Updates in the pathogenesis and management of immune-related enterocolitis, hepatitis and cardiovascular toxicities.

Immune checkpoint inhibitors (ICIs) have become a cornerstone of treatment for many solid organ malignancies. Alongside increasing use, the occurrence of immune-related adverse events (irAEs) has also increased and remains a significant challenge when treating patients with ICI. The underlying pathophysiology of irAE development for many organ systems is yet to be elucidated, but may involve unmasking of latent autoimmunity, increased T-cell recognition of shared antigens on cancer and normal tissue and ICI-triggered immune dysregulation with overactivation of proinflammatory pathways and suppression of immune control pathways. Management strategies for irAEs have historically been borrowed from paradigms for conventional autoimmune conditions such as inflammatory bowel disease and autoimmune hepatitis; however, recent translational efforts have clearly demonstrated key differences in underlying immune signalling pathways. As we begin to understand these differences, we must adapt a more targeted approach to immunosuppression and exercise a more nuanced approach with the multiple biologic agents available to mitigate ICI-related toxicity without reversing the antitumour effect of ICI. In this review, we focus on three key immune-related toxicities where recent clinical and translational work has provided nuanced insights into pathogenesis and treatment strategies: enterocolitis, hepatitis and cardiovascular toxicity including myocarditis.

Feasibility of laparoscopic microwave ablation of caudate tumors: a case series.

Microwave ablation of liver tumors allows preservation of liver parenchyma with good oncologic outcomes. However, ablation of tumors in the caudate lobe is particularly challenging. Adjacent critical anatomy, particularly the biliary hilum, has led to caudate location being considered a relative contraindication to ablation. To date, no series have described laparoscopic microwave ablation of caudate tumors of the liver. We describe our early experience with laparoscopic microwave ablation of caudate tumors. In this retrospective review of a prospectively maintained single-institution database, six patients with six primary or secondary caudate tumors underwent laparoscopic microwave ablation with no complications. At a median follow-up of 10.5 months, five out of six patients are free of caudate recurrence. Laparoscopic microwave ablation of caudate tumors is feasible. Long-term follow-up is needed to determine if local recurrence risk is higher than in other anatomical segments.

Bacterial lipopolysaccharide modulates immune response in the colorectal tumor microenvironment.

Immune responses can have opposing effects in colorectal cancer (CRC), the balance of which may determine whether a cancer regresses, progresses, or potentially metastasizes. These effects are evident in CRC consensus molecular subtypes (CMS) where both CMS1 and CMS4 contain immune infiltrates yet have opposing prognoses. The microbiome has previously been associated with CRC and immune response in CRC but has largely been ignored in the CRC subtype discussion. We used CMS subtyping on surgical resections from patients and aimed to determine the contributions of the microbiome to the pleiotropic effects evident in immune-infiltrated subtypes. We integrated host gene-expression and meta-transcriptomic data to determine the link between immune characteristics and microbiome contributions in these subtypes and identified lipopolysaccharide (LPS) binding as a potential functional mechanism. We identified candidate bacteria with LPS properties that could affect immune response, and tested the effects of their LPS on cytokine production of peripheral blood mononuclear cells (PBMCs). We focused on Fusobacterium periodonticum and Bacteroides fragilis in CMS1, and Porphyromonas asaccharolytica in CMS4. Treatment of PBMCs with LPS isolated from these bacteria showed that F. periodonticum stimulates cytokine production in PBMCs while both B. fragilis and P. asaccharolytica had an inhibitory effect. Furthermore, LPS from the latter two species can inhibit the immunogenic properties of F. periodonticum LPS when co-incubated with PBMCs. We propose that different microbes in the CRC tumor microenvironment can alter the local immune activity, with important implications for prognosis and treatment response.

Comparing Lookback Periods to Ascertain Alzheimer's Disease and Related Dementias.

Claims data are a valuable resource for studying Alzheimer's disease and related dementias (ADRD). Alzheimer's disease and related dementias is often identified using a list of claims codes and a fixed lookback period of 3 years of data. However, a 1-year lookback or an approach using all-available lookback data could be beneficial based on different research questions. Thus, the purpose of this study was to compare 1-year and all-available lookback approaches to ascertaining ADRD compared to the standard 3-year approach. Using a cohort of Veterans hospitalized for heart failure (N = 373, 897), our results suggested high agreement (93% or greater) between the lookback periods. The 1-year lookback period had lower sensitivity (60%) and underestimated the prevalence of ADRD. These results suggest that 1-year and all-available lookback periods are viable approaches when using claims data.

Disparities in post-mastectomy reconstruction use among American Indian and Alaska Native women.

BACKGROUND: American Indian/Alaska Native (AI/AN) breast cancer patients undergo post-mastectomy reconstruction (PMR) infrequently relative to Non-Hispanic White (NHW) patients. Factors associated with low PMR rates among AI/AN are poorly understood. We sought to describe factors associated with this disparity in surgical care. METHODS: A retrospective cohort study of the National Cancer Database (2004 - 2017) identified AI/AN and NHW women, ages 18 - 64, who underwent mastectomy for stage 0 - III breast cancer. Patient characteristics, annual PMR rates, and factors associated with PMR were described with univariable analysis, the Cochran-Armitage test, and multivariable logistical regression. RESULTS: 414,036 NHW and 1,980 AI/AN met inclusion criteria. Relative to NHW, AI/AN had more comorbidities (20% vs 12% Charlson Comorbidity Index ≥ 1, p < 0.001), had non-private insurance (49% vs 20%, p < 0.001), and underwent unilateral mastectomy more frequently (69% vs 61%, p < 0.001). PMR rates increased over the study period, from 13% to 47% for AI/AN and from 29% to 62% for NHW (p <0.001). AI/AN race was independently associated with decreased likelihood of PMR (OR 0.62, 95% CI 0.56-0.69). Among AI/AN, decreased likelihood of PMR was significantly associated with older age at diagnosis, more remote year of diagnosis, advanced disease (tumor size > 5 cm, positive lymph nodes), unilateral mastectomy, non-private insurance, and lower educational attainment in patient's area of residence. CONCLUSION: PMR rates among AI/AN with stage 0 - III breast cancer have increased, yet remain significantly lower than among NHW. Further research should elicit AI/AN perspectives on PMR, and guide early breast cancer detection and treatment.

Mitochondrial impairment but not peripheral inflammation predicts greater Gulf War illness severity.

Gulf War illness (GWI) is an important exemplar of environmentally-triggered chronic multisymptom illness, and a potential model for accelerated aging. Inflammation is the main hypothesized mechanism for GWI, with mitochondrial impairment also proposed. No study has directly assessed mitochondrial respiratory chain function (MRCF) on muscle biopsy in veterans with GWI (VGWI). We recruited 42 participants, half VGWI, with biopsy material successfully secured in 36. Impaired MRCF indexed by complex I and II oxidative phosphorylation with glucose as a fuel source (CI&CIIOXPHOS) related significantly or borderline significantly in the predicted direction to 17 of 20 symptoms in the combined sample. Lower CI&CIIOXPHOS significantly predicted GWI severity in the combined sample and in VGWI separately, with or without adjustment for hsCRP. Higher-hsCRP (peripheral inflammation) related strongly to lower-MRCF (particularly fatty acid oxidation (FAO) indices) in VGWI, but not in controls. Despite this, whereas greater MRCF-impairment predicted greater GWI symptoms and severity, greater inflammation did not. Surprisingly, adjusted for MRCF, higher hsCRP significantly predicted lesser symptom severity in VGWI selectively. Findings comport with a hypothesis in which the increased inflammation observed in GWI is driven by FAO-defect-induced mitochondrial apoptosis. In conclusion, impaired mitochondrial function-but not peripheral inflammation-predicts greater GWI symptoms and severity.

Longitudinal assessment of the sleep suicide link in Veterans: methods and study protocol.

Although sleep disruption has emerged as a theoretically consistent and empirically supported suicide risk factor, the mechanistic pathways underlying the sleep-suicide link are less understood. This paper describes the methodology of a study intended to examine longitudinal mechanisms driving the link between sleep and suicide in Veterans at elevated suicide risk. Participants will be 140 Veterans hospitalized for suicide attempt or ideation with plan and intent or those identified through the Suicide Prevention Coordinator (SPC) office as being at acute risk. After study enrollment, actigraphy and ecological momentary assessment (EMA) data will be collected for 8 weeks, with follow-up assessments occurring at 2, 4, 6, 8, and 26 weeks. Participants respond to EMA questionnaires, derived from psychometrically validated assessments targeting emotional reactivity, emotion regulation, impulsivity, suicide risk, and sleep timing constructs, five times a day. First and last daily EMA target sleep parameters including sleep quantity, quality, timing, nightmares, and nocturnal awakenings. During follow-up assessments, participants will complete self-report assessments and interviews consistent with EMA constructs and the Iowa Gambling Task. The primary outcome for aim 1 is suicide ideation severity and for the primary outcome for aim 2 is suicide behavior. Findings from this study will improve our understanding of the dynamic interactions among sleep disturbance, emotion reactivity/regulation, and impulsivity to inform conceptual Veteran sleep-suicide mechanistic models. Improved models will be critical to optimizing the precision of suicide prevention efforts that aim to intervene and mitigate risk in Veteran populations, especially during a period of acute risk.

Synchronised transcranial magnetic stimulation for substance use-disordered Veterans: protocol for the pilot sham-controlled acceptability trial.

INTRODUCTION: Substance use disorders (SUDs) take an enormous toll on US Veterans and civilians alike. Existing empirically supported interventions vary by substance and demonstrate only moderate efficacy. Non-invasive brain stimulation represents an innovative treatment for SUDs, yet aspects of traditional neurostimulation may hinder its implementation in SUD populations. Synchronised transcranial magnetic stimulation (sTMS) uses rotating rare earth magnets to deliver low-field stimulation synchronised to an individual's alpha peak frequency that is safe for at-home administration. The current trial aims to assess the acceptability and feasibility of sTMS, as well as the safety of at-home sTMS administration for substance-disordered Veterans. METHODS AND ANALYSIS: Sixty Veterans in substance treatment at the Providence Veterans Affairs will be randomised to receive 6 weeks of active or sham sTMS treatment. Eligibility will be confirmed by meeting Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition criteria for an alcohol, cocaine or opioid use disorder. Daily supervised sTMS treatment will occur either in clinic or at home through video monitoring. Clinical and self-report assessments will be completed at baseline, end of treatment and 1-month follow-up. Urine drug screening will occur once per week during the treatment phase. Primary outcomes include treatment adherence/retention and satisfaction to evaluate sTMS feasibility and acceptability in Veterans with SUDs. The safety of at-home sTMS administration will be assessed via adverse event monitoring. ETHICS AND DISSEMINATION: The sTMS device received a significant risk determination for at-home use by the Food and Drug Administration in July 2021. Ethics approval was obtained in August 2021 from the Providence Veterans Affairs institutional review board and research and development committee. Data collection began in September 2021 and is planned to continue through December 2023. Findings will be disseminated at national conferences and in peer-reviewed journals. Results will serve to inform the development of large-scale clinical trials of sTMS efficacy for substance-disordered Veterans. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov Registry (NCT04336293).

Chemotherapy refusal and subsequent survival in healthy older women with high genomic risk estrogen receptor-positive breast cancer.

BACKGROUND: Patients with estrogen receptor (ER)-positive, HER2-negative breast cancer (BC), and high-risk 21-gene recurrence score (RS) results benefit from chemotherapy. We evaluated chemotherapy refusal and survival in healthy older women with high-RS, ER-positive BC. METHODS: Retrospective review of the National Cancer Database (2010-2017) identified women ≥ 65 years of age, with ER-positive, HER2-negative, high-RS (≥ 26) BC. Patients with Charlson Comorbidity Index ≥ 1, stage III/IV disease, or incomplete data were excluded. Women were compared by chemotherapy receipt or refusal using the Cochrane-Armitage test, multivariable logistical regression modeling, the Kaplan-Meier method, and Cox's proportional hazards modeling. RESULTS: 6827 women met study criteria: 5449 (80%) received chemotherapy and 1378 (20%) refused. Compared to women who received chemotherapy, women who refused were older (71 vs 69 years), were diagnosed more recently (2014-2017, 67% vs 61%), and received radiation less frequently (67% vs 71%) (p ≤ 0.05). Refusal was associated with decreased 5-year OS for women 65-74 (92% vs 95%) and 75-79 (85% vs 92%) (p ≤ 0.05), but not for women ≥ 80 years old (84% vs 91%; p = 0.07). On multivariable analysis, hazard of death increased with refusal overall (HR 1.12, 95% CI 1.04-1.2); but, when stratified by age, was not increased for women ≥ 80 years (HR 1.10, 95% CI 0.80-1.51). CONCLUSIONS: Among healthy women with high-RS, ER-positive BC, chemotherapy refusal was associated with decreased OS for women ages 65-79, but did not impact the OS of women ≥ 80 years old. Genomic testing may have limited utility in this population, warranting prudent shared decision-making and further study.

A Review of Resection and Surgical Ablation for Primary and Secondary Liver Cancers.

The surgical management of primary and secondary liver tumors is constantly evolving. Patient selection, particularly with regard to determining resectability, is vital to the success of programs directed toward invasive treatments of liver tumors. Particular attention should be paid toward determining whether patients are best served with surgical resection or ablative therapies. A multidisciplinary approach is necessary to provide optimal care to patients with liver malignancy.

Preying dangerously: black widow spider venom resistance in sympatric lizards.

Lizards and spiders are natural adversaries, yet little is known of adaptations that lizards might possess for dealing with the venomous defences of spider prey. In the Western USA, two lizard species (Elgaria multicarinata and Sceloporus occidentalis) are sympatric with and predate western black widow spiders (Latrodectus hesperus). The consequences of black widow spider venom (BWSV) can be severe, and are well understood for mammals but unknown for reptiles. We evaluated potential resistance to BWSV in the lizards that consume black widows, and a potentially susceptible species (Uta stansburiana) known as prey of widows. We investigated BWSV effects on whole-animal performance (sprint) and muscle tissue at two venom doses compared with control injections. Sprint speed was not significantly decreased in E. multicarinata or S. occidentalis in any treatment, while U. stansburiana suffered significant performance reductions in response to BWSV. Furthermore, E. multicarinata showed minimal tissue damage and immune response, while S. occidentalis and U. stansburiana exhibited increased muscle damage and immune system infiltration in response to BWSV. Our data suggest predator-prey relationships between lizards and spiders are complex, possibly leading to physiological and molecular adaptations that allow some lizards to tolerate or overcome the dangerous defences of their arachnid prey.

The Addition of Chemoradiation to Adjuvant Chemotherapy is Associated With Improved Survival Following Upfront Surgical Resection for Pancreatic Cancer With Nodal Metastases.

BACKGROUND: It is unclear whether the addition of chemoradiation (CRT) to adjuvant chemotherapy (CT) following upfront resection of pancreatic ductal adenocarcinoma (PDAC) provides any benefit. While some studies have suggested a benefit to combined modality therapy (CMT) (adjuvant CT plus CRT), it is not clear if this benefit was related to increased CT usage in patients who received CMT. We sought to clarify the use of CMT in patients who underwent upfront resection of PDAC. METHODS: Patients with non-metastatic PDAC were retrospectively identified from the linked SEER-Medicare database. Those who underwent upfront resection were identified and divided into two cohorts - patients who received adjuvant CT and patients who received adjuvant CMT. Cohorts were compared. Univariate analysis described patient characteristics. Kaplan-Meier and multivariable Cox proportional hazards modeling were used to estimate overall survival (OS). RESULTS: 3555 patients were identified; 856 (24%) received CT and 573 (16%) received CMT. The median number of CT doses was 11 for both groups. Patients who received CMT were younger, diagnosed in the earlier time frame, and had fewer comorbidities. The median OS was 21 months and 18 months for those treated with CMT and CT (P < .0001), respectively, but when stratified by nodal status, the association with improved OS in the CMT cohort was only observed in node-positive patients. On multivariable analysis, receipt of CMT and removal of >15 lymph nodes decreased the risk of death (P < .05). DISCUSSION: Receipt of CMT following upfront resection for PDAC was associated with improved survival, which was confined to node-positive patients. The role of adjuvant CMT in PDAC with nodal metastases warrants further study.

Clinical translational neuroimaging of the antioxidant effect of N-acetylcysteine on neural microstructure.

PURPOSE: Oxidative stress and downstream effectors have emerged as important pathological processes that drive psychiatric illness, suggesting that antioxidants may have a therapeutic role in psychiatric disease. However, no imaging biomarkers are currently available to track therapeutic response. The purpose of this study was to examine whether advanced DWI techniques are able to sensitively detect the potential therapeutic effects of the antioxidant N-acetylcysteine (NAC) in a Disc1 svΔ2 preclinical rat model of psychiatric illness. METHODS: Male and female Disc1 svΔ2 rats and age-matched, sex-matched Sprague-Dawley wild-type controls were treated with a saline vehicle or NAC before ex vivo MRI acquisition at P50. Imaging data were fit to DTI and neurite orientation dispersion and density imaging models and analyzed for region-specific changes in quantitative diffusion metrics. Brains were further processed for cellular quantification of microglial density and morphology. All experiments were repeated for Disc1 svΔ2 rats exposed to chronic early-life stress to test how gene-environment interactions might alter effectiveness of NAC therapy. RESULTS: The DTI and neurite orientation dispersion and density imaging analyses demonstrated amelioration of early-life, sex-specific neural microstructural deficits with concomitant differences in microglial morphology across multiple brain regions relevant to neuropsychiatric illness with NAC treatment, but only in male Disc1 svΔ2 rats. Addition of chronic early-life stress reduced the ability of NAC to restore microstructural deficits. CONCLUSION: These findings provide evidence for a treatment pathway targeting endogenous antioxidant capacity, and the clinical translational utility of neurite orientation dispersion and density imaging microstructural imaging to sensitively detect microstructural alterations resulting from antioxidant treatment.

Overnight variation in tidal expiratory flow limitation in COPD patients and its correction: an observational study.

BACKGROUND: Tidal expiratory flow limitation (EFLT) is common among COPD patients. Whether EFLT changes during sleep and can be abolished during home ventilation is not known. METHODS: COPD patients considered for noninvasive ventilation used a ventilator which measured within-breath reactance change at 5 Hz (∆Xrs) and adjusted EPAP settings to abolish EFLT. Participants flow limited (∆Xrs > 2.8) when supine underwent polysomnography (PSG) and were offered home ventilation for 2 weeks. The EPAP pressure that abolished EFLT was measured and compared to that during supine wakefulness. Ventilator adherence and subjective patient perceptions were obtained after home use. RESULTS: Of 26 patients with supine EFLT, 15 completed overnight PSG and 10 the home study. In single night and 2-week home studies, EFLT within and between participants was highly variable. This was unrelated to sleep stage or body position with only 14.6% of sleep time spent within 1 cmH2O of the awake screening pressure. Over 2 weeks, mean EPAP was almost half the mean maximum EPAP (11.7 vs 6.4 cmH2O respectively). Group mean ∆Xrs was ≤ 2.8 for 77.3% of their home use with a mean time to abolish new EFLT of 5.91 min. Adherence to the ventilator varied between 71 and 100% in prior NIV users and 36-100% for naïve users with most users rating therapy as comfortable. CONCLUSIONS: Tidal expiratory flow limitation varies significant during sleep in COPD patients. This can be controlled by auto-titrating the amount of EPAP delivered. This approach appears to be practical and well tolerated by patients. TRIAL REGISTRATION: The trial was retrospectively registered at CT.gov NCT04725500.

Staff and participant perceptions of optimal recruitment and retention strategies for biomedical cohort studies in the Caribbean.

PURPOSE: To identify staff and participants perspectives of best practices that facilitate achieving enrollment and retention targets in biomedical cohort studies in Caribbean populations. METHODS: Eight focus group discussions (FGDs) were held with research stakeholders including research (i) nurses/study supervisors, (ii) field staff/data collectors, and (iii) rural and urban participants of the Third Jamaica Health and Lifestyle Survey (a national NCD risk factor survey with biospecimen collection) to capture qualitative data on experiences with recruitment, training, retention challenges and potential solutions or strategies for strengthening future efforts. RESULTS: Our findings indicate that trained, experienced study staff with good interpersonal communication skills enhanced the proficiency of field operations and attracted study participants. Targeted community and stakeholder engagement alongside strong support from the coordinating center increased the reach and efficiency of the data collectors. Timely participant feedback, gender-appropriate approaches, and socioeconomic balance enhanced equitable enrollment and retention of participants of cohort studies particularly the hard to reach groups. CONCLUSION: Well-functioning research teams using traditional and social media promotion, applying gender-appropriate and personalized approaches together with strategies for reaching the less accessible socioeconomic groups, are effective for recruiting and retaining members of a Caribbean cohort. These strategies may also enhance the recruitment of other Black populations in the Diaspora including the US and Caribbean into biomedical studies including cancer research.