Abstract
Background
High-grade anal intraepithelial neoplasia (HGAIN; AIN2–3) is highly prevalent in HIV+ men, but only a minority of these lesions progress towards cancer. Currently, cancer ...progression risk cannot be established; therefore, no consensus exists on whether HGAIN should be treated. This study aimed to validate previously identified host cell DNA methylation markers for detection and cancer risk stratification of HGAIN.
Methods
A large independent cross-sectional series of 345 anal cancer, AIN3, AIN2, AIN1, and normal control biopsies of HIV+ men was tested for DNA methylation of 6 genes using quantitative methylation-specific PCR. We determined accuracy for detection of AIN3 and cancer (AIN3+) by univariable and multivariable logistic regression analysis, followed by leave-one-out cross-validation. Methylation levels were assessed in a series of 10 anal cancer cases with preceding HGAIN at similar anatomic locations, and compared with the cross-sectional series.
Results
Methylation levels of all genes increased with increasing severity of disease (P < .05). HGAIN revealed a heterogeneous methylation pattern, with a subset resembling cancer. ZNF582 showed highest accuracy (AUC = 0.88) for AIN3+ detection, slightly improved by addition of ASCL1 and SST (AUC = 0.89), forming a marker panel. In the longitudinal series, HGAIN preceding cancer displayed high methylation levels similar to cancers.
Conclusions
We validated the accuracy of 5 methylation markers for the detection of anal (pre-) cancer. High methylation levels in HGAIN were associated with progression to cancer. These markers provide a promising tool to identify HGAIN in need of treatment, preventing overtreatment of HGAIN with a low cancer progression risk.
Independent validation of host cell DNA methylation markers associated with anal carcinogenesis demonstrates their significant prognostic value for treatment decision making of high-grade anal intraepithelial neoplasia. This is further emphasised by a longitudinal analysis-based association with progression to anal cancer.
Human papillomavirus (HPV)‐induced anal intraepithelial neoplasia (AIN, graded 1‐3) is highly prevalent in HIV‐positive (HIV+) men who have sex with men (MSM), but only a minority of lesions ...progresses to cancer. Our study aimed to characterise comprehensively anal tissue samples from a cross‐sectional series (n = 104) of HIV+ MSM and longitudinal series (n = 40) of AIN2/3 progressing to cancer using different biomarkers. The cross‐sectional series consisted of 8 normal, 26 AIN1, 45 AIN2, 15 AIN3 and 10 anal squamous cell carcinoma. Tissue sections were immunohistochemically (IHC) stained for p16 (viral transformation marker), Ki‐67 (cellular proliferation marker) and HPV‐E4 (viral production marker). We evaluated the expression of IHC markers and compared it with DNA methylation, a marker for malignant transformation. E4 positivity decreased, whereas p16 and Ki‐67 scores and methylation marker positivity increased (P values < .001) with increasing severity of anal lesions. Within AIN2, a heterogeneous biomarker pattern was observed concerning E4, p16 and methylation status, reflecting the biological heterogeneity of these lesions. In the longitudinal series, all AIN2/3 and carcinomas showed high p16 and Ki‐67 expression, strong methylation positivity and occasional E4 positivity. We earlier showed that high methylation levels are associated with progression to cancer. The observed E4 expression in some AIN2/3 during the course of progression to cancer and absence of E4 in a considerable number of AIN1 lesions make the potential clinical significance of E4 expression difficult to interpret. Our data show that IHC biomarkers can help to characterise AIN; however, their prognostic value for cancer risk stratification, next to objective methylation analysis, appears to be limited.
What's new?
Anal high‐grade squamous intraepithelial lesions (HSILs) constitute a heterogeneous group of precancerous lesions. Understanding which HSILs progress to cancer could facilitate early detection and treatment of anal cancer. Here, the prognostic value of expression of the immunohistochemical (IHC) markers p16, Ki‐67, and HPV‐E4 was evaluated in anal tissues with evidence of precancerous lesions. While analyses revealed positive associations between p16 and Ki‐67 expression and severity of anal dysplasia, HSILs overall exhibited complex biomarker patterns, reflecting their ambiguous clinical behaviour. Thus, while IHC markers are useful for molecular characterisation of HSIL, their prognostic value, particularly compared to methylation analysis, is limited.
Abstract Objectives To investigate the diagnostic accuracy of fluoro-2-deoxy- d -glucose positron emission tomography (FDG-PET) compared with computed tomography (CT) scanning and added value of ...fused FDG-PET–CT in diagnosing vascular prosthetic graft infection. Design Prospective cohort study with retrospective analysis. Materials Twenty five patients with clinically suspected vascular prosthetic infection underwent CT and FDG-PET scanning. Methods Two nuclear medicine physicians assessed the FDG-PET scans; all CT scans were assessed by two radiologists. Fused FDG-PET/CT were judged by the radiologist and the nuclear medicine physician. The concordance between CT and FDG-PET and the inter-observer agreement between the different readers were investigated. Results Fifteen patients had a proven infection by culture. Single FDG-PET had the best results (sensitivity 93%, specificity 70%, positive predictive value 82% and negative predictive value 88%). For CT, these values were 56%, 57%, 60% and 58%, respectively. Fused CT and FDG-PET imaging also showed high sensitivity and specificity rates and high positive and negative values. Inter-observer agreement for FDG-PET analysis was excellent (kappa = 1.00) and moderate for CT and fused FDG-PET–CT analysis (0.63 and 0.66, respectively). Conclusion FDG-PET scanning showed a better diagnostic accuracy than CT for the detection of vascular prosthetic infection. This study suggests that FDG-PET provides a useful tool in the work-up for diagnosis of vascular prosthetic graft infection.
Display omitted
► Incidence of repeat traumatic brain injury. ► Clinical considerations for pediatric repeat traumatic brain injury. ► Experimental models of developmental repeat traumatic brain ...injury.
The Center for Disease Control estimates that there are 1.7 million brain injuries in the US each year with 51% of these injuries occurring during periods of cerebral development. Among this population there is a growing population of individuals with repeat traumatic brain injury (RTBI). While the exact incidence is unknown, estimates range from 5.6 to 36% of the TBI population. This review summarizes the clinical problems/challenges and experimental research models that currently exist. It is intended to reveal the critical areas that need to be addressed so that age-relevant clinical management guidelines can be established to protect this population.
Purpose
Knowledge of caregivers’ burden and fatigue before and after patients’ treatment for locally advanced head and neck cancer is scarce. Therefore, we aimed to explore caregivers’ fatigue and ...burden in relation to patients’ fatigue, distress, and quality of life.
Methods
For caregivers, burden and fatigue were assessed. For patients, fatigue severity, distress, and health-related quality of life (HRQoL) were assessed. Measurements were conducted prior to treatment, 1 week, and 3 months after chemoradiotherapy.
Results
Caregivers’ burden and fatigue followed patients’ high peak in distress, fatigue, and diminished HRQoL as a consequence of treatment. Caregivers’ baseline fatigue was a predictor for fatigue after chemoradiotherapy. Female spouses with higher baseline levels of fatigue and burden and caring for patients with lower levels of HRQoL seem risk factors for burden after chemoradiotherapy.
Conclusions
Attention should be paid to caregivers’ burden and fatigue before starting patients’ intense treatment with chemoradiotherapy, as both burden and fatigue before starting treatment may contribute to burden and fatigue after chemoradiotherapy.
To identify the effects of a 1-year exercise intervention on myocardial dysfunction in patients with type 2 diabetes mellitus (T2DM).
Randomised controlled trial, the Diabetes Lifestyle Intervention ...Study.
University hospital.
223 T2DM patients without occult coronary artery disease, aged 18-75 were randomised to an exercise training group (n = 111) or a usual care group (n = 112). Complete follow-up data were available in 176 (88 exercise, 88 usual care).
Exercise training consisted of gym, followed by telephone-monitored home-based exercise training.
Tissue Doppler-derived myocardial velocities, strain-rate and strain, body composition, glycated haemoglobin (HbA(1c)), maximum oxygen consumption (VO(2max)) and physical activity.
Overall changes in myocardial function were not different between groups despite improvements in waist circumference, fat mass, blood glucose, HbA(1c), insulin sensitivity, VO(2max) and 6-minute walk distance in the intervention group (p<0.05). The latter also spent significantly more time in vigorous activity (p<0.05). A post-hoc analysis revealed that intervention patients who spent more time in both moderate and vigorous activity showed a significant improvement in myocardial tissue velocity (p<0.01), HbA(1c) (p = 0.03) and VO(2max) (p = 0.03) compared to controls. Myocardial strain rate (p = 0.03) and HbA(1c) improved in intervention patients with the greatest increase in moderate activity (p = 0.03).
In patients with T2DM, current exercise recommendations led to an improvement in metabolic function, but failed to improve myocardial function in the overall group. Patients with greater increases in both moderate and vigorous activity showed improvements in myocardial function, glycaemic control and cardiorespiratory fitness.
ACTRN12607000060448.
Purpose
To investigate whether locoregional staging of colon cancer by experienced radiologists can be improved by training and feedback to minimize the risk of over-staging into the context of ...patient selection for neoadjuvant therapy and to identify potential pitfalls of CT staging by characterizing pathologic traits of tumors that remain challenging for radiologists.
Methods
Forty-five cases of stage I-III colon cancer were included in this retrospective study. Five experienced radiologists evaluated the CTs; 5 baseline scans followed by 4 sequential batches of 10 scans. All radiologists were trained after baseline scoring and 2 radiologists received feedback. The learning curve, diagnostic performance, reader confidence, and reading time were evaluated with pathologic staging as reference. Pathology reports and H&E slides of challenging cases were reviewed to identify potential pitfalls.
Results
Diagnostic performance in distinguishing T1-2 vs. T3-4 improved significantly after training and with increasing number of reviewed cases. Inaccurate staging was more frequently related to under-staging rather than over-staging. Risk of over-staging was minimized to 7% in batch 3–4. N-staging remained unreliable with an overall accuracy of 61%. Pathologic review identified two tumor characteristics causing under-staging for T-stage in 5/7 cases: (1) very limited invasive part beyond the muscularis propria and (2) mucinous composition of the invading part.
Conclusion
The high accuracy and specificity of T-staging reached in our study indicate that sufficient training and practice of experienced radiologists can ensure high validity for CT staging in colon cancer to safely use neoadjuvant therapy without significant risk of over-treatment, while N-staging remained unreliable.
Background
In May 2022, an outbreak of mpox (monkeypox) in men‐who‐have‐sex‐with‐men (MSM) emerged and quickly affected over 100 countries. In the early stages of the outbreak, overlap in symptoms ...with sexually transmitted infections (STI) made triage for mpox testing challenging. More information was needed on whom to screen and the main route of transmission.
Objectives
We aimed to identify characteristics of mpox cases to further strengthen case definitions. We also compared Cycle threshold (Ct) values of the DNA positive mpox samples as a proxy for viral load by body location.
Methods
From 20 May 2022 to 15 September 2022, we tested all MSM who presented with malaise, and/or ulcerative lesions, and/or proctitis and/or a papular‐vesicular‐pustular eruption attending the Centre of Sexual Health in Amsterdam, the Netherlands, for mpox, with a PCR test. In the same period, 6932 MSM mpox unsuspected clients were not tested. We compared those tested positive for mpox with those tested negative and those unsuspected for mpox.
Results
Of the 374 MSM tested, 135 (36%) were positive for mpox. The mpox‐positive MSM were older (median age, respectively, 36, 34 and 34 years, p = 0.019) and more often lived with HIV (30% vs. 16% and 7%, p < 0.001). Furthermore, mpox‐positive patients more often reported receptive anal sex without a condom, sexualized drug use, more sex partners, and were more often diagnosed with bacterial STI (p < 0.001). Systemic symptoms and anogenital lesions were associated with mpox infection. For mpox‐positive patients, anal samples (p = 0.009) and lesional samples (p = 0.006) showed significantly lower median mpox Ct values compared to throat samples.
Conclusions
Mpox‐positive patients more often reported receptive anal sex without a condom, had more sex partners and more often lived with HIV. Our results suggest that in the current mpox outbreak among MSM, sexual transmission is the main route.
The aim of this study was to assess the safety and immunogenicity of a dose-sparing fractional intradermal (ID) booster strategy with the mRNA-1273 COVID-19 vaccine.
COVID-19 naive adults aged ...18–30 years were recruited from a previous study on primary vaccination regimens that compared 20 μg ID vaccinations with 100 μg intramuscular (IM) vaccinations with mRNA-1273 as the primary vaccination series. Participants previously immunized with ID regimens were randomly assigned (1:1) to receive a fractional ID booster dose (20 μg) or the standard-of-care intramuscular (IM) booster dose (50 μg) of the mRNA-1273 vaccine, 6 months after completing their primary series (ID-ID and ID-IM group, respectively). Participants that had received a full dose IM regimen as the primary series, received the IM standard-of-care booster dose (IM-IM group). In addition, COVID-19 naive individuals aged 18–40 years who had received an IM mRNA vaccine as the primary series were recruited from the general population to receive a fractional ID booster dose (IM-ID group). Immunogenicity was assessed using IgG anti-spike antibody responses and neutralizing capacity against SARS-CoV-2. Cellular immune responses were measured in a sub-group. Safety and tolerability were monitored.
In January 2022, 129 participants were included in the study. Fractional ID boosting was safe and well tolerated, with fewer systemic adverse events compared with IM boosting. At day 28 post-booster, anti-spike S1 IgG geometric mean concentrations were 9106 (95% CI, 7150–11 597) binding antibody units (BAU)/mL in the IM-IM group and 4357 (3003–6322) BAU/mL; 6629 (4913–8946) BAU/mL; and 5264 (4032–6873) BAU/mL in the ID-IM, ID-ID, and IM-ID groups, respectively.
Intradermal boosting provides robust immune responses and is a viable dose-sparing strategy for mRNA COVID-19 vaccines. The favourable side-effect profile supports its potential to reduce vaccine hesitancy. Fractional dosing strategies should be considered early in the clinical development of future mRNA vaccines to enhance vaccine availability and pandemic preparedness.
Guidelines for developing and implementing stewardship programmes include recommendations on appropriate antibiotic use to guide the stewardship team’s choice of potential stewardship objectives. ...They also include recommendations on behavioural change interventions to guide the team’s choice of potential interventions to ensure that professionals actually use antibiotics appropriately in daily practice.
To summarize the evidence base of both appropriate antibiotic use recommendations (the ‘what’) and behavioural change interventions (the ‘how’) in hospital practice.
Published systematic reviews/Medline.
The literature shows low-quality evidence of the positive effects of appropriate antibiotic use in hospital patients. The literature shows that any behavioural change intervention might work to ensure that professionals actually perform appropriate antibiotic use recommendations in daily practice. Although effects were overall positive, there were large differences in improvement between studies that tested similar change interventions.
The literature showed a clear need for studies that apply appropriate study designs– (randomized) controlled designs—to test the effectiveness of appropriate antibiotic use on achieving meaningful outcomes. Most current studies used designs prone to confounding by indication. In the process of selecting behavioural change interventions that might work best in a chosen setting, much should be learned from behavioural sciences. The challenge for stewardship teams lies in selecting change interventions on the careful assessment of barriers and facilitators, and on a theoretical base while linking determinants to change interventions. Future studies should apply more robust designs and evaluations when assessing behavioural change interventions.
PDF
