AUDIENCE: Oncology, Cardiology
KEY FINDINGS: Within the cohort, LAAO in cancer patients was achieved with good procedural success and offered a reduction in stroke at no increased bleeding risk similar to noncancer patients.
BACKGROUND: The prevention of stroke in patients with atrial fibrillation (AF) and cancer is challenging because patients are at increased bleeding and thrombotic risk. Purpose of the study is to to assess left atrial appendage occlusion (LAAO) as a safe and effective strategy for reducing stroke at no increased bleeding risk in cancer patients with AF.
DETAILS: Authors reviewed patients with nonvalvular AF who underwent LAAO at Mayo Clinic sites from 2017 to 2020 and identified those who had undergone prior or current treatment for cancer. Compared the incidence of stroke, bleeding, device complications, and death with a control group who underwent LAAO without malignancy. Fifty-five patients were included; 44 (80.0%) were male, and the mean age was 79.0 ± 6.1 years. The median CHA2Ds2-VASc score was 5 (Q1-Q3: 4-6), with 47 (85.5%) having a prior bleeding event. Over the first year, ischemic stroke occurred in 1 (1.4%) patient, bleeding complications in 5 (10.7%) patients, and death in 3 (6.5%) patients. Compared with controls who underwent LAAO without cancer, there was no significant difference in ischemic stroke (HR: 0.44; 95% CI: 0.10-1.97; P = 0.28), bleeding complication (HR: 0.71; 95% CI: 0.28-1.86; P = 0.19), or death (HR: 1.39; 95% CI: 0.73-2.64; P = 0.32).
Copyright © merican College of Cardiology Foundation. All rights reserved.
Source: Shabtaie, S., Tan, N., Ward, R., et al. (2023). Left Atrial Appendage Occlusion in Patients With Atrial Fibrillation and Cancer. J Am Coll Cardiol CardioOnc. 2023; 5(2): 203-212. Published: May, 2023. DOI: 10.1016/j.jaccao.2022.10.016.
AUDIENCE: Hematology, Infectious Disease
DETAILS: The U.S. Food and Drug Administration finalized recommendations for assessing blood donor eligibility using a set of individual risk-based questions to reduce the risk of transfusion-transmitted HIV. These questions will be the same for every donor, regardless of sexual orientation, sex or gender. Blood establishments may now implement these recommendations by revising their donor history questionnaires and procedures.
This updated policy is based on the best available scientific evidence and is in line with policies in place in countries like the United Kingdom and Canada. It will potentially expand the number of people eligible to donate blood, while also maintaining the appropriate safeguards to protect the safety of the blood supply.
These final recommendations are consistent with the policy initially proposed in January. The FDA worked diligently to review and consider all comments submitted to the agency to finalize these recommendations as quickly as possible. "The FDA has worked diligently to evaluate our policies and ensure we had the scientific evidence to support individual risk assessment for donor eligibility while maintaining appropriate safeguards to protect recipients of blood products. The implementation of these recommendations will represent a significant milestone for the agency and the LGBTQI+ community," said Peter Marks, M.D., PhD., director of the FDA’s Center for Biologics Evaluation and Research. "The FDA is committed to working closely with the blood collection industry to help ensure timely implementation of the new recommendations and we will continue to monitor the safety of the blood supply once this individual risk-based approach is in place."
This policy eliminates time-based deferrals and screening questions specific to men who have sex with men (MSM) and women who have sex with MSM. Under the final guidance issued today, all prospective blood donors will answer a series of individual, risk-based questions to determine eligibility. All prospective donors who report having a new sexual partner, or more than one sexual partner in the past three months, and anal sex in the past three months, would be deferred to reduce the likelihood of donations by individuals with new or recent HIV infection who may be in the window period for detection of HIV by nucleic acid testing.
Additionally, under these final recommendations, those taking medications to treat or prevent HIV infection (e.g., antiretroviral therapy (ART), pre-exposure prophylaxis (PrEP) and post-exposure prophylaxis (PEP)), will also be deferred. Though these antiretroviral drugs are safe, effective, and an important public health tool, the available data demonstrate that their use may delay detection of HIV by currently licensed screening tests for blood donations, which may potentially give false negative results. Although HIV is not transmitted sexually by individuals with undetectable viral levels, this does not apply to transfusion transmission of HIV because a blood transfusion is administered intravenously, and a transfusion involves a large volume of blood compared to exposure with sexual contact. As stated in the guidance, individuals should not stop taking their prescribed medications, including PrEP, or PEP, in order to donate blood. The FDA remains committed to evaluating additional data and new technological developments as they become available to inform our donor eligibility recommendations.
The FDA has been evaluating alternatives to time-based deferrals for MSM and helping to facilitate the generation of scientific evidence that would support an individual risk based- assessment blood donor questionnaire. This scientific information has given the agency a solid foundation to support this new policy. The FDA strongly believes the implementation of an individual risk-based approach will not adversely affect the safety or availability of the U.S. blood supply.
The FDA carefully reviewed numerous data sources, including data from countries with similar HIV epidemiology that have implemented an individual risk-based approach for assessing donor eligibility, surveillance information obtained from the Transfusion Transmissible Infections Monitoring System, performance characteristics of nucleic acid testing for HIV and the FDA-funded Assessing Donor Variability And New Concepts in Eligibility study. The ADVANCE study examined the rates of HIV risk factors, such as anal sex and rates of HIV infection, as well as the usage of medications to treat or prevent HIV infection, among MSM study participants.
Copyright © FDA. All rights reserved.
Source: FDA Finalizes Move to Recommend Individual Risk Assessment to Determine Eligibility for Blood Donations. FDA. Published: May 11, 2023.
AUDIENCE: Gastroenterology, Oncology, Internal Medicine
KEY FINDINGS: The findings identify an important role for a subgroup of highly connected enhancers (iHUBs) in regulating chemotherapy response and demonstrate targetability in sensitisation to chemotherapy.
BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) displays a remarkable propensity towards therapy resistance. However, molecular epigenetic and transcriptional mechanisms enabling this are poorly understood. In this study, we aimed to identify novel mechanistic approaches to overcome or prevent resistance in PDAC.
DETAILS: Authors used in vitro and in vivo models of resistant PDAC and integrated epigenomic, transcriptomic, nascent RNA and chromatin topology data. They identified a JunD-driven subgroup of enhancers, called interactive hubs (iHUBs), which mediate transcriptional reprogramming and chemoresistance in PDAC. iHUBs display characteristics typical for active enhancers (H3K27ac enrichment) in both therapy sensitive and resistant states but exhibit increased interactions and production of enhancer RNA (eRNA) in the resistant state. Notably, deletion of individual iHUBs was sufficient to decrease transcription of target genes and sensitise resistant cells to chemotherapy. Overlapping motif analysis and transcriptional profiling identified the activator protein 1 (AP1) transcription factor JunD as a master transcription factor of these enhancers. JunD depletion decreased iHUB interaction frequency and transcription of target genes. Moreover, targeting either eRNA production or signaling pathways upstream of iHUB activation using clinically tested small molecule inhibitors decreased eRNA production and interaction frequency, and restored chemotherapy responsiveness in vitro and in vivo. Representative iHUB target genes were found to be more expressed in patients with poor response to chemotherapy compared with responsive patients.
Copyright © BMJ Publishing Group Ltd & British Society of Gastroenterology. All rights reserved.
Source: Hamdan, F. H., Abdelrahman, A. M., Kutschat, A. P., et al. (2023). Interactive Enhancer Hubs (iHUBs) Mediate Transcriptional Reprogramming And Adaptive Resistance In Pancreatic Cancer. Gut. 2023; 72(6): 1174-1185. Published: June, 2023. DOI: 10.1136/gutjnl-2022-328154.
AUDIENCE: Dermatology, Oncology
KEY FINDINGS: Patients with second primary melanomas demonstrated a significant survival advantage and thinner lesions compared with those with single primary melanomas. The reported tumor distributions support the role of full body skin examinations, with attention to the region of initial diagnosis.
BACKGROUND: Patients with single primary melanomas have an increased risk of developing subsequent melanomas. Secondary tumors diagnosed within and after 3 months are termed "synchronous" and "asynchronous," respectively. Purpose of the study is to compare tumor distributions and survival characteristics between patients with second primary melanomas and those with single primary melanomas.
DETAILS: Retrospective cohort study. Data were collected from an institutional database from 14,029 patients with a diagnosis of a primary melanoma seen between 1970 and 2004. The synchronous and asynchronous cohorts demonstrated significantly improved survival probabilities compared with the single primary cohort (P = .04 and .002, respectively). Single primary lesions (2.2 ± 2.3 mm) were significantly thicker than the first-identified synchronous (2.0 ± 1.7 mm) and asynchronous (1.7 ± 1.3 mm) lesions. Synchronous lesions were more likely to be anatomically concordant compared with asynchronous lesions (55.7% vs 38.2%, P < .001).
Copyright © Elsevier Ltd. All rights reserved.
Source: Sarver, M. M., Rames, J. D., Beasley, G. M., et al. (2023). Survival and Tumor Characteristics Of Patients Presenting With Single Primary Versus Second Primary Melanoma Lesions. Journal of the American Academy of Dermatology. 2023; 88(5): 1033-1039. Published: May, 2023. DOI: 10.1016/j.jaad.2022.04.046.
AUDIENCE: Neurology, Internal Medicine
KEY FINDINGS: The results show that combining scRNA-seq and WGS data can successfully detect putative somatic mutations. The putative somatic mutations detected from ROSMAP data set have provided new insights into the association of AD and aging with brain somatic mutagenesis.
BACKGROUND: With age, somatic mutations accumulated in human brain cells can lead to various neurologic disorders and brain tumors. Because the incidence rate of Alzheimer disease (AD) increases exponentially with age, investigating the association between AD and the accumulation of somatic mutation can help understand the etiology of AD.
DETAILS: Authors designed a somatic mutation detection workflow by contrasting genotypes derived from whole-genome sequencing (WGS) data with genotypes derived from scRNA-seq data and applied this workflow to 76 participants from the Religious Order Study and the Rush Memory and Aging Project (ROSMAP) cohort. We focused only on excitatory neurons, the dominant cell type in the scRNA-seq data. 196 sites were identified that harbored at least 1 individual with an excitatory neuron–specific somatic mutation (ENSM), and these 196 sites were mapped to 127 genes. The single base substitution (SBS) pattern of the putative ENSMs was best explained by signature SBS5 from the Catalogue of Somatic Mutations in Cancer (COSMIC) mutational signatures, a clock-like pattern correlating with the age of the individual. The count of ENSMs per individual also showed an increasing trend with age. Among the mutated sites, we found 2 sites tend to have more mutations in older individuals (16:6899517 [RBFOX1], p = 0.04; 4:21788463 [KCNIP4], p < lt; 0.05). In addition, 2 sites were found to have a higher odds ratio to detect a somatic mutation in AD samples (6:73374221 [KCNQ5], p = 0.01 and 13:36667102 [DCLK1], p = 0.02). Thirty-two genes that harbor somatic mutations unique to AD and the KCNQ5 and DCLK1 genes were used for gene ontology (GO)–term enrichment analysis. We found the AD-specific ENSMs enriched in the GO-term "vocalization behavior" and "intraspecies interaction between organisms." Of interest we observed both age-specific and AD-specific ENSMs enriched in the K+ channel–associated genes.
Copyright © American Academy of Neurology. All Rights Reserved.
Source: Zhang, M., Bouland, G. A., Holstege, H., et al. (2023). Identifying Aging and Alzheimer Disease-Associated Somatic Variations in Excitatory Neurons From the Human Frontal Cortex. Neuro Genetics. 2023; 9(3): e200066. Published: June, 2023. DOI: 10.1212/NXG.0000000000200066.
AUDIENCE: Ob/Gyn, Oncology, Family Medicine
KEY FINDINGS: HPV DNA detection from urine has good concordance with the histopathology for detection of precancerous and cancerous lesions of the cervix. Further studies on optimization of urine sampling and processing techniques are warranted.
BACKGROUND: Purpose of the study was to evaluate clinical performance and diagnostic accuracy of urinary HPV for non-invasive screening of high-grade precancerous and cancerous cervical lesions in a visual inspection under acetic acid (VIA) -positive cohort.
DETAILS: The study included 180 women aged 35-65 years, who were VIA positive in a colposcopy clinic. All participants had the initial stream of a random urine sample tested for the presence of high-risk HPV (hrHPV) types 16 and 18 and acetowhite lesions were biopsied per protocol. Concordance analysis was conducted to assess agreement between detection of hrHPV in urine and the presence of premalignant and malignant lesions in cervix on histopathology. Measures of diagnostic accuracy were estimated to evaluate the performance of urinary HPV against histopathology (reference standard). Substantial agreement between urinary HPV detection and histopathology was found (Cohen's κ is 0.696, P = 0.001), with an agreement in 88.9% of the cases and disagreement in 11.1%. The diagnostic performance of urinary HPV in predicting the presence of a high-grade precancerous or cancerous lesion was as follows: sensitivity 67%, specificity 97%, positive predictive value 89%, and negative predictive value 88.8%.
Copyright © John Wiley & Sons, Inc. All rights reserved
Source: John, J. H., Halder, A., Purwar, S., et al. (2023). Study To Determine Efficacy Of Urinary HPV 16 & HPV 18 Detection In Predicting Premalignant and Malignant Lesions Of Uterine Cervix. Intl J Gynecol Obstet.. 2023; 161(1): 79-85. Published: April, 2023. DOI: 10.1002/ijgo.14486.