Cancer screening with multicancer detection tests: A translational science review.

Multicancer detection (MCD) tests use a single, easily obtainable biospecimen, such as blood, to screen for more than one cancer concurrently. MCD tests can potentially be used to improve early cancer detection, including cancers that currently lack effective screening methods. However, these tests have unknown and unquantified benefits and harms. MCD tests differ from conventional cancer screening tests in that the organ responsible for a positive test is unknown, and a broad diagnostic workup may be necessary to confirm the location and type of underlying cancer. Among two prospective studies involving greater than 16,000 individuals, MCD tests identified those who had some cancers without currently recommended screening tests, including pancreas, ovary, liver, uterus, small intestine, oropharyngeal, bone, thyroid, and hematologic malignancies, at early stages. Reported MCD test sensitivities range from 27% to 95% but differ by organ and are lower for early stage cancers, for which treatment toxicity would be lowest and the potential for cure might be highest. False reassurance from a negative MCD result may reduce screening adherence, risking a loss in proven public health benefits from standard-of-care screening. Prospective clinical trials are needed to address uncertainties about MCD accuracy to detect different cancers in asymptomatic individuals, whether these tests can detect cancer sufficiently early for effective treatment and mortality reduction, the degree to which these tests may contribute to cancer overdiagnosis and overtreatment, whether MCD tests work equally well across all populations, and the appropriate diagnostic evaluation and follow-up for patients with a positive test.

Predictive Performance of Cell-Free Nucleic Acid-Based Multi-Cancer Early Detection Tests: A Systematic Review.

BACKGROUND: Cancer-screening tests that can detect multiple cancer types, or multi-cancer early detection (MCED) tests, have emerged recently as a potential new tool in decreasing cancer morbidity and mortality. Most MCED assays are based on detecting cell-free tumor DNA (CF-DNA) in the blood. MCEDs offer the potential for screening for cancer organ sites with high mortality, both with and without recommended screening. However, their clinical utility has not been established. Before clinical utility can be established, the clinical validity of MCEDs, i.e., their ability to predict cancer status, must be demonstrated. In this study we performed a systematic review of the predictive ability for cancer of cell-free-nucleic acid-based MCED tests. CONTENT: We searched PubMed for relevant publications from January 2017 to February 2023, using MeSH terms related to multi-cancer detection, circulating DNA, and related concepts. Of 1811 publications assessed, 61 were reviewed in depth and 20 are included in this review. For almost all studies, the cancer cases were assessed at time of diagnosis. Most studies reported specificity (generally 95% or higher) and overall sensitivity (73% median). The median number of cancer types assessed per assay was 5. Many studies also reported sensitivity by stage and/or cancer type. Sensitivity generally increased with stage. SUMMARY: To date, relatively few published studies have assessed the clinical validity of MCED tests. Most used cancer cases assessed at diagnosis, with generally high specificity and variable sensitivity depending on cancer type and stage. The next steps should be testing in the intended-use population, i.e., asymptomatic persons.

Use of MarginProbe as an adjunct to standard operating procedure does not significantly reduce re-excision rates in breast conserving surgery.

PURPOSE: A positive margin after breast conserving surgery has consistently been shown to be a significant predictor for ipsilateral breast tumor recurrence. Currently, there is no standard for intraoperative margin assessment during lumpectomy, and up to 20% of cases result in positive margins. MarginProbe is a device that provides real-time evaluation of lumpectomy margins during surgery. The aim of this study was to evaluate the impact of MarginProbe as an adjunct to standard operating procedure (SOP). METHODS: Patients diagnosed with breast cancer scheduled for breast conserving surgery were consented for intraoperative use of MarginProbe. Shaved margins were excised based on margin assessment using the surgeon's SOP which included specimen radiography and gross pathologic examination, and feedback from the device. The primary endpoint was re-excision rate. Secondary endpoints included sensitivity, specificity, false-positive and negative rates. RESULTS: Of the 60 breast cancers, initial histologically close/positive margins were identified in 18 patients (30%). The re-excision rate in the overall cohort was 6.6%, compared to a historical re-excision rate of 8.6% (p < 0.01). Based on 360 measurement sites, MarginProbe demonstrated a sensitivity of 67% and specificity of 60%, with a positive predictive value of 16%, and of negative predictive value of 94%, which was similar to the accuracy of SOP. CONCLUSIONS: MarginProbe performs equally as well as specimen radiography and gross pathologic examination. In this setting where the baseline re-excision rate was low, the use of MarginProbe as an adjunct to SOP resulted in a small 2% absolute reduction in re-excision rate.

Blood-based multi-cancer detection: A state-of-the-art update.

The early detection of cancer is a key goal of the National Cancer Plan formally released by the National Institutes of Health's (NIH) National Cancer Institute (NCI) in April 2023. To support this effort, many laboratories and vendors are developing multi-cancer detection (MCD) assays that interrogate blood and other bodily fluids for cancer-related biomarkers, most commonly circulating tumor DNA (ctDNA). While this approach holds promise for non-invasively detecting early signals of multiple different cancers and potentially reducing cancer-related mortality, there is a dearth of prospective clinical data to inform the deployment of MCD assays for cancer screening in the general adult population. In this review we highlight differing technologies that underpin various MCD assays in clinical development, the importance of achieving adequate performance specifications for MCD assays, ongoing clinical studies investigating the utility of MCD assays in cancer screening and detection, and efforts by the NCI's Division of Cancer Prevention (DCP) to establish a network infrastructure that has the capacity to comprehensively address the scientific and logistical challenges of evaluating blood-based MCD approaches and other cancer screening tools.

Primary care physicians and laypersons' perceptions of multicancer detection clinical trial designs.

BACKGROUND: The National Cancer Institute Cancer Screening Research Network is launching a pilot study (Vanguard) to determine feasibility of successful completion of a clinical trial of multicancer detection tests. This focus group study reports perceptions of primary care physicians and laypersons of different clinical trial designs and willingness to participate in a multicancer detection clinical trial. METHODS: We undertook 14 focus groups with 88 laypersons and 6 focus groups with 45 primary care physicians. Participants were shown graphics of clinical trial designs and asked for their reactions. Focus group recordings were transcribed verbatim, and thematic analysis of the transcripts were conducted to identify emergent themes. RESULTS: Primary care physician and layperson participants recognized the importance of conducting clinical trials to determine the clinical utility of multicancer detection tests. Primary care physicians expressed reluctance to participate in trials because of workload burden, and laypersons expressed hesitancy about enrolling in the control group. Primary care physicians and laypersons expressed concern about a study design in which multicancer detection test results would not be returned to the control group (intended effect), but they respectively indicated a willingness to refer patients to, or participate in, a multicancer detection test clinical trial given transparent and clear communication on collection and use of biospecimens and data, particularly if a multicancer detection test would eventually be run and results eventually returned. CONCLUSION: This study yielded important insights to guide trial design in planning prospective evaluation of multicancer detection testing. Maintaining transparency and trust while possibly withholding multicancer detection test results to maximize trial feasibility and efficiency is of particular concern.

Molecular mimicry between cockroach and helminth glutathione S-transferases promotes cross-reactivity and cross-sensitization.

BACKGROUND: The extensive similarities between helminth proteins and allergens are thought to contribute to helminth-driven allergic sensitization. OBJECTIVE: The objective of this study was to investigate the cross-reactivity between a major glutathione-S transferase allergen of cockroach (Bla g 5) and the glutathione-S transferase of Wuchereria bancrofti (WbGST), a major lymphatic filarial pathogen of humans. METHODS: We compared the molecular and structural similarities between Bla g 5 and WbGST by in silico analysis and by linear epitope mapping. The levels of IgE, IgG, and IgG(4) antibodies were measured in filarial-infected and filarial-uninfected patients. Mice were infected with Heligmosomoides bakeri, and their skin was tested for cross-reactive allergic responses. RESULTS: These 2 proteins are 30% identical at the amino acid level with remarkable similarity in the N-terminal region and overall structural conservation based on predicted 3-dimensional models. Filarial infection was associated with IgE, IgG, and IgG(4) anti-Bla g 5 antibody production, with a significant correlation between antibodies (irrespective of isotype) to Bla g 5 and WbGST (P< .0003). Preincubation of sera from cockroach-allergic subjects with WbGST partially depleted (by 50%-70%) anti-Bla g 5 IgE, IgG, and IgG(4) antibodies. IgE epitope mapping of Bla g 5 revealed that 2 linear N-terminal epitopes are highly conserved in WbGST corresponding to Bla g 5 peptides partially involved in the inhibition of WbGST binding. Finally, mice infected with H bakeri developed anti-HbGST IgE and showed immediate-type skin test reactivity to Bla g 5. CONCLUSION: These data demonstrate that helminth glutathione-S transferase and the aeroallergen Bla g 5 share epitopes that can induce allergic cross-sensitization.

Recurrent Lateral Abdominal Wall Hernias: Options for Reconstruction.

Management of lateral abdominal wall hernias presents a surgical challenge, and best management is controversial. Flank hernias as a surgical sequela occur more commonly, whereas flank hernias resulting from trauma are a rare occurrence. In this article, we present a review of the literature and a case of flank hernia presenting after trauma and recurring after repair. An anchored suture repair was performed and reinforced by the addition of a polyester underlay mesh.

Coaching for impact: successful implementation of a multi-national, multi-institutional synchronous research course in Ethiopia.

Purpose: Under the American College of Surgeons' Operation Giving Back, several US institutions collaborated with a teaching and regional referral hospital in Ethiopia to develop a surgical research curriculum. Methods: A virtual, interactive, introductory research course which utilized a web-based classroom platform and live educational sessions via an online teleconferencing application was implemented. Surgical and public health faculty from the US and Ethiopia taught webinars and led breakout coaching sessions to facilitate participants' project development. Both a pre-course needs assessment survey and a post-course participation survey were used to examine the impact of the course. Results: Twenty participants were invited to participate in the course. Despite the majority of participants having connection issues (88%), 11 participants completed the course with an 83% average attendance rate. Ten participants successfully developed structured research proposals based on their local clinical needs. Conclusion: This novel multi-institutional and multi-national research course design was successfully implemented and could serve as a template for greater development of research capacity building in the low- and middle-income country (LMIC) setting.

Associations of gender identity with sexual behaviours, social stigma and sexually transmitted infections among adults who have sex with men in Abuja and Lagos, Nigeria.

INTRODUCTION: Sexual and gender minority populations are disproportionately affected by the global syndemic of HIV and other sexually transmitted infections (STIs). We hypothesized that transgender women (TGW) and non-binary individuals in Nigeria have more STIs than cis-gender men who have sex with men (cis-MSM), and that experiences of stigma and sexual practices differ between these three groups. METHODS: From 2013 to 2020, TRUST/RV368 enrolled adults assigned male sex at birth who reported anal sex with men in Abuja and Lagos, Nigeria. Participants were tested for STIs and completed questionnaires about sexual behaviours and social stigma every 3 months. Participants were categorized as cis-MSM, TGW or non-binary/other based on self-reported gender identity. Gender group comparisons were made of HIV, gonorrhoea and chlamydia prevalence and incidence; stigma indicators; and condom use during anal sex. RESULTS: Among 2795 participants, there were 2260 (80.8%) cis-MSM, 284 (10.2%) TGW and 251 (9.0%) non-binary/other individuals with median age of 23 years (interquartile range 20-27). HIV prevalence among cis-MSM, TGW and non-binary/other participants was 40.8%, 51.5% and 47.6%, respectively (p = 0.002). HIV incidence was 8.7 cases per 100 person-years (PY) (95% confidence interval [CI] 6.9-10.8), 13.1 cases/100 PY (95% CI 6.5-23.4) and 17.6 cases/100 PY (95% CI 9.8-29.0, p = 0.025), respectively. Anorectal gonorrhoea incidence was lower in cis-MSM than TGW (22.2 [95% CI 19.6-25.0] vs. 35.9 [95% CI 27.3-46.3]). TGW were more likely than cis-MSM to report being affected by stigma, including assault (47.2% vs. 32.3%), fear of walking around (32.4% vs. 19.2%) and healthcare avoidance (25.0% vs. 19.1%; all p < 0.05). TGW were more likely to report always using condoms than non-binary/other individuals (35.3% vs. 26.2%, p = 0.041) during receptive anal sex. CONCLUSIONS: Sexual and gender minorities in Nigeria have heterogeneous sexual behaviours and experiences of social stigma that may influence the vulnerability to HIV and other STIs. There is a need for tailored interventions that acknowledge and are informed by gender. Further research is needed, particularly among understudied non-binary individuals, to better understand disparities and inform tailored interventions to improve outcomes among these communities.

Biliary-Enteric Drainage vs Primary Liver Transplant as Initial Treatment for Children With Biliary Atresia.

Importance: Some infants with biliary atresia are treated with primary liver transplant (pLT), but most are initially treated with biliary-enteric drainage (BED) with a subsequent salvage liver transplant. Given the improvements in liver transplant outcomes, it is important to determine whether BED treatment remains the optimal surgical algorithm for patients with biliary atresia. Objective: To compare the survival of patients with biliary atresia initially treated with BED with patients who underwent pLT. Design, Setting, and Participants: This cohort study used deidentified records from the California Office of Statewide Health Planning and Development database to identify patients with biliary atresia (n = 1252) between January 1, 1990, through December 31, 2015. Patients were categorized into 1 of 2 cohorts: those who received BED treatment and those who underwent pLT. Excluded from the study were those born before January 1, 1995, and those without any documented operative intervention by age 5 years. Data analysis was performed from January 1, 1990, to December 31, 2015. Main Outcomes and Measures: Overall survival was compared between the BED and pLT cohorts using the Kaplan-Meier method. The treatment's association with treatment era was examined by comparing survival before 2002 and on or after January 1, 2002. Results: In total, 1252 patients with biliary atresia were identified. After exclusions, 626 remained; of these patients, 351 (56.1%) were female and 275 (43.9%) were male with a median (interquartile range) age at intervention for initial BED treatment of 65 (48-81) days. Among the 626 patients studied, initial BED treatment was performed in 313 patients (50.0%), and pLT was performed in 313 patients (50.0%). Although patients who underwent pLT had a higher mortality rate within the first 3 months after the procedure, they had a reduced risk of long-term mortality compared with patients initially managed with BED treatment (hazard ratio [HR] ≥6 months after the initial procedure, 0.19; 95% CI, 0.08-0.42; P = .01). Patients requiring salvage liver transplant had a substantially higher risk of mortality than patients who received pLT (HR, 0.43; 95% CI 0.25-0.76; P = .003). Those who underwent pLT had superior survival compared with BED treatment recipients on or after 2002 (HR, 0.16; 95% CI, 0.05-0.54; P < .001), and that persisted when censoring patients who underwent salvage liver transplant (HR, 0.23; 95% CI, 0.07-0.82; P = .01). Conclusions and Relevance: Patients who underwent pLT experienced superior long-term survival compared with patients who underwent BED treatment. Multi-institutional trials are needed to determine which initial treatment is most advantageous to patients with biliary atresia.

No relationship between mild limb length discrepancy and spine, hip or knee degenerative disease in a large cadaveric collection.

BACKGROUND: Although asymptomatic mild limb length discrepancy (LLD) in children is generally treated non-operatively, there is limited high quality follow up data to support this recommendation. HYPOTHESIS: We hypothesized that there would be no association between LLD and arthritic changes with mild limb length discrepancy. MATERIALS AND METHODS: We studied 576 well-preserved cadaveric skeletons ranging from 40 to 79 years of age. Limb length discrepancy was based on combined femoral and tibial lengths measured using digital calipers. Degenerative disease was hand graded in the spine, hips and knees using a previously described classification system. Power was set at 90%. RESULTS: Average age was 56±10 years and average LLD was 4.8±4.0mm. Multiple regression analysis did not demonstrate any correlation between LLD and degenerative disease. After screening to find 26 additional specimens with LLD 10mm or greater, and assessing a potentially quadratic relationship, we still did not find any detrimental effects of LLD. DISCUSSION: Our data support the general clinical recommendation of observation for mild asymptomatic LLD. These results do not apply to larger LLD nor LLD associated with other deformities or clinical symptoms. LEVEL OF EVIDENCE: Not applicable, anatomic basic science study.

Management of pediatric blunt renal trauma: A systematic review.

BACKGROUND: Blunt trauma remains a significant cause of morbidity and mortality in the pediatric population. The use of conservative management for blunt renal trauma is widely accepted in adult trauma literature and is now increasingly accepted for use in the pediatric patient population. This study aimed to review current practices in pediatric blunt renal trauma management and to highlight current practices in conservative protocols, success rates of conservative management strategies, as well as short- and long-term outcomes of blunt renal trauma management. METHODS: This is a systematic review of PubMed, Ovid, and the Cochrane Library. The following search was performed in each of the three databases: (Renal or Kidney) AND (Pediatric or Children) AND Trauma AND Management. Publications were limited to publish date after January 1, 2000. Inclusion criteria were (1) original research articles regarding management of pediatric blunt renal trauma, (2) involvement of cases of high-grade renal (Grades IV and V) trauma, and (3) more than one patient presented per study. Literature reviews and meta-analyses were excluded. RESULTS: Titles and abstracts (n = 308) were screened to identify scientific articles reporting original research findings. A total of 32 articles met the selection criteria and were included in the review. CONCLUSION: The literature supports application of conservative management protocols to high-grade blunt pediatric renal trauma. Criteria for early operative intervention are not well understood. At this time, emergent operative intervention only for hemodynamic instability is recommended. Minimally invasive interventions including angioembolization, stenting, and percutaneous drainage should be used when indicated. Short- and long-term outcomes are favorable when using conservative management approaches to Grade IV and V renal injuries. Further studies including prospective studies and randomized control trials are necessary. Cost analyses of current treatment protocols are also necessary to guide efficient management strategies. LEVEL OF EVIDENCE: Systematic review, level III.