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Nongenetic predisposition to colorectal cancer continues to be difficult to measure precisely, hampering efforts in targeted prevention and screening. Epigenetic changes in the normal mucosa of patients with colorectal cancer can serve as a tool in predicting colorectal cancer outcomes. We identified epigenetic changes affecting the normal mucosa of patients with colorectal cancer. DNA methylation profiling on normal colon mucosa from 77 patients with colorectal cancer and 68 controls identified a distinct subgroup of normally-appearing mucosa with markedly disrupted DNA methylation at a large number of CpGs, termed as “Outlier Methylation Phenotype” (OMP) and are present in 15 of 77 patients with cancer versus 0 of 68 controls (P < 0.001). Similar findings were also seen in publicly available datasets. Comparison of normal colon mucosa transcription profiles of patients with OMP cancer with those of patients with non-OMP cancer indicates genes whose promoters are hypermethylated in the OMP patients are also transcriptionally downregulated, and that many of the genes most affected are involved in interactions between epithelial cells, the mucus layer, and the microbiome. Analysis of 16S rRNA profiles suggests that normal colon mucosa of OMPs are enriched in bacterial genera associated with colorectal cancer risk, advanced tumor stage, chronic intestinal inflammation, malignant transformation, nosocomial infections, and KRAS mutations. In conclusion, our study identifies an epigenetically distinct OMP group in the normal mucosa of patients with colorectal cancer that is characterized by a disrupted methylome, altered gene expression, and microbial dysbiosis. Prospective studies are needed to determine whether OMP could serve as a biomarker for an elevated epigenetic risk for colorectal cancer development. Prevention Relevance: Our study identifies an epigenetically distinct OMP group in the normal mucosa of patients with colorectal cancer that is characterized by a disrupted methylome, altered gene expression, and microbial dysbiosis. Identification of OMPs in healthy controls and patients with colorectal cancer will lead to prevention and better prognosis, respectively.

Supplementary Figure from Epigenome-Wide Study Identifies Epigenetic Outliers in Normal Mucosa of Patients with Colorectal Cancer

Supplementary Table from Epigenome-Wide Study Identifies Epigenetic Outliers in Normal Mucosa of Patients with Colorectal Cancer

Supplementary Data from Epigenome-Wide Study Identifies Epigenetic Outliers in Normal Mucosa of Patients with Colorectal Cancer

Nongenetic predisposition to colorectal cancer continues to be difficult to measure precisely, hampering efforts in targeted prevention and screening. Epigenetic changes in the normal mucosa of patients with colorectal cancer can serve as a tool in predicting colorectal cancer outcomes. We identified epigenetic changes affecting the normal mucosa of patients with colorectal cancer. DNA methylation profiling on normal colon mucosa from 77 patients with colorectal cancer and 68 controls identified a distinct subgroup of normally-appearing mucosa with markedly disrupted DNA methylation at a large number of CpGs, termed as “Outlier Methylation Phenotype” (OMP) and are present in 15 of 77 patients with cancer versus 0 of 68 controls (P < 0.001). Similar findings were also seen in publicly available datasets. Comparison of normal colon mucosa transcription profiles of patients with OMP cancer with those of patients with non-OMP cancer indicates genes whose promoters are hypermethylated in the OMP patients are also transcriptionally downregulated, and that many of the genes most affected are involved in interactions between epithelial cells, the mucus layer, and the microbiome. Analysis of 16S rRNA profiles suggests that normal colon mucosa of OMPs are enriched in bacterial genera associated with colorectal cancer risk, advanced tumor stage, chronic intestinal inflammation, malignant transformation, nosocomial infections, and KRAS mutations. In conclusion, our study identifies an epigenetically distinct OMP group in the normal mucosa of patients with colorectal cancer that is characterized by a disrupted methylome, altered gene expression, and microbial dysbiosis. Prospective studies are needed to determine whether OMP could serve as a biomarker for an elevated epigenetic risk for colorectal cancer development.Prevention Relevance:Our study identifies an epigenetically distinct OMP group in the normal mucosa of patients with colorectal cancer that is characterized by a disrupted methylome, altered gene expression, and microbial dysbiosis. Identification of OMPs in healthy controls and patients with colorectal cancer will lead to prevention and better prognosis, respectively.

Treatment of advanced ovarian cancer using PD-1/PD-L1 immune checkpoint blockade shows promise; however, current clinical trials are limited by modest response rates. Radiotherapy has been shown to synergize with PD-1/PD-L1 blockade in some cancers but has not been utilized in advanced ovarian cancer due to toxicity associated with conventional abdominopelvic irradiation. Ultrahigh-dose rate (FLASH) irradiation has emerged as a strategy to reduce radiation-induced toxicity, however, the immunomodulatory properties of FLASH irradiation remain unknown. Here, we demonstrate that single high-dose abdominopelvic FLASH irradiation promoted intestinal regeneration and maintained tumor control in a preclinical mouse model of ovarian cancer. Reduced tumor burden in conventional and FLASH-treated mice was associated with an early decrease in intratumoral regulatory T cells and a late increase in cytolytic CD8+ T cells. Compared with conventional irradiation, FLASH irradiation increased intratumoral T-cell infiltration at early timepoints. Moreover, FLASH irradiation maintained the ability to increase intratumoral CD8+ T-cell infiltration and enhance the efficacy of αPD-1 therapy in preclinical models of ovarian cancer. These data highlight the potential for FLASH irradiation to improve the therapeutic efficacy of checkpoint inhibition in the treatment of ovarian cancer.

BackgroundSevere acute respiratory infections (SARIs) are the leading cause of pediatric death globally, particularly in low- and middle-income countries (LMICs). Given the potential rapid clinical decompensation and high mortality rate from SARIs, interventions that facilitate the early care of patients are critical to improving patient outcomes. The aim of this systematic review was to evaluate the impact of emergency care interventions on improving clinical outcomes of pediatric patients with SARIs in LMICs.MethodsPubMed, Global Health, and Global Index Medicus electronic databases were searched to identify peer-reviewed clinical trials or studies with comparator groups published before November 2020. All studies which evaluated acute and emergency care interventions on clinical outcomes for children (29 days to 19 years) with SARIs conducted in LMICs were included. Given the heterogeneity of interventions and outcomes, a narrative synthesis was performed. Bias was assessed using the Risk of Bias 2 and Risk of Bias in Non-Randomized Studies of Interventions.Results20,583 studies were screened, with 99 meeting criteria for final inclusion. The most common conditions studied were pneumonia or acute lower respiratory infection (61.6%) and bronchiolitis (29.3%). The majority of studies evaluated medications (80.8%), followed by respiratory support (14.1%) and supportive care (5%). The strongest evidence of benefit was found for respiratory support interventions such as improved medical oxygen systems to decrease risk of death. Results were notably inconclusive on the utility of continuus positive airway pressure (CPAP). Mixed results were found for interventions for bronchiolitis, although possible benefit was found for hypertonic nebulized saline to decrease hospital length of stay. Early use of adjuvant treatments such as Vitamin A, D, and zinc for pneumonia and bronchiolitis did not appear to have convincing evidence of benefit on clinical outcomes.ConclusionsWhile the burden of SARI in pediatric populations is high, few emergency care (EC) interventions have high quality evidence for benefit on clinical outcomes in LMICs. Respiratory support interventions have the strongest evidence for decreasing hospital length of stay and mortality and improvement of clinical status. Further research on the use of CPAP in diverse settings and populations is needed. A stronger evidence base for EC interventions for children with SARI, including metrics on the timing of interventions, is greatly needed.

To provide an overview of the current knowledge and recent advances of sentinel lymph node (SLN) assessment in uterine, cervical, vulvar, and ovarian cancers.In endometrial cancer, SLN evaluation has become increasingly utilized as part of the treatment of early-stage disease, with data showing improved detection of pelvic lymph node metastasis. In cervical cancer, SLN biopsy has also gained increasing traction with studies demonstrating the feasibility and accuracy of SLN detection. Evaluation with frozen section, however, remains limited in the detection of metastases. The prognostic significance of positive SLN in vulvar cancer is currently being investigated, with preliminary data showing lower recurrence rates in patients receiving adjuvant radiation.SLN evaluation remains standard of care to detect lymph node metastasis in early-staged endometrial cancer. In cervical cancer, SLN biopsy has been shown to be reliable, while decreasing morbidity without impacting disease-free survival in select patients. The technique and high sensitivity of SLN biopsy in vulvar cancer has been demonstrated in large prospective trials. There are no randomized controlled trials in ovarian cancer that evaluate the role of SLN biopsy on treatment and outcome; current SLN evaluation remains investigational.

Background Vulvar masses in adolescents have a broad differential diagnosis, yet few reports exist detailing masses of mammary origin. Case A nulliparous, healthy 16-year-old adolescent presented with a longstanding, ulcerated, 17-cm vulvar mass of unknown origin and pronounced inguinal lymphadenopathy. The patient underwent a left radical partial vulvectomy, with pathology revealing terminal duct lobular units consistent with polymastia. Conclusion Differential diagnosis of a vulvar mass in an adolescent should include polymastia.

Severe acute respiratory infections (SARIs) remain a leading cause of death globally, particularly in low- and middle-income countries (LMICs). Early intervention is critical, considering the potential for rapid decompensation in patients with SARIs. We aimed to evaluate the impact of acute and emergency care interventions on improving clinical outcomes in patients10 years old with SARIs in LMICs.A systematic literature search was performed in PubMed, Global Health, and Global Index Medicus databases to identify peer-reviewed studies containing SARI, LMICs, and emergency care interventions. Studies published prior to November 2020 focusing on patients10 years old were included. A narrative synthesis was performed due to the heterogeneity of identified articles. Risk of bias was assessed using the Risk of Bias 2 and Risk of Bias In Non-Randomized Studies of Interventions tools.20 223 studies were screened and 58 met the inclusion criteria. Thirty-four studies focused on coronavirus-2019 (COVID-19), 15 on pneumonia, seven on influenza, one study on severe acute respiratory syndrome, and one on undifferentiated SARI. Few COVID-19 studies found a benefit of the tested intervention on clinical status, mortality, or hospital length-of-stay. Little to no benefit was found for azithromycin, convalescent plasma, or zinc, and potential harm was found for hydroxychloroquine/chloroquine. There was mixed evidence for immunomodulators, traditional Chinese medicine, and corticosteroids among COVID-19 studies, with notable confounding due to a lack of consistency of control group treatments. Neuraminidase inhibitor antivirals for influenza had the highest quality of evidence for shortening symptom duration and decreasing disease severity.We found few interventions for SARIs in LMICs with have high-quality evidence for improving clinical outcomes. None of the included studies evaluated non-pharmacologic interventions or were conducted in low-income countries. Further studies evaluating the impact of antivirals, immunomodulators, corticosteroids, and non-pharmacologic interventions for SARIs in LMICs are urgently needed.PROSPERO registration number: CRD42020216117.

IntroductionA recent randomized clinical trial showed that minimally invasive surgery led to poorer survival compared with open surgery in early stage cervical cancer. We determined the trends in adoption of minimally invasive surgery and 5-year overall survival outcomes after open, laparoscopic-assisted, and robotic-assisted hysterectomy for stage II uterine cancer with cervical stromal involvement.MethodsData for patients with stage II uterine cancer were acquired from the National Cancer Database from 2010 to 2015. χ2testing, Kaplan–Meier methods, and Cox models were used for statistical analyses.ResultsOf 2949 patients, 44.3% underwent open hysterectomy, 13.9% underwent laparoscopic hysterectomy, and 41.8% underwent robotic hysterectomy. The proportion of robotic cases increased from 26.8% in 2010 to 48.3% in 2015 (annual percent change 10.1%), with a decrease in open hysterectomy from 63.3% to 34.3% (annual percent change –12.5%). The overall 5-year survival was 77.6% in robotic, 76.8% in laparoscopic, and 72.5% in open hysterectomy (p=0.045); however, after adjusting for known prognostic factors, robotic (HR 1.00, 95% CI 0.82 to 1.21; p=0.97) and laparoscopic hysterectomy (HR 1.09, 95% CI 0.83 to 1.44; p=0.54) did not portend for improved survival compared with open hysterectomy. Black women (HR 1.59, 95% CI 1.25 to 2.02; pConclusionThe use of minimally invasive surgery for stage II uterine cancer has increased over time, with comparable adjusted 5-year survival after robotic or laparoscopic hysterectomy compared with open hysterectomy. Black women and those with co-morbidities had lowest rates of minimally invasive surgery and the poorest adjusted survival.

IntroductionHigh-income country (HIC) authors are disproportionately represented in authorship bylines compared with those affiliated with low and middle-income countries (LMICs) in global health research. An assessment of authorship representation in the global emergency medicine (GEM) literature is lacking but may inform equitable academic collaborations in this relatively new field.MethodsWe conducted a bibliometric analysis of original research articles reporting studies conducted in LMICs from the annual GEM Literature Review from 2016 to 2020. Data extracted included study topic, journal, study country(s) and region, country income classification, author order, country(s) of authors’ affiliations and funding sources. We compared the proportion of authors affiliated with each income bracket using Χ2 analysis. We conducted logistic regression to identify factors associated with first or last authorship affiliated with the study country.ResultsThere were 14 113 authors in 1751 articles. Nearly half (45.5%) of the articles reported work conducted in lower middle-income countries (MICs), 23.6% in upper MICs, 22.5% in low-income countries (LICs). Authors affiliated with HICs were most represented (40.7%); 26.4% were affiliated with lower MICs, 17.4% with upper MICs, 10.3% with LICs and 5.1% with mixed affiliations. Among single-country studies, those without any local authors (8.7%) were most common among those conducted in LICs (14.4%). Only 31.0% of first authors and 21.3% of last authors were affiliated with LIC study countries. Studies in upper MICs (adjusted OR (aOR) 3.6, 95% CI 2.46 to 5.26) and those funded by the study country (aOR 2.94, 95% CI 2.05 to 4.20) had greater odds of having a local first author.ConclusionsThere were significant disparities in authorship representation. Authors affiliated with HICs more commonly occupied the most prominent authorship positions. Recognising and addressing power imbalances in international, collaborative emergency medicine (EM) research is warranted. Innovative methods are needed to increase funding opportunities and other support for EM researchers in LMICs, particularly in LICs.

Pre-operative geriatric evaluation in frail older patients that addresses both medical and psychosocial needs is often not completed prior to surgery, leaving frail older adults ill prepared for surgery. The ALIGN-CARE interprofessional co-management model uniquely serves to standardize care and coordination amongst the surgeon, geriatrician and social worker in ambulatory settings to allow a greater window of time to intervene for surgical optimization. Program elements include assessment of preoperative medications, functional status, cognition, nutrition, What Matters Most, advance care planning (ACP), and social determinants of health. Recommendations and action items from the geriatric-social work team are presented to surgeon and primary care physicians for follow-up and optimization. Program and process elements recorded in a REDCap database facilitate longitudinal evaluation of ALIGN-CARE model implementation feasibility. Initial data of 9 frail surgical oncology patients indicate increases in meaningful ACP discussions, patient-oriented decisions regarding surgery candidacy, and surgeon referrals for inpatient geriatric consultation post-operatively as a result of ALIGN-CARE. Current analyses to assess feasibility and quality of the program include thematic coding of program documents, semi-structured interviews of key stakeholders (surgeons, geriatricians, social workers, patients), and quantitative analysis of program outcomes, including uptake of program elements and process measures. Planned areas of analytic focus include workflow, cross-specialty coordination, and patient and primary care engagement and activation. We anticipate identifying specific barriers and facilitators of ALIGN-CARE implementation in our evaluation to aid the dissemination and upscaling of interprofessional co-management programs aimed to improve outcomes and quality of life for frail, older surgical patients.

Gerontological researchers are encouraged to include older adults from underrepresented populations in their research and to think broadly about how they conceptualize diversity, equity, and inclusion (DEI) efforts in their work. This includes not only research on older adults from minority racial and ethnic communities, but also lesbian/gay/bisexual/trans*/queer+ (LGBTQ+) communities, as well as other cultural, religious, and socioeconomic groups. One of the most successful ways for reaching older adults in these populations is through community-based participatory research (CBPR). CBPR is a partnership approach to research that equitably involves community members, organizational representatives, researchers, and others in all aspects of the research process, with all partners in the process contributing expertise and sharing in the decision-making and ownership. Two papers in this symposium use CBPR to identify and include older adults from minority populations in their studies. A third paper reports on working with a Community Advisory Board to recruit bereaved dementia caregivers for research. The final paper walks us through steps to increase DEI efforts by meticulous research question development and thoughtful determinations regarding literature review terminology, recruitment efforts, data collection, and reporting and dissemination techniques.

Background: Catalyzed by social injustice and worsening racial inequities highlighted by the COVID-19 pandemic, a diverse academic geriatrics and palliative medicine department in NYC launched a DEI initiative. This report presents key program components and lessons learned in launching this initiative in the interprofessional academic medicine setting. Methods: First, DEI core and departmental administration met 2-4 times/month to plan and review program activities, vision, and mission. The team conducted confidential roundtable discussions about DEI issues and 1:1 interviews to assess needs. A monthly Humanities, Arts, and Books (HAB) Initiative provided a safe space for discussion and learning. The HAB platform supported a longitudinal curriculum emphasizing (1) group discussion and self-reflection on DEI concerns, (2) knowledge dissemination including a “Learning Pathway” series, and (3) skill-based workshops. With each event, we collected anonymous feedback. Comments were systematically recorded and an engagement evaluation was conducted to iteratively shape future sessions. Departmental administration was engaged to track DEI-focused measures of recruitment, career advancement, and retention. Finally, we centralized DEI activities on a departmental website, including an anonymous online feedback box. Results: Quantitative and qualitative assessment of DEI initiatives are forthcoming. Metrics include DEI and professional development surveys, departmental demographic and diversity measures, increase in DEI-related projects and grants, and individual participation in DEI programs. Conclusions: Creating a strong and sustainable DEI initiative within an academic medical setting requires a passionate and diverse core team, deliberate backing by administration, and thoughtful dissemination of sensitive content in the midst of a highly charged social justice landscape.

Introduction To determine the incidence of clear cell ovarian carcinoma in Asians vs. Whites and within Asian sub-populations. Methods Data from 2004 to 2016 were obtained from the United States Cancer Statistics (USCS) and National Cancer Database (NCDB). Chi squared tests were used for statistical analyses. Results Based on USCS, the overall age-adjusted incidence of epithelial ovarian cancer was 11.0 (per 100,000 women) compared to 0.56 with clear cell histology. Asians had a higher incidence of clear cell cancer compared to Whites (0.97 vs. 0.58). Of 200,790 women with epithelial ovarian cancer from the NCDB database, the mean age was 57. Asians presented at a younger age compared to Whites (53 vs. 58 years). Of all epithelial cancers, the proportion of clear cell cancer in Whites and Blacks was only 5.2% and 3.2% respectively. However, in the Asian subgroups, the proportion of clear cell histology were significantly higher: 16.6% in Vietnamese, 14.2% Chinese, 13.8% Japanese, 12.9% Filipino, 10.2% Korean, 7.5% Indian/Pakistani, 8.3% Pacific Islander. Geographically, the Northeast region of the U.S. contained the highest proportion of Indian/Pakistanis diagnosed with clear cell. All other Asian sub-populations were more likely to be diagnosed in the Western region. Conclusions Our data suggested that Asians have a higher incidence of clear cell ovarian carcinoma compared to other races. Moreover, Vietnamese, Chinese, and Japanese demonstrate a higher proportion of clear cell cancer compared to other Asian sub-populations.

African Americans (AA) have a higher incidence and mortality rate for colorectal cancer (CRC) compared to Caucasians. DNA methylation profiling on normal colon mucosa from 77 CRC patients and 68 patients without cancer (controls) of AA and Caucasian descent identified a distinct subgroup of CRC patients (11AA and 4 Caucasians) who are statistical “outliers” at a large number of CpGs. Such highly epigenetically disrupted CRC patients are termed “Outlier Methylation Phenotype” (OMP). Comparison of methylome profiles of CRC patients and controls revealed that AA CRC patients have greater disruption of the normal colon methylome than do Caucasian patients. A large fraction of the overall methylation differences found between CRC patients and controls is attributable to OMPs. Estimation of epigenetic ages shows that OMPs have lower epigenetic ages compared to their chronological ages. In other words, OMPs undergo epigenetic age deceleration. Comparison of normal colon mucosa transcription profiles of OMP cancer patients with those of non-OMP cancer patients indicates genes whose promoters are hypermethylated in the OMP patients are also transcriptionally down-regulated, and that many of the genes most affected are involved in interactions between epithelial cells, the mucus layer, and the microbiome. Analysis of 16S RDNA profiles suggests that normal colon mucosa of OMPs are enriched in bacterial genera associated with CRC risk, advanced tumor stage, chronic intestinal inflammation, malignant transformation, nosocomial infections and KRAS mutations. In conclusion, our study suggests a distinct epigenetically disrupted OMP group in CRC that are responsible for disrupted methylome, altered gene expression and microbial dysbiosis. Furthermore, a higher frequency of OMPs among African Americans (11/42) than among Caucasians (5/35) may contribute to observed racial disparities in CRC incidence and outcome. Citation Format: Jayashri Ghosh, Bryant M. Schultz, Joe Chan, Claudia Wultsch, Imad Shureiqi, Stephanie Chow, Ahmet Doymaz, Sophia Varriano, Melissa Driscoll, Jen Muse, Frida E. Kleiman, Konstantinos Krampis, Jean-Pierre J. Issa, Carmen Sapienza. Do epigenetic outliers impact racial disparities in colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 6265.

Objective To identify the trends in incidence of serous fallopian tube, ovarian, and peritoneal epithelial cancers in the United States. Methods Data was obtained from United States Cancer Statistics (USCS) from 2001 to 2014. All incidences are per 100,000 women. Analyses were performed using SEER*Stat and Joinpoint regression programs. Results Of the 146,470 patients with serous cancers, 9381 (6.4%) were fallopian tube, 121,418 (82.9%) were ovarian, and 15,671 (10.7%) were primary peritoneal. The study period was divided from 2001 to 2005, 2006–2010, and 2011–2014, and there was an increase in fallopian tube incidence from 0.19 to 0.35 to 0.63, with a corresponding decrease in ovarian incidence from 5.31 to 5.08 to 4.86. There was no significant change in peritoneal cancers from 0.64 to 0.69 to 0.62. The age-specific peak incidence of fallopian tube cancer was younger at age 70–74, compared to ovarian and peritoneal cancer at age 75–79. Further, the incidence of serous fallopian tube cancer was highest in Whites at 0.42, compared to Blacks at 0.24, Hispanics at 0.27, and Asians at 0.28. Conclusion From 2001 to 2014, the diagnosis of serous fallopian tube cancer increased fourfold with a corresponding decrease in ovarian cancer. The peak incidence of tubal cancer was 70–74years with an increased incidence in Whites.