Citations

AbstractBackgroundThe use of spinal anesthesia in infants is seeing resurgence as an alternative to general anesthesia.AimsOur primary aims are to describe our institution's experience introducing a spinal anesthesia and sedation protocol for infants undergoing urologic surgery, to describe methods of improving prolonged anesthesia, and to describe the failure rate of spinal anesthesia in these patients. Sedation was provided for some infants with intranasal dexmedetomidine ± fentanyl.MethodsThis is a retrospective case series examining infants aged 1‐<14 months who received spinal anesthesia for circumcision, orchiopexy, orchiectomy, hypospadias repair, or epispadias repair. The electronic medical record was reviewed and compared with unmatched historical controls who received general anesthesia.ResultsA total of 230 patients underwent a urologic procedure; 102 patients received spinal anesthesia and 128 received general anesthesia. Length of surgical time with spinal anesthesia ranged from 4 to 189 minutes. The hospital length of stay was shorter in the spinal anesthesia group (median [IQR] of 5.3 hours [4.3, 7.2]) compared to the general anesthesia group (17.1 hours [15.6, 17.5]).The median bupivacaine dose was 0.75 mg/kg [0.67, 0.85]. There was one case in which cerebral spinal fluid was unable to be obtained, and one case that required conversion to general anesthesia after surgery had started. There were no cases of apnea, bleeding, infection, or neurologic compromise.ConclusionsWe describe the successful implementation of an infant spinal anesthesia and sedation protocol and a technique that uniquely provides prolonged surgical anesthesia with a low failure rate. We also report shorter anesthesia time, surgical time, and recovery room length of stay in patients who received spinal anesthesia compared to general anesthesia.

AbstractBackgroundAlthough coronavirus disease 2019 (COVID-19) is a mild infection in most children, a small proportion develop severe or critical illness. Data describing agents with potential antiviral activity continue to expand such that updated guidance is needed regarding use of these agents in children.MethodsA panel of pediatric infectious diseases physicians and pharmacists from 20 geographically diverse North American institutions was convened. Through a series of teleconferences and web-based surveys, a set of guidance statements was developed and refined based on review of the best available evidence and expert opinion.ResultsGiven the typically mild course of COVID-19 in children, supportive care alone is suggested for most cases. For children with severe illness, defined as a supplemental oxygen requirement without need for noninvasive or invasive mechanical ventilation or extracorporeal membrane oxygenation (ECMO), remdesivir is suggested, preferably as part of a clinical trial if available. Remdesivir should also be considered for critically ill children requiring invasive or noninvasive mechanical ventilation or ECMO. A duration of 5 days is appropriate for most patients. The panel recommends against the use of hydroxychloroquine or lopinavir-ritonavir (or other protease inhibitors) for COVID-19 in children.ConclusionsAntiviral therapy for COVID-19 is not necessary for the great majority of pediatric patients. For children with severe or critical disease, this guidance offers an approach for decision-making regarding use of remdesivir.

Abstract Background: Previous research studies have demonstrated abnormalities in the metabolism of mothers of young children with autism.Method: Metabolic analysis was performed on blood samples from 30 mothers of young children with Autism Spectrum Disorder (ASD-M) and from 29 mothers of young typically-developing children (TD-M). Targeted metabolic analysis focusing on the folate one-carbon metabolism (FOCM) and the transsulfuration pathway (TS) as well as broad metabolic analysis were performed. Statistical analysis of the data involved both univariate and multivariate statistical methods.Results: Univariate analysis revealed significant differences in 5 metabolites from the folate one-carbon metabolism and the transsulfuration pathway and differences in an additional 48 metabolites identified by broad metabolic analysis, including lower levels of many carnitine-conjugated molecules. Multivariate analysis with leave-one-out cross-validation allowed classification of samples as belonging to one of the two groups of mothers with 93% sensitivity and 97% specificity with five metabolites. Furthermore, each of these five metabolites correlated with 8-15 other metabolites indicating that there are five clusters of correlated metabolites. In fact, all but 5 of the 50 metabolites with the highest area under the receiver operating characteristic curve were associated with the five identified groups. Many of the abnormalities appear linked to low levels of folate, vitamin B12, and carnitine-conjugated molecules.Conclusions: Mothers of children with ASD have many significantly different metabolite levels compared to mothers of typically developing children at 2-5 years after birth.

Abstract Background: The Circulating Cell-free Genome Atlas study (NCT02889978) is a multi-center, case-control, observational study with longitudinal follow-up (n=15,254; 56% cancer, 44% non-cancer) to support development of a cell-free DNA (cfDNA) multi-cancer early detection test. Previously, we reported that a targeted methylation assay detected and localized &gt;20 cancer types at &gt;99% specificity in individuals with cancer.1,2 Here, we report prediction of cancer (presence/absence) and tissue of origin (TOO) in individuals enrolled with clinical suspicion of cancer but without pathologic diagnosis or treatment at time of enrollment. Methods: Plasma cfDNA from blood samples collected prior to clinical diagnosis was subjected to targeted methylation sequencing. Samples were divided into a training set and an independent validation set to train and validate a machine learning classifier to assess cancer and predict TOO. Performance was assessed in a subset of participants enrolled with suspicion of cancer; subsequently, cancer was confirmed by evaluating a pathologic specimen. Results: Participants being evaluated for suspicion of cancer were classified as confirmed cancer (&gt;20 cancer types; n=164 in training, n=75 in validation) or confirmed non-cancer (n=49 training, n=15 validation). In the confirmed non-cancer group, all training and validation samples were correctly predicted as non-cancer (100% specificity). In the confirmed cancer group, cancer detection across all stages was 40.2% (66/164; 95% confidence interval [CI], 32.7-48.2%) in training and 46.7% (35/75; 95% CI, 35.1-58.6%) in validation. Excluding stage I renal cancers (where detection/tumor fraction is low in plasma and which comprised 20% of participants in this subset) detection across stages was 50.4% (66/131; 95% CI, 41.5-59.2%) and 59.3% (35/59; 95% CI, 45.7-71.9%), respectively. In stages II and above, detection was 70.7% (58/82; 95% CI, 59.6-80.3%) and 78.9% (30/38; 95% CI, 62.7-90.4%), respectively. For detected cancers, TOO was predicted in 93.9% (62/66) samples in training and 100% (35/35) in validation. Of those with a TOO call, accuracy was 85.5% (53/62; 95% CI, 74.2-93.1%) and 97.1% (34/35; 95% CI, 85.1-99.9%), respectively. Conclusion: A cfDNA multi-cancer detection test has shown the potential to predict cancer and TOO in individuals with suspicion of cancer ahead of histologic diagnosis with performance comparable to those with confirmed cancer at the time of blood collection. This was achieved with high specificity and TOO accuracy. The high specificity suggests that the false positive rate could be comparable in populations with average versus higher risk (suspicion) of cancer. These findings suggest that a cfDNA multi-cancer detection test could accelerate the diagnostic resolution of suspicion of cancer. References: 1. Oxnard GR, et al. ASCO Breakthrough Meeting 2019; Abstract 44. 2. Oxnard GR, et al. ESMO Annual Meeting 2019; Abstract 5639. Citation Format: David D. Thiel, Xiaoji Chen, Kathryn N. Kurtzman, Jessica Yecies, Tony Wu, Quan Zhang, Hai Liu, Nan Zhang, Eric T. Fung, Michael V. Seiden, Minetta C. Liu, Geoffrey R. Oxnard, Earl Hubbell, Alexander M. Aravanis, Anne-Renee Hartman, Eric A. Klein. Prediction of cancer and tissue of origin in individuals with suspicion of cancer using a cell-free DNA multi-cancer early detection test [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr CT021.

Women have historically faced gendered patterns of disadvantage during times of emergency. Evidence demonstrates differences in gendered exposures and inequities during acute crises such as natural disasters and pandemics, including Covid-19, and longer-term emergencies such as climate change. These patterns, without intervention, may be perpetuated in future crises. Threats to women's health in times of emergency can arise from restricted access to health care, economic disadvantages, and harmful social norms. During crises, women face additional barriers to accessing maternal, contraceptive, and abortion care, likely exacerbating existing inequities in reproductive health outcomes. Gendered inequalities in financial and economic stability can become even more stark. Globally, women perform the majority of health care and unpaid caregiving work, but face barriers to affording costs of living and obtaining health insurance due to over-representation in low-wage jobs. Finally, gendered expectations of social roles contribute to increased vulnerabilities, such as displacement and poverty. Violence against women rises in times of emergency and pathways to escaping trauma can be limited. In addition to directly addressing women's unique barriers and providing support in times of emergency through bolstering health care access, economic, and social support systems, thoughtful solutions such as trauma-informed care, increasing the number of women in leadership roles, educational initiatives, and advocacy from health professionals are needed to protect and advance women's health.

Abstract A majority of patients with high-grade serous ovarian cancer (HGSC) develop progressive disease following primary treatment, with a five-year survival rate of approximately 40%, and less than 10% survive more than 10 years. Profound genomic instability, treatment with DNA-damaging drugs, and a large tumor burden promote the development of acquired resistance in a large proportion of patients, including multiple convergent resistant events within individuals. Despite the propensity of HGSC to develop drug resistance, a small proportion of patients with advanced disease at diagnosis become long-term survivors. These exceptional patients include those who had suboptimal surgical clearance, and therefore were not cured surgically, and others who have had no evidence of disease recurrence following initial surgery and adjuvant chemotherapy. Our study, which is part of the international collaborative Multidisciplinary Ovarian Cancer Outcomes Group (MOCOG), seeks to identify molecular, immunologic, and epidemiologic factors that influence long-term survival in HGSC. This presentation describes our genomic and immunologic analysis of exceptional survival of this deadly disease. Patient characteristics and clinical histories were evaluated to identify patients diagnosed with advanced stage (Stage IIIC/IV) and histopathologically confirmed HGSC with greater than 10-year overall survival. Whole-genome sequencing (WGS) was performed on primary tumors (median 78x coverage) and germline samples (median 39x coverage) of 55 long-term survivors. Primary tumor samples were also characterized by RNA sequencing, DNA methylation profiling, and immunohistochemistry. Thirty-eight (69%) of long-term surviving patients had residual disease following surgery, suggestive of highly chemosensitive disease. Most patients (41, 75%) were alive at last follow-up and 26 (47%) were progression free. Somatic mutation burden was higher in primary tumors of long-term survivors relative to controls. Genome-wide mutational signatures were predominantly Signature 3 (associated with homologous recombination deficiency), Signature 1 (age related), and Signatures 5, 8, and 16 (unknown etiology). Inactivation of the tumor suppressor RB1 by structural rearrangements or homozygous deletion was frequent in long-term survivors, with 33% of tumors showing associated loss of RB1 protein expression by immunohistochemistry compared to 13% of unselected HGSC controls (n=207; P = 0.001). In an independent HGSC cohort (n=847), RB1 protein loss was associated with prolonged survival (HR: 0.75, P &lt; 0.001) compared to patients with RB1-positive tumors. Furthermore, co-occurrence of germline mutations in BRCA1 or BRCA2 and RB1 loss was associated with a significantly longer overall survival compared to patients with retained RB1 protein expression and no germline BRCA mutation (HR: 0.44, P &lt; 0.001). Multiplexed immunohistochemical analysis with immune cell panels demonstrated distinct associations with long-term survivors. This study delineates the full landscape of genomic alterations in HGSC of long-term survivors. Our findings indicate that specific mutations are associated with enhanced host immune responses and long-term survival. Citation Format: Dale Garsed, Ahwan Pandey, Sian Fereday, Kathryn Alsop, Maartje Wouters, Flurina Saner, Catherine Kennedy, Celeste Pearce, Malcolm Pike, Susan Ramus, Martin Kobel, Anna deFazio, Ellen Goode, Brad Nelson, David Bowtell. Molecular analysis of exceptional response in high-grade serous ovarian cancer [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research; 2019 Sep 13-16, 2019; Atlanta, GA. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(13_Suppl):Abstract nr IA05.

4045 Background: Our group previously reported on patient (Pt) recollections of adjuvant therapy (AT) for colon cancer and their grading of medical oncologists (MO) regarding various aspects of care. Overall, MO were highly rated, but grades for presenting information were lower, and patient expectations about side effects often did not match experiences. To further examine the Pt experience with AT, a prospective study was launched in Feb 2008. Methods: Pts with Stage II/III colon cancer about to begin or within 4 months of starting AT were recruited for a 4-part survey regarding sources and quality of treatment information and their experiences with AT. The survey also asked Pts to provide a grade (A-F) for their MO in 8 areas. Results: 85 Pts (71% female, 79% Stage III, median age 52 years) completed Part 1 of the survey. 93% stated that their MO explained the risks and benefits of AT. Of those, 92% stated they understood this information completely or almost completely (3 or 4 on a 0–4 scale) and 79% received numerical estimates of recurrence risk with and without treatment. When questioned about the potential absolute benefit of AT, 26% of Pts who received numerical estimates “had no idea” and other answers ranged from 3% to 100% for recurrence risk. Pt grade point averages for their MO ranged from 3.0 to 3.6 ( Table 1 ). As in the prior survey, expectations about side effects frequently did not accurately reflect experiences. For example, 54% of Pts expected alopecia but only 5% experienced it to a significant degree. 84% of Pts also sought information from websites, and 87% rated this as helpful and valuable (3 or 4 on a 0–4 scale). Conclusions: Pts are generally satisfied with their MO but less so with the presentation of treatment-related information and thus frequently consult additional resources, such as cancer information websites. This suggests an opportunity for improved information delivery within oncology offices and via the Internet. [Table: see text] [Table: see text]