6.1 months. Adverse events include corneal toxicity (31%), neuro-ophthalmic (14%), uveitis and scleritis (13%), retinopathy (13%), periocular disorders (11%), and others. IrAEs occurred most frequently with nivolumab (26%). Most ocular irAEs were treated with topical therapy. Advanced cases required systemic corticosteroids and even cessation of ICIs. Conclusion: Our cohort is a large case series highlighting the increased potential of ocular toxicity associated with ICIs. Prompt recognition and management of ocular irAEs can minimize their effect.

Rehabilitation for torture survivors: Six evidence myths and their implications for future research.

Whilst it is established that torture survivors suffer from complex, multiple and often severe and enduring physical, psychological, social, welfare and many other difficulties; and that rehabilitation as reparation should be holistic, interdisciplinary and specialist, majority of the research on rehabilitation focuses increasingly and almost exclusively on psychological interventions. Further, as-sumptions that this research provides evi-dence of which are effective psychological interventions may underpin and skew ser-vices funded and provided to torture sur-vivors. In this paper we challenge some of those assumptions, and discuss the concep-tual, theoretical, epistemological and meth-odological limitations of this research and implications for future research.

Psychological, social, and welfare interventions for torture survivors: A systematic review and meta-analysis of randomised controlled trials.

BACKGROUND: Torture and other forms of ill treatment have been reported in at least 141 countries, exposing a global crisis. Survivors face multiple physical, psychological, and social difficulties. Psychological consequences for survivors are varied, and evidence on treatment is mixed. We conducted a systematic review and meta-analysis to estimate the benefits and harms of psychological, social, and welfare interventions for torture survivors. METHODS AND FINDINGS: We updated a 2014 review with published randomised controlled trials (RCTs) for adult survivors of torture comparing any psychological, social, or welfare intervention against treatment as usual or active control from 1 January 2014 through 22 June 2019. Primary outcome was post-traumatic stress disorder (PTSD) symptoms or caseness, and secondary outcomes were depression symptoms, functioning, quality of life, and adverse effects, after treatment and at follow-up of at least 3 months. Standardised mean differences (SMDs) and odds ratios were estimated using meta-analysis with random effects. The Cochrane tool was used to derive risk of bias. Fifteen RCTs were included, with data from 1,373 participants (589 females and 784 males) in 10 countries (7 trials in Europe, 5 in Asia, and 3 in Africa). No trials of social or welfare interventions were found. Compared to mostly inactive (waiting list) controls, psychological interventions reduced PTSD symptoms by the end of treatment (SMD -0.31, 95% confidence interval [CI] -0.52 to -0.09, p = 0.005), but PTSD symptoms at follow-up were not significantly reduced (SMD -0.34, 95% CI -0.74 to 0.06, p = 0.09). No significant improvement was found for PTSD caseness at the end of treatment, and there was possible worsening at follow-up from one study (n = 28). Interventions showed no benefits for depression symptoms at end of treatment (SMD -0.23, 95% CI -0.50 to 0.03, p = 0.09) or follow-up (SMD -0.23, 95% CI -0.70 to 0.24, p = 0.34). A significant improvement in functioning for psychological interventions compared to control was found at end of treatment (SMD -0.38, 95% CI -0.58 to -0.18, p = 0.0002) but not at follow-up from only one study. No significant improvement emerged for quality of life at end of treatment (SMD 0.38, 95% CI -0.28 to 1.05, p = 0.26) with no data available at follow-up. The main study limitations were the difficulty in this field of being certain of capturing all eligible studies, the lack of modelling of maintenance of treatment gains, and the low precision of most SMDs making findings liable to change with the addition of further studies as they are published. CONCLUSIONS: Our findings show evidence that psychological interventions improve PTSD symptoms and functioning at the end of treatment, but it is unknown whether this is maintained at follow-up, with a possible worsening of PTSD caseness at follow-up from one study. Further interventions in this population should address broader psychological needs beyond PTSD while taking into account the effect of multiple daily stressors. Additional studies, including social and welfare interventions, will improve precision of estimates of effect, particularly over the longer term.

Reviewing outcomes of psychological interventions with torture survivors: Conceptual, methodological and ethical Issues.

BACKGROUND: Torture survivors face multiple problems, including psychological difficulties, whether they are refugees or remain in the country where they were tortured. Provision of rehabilitation varies not only with the needs of survivors and resources available, but also with service models, service provider preferences and the local and country context. Despite increasing efforts in research on effectiveness of psychological interventions with torture survivors, results are inconclusive. METHODS: We undertook a Cochrane systematic review of psychological, social and welfare provision, with meta-analysis to best estimate efficacy. The process raised conceptual, methodological and ethical issues of relevance to the wider field. FINDINGS: We searched very widely, but rejected hundreds of papers which recommended treatment without providing evidence. We found nine randomised controlled trials, from developed and under-resourced settings. All conceptualised survivors' problems in psychiatric terms, using outcomes of post-traumatic stress symptoms, distress, and quality of life, by self-report, with or without translation or unstandardised interpretation, and with little mention of cultural or language issues. None used social or welfare interventions. Four related studies used narrative exposure therapy (NET) in a brief form, and without ensuring a safe setting as recommended. Five used mixed methods, including exposure, cognitive behavioural therapy, and eye movement desensitisation. Combined, the studies showed no immediate improvement in PTSD, distress, or quality of life; at six months follow-up, a minority showed some improvement in PTSD and distress, although participants remained severely affected. CONCLUSIONS: While applauding researchers' commitment in running these trials, we raise ethical issues about exposure in particular, and about the effects of shortcomings in methodology, particularly around assessment using unfamiliar cultural frameworks and language, and the lack of concern about dropout which may indicate harm. The issues addressed aid interpretation of existing research, and guide clinical practice as well as future studies evaluating its effectiveness.

Psychological, social and welfare interventions for psychological health and well-being of torture survivors.

BACKGROUND: Torture is widespread, with potentially broad and long-lasting impact across physical, psychological, social and other areas of life. Its complex and diverse effects interact with ethnicity, gender, and refugee experience. Health and welfare agencies offer varied rehabilitation services, from conventional mental health treatment to eclectic or needs-based interventions. This review is needed because relatively little outcome research has been done in this field, and no previous systematic review has been conducted. Resources are scarce, and the challenges of providing services can be considerable. OBJECTIVES: To assess beneficial and adverse effects of psychological, social and welfare interventions for torture survivors, and to compare these effects with those reported by active and inactive controls. SEARCH METHODS: Randomised controlled trials (RCTs) were identified through a search of PsycINFO, MEDLINE, EMBASE, Web of Science, the Cumulative Index to Nursing and Allied Health Literature (CINAHL), the Cochrane Central Register of Controlled Trials (CENTRAL) and the Cochrane Depression, Anxiety and Neurosis Specialised Register (CCDANCTR), the Latin American and Caribbean Health Science Information Database (LILACS), the Open System for Information on Grey Literature in Europe (OpenSIGLE), the World Health Organization International Clinical Trials Registry Platform (WHO ICTRP) and Published International Literature On Traumatic Stress (PILOTS) all years to 11 April 2013; searches of Cochrane resources, international trial registries and the main biomedical databases were updated on 20 June 2014. We also searched the Online Library of Dignity (Danish Institute against Torture), reference lists of reviews and included studies and the most frequently cited journals, up to April 2013 but not repeated for 2014. Investigators were contacted to provide updates or details as necessary. SELECTION CRITERIA: Full publications of RCTs or quasi-RCTs of psychological, social or welfare interventions for survivors of torture against any active or inactive comparison condition. DATA COLLECTION AND ANALYSIS: We included all major sources of grey literature in our search and used standard methodological procedures as expected by The Cochrane Collaboration for collecting data, evaluating risk of bias and using GRADE (Grades of Recommendation, Assessment, Development and Evaluation) methods to assess the quality of evidence. MAIN RESULTS: Nine RCTs were included in this review. All were of psychological interventions; none provided social or welfare interventions. The nine trials provided data for 507 adults; none involved children or adolescents. Eight of the nine studies described individual treatment, and one discussed group treatment. Six trials were conducted in Europe, and three in different African countries. Most people were refugees in their thirties and forties; most met the criteria for post-traumatic stress disorder (PTSD) at the outset. Four trials used narrative exposure therapy (NET), one cognitive-behavioural therapy (CBT) and the other four used mixed methods for trauma symptoms, one of which included reconciliation methods. Five interventions were compared with active controls, such as psychoeducation; four used treatment as usual or waiting list/no treatment; we analysed all control conditions together. Duration of therapy varied from one hour to longer than 20 hours with a median of around 12 to 15 hours. All trials reported effects on distress and on PTSD, and two reported on quality of life. Five studies followed up participants for at least six months.No immediate benefits of psychological therapy were noted in comparison with controls in terms of our primary outcome of distress (usually depression), nor for PTSD symptoms, PTSD caseness, or quality of life. At six-month follow-up, three NET and one CBT study (86 participants) showed moderate effect sizes for intervention over control in reduction of distress (standardised mean difference (SMD) -0.63, 95% confidence interval (CI) -1.07 to -0.19) and of PTSD symptoms (SMD -0.52, 95% CI -0.97 to -0.07). However, the quality of evidence was very low, and risk of bias resulted from researcher/therapist allegiance to treatment methods, effects of uncertain asylum status of some people and real-time non-standardised translation of assessment measures. No measures of adverse events were described, nor of participation, social functioning, quantity of social or family relationships, proxy measures by third parties or satisfaction with treatment. Too few studies were identified for review authors to attempt sensitivity analyses. AUTHORS' CONCLUSIONS: Very low-quality evidence suggests no differences between psychological therapies and controls in terms of immediate effects on post-traumatic symptoms, distress or quality of life; however, NET and CBT were found to confer moderate benefits in reducing distress and PTSD symptoms over the medium term (six months after treatment). Evidence was of very low quality, mainly because non-standardised assessment methods using interpreters were applied, and sample sizes were very small. Most eligible trials also revealed medium to high risk of bias. Further, attention to the cultural appropriateness of interventions or to their psychometric qualities was inadequate, and assessment measures used were unsuitable. As such, these findings should be interpreted with caution.No data were available on whether symptom reduction enabled improvements in quality of life, participation in community life, or in social and family relationships in the medium term. Details of adverse events and treatment satisfaction were not available immediately after treatment nor in the medium term. Future research should aim to address these gaps in the evidence and should include larger sample sizes when possible. Problems of torture survivors need to be defined far more broadly than by PTSD symptoms, and recognition given to the contextual influences of being a torture survivor, including as an asylum seeker or refugee, on psychological and social health.

Resveratrol decreases noise-induced cyclooxygenase-2 expression in the rat cochlea.

OBJECTIVE: Our previous studies have demonstrated the efficacy of resveratrol, a grape constituent noted for its antioxidant and anti-inflammatory properties, in reducing temporary threshold shifts and decreasing cochlear hair cell damage following noise exposure. This study was designed to identify the potential protective mechanism of resveratrol by measuring its effect on cyclooxygenase-2 (COX-2) protein expression and reactive oxygen species (ROS) formation following noise exposure. STUDY DESIGN: Controlled animal intervention study. SETTING: Otology Laboratory, Henry Ford Health System. SUBJECTS AND METHODS: Twenty-two healthy male Fischer 344 rats (2-3 months old) were exposed to acoustic trauma of variable duration with or without intervention. An additional 20 healthy male rats were used to study COX-2 expression at different time points during and following treatment of 24 hours of noise exposure. Cochlear harvest was performed at various time intervals for measurement of COX-2 protein expression via Western blot analysis and immunostaining. Peripheral blood was also obtained for ROS analysis using flow cytometry. RESULTS: Acoustic trauma exposure resulted in a progressive up-regulation of COX-2 protein expression, commencing at 8 hours and peaking at 32 hours. Similarly, ROS production increased after noise exposure. However, treatment with resveratrol reduced noise-induced COX-2 expression as well as ROS formation in the blood as compared with the controls. CONCLUSION: COX-2 levels are induced dramatically following noise exposure. This increased expression may be a potential mechanism of noise-induced hearing loss (NIHL) and a possible mechanism of resveratrol's ability to mitigate NIHL by its ability to reduce COX-2 expression.

Disparities in disability among non-Hispanic black elders: results from the National Interview Survey 2001-2003.

A drastically increasing elderly population and disparity among disability poses a concern for the U.S. health care industry. This retrospective cross-sectional study analyzed whether ADL and IADL disabilities were different among non-Hispanic white (NHW) and non-Hispanic black (NHB) populations age 65 and over. Data was retrieved from the 2001-2003 National Health Interview Survey (NHIS) for comparing NHBs and NHWs using chi-square analysis for bivariate comparisons. For both elderly NHBs and elderly NHWs, increased rates of disability were reported for being over 75, female, single, and having lower education. NHBs reported statistically higher disability rates for ADL, IADL, and for any disability, with 10.0%, 18.0%, and 19.3%, respectively, compared to NHWs. There is a need to increase the access for NHBs to nursing home, hospice, and assisted-living facilities. Of further concern is the finding of lower institutionalization rates in the NHB population despite the significant presence of increased disability. The growing NHB elderly population needs an urgent societal intervention to address the persistent disparity, which has been neglected for so many years.

Regulation of protein synthesis in Y-organs of the blue crab (Callinectes sapidus): involvement of cyclic AMP.

Paired Y-organs secrete ecdysteroid hormones that control cycles of growth and molting in crustaceans. Y-Organs are regulated, at least in part, by molt-inhibiting hormone (MIH), a polypeptide produced and released by the X-organ/sinus gland complex of the eyestalks. In the present studies, crab (Callinectes sapidus) Y-organs were incubated in vitro in the presence of [(35)S]methionine, and cyclic nucleotide analogs or experimental agents that influence the cAMP signaling pathway. In 4-hr incubations, 8-Br-cAMP and db-cAMP (but not 8-Br-cGMP) suppressed incorporation of [(35)S]methionine into Y-organ proteins; the effect of 8-Br-cAMP was concentration-dependent. Autoradiograms of radiolabeled Y-organ proteins separated on SDS-PAGE gels indicated the effect of 8-Br-cAMP was general (as opposed to selective) suppression of protein synthesis. Addition of both forskolin (an adenylyl cyclase activator) and 3-isobutyl-1-methylxanthine (a phosphodiesterase inhibitor) likewise suppressed incorporation of [(35)S]methionine into Y-organ proteins. Cycloheximide (a protein synthesis inhibitor) suppressed incorporation of [(35)S]methionine into Y-organ proteins and secretion of ecdysteroids. The combined results suggest that cAMP is involved in regulation of protein synthesis in C. sapidus Y-organs. We are currently investigating the link of protein synthesis to ecdysteroid production, and the possibility of cross-talk between cAMP and other cellular signaling pathways in Y-organs.