Early Onset Colorectal Cancer: An Emerging Cancer Risk in Patients with Diamond Blackfan Anemia

Diamond Blackfan anemia (DBA) is a rare inherited bone marrow failure syndrome, the founding member of a class of disorders known as ribosomopathies. Most cases result from loss of function mutations or deletions in 1 of 23 genes encoding either a small or large subunit-associated ribosomal protein (RP), resulting in RP haploinsufficiency. DBA is characterized by red cell hypoplasia or aplasia, poor linear growth and congenital anomalies. Small case series and case reports demonstrate DBA to be a cancer predisposition syndrome. Recent analyses from the Diamond Blackfan Anemia Registry of North America (DBAR) have quantified the cancer risk in DBA. These studies reveal the most prevalent solid tumor, presenting in young adults and in children and adolescents, to be colorectal cancer (CRC) and osteogenic sarcoma, respectively. Of concern is that these cancers are typically detected at an advanced stage in patients who, because of their constitutional bone marrow failure, may not tolerate full-dose chemotherapy. Thus, the inability to provide optimal therapy contributes to poor outcomes. CRC screening in individuals over the age of 50 years, and now 45 years, has led to early detection and significant improvements in outcomes for non-DBA patients with CRC. These screening and surveillance strategies have been adapted to detect familial early onset CRC. With the recognition of DBA as a moderately penetrant cancer risk syndrome a rational screening and surveillance strategy will be implemented. The downstream molecular events, resulting from RP haploinsufficiency and leading to cancer, are the subject of significant scientific inquiry.

Alterations in Co-abundant Bacteriome in Colorectal Cancer and Persistent Microbial Dysbiosis After Surgery

ObjectiveThere is growing interest in the role of gut microbiome in colorectal cancer (CRC), ranging from screening to disease recurrence. Our study aims to identify microbial markers characteristic of CRC and to examine if changes in bacteriome persist after surgery. Design49 fecal samples from non-cancer (NC) individuals and CRC patients, before and after surgery, were collected for analysis by bacterial 16S rRNA gene sequencing. ResultsBacterial richness and diversity were reduced in the CRC patients compared to NC individuals. Pro-carcinogenic bacteria such as Bacteroides fragilis and Odoribacter splanchnicus were increased in pre-op CRC compared to NC group. These differences were no longer observed after surgery. Comparison between post- and pre-op CRC showed increased abundance of probiotic bacteria after surgery. Concomitantly, bacteria associated with CRC progression were observed to have increased after surgery, implying persistent dysbiosis. ConclusionMicrobiome signatures characteristic of CRC likely comprise a set of significant alteration in specific bacterial strains. Elements of these dysbiotic signatures persists even after surgery, suggesting possible field-change in remnant non-diseased colon. Future studies should seek to examine if these signatures are also associated with pre-malignant colonic polyps and, explore if these profiles can be used to guide CRC screening and surveillance.

Newborn Screening for the Detection of the TP53 R337H Variant and Surveillance for Early Diagnosis of Pediatric Adrenocortical Tumors: Lessons Learned and Way Forward

The incidence of pediatric adrenocortical tumors (ACT) is high in southern Brazil due to the founder TP53 R337H variant. Neonatal screening/surveillance (NSS) for this variant resulted in early ACT detection and improved outcomes. The medical records of children with ACT who did not participate in newborn screening (non-NSS) were reviewed (2012–2018). We compared known prognostic factors between the NSS and non-NSS cohorts and estimated surveillance and treatment costs. Of the 16 non-NSS children with ACT carrying the R337H variant, the disease stages I, II, III, and IV were observed in five, five, one, and five children, respectively. The tumor weight ranged from 22 to 608 g. The 11 NSS children with ACT all had disease stage I and were alive. The median tumor weight, age of diagnosis, and interval between symptoms and diagnosis were 21 g, 1.9 years, and two weeks, respectively, for the NSS cohort and 210 g, 5.2 years, and 15 weeks, respectively, for the non-NSS cohort. The estimated surveillance/screening cost per year of life saved is US$623/patient. NSS is critical for improving the outcome of pediatric ACT in this region. Hence, we strongly advocate for the inclusion of R337H in the state-mandated universal screening and surveillance.

Persistent and Emergent Clinical Sequelae of Mild COVID-19

BACKGROUND: Knowledge of the clinical course and consequences of COVID-19 initially evolved in the context of severe presentations and among those with comorbidities. However, understanding the outcomes of milder infections in healthy individuals is important for safe return-to-duty in extreme environments or to occupations requiring significant fitness. We reviewed the literature to characterize the nature and timing of persistent and emergent clinical sequelae in milder COVID-19 cases to facilitate development of post-COVID-19 screening and surveillance protocols.METHODS: We searched databases including EMBASE, MEDLINE, Cochrane COVID-19 study register, gray literature, clinical trial registries, and relevant health and disease prevention sources for publications from 2019 to February 18th, 2021, documenting COVID-19 sequelae. Articles were included if the COVID-19 severity was mild and there were no, or only minor, pre-existing comorbidities. Persistent and emergent sequelae were then stratified based on time since diagnosis.RESULTS: Among those with mild COVID-19, sequelae were shown to emerge or persist for months following presumed recovery. Among those with no comorbidities, cardiac, hematological, and respiratory sequelae emerged after 1-2 mo, and primarily cardiac abnormalities persisted at ≥ 3 mo. Among those with minor comorbidities, persistent respiratory abnormalities, fatigue, dyspnea, and headache were common, and mental health symptoms emerged by 1-2 mo postinfection.DISCUSSION: After presumed recovery from mild COVID-19, a range of symptoms can persist and later emerge. Whether these are new or previously unrecognized is unclear. Under-recognized COVID-19 sequelae may increase the risk of subtle or sudden incapacitation and have implications for return-to-work (RTW) screening and surveillance for safety-critical roles.Tucci V, Saary J. Persistent and emergent clinical sequelae of mild COVID-19. Aerosp Med Hum Perform. 2021; 92(12):962–969.

Strategy for a rapid screening and surveillance of SARS-CoV-2 variants by real time RT-PCR: a key tool that allowed control and delay in Delta spread in Cordoba, Argentina

Background: SARS-CoV-2 variants of concern (VOC) and interest (VOI) present mutations in reference to the original virus, being more transmissible. We implemented a rapid strategy for the screening of SARS-CoV-2 VOC/VOIs using real time RT-PCR and performed monitoring and surveillance of the variants in our region. Methods: consecutive real-time RT-PCRs for detection of the relevant mutations/deletions present in the Spike protein in VOC/VOIs (TaqMan SARS-CoV-2 Mutation Panel, Applied Biosystems) were implemented. An algorithm was established and 3941 SARS-CoV-2 RNA samples (Cts<30) obtained from oropharyngeal swabs from infected individuals in Cordoba, Argentina, between January and October 2021, were analyzed. Results: the strategy of choice included a first screening of 3 mutations (N501Y, E484K, L452R) followed by the detection of other mutations/deletions based on the results. The analyses of the samples showed introductions of VOCs Alpha and Gamma in February and March 2021, respectively. Since then, Alpha presented a low to moderate circulation (1.7% of the SARS-CoV-2 currently detected). Gamma showed an exponential increase, with a peak of detection in July (72%), until reaching a current frequency of 41.1%. VOC Delta was first detected in July in travellers and currently represents 35% of detections in the community. VOI Lambda presented a gradual increase, showing a current frequency of 29%. Conclusions: we report a useful tool for VOC/VOI detection, innovative for Argentina, capable to quickly and cost-effectively monitor currently recognized variants. It was key in the early detection of Delta, being able to implement measures to delay its dissemination.

Gender differences in Barrett’s esophagus and progression of disease: a systematic review and meta-analysis

Summary It is known that Barrett’s esophagus (BE) and esophageal adenocarcinoma occur more commonly in men. What is unknown are the prevalence of BE and rates of neoplastic progression in women. Our aim was to determine the prevalence of Barrett’s and its progression to esophageal cancer in women through systematic review and meta-analysis. A comprehensive search was conducted using PubMed, Scopus, and Google Scholar. Studies were included that reported prevalence rates of BE or progression rates to neoplastic disease stratified by gender. Barrett’s was defined by updated criteria as salmon-colored mucosa ≥1 cm proximal to the gastroesophageal junction. Pooled rates and odds ratios (ORs) at 95% confidence interval (CI) of the prevalence of BE and its progression to neoplastic disease were calculated. Ten studies with 19,337 patients (50.6% women) reported on prevalence and six studies with 5137 patients (24.3% women) reported on neoplastic progression of disease between genders. The rate of BE in women was 1.29% ([95% CI: 0.76–2.19], I2 = 91%) compared to men at 4.66% ([95% CI: 3.31–6.53], I2 = 89%); OR: 0.33 ([95% CI: 0.27–0.42], I2 = 0%). The rate of annual progression of Barrett’s to high-grade dysplasia or adenocarcinoma was 0.62% ([95% CI: 0.22–1.75]) in women compared to 1.54% ([95% CI: 0.83–2.81], I2 = 96%) in men; OR: 0.44 ([95% CI: 0.30–0.65], I2 = 22%). This study demonstrates a 70% lower rate of prevalence and a 60% lower rate of neoplastic progression of Barrett’s in women. Future BE guidelines should tailor screening and surveillance practices by gender.

Screening and surveillance of venous stenosis in AVG: Is it time to rethink our assumptions?

Guidelines make no firm recommendations about surveillance of arteriovenous grafts as several randomised trials (RCT) have not shown a clear benefit in patency. However a more thorough review of these RCT based on epidemiological principles reveals significant limitations. In particular a key weakness of these older studies is the interventions performed for venous stenosis detected that was largely angioplasty. However, the observational data of modern stent-grafts shows a clear benefit over angioplasty, and thus seems to suggest that a modern well considered RCT is now mandated.

Neurodevelopmental Screening in Young Children with Sickle Cell Disease

It is important to prioritize screening and surveillance for neurodevelopmental dysfunction in children with SCD because this vulnerable population is at higher risk for neurological complications including stroke, silent cerebral infarction, and neurodevelopmental disorders (NDD) such as language disorders, attention deficit hyperactivity disorder, and autism spectrum disorder (ASD). The American Society of Hematology (ASH) and American Academy of Pediatrics (AAP) have published guidelines to accomplish this, as well as to improve quality of life for people with SCD and NDDs. Despite the recognition of the increased risk and the clinical guidelines, the co-occurrence rates of SCD and NDD remain lower than expected. We hypothesize that the risk of NDDs is lower than expected in children with SCD due to low rates of neurodevelopmental screening and surveillance among primary care providers and hematologists, particularly in young children. Therefore, we examined the frequency of neurodevelopmental screening and surveillance among young children with SCD and identified clinical characteristics of young children with SCD who did not receive appropriate neurodevelopmental screening and surveillance. We conducted a retrospective chart review using the clinic rosters of two affiliated inner-city hospitals with a pediatric hematology clinic and sickle cell neurodevelopmental clinic. Children under 5 years old with SCD confirmed by their hematologists who were not adopted or in foster care were included in the study. A total of 276 patients were identified and reviewed. NDD and ASD specific screenings were documented at the time of review, although participants may have been diagnosed later in life. Analyses were completed using chi squared test, Fisher exact test, t-test in Stata IC-15. Patients were screened by a variety of providers, most commonly pediatricians and hematologists (see Figure 1). Table 1a shows the characteristics of the SCD patients assessed/not assessed for appropriate neurodevelopment (ND) by their pediatrician and/or hematologist. A total of 214 participants qualified for study inclusion and 148 participants (70%) were assessed for neurodevelopment. Ages and Stages Questionnaire- 3 (32%) and other non-standardized screening tools (85%) were the most common tool used (see Table 2a). Of the ND assessed patients (N=148), 37 (25%) were diagnosed with NDDs (see Table 3a). Among the not assessed ND patients (N=66), 16 (24%) were diagnosed with NDDs. Table 1b shows the characteristics of the SCD patients assessed/not assessed specifically for ASD by their pediatrician and/or hematologist. A total of 207 participants qualified for study inclusion and 39 participants (19%) were assessed for ASD. Modified Checklist for Autism in Toddlers (92%) was the most utilized screening tool (see Table 2b). None of these patients had ASD. Of the ASD assessed patients (N=39), 9 (23%) were diagnosed with NDDs (see Table 3a). Among the not assessed ASD patients (N=168), 41 (24%) were diagnosed with NDDs. Children with SCD are being screened by their healthcare providers at a much lower rate than the general pediatric population. More specifically, many children with SCD were being screened for NDD, but not ASD. Among screened children, a majority were screened with non-standardized (or poorly documented) tools or outside the age guidelines recommended by ASH and AAP (see Figure 2). Children among ND and ASD assessment groups exhibited similar percentages of NDD diagnosis, which may highlight disparities in screening and early detection of these disorders; NDDs may have also been diagnosed later in life these patients. Guidelines regarding developmental screening in pediatric SCD were released in mid-2020; given the short timeline, we did not expect to see changes in practice from this chart review. However, the AAP has guidelines for developmental surveillance and screening since 2004. Due to study design, limitations include lack of access to some data at the time of review, as patient medical records were switched to another electronic system. Additionally, standardized tools may have been used but not documented in patient charts. In conclusion, it is crucial to know the utility of these assessments in this vulnerable population. A future study could examine how the rates of screening and surveillance have changed since the guidelines release, using these data for comparison purposes. Figure 1 Figure 1. Disclosures Casella: Mast Pharmaceuticals (previously Adventrx Pharmaceuticals): Consultancy, Honoraria, Patents & Royalties. Lance: Novartis: Other: participated in research advisory board in 2020.

Rapid Review: Diagnostic Accuracy of Pooled Testing versus Individual Testing Using RT-PCR for SARS-CoV-2 for Screening and Surveillance of Individuals with Suspected COVID-19

Background. Pooled testing has been implemented on a limited scale, mainly for screening and surveillance in populations with a low prevalence of COVID-19 to save on limited resources. Objective. To determine the diagnostic accuracy of pooled compared with individual RT-PCR testing for SARS-CoV-2 in individuals suspected of COVID-19. Methods. We searched websites of living CPGs on COVID-19 (Australian COVID-19, COVID NMA, CEBM Oxford), Philippine DOH HTA, databases (PubMed, CENTRAL, medRXIV/bioRXIV), and Clinicaltrials.gov for studies that used pooled testing on individuals suspected of COVID-19. When appropriate, we pooled data for sensitivity and specificity and obtained the range and median of other data, such as positive predictive value and resource savings. We did a priori subgroup analysis for pool size, presence or absence of symptoms and use case, type of specimen, cutoff for positivity, type of kit, and post hoc subgroup analysis for method of pooling and timing of processing. Results. We included 21 studies: 6 diagnostic accuracy studies, and 15 clinical validation studies. Studies had varying populations, index test kit and performance characteristics, positivity rate (0.02 to 15%), and pool size (5 to 16). There was moderate pooled sensitivity, 81% (95% CI 72, 88; I2=73.6%; 6 studies, 776 pools) and high pooled specificity, 99% (95% CI, 98 to 100; I2=1.84%; 5 studies, 666 pools). Positive predictive value based on 21 studies ranged from 67% to 100%. Resource savings in the number of test kits used ranged from 49 to 89%. Identified harms of pooled testing were delayed turnaround time for positive samples and laboratory errors. Conclusion. There is moderate sensitivity and high specificity with pooled testing for the screening of individuals with suspected COVID-19. We recommend further studies to validate the utility based on community prevalence and other test variables.