Whole genome and transcriptome integrated analyses guide clinical care of pediatric poor prognosis cancers.

The role for routine whole genome and transcriptome analysis (WGTA) for poor prognosis pediatric cancers remains undetermined. Here, we characterize somatic mutations, structural rearrangements, copy number variants, gene expression, immuno-profiles and germline cancer predisposition variants in children and adolescents with relapsed, refractory or poor prognosis malignancies who underwent somatic WGTA and matched germline sequencing. Seventy-nine participants with a median age at enrollment of 8.8 y (range 6 months to 21.2 y) are included. Germline pathogenic/likely pathogenic variants are identified in 12% of participants, of which 60% were not known prior. Therapeutically actionable variants are identified by targeted gene report and whole genome in 32% and 62% of participants, respectively, and increase to 96% after integrating transcriptome analyses. Thirty-two molecularly informed therapies are pursued in 28 participants with 54% achieving a clinical benefit rate; objective response or stable disease ≥6 months. Integrated WGTA identifies therapeutically actionable variants in almost all tumors and are directly translatable to clinical care of children with poor prognosis cancers.

Demystifying Giant Cell Tumours of Tendon Sheath (GCTTS): A Case Series of 18 Cases with Review of Literature.

Background: The giant cell tumour of the tendon sheath (GCTTS) is the second most frequent soft tissue tumour affecting the hand. No consensus exists on the etiology, prognostic factors, or recurrence rate of GCTTS. This article presents a series of 18 cases supplemented by a literature review that examines the epidemiology, presentation, gross and microscopic characteristics, and recurrence rate of GCTTS. Methods: A total of 18 patients with a histo-pathological diagnosis of a GCTTS of the hand or finger were reviewed. The location for the tumour was limited to the wrist and hand. All cases were operated under Wide Awake Local anaesthesia (WALANT), and using a magnifying loupe. Results: A total of 18 patients presented at our institution with a diagnosis of GCTTS from 2016 to 2018. Of the 18 patients, 11 were female and 7 were male. The mean age of included patients was 43.6 years (31-59 years). The most common site for the lesion was the middle finger (4/18), followed by the index finger, wrist, and thumb (3/18 each). The little and ring finger were least commonly affected with one case each. The mean size of the tumour was 2.4 cm (0.5-5 cm). None of the patients reported recurrence of the lesion on an average follow-up of 18.8 months. Conclusion: GCTTS is a benign, slowly growing lesion of the hand that typically does not cause any symptoms and is treated with surgical resection. Meticulous excision of the GCTTS using magnification loupes to ensure appropriate wide excision of the tumour is the treatment of choice to prevent a recurrence. In addition, a radiographic and histopathological examination must be performed on the tumour to rule out other diagnoses. Finally, the function of the hand should be reconstructed to minimize the loss of any functional unit.

Implementation of pharmacogenetic testing in oncology: DPYD-guided dosing to prevent fluoropyrimidine toxicity in British Columbia.

Background: Fluoropyrimidine toxicity is often due to variations in the gene (DPYD) encoding dihydropyrimidine dehydrogenase (DPD). DPYD genotyping can be used to adjust doses to reduce the likelihood of fluoropyrimidine toxicity while maintaining therapeutically effective drug levels. Methods: A multiplex QPCR assay was locally developed to allow genotyping for six DPYD variants. The test was offered prospectively for all patients starting on fluoropyrimidines at the BC Cancer Centre in Vancouver and then across B.C., Canada as well as retrospectively for patients suspected to have had an adverse reaction to therapy. Dose adjustments were made for variant carriers. The incidence of toxicity in the first three cycles was compared between DPYD variant allele carriers and non-variant carriers. Subsequent to an initial implementation phase, this test was made available province-wide. Results: In 9 months, 186 patients were tested and 14 were found to be heterozygous variant carriers. Fluoropyrimidine-related toxicity was higher in DPYD variant carriers. Of 127 non-variant carriers who have completed chemotherapy, 18 (14%) experienced severe (grade ≥3, Common Terminology Criteria for Adverse Events version 5.0). Of note, 22% (3 patients) of the variant carriers experienced severe toxicity even after DPYD-guided dose reductions. For one of these carriers who experienced severe thrombocytopenia within the first week, DPYD testing likely prevented lethal toxicity. In DPYD variant carriers who tolerate reduced doses, a later 25% increase led to chemotherapy discontinuation. As a result, a recommendation was made to clinicians based on available literature and expert opinion specifying that variant carriers who tolerated two cycles without toxicity can have a dose escalation of only 10%. Conclusion: DPYD-guided dose reductions were a feasible and acceptable method of preventing severe toxicity in DPYD variant carriers. Even with dose reductions, there were variant carriers who still experienced severe fluoropyrimidine toxicity, highlighting the importance of adhering to guideline-recommended dose reductions. Following the completion of the pilot phase of this study, DPYD genotyping was made available province-wide in British Columbia.

Factors Associated with COVID-19 Testing, Vaccination, and Use of Digital Contact Tracing Apps among Black and Latinx MSM (BLMSM) in Los Angeles.

This study examines the factors associated with COVID-19 testing, vaccination intent (both individually and jointly), and willingness to use contact tracing digital apps among a cohort of Black and Latinx men who have sex with men (BLMSM) living in Los Angeles during the initial peak (July 2020) of the COVID-19 pandemic. A questionnaire detailing participants COVID-19 experiences was sent to 300 primarily BLMSM after the first state-wide COVID-19 lockdown. Logistic regression models with random cluster effects were used for analyses. Forty-two percent (42%) tested for COVID-19, 27% were willing to get vaccinated, and about 45% reported willingness to use contact tracing digital apps. Controlling for intervention participation, age, education, marital status, employment, health, tobacco, binge drinking, and self-reported anxiety, those who were depressed had 33% (95% CI: 0.13 to 0.82) odds of using a prevention strategy (either test for COVID-19 or vaccination intent) as the group who were not depressed. Those who had high school diploma or less had 23% (95% CI: 0.11 to 0.48) odds to use digital contact tracing apps as the group with education level of at least Associate's or Bachelor's degree. Without considering the format of the test kits, vaccine side effects, and ease of use for digital contact tracing apps, participants appeared to still be hesitant in using COVID-19 prevention strategies at the initial height of the pandemic. Our findings suggest the need for further investigation into this hesitancy to better inform and prepare for future epidemics.

Spatial investigation of the links between aflatoxins legislation, climate, and liver cancer at the global scale.

Aflatoxins are carcinogenic toxins produced by fungi, and many countries legislate limits in food. Previous research suggests elevated liver cancer (LC) mortality in some areas may be due to aflatoxin exposure, but this has not been investigated spatially. We investigate links between aflatoxin legislation, climate, and LC mortality and other covariates globally. Comparison tests of LC mortality showed expected patterns with legislation and climate. They also showed associations between high LC mortality and high Hepatitis, low alcohol consumption, low health expenditure and high family agriculture rates. Spatial analysis showed latitudinal trend with significant clusters of low LC mortality in Europe and high rates in West Africa, Central America, East and South-East Asia. Only health expenditure and Hepatitis were significant in spatial regression, but climate and family agriculture were also significant in multiple linear regression (MLR). Results suggest that aflatoxin education and legislation should be expanded, particularly in hot/wet climates.

Internet Searches for Self-Managed Abortion After Roe v Wade Overturned.

This cross-sectional study used search data from Google Trends to estimate public interest in self-managed abortion.

The Impact of Surgical Timing After Ankle Fracture on Clinical and Long-Term Patient Reported Outcomes.

The goal of this study is to evaluate the effect of time-to-surgery following closed ankle fractures on long-term patient reported outcomes, fracture healing, and wound complications. To date, little research has been done focusing on the impact "time to definitive fixation" has on patient reported outcomes. We performed a retrospective analysis of 215 patient records who underwent open reduction and internal fixation (ORIF) for an ankle fracture from July 2011 to July 2018. A total of 86 patients completed the patient reported outcome measurement information systems (PROMIS) survey at long-term follow-up. Primary outcomes were the rate of delayed union, postoperative wound complications, patient reported outcome measurement information system (PROMIS) pain interference (PI), and physical function (PF) scores. No differences were found when comparing time to surgery on a continuous scale with rates of delayed union, nonunion, or wound complications (p = .84, .47, and .63, respectively). PROMIS scores were collected at a median of 4.5 years (2.0 interquartile range (IQR), range 2.5-12.3) postoperatively. The time from ankle fracture to surgery was independently associated with worse PROMIS PI scores (unstandardized ß 0.38, 95% CI 0.07-0.68) but not PROMIS PF scores. Severe Lauge-Hansen injuries were independently associated with decreased PROMIS PF scores (unstandardized ß -7.02, 95% CI -12.0 to -2.04). Increased time to surgical intervention and severe Lauge-Hansen injuries were independently associated with worse long-term patient reported outcomes. Surgical timing did not impact union rates or wound complications. Surgeons should be aware that delaying ankle fracture repair beyond 12 days after injury may negatively affect long-term patient reported pain scores.

A Review of Pediatric Heel Pain.

The objective of this review article is to provide orthopaedic surgeons and general practitioners a reference and guidance for the evaluation and workup of heel pain in pediatric patients. The authors performed a comprehensive literature search to review the etiologies and management of heel pain in patients <18 years of age. Relevant studies in Medline/PubMed and EMBASE were searched from inception to March 3, 2022 using medical subject headings and text words without limitations on language or study type. The initial search utilized the following Boolean operators: (children) AND (heel pain); (pediatric) AND (heel pain). Heel pain in the pediatric population is usually a benign condition. Sever's apophysitis is the most common etiology of heel pain in pediatric patients. Most causes of heel pain in the pediatric population do not require imaging or extensive workup. However, providers must maintain a high index of suspicion for symptoms that could indicate a more severe pathology.

Surgical treatment of a hindfoot plantar leiomyoma: A case study.

Leiomyomas within the foot are rare and are difficult to diagnose with only the radiographic and clinical picture. They are benign, slow growing, and very rarely cause pain. We present an unusual case of a dermatology referral patient complaining of callus formation on the plantar aspect of the foot as well as shoe discomfort. The mass was believed to be a lipoma or a fibroma but after surgical excision was found to be a leiomyoma. Our case highlights the rarity of this diagnosis and presents a unique surgical technique utilizing a medial approach to the plantar hindfoot for lesion removal.

Influenza vaccination during pregnancy and risk of selected major structural congenital heart defects, National Birth Defects Prevention Study 2006-2011.

BACKGROUND: Although results from studies of first-trimester influenza vaccination and congenital heart defects (CHDs) have been reassuring, data are limited for specific CHDs. METHODS: We assessed associations between reported maternal influenza vaccination, 1 month before pregnancy (B1) through end of third pregnancy month (P3), and specific CHDs using data from a multisite, population-based case-control study. Analysis included 2,982 case children diagnosed with a simple CHD (no other cardiac involvement with or without extracardiac defects) and 4,937 control children without a birth defect with estimated delivery dates during 2006-2011. For defects with ≥5 exposed case children, we used logistic regression to estimate propensity score-adjusted odds ratios (aORs) and 95% confidence intervals (CIs), adjusting for estimated delivery year and season; plurality; and maternal age at delivery, race/ethnicity, low folate intake, and smoking and alcohol use during B1P3. RESULTS: Overall, 124 (4.2%) simple CHD case mothers and 197 (4.0%) control mothers reported influenza vaccination from 1 month before through the third pregnancy month. The aOR for any simple CHD was 0.97 (95% CI: 0.76-1.23). Adjusted ORs for specific simple CHDs ranged from 0.62 for hypoplastic left heart syndrome to 2.34 for total anomalous pulmonary venous return (TAPVR). All adjusted CIs included the null except for TAPVR. CONCLUSIONS: Although we cannot fully exclude that exposure misclassification may have masked risks for some CHDs, findings add to existing evidence supporting the safety of inactivated influenza vaccination during pregnancy. The TAPVR result may be due to chance, but it may help inform future studies.

Potential application of conversational agents in HIV testing uptake among high-risk populations.

Human Immunodeficiency Virus (HIV) continues to be a significant public health problem, with ~1.2 million Americans living with HIV and ~14% unaware of their infection. The Centers for Disease Control and Prevention recommends that patients 13 to 64 years of age get screened for HIV at least once, and those with higher risk profiles screen at least annually. Unfortunately, screening rates are below recommendations for high-risk populations, leading to problems of delayed diagnosis. Novel technologies have been applied in HIV research to increase prevention, testing and treatment. Conversational agents, with potential for integrating artificial intelligence and natural language processing, may offer an opportunity to improve outreach to these high-risk populations. The feasibility, accessibility and acceptance of using conversational agents for HIV testing outreach is important to evaluate, especially amidst a global coronavirus disease 2019 pandemic when clinical services have been drastically affected. This viewpoint explores the application of a conversational agent in increasing HIV testing among high-risk populations.

Cytogenetic and epigenetic aberrations in peripheral lymphocytes of northwest Arkansas Marshallese.

PURPOSE: Nuclear weapons testing in the northern Marshall Islands between 1946 and 1958 resulted in ionizing radiation (IR) exposure of the thousands of Marshallese. Furthermore, numerous islands were contaminated by radioactive fallout. Significant increases in cancer and metabolic syndrome incidences have been reported among Marshallese, and potential for further increases looms due to the latency of radiation-induced health effects. The purpose of this study was to investigate the genetic and epigenetic effects of exposure to IR that could be associated with radiation-induced disease among the Northwest Arkansas (NWA) Marshallese. MATERIALS AND METHODS: We performed analysis of chromosomal aberrations and DNA methylation based on residential and exposure history of NWA Marshallese. RESULTS: Analysis of chromosomal aberrations demonstrated higher incidence of genetic rearrangements in women with self-reported history of radiation exposure (95% CI: 0.10, 1.22; p=.022). Further clustering of study participants based on their residential history demonstrated that participants who spent substantial amounts of time (≥6 months) in the northern atolls (thus, in the proximity of nuclear tests) before 1980 had more chromosomal aberrations than their peers who lived only in the southern atolls (95% CI: 0.08, -0.95; p=.021), and that this difference was driven by women. A relationship between the time spent in the northern atolls and increase in chromosomal aberrations was observed: 0.31 increase in chromosomal aberrations for every 10 years spent at northern atolls (95% CI: 0.06, 0.57; p=.020). Finally, significant inverse correlations between the chromosomal aberrations and the extent of DNA methylation of four LINE-1 elements L1PA2, L1PA16, L1PREC1, and L1P4B were identified. CONCLUSIONS: The results of this study provide first evidence of the presence of stable genetic and epigenetic rearrangements in peripheral lymphocytes of NWA Marshallese and warrant further studies to analyze the role of radiation exposure in health disparities experienced by this Pacific Island nation.

Tibiotalocalcaneal Arthrodesis with Intramedullary Fibular Strut Graft and Adjuvant Hardware Fixation.

Background: In patients with irreparable damage to the articular surfaces of the hindfoot, hindfoot arthrodesis is frequently chosen to provide pain relief and improve activities of daily living. Common etiologies leading to hindfoot arthrodesis procedures include osteonecrosis, failed total ankle arthroplasty, and deformities resulting from Charcot arthropathy or rheumatoid arthritis. Traditionally, this operation utilizes an intramedullary nail to obtain fusion of the tibiotalocalcaneal joint. Although 80% to 90% of patients achieve postoperative union, the remaining 10% to 20% experience nonunion1-3. Factors affecting the rate of nonunion include Charcot neuroarthropathy, use of nonsteroidal anti-inflammatory drugs or methotrexate, osteopenic bone, and smoking4. In the present video article, we describe a tibiotalocalcaneal arthrodesis performed with use of a fibular strut autograft for repeat arthrodesis following failure of primary tibiotalocalcaneal arthrodesis or as a salvage operation in end-stage pathologies of the hindfoot. Our surgical technique yields union rates of approximately 80% and provides surgeons with a viable surgical technique for patients with complex hindfoot pathologies or fusion failure. Description: The patient is placed in the supine position, and a 10-cm curvilinear incision is made including the distal 6 to 8 cm of the fibula. The incision is centered directly lateral on the fibula proximally and transitions to the posterolateral aspect of the fibula distally. As the incision continues distally, it extends inferiorly and anteriorly over the sinus tarsi and toward the base of the 4th metatarsal, using an internervous plane between the superficial peroneal nerve anteriorly and the sural nerve posteriorly. Exposure of the periosteum is carried out through development of full-thickness skin flaps. The periosteum is stripped, and a sagittal saw is used to make a beveled cut on the fibula at a 45° angle, approximately 6 to 8 cm proximal to the ankle. The fibular strut is decorticated, drilled, and stripped of the cartilage on the distal end. Preparation of the tibiotalar and subtalar joints for arthrodesis are completed through the lateral incision. The foot is placed in 0° of dorsiflexion, 5° of external rotation in relation to the tibial crest, and 5° of hindfoot valgus while maintaining a plantigrade foot. This placement can be temporarily maintained with Kirschner wires if needed. Next, the plantar surface overlying the heel pad is incised, and a guidewire is passed through the center of the calcaneus and into the medullary cavity of the tibia. Correct alignment of the guidewire is then confirmed on fluoroscopy. The fibular strut autograft is prepared for insertion while the tibiotalocalcaneal canal is reamed to 1 to 2 mm larger than the graft. The graft is tapped into position, followed by placement of two 6.5-mm cancellous screws to immobilize the joint, taking care to avoid excess contact of the fibular graft with the screws. Alternatives: Alternatives to this procedure include traditional arthrodesis techniques, nonoperative treatment (such as rehabilitation or bracing), or no intervention. Patients with failed primary hindfoot arthrodesis may undergo an additional traditional arthrodesis, but may face an increased risk of complications and failure1,2. Rationale: A recent study1 has shown that the use of a fibular strut autograft for tibiotalocalcaneal arthrodesis produces union rates similar to those seen with the traditional intramedullary nailing technique4,5. These results are important to note, as the presently described technique, which is used as a salvage procedure, produces outcomes that are equivalent to those observed for primary tibiotalocalcaneal arthrodesis with nailing, which is used for the treatment of severe trauma, extensive bone loss, or severe hindfoot pathologies. We recommend using this technique particularly in cases of failed primary tibiotalocalcaneal arthrodesis or in patients with end-stage hindfoot pathologies. The fibular strut autograft is a viable salvage option to decrease daily pain and provide quality improvement in patient activities of daily living. Expected Outcomes: Tibiotalocalcaneal arthrodesis with a fibular strut autograft has been shown to produce a union rate (81.2%) similar to that of the traditional arthrodesis technique with intramedullary nailing (74.4% to 90%). The strut graft provides an osteoinductive environment for healing and increases the post-arthrodesis load tolerance1. Mean visual analog scale pain scores improved from 6.9 preoperatively to 1.2 postoperatively with use of this procedure1. The most common complication was wound dehiscence requiring additional wound care (37.5%); its rate was higher than the rates reported in other studies of tibiotalocalcaneal arthrodesis, possibly because of the small sample size of patients undergoing such a complex procedure for a complex medical issue2,11. Although 7 patients required a reoperation, all ultimately experienced a union and recovered postoperatively. All non-retired patients were all able to return to work1. Important Tips: Place your incision precisely to allow adequate exposure of both the tibiotalar and subtalar joints.Curvilinear incision should begin 6 to 8 cm proximal to, and directly lateral to, the distal end of the fibula. It should continue posterolaterally to the fibula distally and extend inferiorly and anteriorly over the sinus tarsi, toward the base of the 4th metatarsal.Prepare the tibiotalar and subtalar joints this same incision.Decorticate the fibular strut autograft; this plays a key role in obtaining fusion.Harvest the fibula 6 to 8 cm above the ankle joint line. Once the graft is harvested, smooth the edges of the fibula with a burr; this facilitates graft insertion.Finally, when immobilizing the joint, take care to avoid excessive perforation of the graft as this increases the likelihood of fracture. Acronyms and Abbreviations: OR = operating roomIM = intramedullaryCT = computed tomographyTTCA = tibiotalocalcaneal arthrodesisTTC = tibiotalocalcanealK-wire - Kirschner wire.

Patient and Surgical Factors Affecting Fusion Rates After Arthroscopic and Open Ankle Fusion: A Review of a High-Risk Cohort.

Abstract: We present a case series with the objective of identifying risk factors for nonunion after open and arthroscopic primary ankle arthrodesis. Eighty-seven patients who underwent primary ankle arthrodesis and met inclusion criteria were divided into open (N = 46) and arthroscopic (N = 41) groups. Patient and operative characteristics were retrospectively analyzed as possible risk factors for nonunion within each technique. The nonunion rate was 11% in the open and 12% in the arthroscopic group. Obesity, smoking, and ASA class 3 were highly prevalent in both groups. In the arthroscopic group, a remote history of infection and the use of headed screws had notably higher risk of nonunion, though not statistically significant. In the open group, use of bone graft trended toward lower risk of nonunion, though also not statistically significant. The results of this study demonstrated, nonunion rates are comparable between open and arthroscopic ankle arthrodesis in high-risk patients. For patients with a remote history of infection, open ankle arthrodesis may be preferable, and bone graft importance may vary with open versus arthroscopic technique. Level of evidence: III.

Exposure of the Calcaneus in the Sinus Tarsi Approach Versus the Lateral Extensile Approach: A Cadaveric Study.

BACKGROUND: The lateral extensile approach (LEA) is an operative approach for calcaneal fractures. High rates of wound complications have led to alternative approaches such as the sinus tarsi approach to grow in popularity. The LEA affords substantial visualization of the calcaneus. This visualization has never been compared in a quantitative manner with the sinus tarsi approach (STA). We aim to quantify the calcaneal visualization afforded by STA and LEA. METHODS: Seven pair-matched, fresh-frozen, below-knee cadaver extremities were included. For each pair, one side received an LEA and the other side received an STA. RESULTS: There were no statistically significant differences in the articular surfaces accessible between the 2 approaches. The total calcaneal surface area accessible was 3107.08 mm2 for LEA and 1444.19 mm2 for STA (P = .02). The LEA allowed better exposure to the lateral wall (P = .01) and the dorsal tuberosity of the calcaneus (P = .04). CONCLUSION: The STA allows for equivalent articular surface exposure when compared with the LEA. Although LEA allows for greater exposure of the lateral wall and dorsal tuberosity, direct visualization of these structures may not warrant the higher risk of wound complications. Surgeons should consider these differences when choosing an operative approach in the treatment of calcaneal fractures.Level III.

Prevalence and Risk Factors of Postoperative Falls Following Foot and Ankle Surgery.

BACKGROUND: No study has examined the incidence of risk factors for postoperative falls following foot and ankle surgery. We investigated the incidence and risk factors for postoperative falls in foot and ankle surgery using inpatient and outpatient population. METHODS: A single fellowship-trained foot and ankle surgeon instituted collection of a postoperative fall questionnaire at 2 and 6 weeks postoperatively. A retrospective review of 135 patients with complete prospectively collected fall questionnaire data was performed. Patient demographic information, injury characteristics, comorbidities, baseline medications, length of hospital stay, visual analog scale (VAS) pain scores were collected. After univariable analysis, a multivariable binary logistic regression was conducted to assess independent risk factors for postoperative falls. RESULTS: The median (interquartile range) age was 52 (21) and body mass index was 32.7 (11.1). A total of 108 patients (80%) underwent outpatient procedures. Thirty-nine of the 135 patients (28.9%) reported experiencing a fall in the first 6 weeks after surgery. In multivariable analysis, antidepressant use (adjusted odds ratio 3.41, 95% CI 1.19-9.81) and higher VAS pain scores at 2 weeks postoperatively (adjusted odds ratio 1.27, 95% CI 1.08-1.50) were found to be independent risk factors for postoperative falls. CONCLUSION: This study found a high incidence of postoperative falls in the first 6 weeks after foot and ankle surgery. Baseline antidepressant use and higher 2-week VAS pain scores were associated with postoperative falls. Foot and ankle surgeons should discuss the risk of falling with patients especially those with risk factors. LEVEL OF EVIDENCE: Level III, retrospective cohort study at a single institution.

Influenza vaccination during pregnancy and risk of selected major structural noncardiac birth defects, National Birth Defects Prevention Study 2006-2011.

PURPOSE: To assess associations between influenza vaccination during etiologically-relevant windows and selected major structural non-cardiac birth defects. STUDY DESIGN: We analyzed data from the National Birth Defects Prevention Study, a multisite, population-based case-control study, for 8233 case children diagnosed with a birth defect and 4937 control children without a birth defect with delivery dates during 2006-2011. For all analyses except for neural tube defects (NTDs), we classified mothers who reported influenza vaccination 1 month before through the third pregnancy month as exposed; the exposure window for NTDs was 1 month before through the first pregnancy month. For defects with five or more exposed case children, we used logistic regression to estimate propensity score-adjusted odds ratios (aORs) and 95% confidence intervals (CIs), adjusting for estimated delivery year and season; plurality; maternal age, race/ethnicity, smoking and alcohol use, low folate intake; and, for NTDs, folate antagonist medications. RESULTS: There were 334 (4.1%) case and 197 (4.0%) control mothers who reported influenza vaccination from 1 month before through the third pregnancy month. Adjusted ORs ranged from 0.53 for omphalocele to 1.74 for duodenal atresia/stenosis. Most aORs (11 of 19) were ≤1 and all adjusted CIs included the null. The unadjusted CIs for two defects, hypospadias and craniosynostosis, excluded the null. These estimates were attenuated upon covariate adjustment (hypospadias aOR: 1.25 (95% CI 0.89, 1.76); craniosynostosis aOR: 1.23 (95% CI: 0.88, 1.74)). CONCLUSIONS: Results for several non-cardiac major birth defects add to the existing evidence supporting the safety of inactivated influenza vaccination during pregnancy. Under-reporting of vaccination may have biased estimates downward.

Geospatial Assessment of Pesticide Concentration in Ambient Air and Colorectal Cancer Incidence in Arkansas, 2013-2017.

Exposure to various agricultural pesticides has been linked to colorectal cancer (CRC), mostly among farmworkers and applicators. Given the potential pesticide drift in ambient air, residents near farmland may be exposed to carcinogenic pesticides even if they are not actively engaged in pesticide application. Pesticide air pollution at the county level was estimated using the 2014 National Air Toxics Assessment. CRC incidence data were acquired from the Arkansas Central Cancer Registry for 2013-2017. We ran ordinary least squares (OLS) regression models, finding significant spatial autocorrelation of residuals for most models. Using geographically weighted regression (GWR) we found age-adjusted CRC incidence rates vary in an increasing west-to-east gradient, with the highest rates in the Arkansas Delta region. A similar gradient was observed in the distribution of the population living below the poverty line and the population percentage of Black people. Significant associations between Trifluralin (crude model only), Carbon Tetrachloride, and Ethylene Dibromide with CRC incidence rates in OLS models only explained 5-7% of the variation and exhibited spatial autocorrelation of residuals. GWR models explained 24-32% (adjusted r2 9-16%) of CRC incidence rate variation, suggesting additional factors may contribute to the association between pesticides and CRC.

Integrating Tumor Sequencing Into Clinical Practice for Patients With Mismatch Repair-Deficient Lynch Syndrome Spectrum Cancers.

INTRODUCTION: Uninformative germline genetic testing presents a challenge to clinical management for patients suspected to have Lynch syndrome, a cancer predisposition syndrome caused by germline variants in the mismatch repair (MMR) genes or EPCAM. METHODS: Among a consecutive series of MMR-deficient Lynch syndrome spectrum cancers identified through immunohistochemistry-based tumor screening, we investigated the clinical utility of tumor sequencing for the molecular diagnosis and management of suspected Lynch syndrome families. MLH1-deficient colorectal cancers were prescreened for BRAF V600E before referral for genetic counseling. Microsatellite instability, MLH1 promoter hypermethylation, and somatic and germline genetic variants in the MMR genes were assessed according to an established clinical protocol. RESULTS: Eighty-four individuals with primarily colorectal (62%) and endometrial (31%) cancers received tumor-normal sequencing as part of routine clinical genetic assessment. Overall, 27% received a molecular diagnosis of Lynch syndrome. Most of the MLH1-deficient tumors were more likely of sporadic origin, mediated by MLH1 promoter hypermethylation in 54% and double somatic genetic alterations in MLH1 (17%). MSH2-deficient, MSH6-deficient, and/or PMS2-deficient tumors could be attributed to pathogenic germline variants in 37% and double somatic events in 28%. Notably, tumor sequencing could explain 49% of cases without causal germline variants, somatic MLH1 promoter hypermethylation, or somatic variants in BRAF. DISCUSSION: Our findings support the integration of tumor sequencing into current Lynch syndrome screening programs to improve clinical management for individuals whose germline testing is uninformative.

Use of Treatment-Focused Tumor Sequencing to Screen for Germline Cancer Predisposition.

Next-generation sequencing assays are capable of identifying cancer patients eligible for targeted therapies and can also detect germline variants associated with increased cancer susceptibility. However, these capabilities have yet to be routinely harmonized in a single assay because of challenges with accurately identifying germline variants from tumor-only data. We have developed the Oncology and Hereditary Cancer Program targeted capture panel, which uses tumor tissue to simultaneously screen for both clinically actionable solid tumor variants and germline variants across 45 genes. Validation using 14 tumor specimens, composed of patient samples and cell lines analyzed in triplicate, demonstrated high coverage with sensitive and specific identification of single-nucleotide variants and small insertions and deletions. Average coverage across all targets remained >2000× in 198 additional patient tumor samples. Analysis of 55 formalin-fixed, paraffin-embedded tumor samples for the detection of known germline variants within a subset of cancer-predisposition genes, including one multiexon deletion, yielded a 100% detection rate, demonstrating that germline variants can be reliably detected in tumor samples using a single panel. Combining targetable somatic and actionable germline variants into a single tumor tissue assay represents a streamlined approach that can inform treatment for patients with advanced cancers as well as identify those with potential germline variants who are eligible for confirmatory testing, but would not otherwise have been identified.