Citations

Abstract Background: The genotoxin colibactin causes a tumor single-base substitution (SBS) mutational signature, SBS88. It is unknown whether epidemiologic factors’ association with colorectal cancer risk and survival differs by SBS88. Methods: Within the Genetic Epidemiology of Colorectal Cancer Consortium and Colon Cancer Family Registry, we measured SBS88 in 4,308 microsatellite stable/microsatellite instability low tumors. Associations of epidemiologic factors with colorectal cancer risk by SBS88 were assessed using multinomial regression (N = 4,308 cases, 14,192 controls; cohort-only cases N = 1,911), and with colorectal cancer–specific survival using Cox proportional hazards regression (N = 3,465 cases). Results: 392 (9%) tumors were SBS88 positive. Among all cases, the highest quartile of fruit intake was associated with lower risk of SBS88-positive colorectal cancer than SBS88-negative colorectal cancer [odds ratio (OR) = 0.53, 95% confidence interval (CI) 0.37-0.76; OR = 0.75, 95% CI 0.66–0.85, respectively, Pheterogeneity = 0.047]. Among cohort studies, associations of body mass index (BMI), alcohol, and fruit intake with colorectal cancer risk differed by SBS88. BMI ≥30 kg/m2 was associated with worse colorectal cancer–specific survival among those SBS88-positive [hazard ratio (HR) = 3.40, 95% CI 1.47–7.84], but not among those SBS88-negative (HR = 0.97, 95% CI 0.78–1.21, Pheterogeneity = 0.066). Conclusions: Most epidemiologic factors did not differ by SBS88 for colorectal cancer risk or survival. Higher BMI may be associated with worse colorectal cancer–specific survival among those SBS88-positive; however, validation is needed in samples with whole-genome or whole-exome sequencing available. Impact: This study highlights the importance of identification of tumor phenotypes related to colorectal cancer and understanding potential heterogeneity for risk and survival.

SummaryBackgroundRacial and ethnic disparities exist for hepatitis C virus (HCV) treatment and hepatocellular carcinoma (HCC) survival.AimTo evaluate the impact of HCV treatment on such disparities.MethodsIn a retrospective cohort study, we analysed 6069 patients with HCV‐related HCC (54.2% Asian, 30.1% White, 8.5% Black, and 7.3% Hispanic) from centres in the United States and Asia.ResultsThe mean age was 61, 60, 59 and 68, respectively, for White, Black, Hispanic and Asian patients. Black patients were most likely to have Barcelona Clinic Liver Cancer stage D, vascular invasion and distant metastasis (23% vs. 5%–15%, 20% vs. 10%–17% and 10% vs. 5%–7%, respectively; all p < 0.0001). Treatment rate with direct‐acting antiviral agents (DAA) was 35.9% for Asian, 34.9% for White, 30.3% for Hispanic (30.3%), and 18.7% for Black patients (p < 0.0001). Among those untreated or without sustained virologic response (SVR), 10‐year survival rates were 35.4, 27.5, 19.3 and 14.0, respectively, for Asian, Hispanic, White and Black patients (p < 0.0001). There were no statistically significant differences among those with SVR (p = 0.44). On multivariable analysis adjusted for relevant confounders, there was no statistically significant association between survival and being Hispanic (aHR: 0.68, p = 0.26) or Black (aHR: 1.18, p = 0.60) versus White. There was a significant association between being Asian American and survival (aHR: 0.24, p = 0.001; non‐U.S. Asian: aHR: 0.66, p = 0.05), and for SVR (aHR: 0.30, p < 0.0001).ConclusionDAA treatment rates were suboptimal. Racial and ethnic disparities resolved with HCV cure. Early diagnosis and improved access to HCV treatment is needed for all patients with HCV infection.

Abstract Background: Lithium (Li) remains the treatment of choice for bipolar disorders (BP). Its mood-stabilizing effects help reduce the long-term burden of mania, depression and suicide risk in patients with BP. It also has been shown to have beneficial effects on disease-associated conditions, including sleep and cardiovascular disorders. However, the individual responses to Li treatment vary within and between diagnostic subtypes of BP (e.g. BP-I and BP-II) according to the clinical presentation. Moreover, long-term Li treatment has been linked to adverse side-effects that are a cause of concern and non-adherence, including the risk of developing chronic medical conditions such as thyroid and renal disease. In recent years, studies by the Consortium on Lithium Genetics (ConLiGen) have uncovered a number of genetic factors that contribute to the variability in Li treatment response in patients with BP. Here, we leveraged the ConLiGen cohort (N=2,064) to investigate the genetic basis of Li effects in BP. For this, we studied how Li response and linked genes associate with the psychiatric symptoms and polygenic load for medical comorbidities, placing particular emphasis on identifying differences between BP-I and BP-II. Results: We found that clinical response to Li treatment, measured with the Alda scale, was associated with a diminished burden of mania, depression, substance and alcohol abuse, psychosis and suicidal ideation in patients with BP-I and, in patients with BP-II, of depression only. Our genetic analyses showed that a stronger clinical response to Li was modestly related to lower polygenic load for diabetes and hypertension in BP-I but not BP-II. Moreover, our results suggested that a number of genes that have been previously linked to Li response variability in BP differentially relate to the psychiatric symptomatology, particularly to the numbers of manic and depressive episodes, and to the polygenic load for comorbid conditions, including diabetes, hypertension and hypothyroidism. Conclusions: Taken together, our findings suggest that the effects of Li on symptomatology and comorbidity in BP are partially modulated by common genetic factors, with differential effects between BP-I and BP-II.

Slow, deep breathing (SDB) is thought to lead to reductions in blood pressure by decreasing vascular‐sympathetic coupling. Venous Occlusion Plethysmography (VOP) is used to assess forearm blood flow (FBF) (ml/min/100 dl tissue). We used this technique to determine the vasodilatory effect of device‐guided (DG) vs self‐paced (SP) slow, deep breathing. We hypothesized that SP would lead to a larger vasodilation response than DG due to a more profound reduction in vascular‐sympathetic coupling, and that this would be correlated with psychological evaluations. Young, healthy male subjects (Mean age: 20 yr; DG: n=10; SP: n=11) rested supine for 20 minutes (baseline), followed by 20 minutes of SP or DG slow, deep breathing, then completed 20 minutes of endogenous breathing (recovery). At baseline, there was no difference in breathing rate between SP and DG (14.36±1.03 vs 15.39±1.29 breaths per minute, p=0.27) and respiratory rate was reduced to 8.36±0.74 breaths per minute (BPM) in the SP group (p<0.01 compared to baseline) and to 6.37±0.10 BPM in the DG group (p<0.01 compared to baseline). Respiratory rates between the two groups differed significantly during SDB (p<0.01 between groups). There was a significant increase in SP FBF compared to baseline at the end of the 20 minute intervention (p<0.05),while the DG group saw no significant increases. In DG, there was a strong negative correlation with the cognitive interference scores to VOP responsiveness (−0.77; R2=0.591), as well as between the cognitive failure score and VOP responsiveness (−0.61; R2=0.3693). In contrast, the SP groups had positive correlations when comparing VOP responsiveness to cognitive interference (0.1; R2=0.093) or cognitive failure (0.30; R2=0.011). For subjects in either breathing group, those who had an increase in FBF in response to SDB also had reductions in STAI anxiety score after the intervention whereas those with a decrease in FBF to SDB had an increase in anxiety score during the slow breathing (p=0.04). Overall, male subjects have a variable vasodilator responses to two types of SDB practices related to underlying psychological metrics. Our data underscores the importance of psychological metrics in physiological outcomes related to SDB practices.

Abstract Purpose This systematic review and meta‐analysis aimed to (1) determine the proportion of patients who underwent anterior shoulder instability surgery and did not return to sports for psychological reasons and (2) estimate differences in psychological readiness scores between patients who did and did not return to sports. Methods The EBSCOhost/SPORTDiscus, PubMed/Medline, Scopus, EMBASE and Cochrane Library databases were searched for relevant studies. The data synthesis included the proportion of patients who did not return to sports for psychological reasons and the mean differences in the psychological readiness of athletes who returned and those who did not return to sports. Non‐binomial data were analysed using the inverse‐variance approach and expressed as the mean difference with 95% confidence intervals. Results The search yielded 700 records, of which 13 (1093 patients) were included. Fourteen psychological factors were identified as potential causes for not returning to sports. The rates of return to sports at any level or to the preinjury level were 79.3% and 61.9%, respectively. A total of 55.9% of the patients cited psychological factors as the primary reason for not returning to sports. The pooled estimate showed that patients who returned to sports had a significantly higher Shoulder Instability‐Return to Sport After Injury score ( P < 0.00001) than those who did not, with a mean difference of 30.24 (95% CI 24.95–35.53; I 2 = 0%; n.s.). Conclusions Psychological factors have a substantial impact on the rate of return to sports after anterior shoulder instability surgery. Patients who returned to sports had significantly higher psychological readiness than those who did not return to sports. Based on these results, healthcare professionals should include psychological and functional measurements when assessing athletes’ readiness to return to sports. Level of evidence Level IV.

Patients with advanced cancers who either do not experience initial response to or progress while on immune checkpoint inhibitors (ICIs) receive salvage radiotherapy to reduce tumor burden and tumor-related symptoms. Occasionally, some patients experience substantial global tumor regression with a rebound of cytotoxic CD8 + T cells. We have termed the rebound of cytotoxic CD8 + T cells in response to salvage therapy as T cell resilience and examined the underlying mechanisms of resilience. Resilient T cells are enriched for CX3CR1 + CD8 + T cells with low mitochondrial membrane potential, accumulate less reactive oxygen species (ROS), and express more malic enzyme 1 (ME1). ME1 overexpression enhanced the cytotoxicity and expansion of effector CD8 + T cells partially via the type I interferon pathway. ME1 also increased mitochondrial respiration while maintaining the redox state balance. ME1 increased the cytotoxicity of peripheral lymphocytes from patients with advanced cancers. Thus, preserved resilient T cells in patients rebound after salvage therapy and ME1 enhances their resiliency.

Abstract Histopathology is the gold standard for distinguishing tumor recurrence from treatment-induced necrosis but differentiating pseudoprogression from true recurrence is challenging in tumors with ambiguous morphological features. Prior research reported a 36% inter-rater agreement during suspected recurrence (Holdhoff et al., 2019). While serial radiographic and laboratory assessments are common, serial histopathological assessments are not. This study evaluated agreement and factors influencing assessment of active and inactive tumors through single and multiple time-point histopathological assessments. Patients who underwent initial and subsequent reoperation were identified, and their available histology slides were examined retrospectively. Four independent neuropathologists conducted two types of reviews: single time-point reviews using most recent biopsy/surgery slides, and multiple time-point reviews comparing images from initial and repeat biopsies taken 1-3 months apart. Neuropathologists completed a questionnaire assessing various tumor characteristics. Assignments were categorized as "active tumor," "treatment effect," or "unable to classify." 324 assessments were conducted (108 single time-point, 216 multiple time-point). Intraclass correlation coefficients for single vs. multiple time-point assessments were 0.72-0.93 for active tumors and 0.57-0.86 for inactive tumors. Pathologists' assessment of % inactive tumor was influenced by mitotic activity (p= 0.0028), cellularity (p&lt; 0.0001), hyalinized vessels (p= 0.0019), and necrosis (p= 0.0046). Evaluation of % active tumor was influenced by hyalinized vessels (p= 0.0006), mitotic activity (p&lt; 0.0001), cellularity (p&lt; 0.0001), and microvascular proliferation (p= 0.0093), with the latter three factors specifically affecting final sign-out pathology. Serial histopathological assessment didn’t affect determination of % active or inactive tumor. No association between % inactive tumor and fibrinoid necrosis for single time-point (p= 0.34) but a strong negative association was seen for serial assessment (p= 0.0006). Inter-rater agreement was higher for identifying active tumors than inactive tumors in both case reviews. Changes in necrosis between tissue samples in single vs. multiple timepoint assessments influenced pathologists' assessment of % inactive tumor.

AbstractContextEarly inflammatory thyroid eye disease (TED) can lead to symptomatic chronic disease, including disabling proptosis. Teprotumumab, an insulin-like growth factor-1 receptor (IGF-1R) inhibitor, previously demonstrated efficacy in acute, high-inflammation TED trials.ObjectiveWe present data from the first placebo-controlled trial with teprotumumab in chronic/low disease activity TED.MethodsThis randomized double-masked, placebo-controlled trial, conducted at 11 US centers, enrolled adult participants with TED duration of 2 to 10 years, Clinical Activity Score (CAS) ≤ 1 or no additional inflammation or progression in proptosis/diplopia for ≥1 year, proptosis ≥3 mm from before TED and/or from normal, euthyroid/mildly hypo/hyperthyroid, no prior teprotumumab, and no steroids within 3 weeks of baseline. Patients received (2:1) intravenous teprotumumab or placebo once every 3 weeks (total 8 infusions). The primary endpoint was proptosis (mm) improvement at Week 24. Adverse events (AEs) were assessed.ResultsA total of 62 (42 teprotumumab and 20 placebo) patients were randomized. At Week 24, least squares mean (SE) proptosis improvement was greater with teprotumumab (−2.41 [0.228]) than with placebo (−0.92 [0.323]), difference −1.48 (95% CI −2.28, −0.69; P = .0004). Proportions of patients with AEs were similar between groups. Hyperglycemia was reported in 6 (15%) vs 2 (10%) and hearing impairment in 9 (22%) vs 2 (10%) with teprotumumab and placebo, respectively. AEs led to discontinuation in 1 teprotumumab (left ear conductive hearing loss with congenital anomaly) and 1 placebo patient (infusion-related). There were no deaths.ConclusionTeprotumumab significantly improved proptosis vs placebo in longstanding/low inflammation TED, demonstrating efficacy regardless of disease duration/activity. The safety profile was comparable to that previously reported.