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OBJECTIVE: To better understand COVID-19 in newborns, we compared in-hospital illness severity indicators by COVID-19 status during birth hospitalization. STUDY DESIGN: In a retrospective cohort of newborns born March-December 2020 in the Premier Healthcare Database Special COVID-19 Release, we classified COVID-19 status and severe illness indicators using ICD-CM-10 codes, laboratory data, and billing records. Illness severity indicators were compared by COVID-19 status, stratified by gestational age and race/ethnicity. RESULT: Among 701,777 newborns, 209 had a COVID-19 diagnosis during the birth hospitalization. COVID-19 status differed significantly by race/ethnicity, gestational age, payor, and region. Late preterm/term newborns with COVID-19 had increased intensive care unit admission and sepsis risk; early preterm newborns with COVID-19 had increased risk for invasive ventilation. Risk for illness severity varied among racial/ethnic strata. CONCLUSION: From March to December 2020, COVID-19 diagnosis in newborns was rare. More clinical data are needed to describe the risk profiles of newborns with COVID-19.

INTRODUCTION: Zika virus is primarily transmitted through mosquito bites. Because Zika virus infection during pregnancy can cause serious birth defects, reproductive-aged women need protection from Zika virus infection. This report describes Zika virus prevention behaviors among women aged 18–49 years and assesses whether pregnancy status and healthcare provider counseling increases Zika virus prevention behaviors. METHODS: A population-based cell phone survey of women aged 18–49 years living in Puerto Rico was conducted in July–November 2016. Data were analyzed in 2018–2019. Prevalence estimates and 95% CIs were calculated for Zika virus prevention behaviors. Adjusted prevalence ratios were estimated to examine the association of pregnancy status with healthcare provider counseling on Zika virus prevention behaviors, controlling for age, education, and health insurance status. RESULTS: Most women reported using screens on open doors/windows (87.7%) and eliminating standing water in/around their homes (92.3%). Other Zika virus prevention behaviors were less common (

We evaluated nucleic acid amplification testing (NAAT) for Zika virus on whole-blood specimens compared with NAAT on serum and urine specimens among asymptomatic pregnant women during the 2015–2016 Puerto Rico Zika outbreak. Using NAAT, more infections were detected in serum and urine than in whole blood specimens.

ObjectiveTo describe the clinical, pathological and genomic characteristics of pancreatic cancer with DNA mismatch repair deficiency (MMRD) and proficiency (MMRP).DesignWe identified patients with MMRD and MMRP pancreatic cancer in a clinical cohort (N=1213, 519 with genetic testing, 53 with immunohistochemistry (IHC)) and a genomic cohort (N=288 with whole-genome sequencing (WGS)).Results12 out of 1213 (1.0%) in the clinical cohort were MMRD by IHC or WGS. Of the 14 patients with Lynch syndrome, 3 (21.4%) had an MMRP pancreatic cancer by IHC, and 4 (28.6%) were excluded because tissue was unavailable for testing. MMRD cancers had longer overall survival after surgery (weighted HR after coarsened exact matching 0.11, 95% CI 0.02 to 0.78, p=0.001). One patient with an unresectable MMRD cancer has an ongoing partial response 3 years after starting treatment with PD-L1/CTLA-4 inhibition. This tumour showed none of the classical histopathological features of MMRD. 9 out of 288 (3.1%) tumours with WGS were MMRD. Despite markedly higher tumour mutational burden and neoantigen loads, MMRD cancers were significantly less likely to have mutations in usual pancreatic cancer driver genes like KRAS and SMAD4, but more likely to have mutations in genes that drive cancers with microsatellite instability like ACV2RA and JAK1. MMRD tumours were significantly more likely to have a basal-like transcriptional programme and elevated transcriptional markers of immunogenicity.ConclusionsMMRD pancreatic cancers have distinct clinical, pathological and genomic profiles. Patients with MMRD pancreatic cancer should be considered for basket trials targeting enhanced immunogenicity or the unique genomic drivers in these malignancies.

Objectives The objectives of this analysis were to 1) estimate prevalence of contraceptive use among women at risk for unintended pregnancy and 2) identify correlates of contraceptive use among women with ongoing or potential need for contraceptive services in Puerto Rico during the 2016 Zika virus (ZIKV) outbreak. Study design We conducted a cell-phone survey July–November, 2016. Women aged 18–49 years living in Puerto Rico were eligible. We completed 3059 interviews; the overall response rate was 69.2%. After weighting, the data provide population-based estimates. For this analysis, we included women at risk for unintended pregnancy, and assessed ongoing or potential need for contraceptive services in this group, excluding women using permanent contraceptive methods. Results Most women reported using contraception (82.8%), and use increased with age. Female sterilization and male condoms were most frequently reported (40.8% and 17.1%, respectively). Among women with ongoing or potential need for contraceptive services, 24.7% talked to a healthcare provider about ZIKV, and 31.2% reported a change in childbearing intentions due to ZIKV. Most women were at least a little worried about getting infected with ZIKV (74.3%) or having a baby with a birth defect (80.9%). Being very worried about getting infected with ZIKV and already having Zika were significantly associated with use of any contraception (adjusted prevalence ratio: 1.19, 95% CI: 1.03–1.38 and 1.32, 95% CI: 1.01–1.72, respectively). Conclusions These findings underscore the need for regular contraceptive prevalence studies to inform programs about contraceptive needs, especially during public health emergencies. Implications When the 2016 Zika virus outbreak began in Puerto Rico there were no recent population-based data available on contraceptive prevalence. To fill this information gap, we conducted a population-based survey. Our findings provided baseline contraceptive prevalence estimates to support response planning and allocation of health resources.

Pregnant women are at increased risk for severe COVID-19-related illness, and COVID-19 is associated with an increased risk for adverse pregnancy outcomes and maternal and neonatal complications (1-3). To date, studies assessing whether COVID-19 during pregnancy is associated with increased risk for stillbirth have yielded mixed results (2-4). Since the B.1.617.2 (Delta) variant of SARS-CoV-2 (the virus that causes COVID-19) became the predominant circulating variant,* there have been anecdotal reports of increasing rates of stillbirths in women with COVID-19.† CDC used the Premier Healthcare Database Special COVID-19 Release (PHD-SR), a large hospital-based administrative database,§ to assess whether a maternal COVID-19 diagnosis documented at delivery hospitalization was associated with stillbirth during March 2020-September 2021 as well as before and during the period of Delta variant predominance in the United States (March 2020-June 2021 and July-September 2021, respectively). Among 1,249,634 deliveries during March 2020-September 2021, stillbirths were rare (8,154; 0.65%): 273 (1.26%) occurred among 21,653 deliveries to women with COVID-19 documented at the delivery hospitalization, and 7,881 (0.64%) occurred among 1,227,981 deliveries without COVID-19. The adjusted risk for stillbirth was higher in deliveries with COVID-19 compared with deliveries without COVID-19 during March 2020-September 2021 (adjusted relative risk [aRR] = 1.90; 95% CI = 1.69-2.15), including during the pre-Delta (aRR = 1.47; 95% CI = 1.27-1.71) and Delta periods (aRR = 4.04; 95% CI = 3.28-4.97). COVID-19 documented at delivery was associated with increased risk for stillbirth, with a stronger association during the period of Delta variant predominance. Implementing evidence-based COVID-19 prevention strategies, including vaccination before or during pregnancy, is critical to reducing the impact of COVID-19 on stillbirths.

BACKGROUND: Dentists are one of the most at risk of COVID-19 (Coronavirus Disease-19) infection professional category. In fact, the performance of the various treatments could generate a large number of droplets and aerosols that could carry the viruses. Being SARS-CoV-2 (Severe Acute Respiratory Syndrome-Coronavirus-2) a virus that is transmitted mainly by close contact with the droplets that cannot be contained with the standard of protection measures used so far. Patients should go to the dental offices after a telephone triage agreed with the dentist. The aim of this study was to verify whether and how the new protocols could influence dental phobia in patients and how the COVID-19 infection is part of the experience of those who suffer from anxious spectrum disorders. METHODS: Generally, a person who suffers from anxiety disorders tends to avoid and/or postpone visits and dental sessions. RESULTS: The publication of the new protocols relating to the cleaning and disinfection of environments and surfaces, the use of new personal protective equipment (PPE), the questionnaires to be made by telephone and in the studio are a further element of concern or contribute to reassuring this type of patient. CONCLUSIONS: Further studies and clinical trials are needed to highlight these problems in patients.

Introduction: Several studies have found a relationship between familial breast cancer (BC) and pancreatic cancer (PC). Known genes associated with both BC and PC include BRCA1, BRCA2, PALB2, ATM, STK11, and possibly others. For carriers of pathogenic germline variants (PGVs) in these genes with family history of PC (FHPC), pancreas surveillance is recommended and can lead to an earlier detection of disease. Current genetics practice typically involves use of multi-gene panel (MGP) testing covering all of these genes linked to both cancers, but not all patients have had complete testing leading to likely under appreciation of PC risk in BC cohorts. With improved treatment options and survival for BC and ovarian cancer in PGV carriers, we may begin to observe an increased prevalence of PC in this group. The purpose of our study was to evaluate the clinicopathologic characteristics including genetic testing uptake and outcomes in BC patients with and without a family history of pancreatic cancer (FHPC). Methods: We queried the Institutional Breast Cancer Database, which includes patients diagnosed with BC between January 2010 and December 2018. Variables analyzed included FHPC in a first or second-degree relative, and other clinical and tumor characteristics. Statistical analyses included Pearson’s Chi Square and logistic regression. Results: A total of 232 BC patients (7%) had a positive FHPC, including 115 (50%) with a first-degree relative and 117 (50%) with other relatives affected. When comparing BC patients with and without any FHPC, those with FHPC were 1.93 times more likely to be of White race (p Conclusions: Within a contemporary cohort of newly diagnosed breast cancer patients, 7% had a positive FHPC. Although these patients were more likely than those without FHPC to have genetic testing, the majority, 77%, had incomplete or no genetic testing suggesting likely under-diagnosis of PC risk. Our study underscores the importance of querying and documenting FHPC in patients with BC and the consideration of germline testing and evaluation for pancreas surveillance in these patients and their family members. Citation Format: Annie Wang, Jessica Everett, Jennifer Chun, Elianna Kaplowitz, Diane Simeone, Freya Schnabel. Family history of pancreatic cancer and the prevalence of pathogenic germline variants in a contemporary cohort of newly diagnosed breast cancers [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P6-08-24.

Hepatocellular Carcinoma (HCC) is one of the most lethal cancers with a high mortality and recurrence rate. Circulating tumor cell (CTC) detection offers various opportunities to advance early detection and monitoring of HCC tumors which is crucial for improving patient outcome. We developed and optimized a novel Labyrinth microfluidic device to efficiently isolate CTCs from peripheral blood of HCC patients. CTCs were identified in 88.1% of the HCC patients over different tumor stages. The CTC positivity rate was significantly higher in patients with more advanced HCC stages. In addition, 71.4% of the HCC patients demonstrated CTCs positive for cancer stem cell marker, CD44, suggesting that the major population of CTCs could possess stemness properties to facilitate tumor cell survival and dissemination. Furthermore, 55% of the patients had the presence of circulating tumor microemboli (CTM) which also correlated with advanced HCC stage, indicating the association of CTM with tumor progression. Our results show effective CTC capture from HCC patients, presenting a new method for future noninvasive screening and surveillance strategies. Importantly, the detection of CTCs with stemness markers and CTM provides unique insights into the biology of CTCs and their mechanisms influencing metastasis, recurrence and therapeutic resistance.

Despite untiring efforts to develop therapies for pancreatic ductal adenocarcinoma (PDAC), survival statistics remain dismal, necessitating distinct approaches. Photodynamic priming (PDP), which improves drug delivery and combination regimens, as well as tumor photodestruction are key attributes of photodynamic therapy (PDT), making it a distinctive clinical option for PDAC. Localized, high-payload nanomedicine-assisted delivery of photosensitizers (PSs), with molecular specificity and controlled photoactivation, thus becomes critical in order to reduce collateral toxicity during more expansive photodynamic activation procedures with curative intent. As such, targeted photoactivable lipid-based nanomedicines are an ideal candidate but have failed to provide greater than two-fold cancer cell selectivity, if at all, due to their extensive multivariant physical, optical, and chemical complexity. Here, we report (1) a systematic multivariant tuning approach to engineer (Cet, anti-EGFR mAb) photoimmunonanoconjugates (PINs), and (2) stroma-rich heterotypic PDAC in vitro and in vivo models incorporating patient-derived pancreatic cancer-associated fibroblasts (PCAFs) that recapitulate the desmoplasia observed in the clinic. These offer a comprehensive, disease-specific framework for the development of Cet-PINs. Specificity-tuning of the PINs, in terms of PS lipid anchoring, electrostatic modulation, Cet orientation, and Cet surface densities, achieved ∼16-fold binding specificities and rapid penetration of the heterotypic organoids within 1 h, thereby providing a ∼16-fold enhancement in molecular targeted NIR photodestruction. As a demonstration of their inherent amenability for multifunctionality, encapsulation of high payloads of gemcitabine hydrochloride, 5-fluorouracil, and oxaliplatin within the Cet-PINs further improved their antitumor efficacy in the heterotypic organoids. In heterotypic desmoplastic tumors, the Cet-PINs efficiently penetrated up to 470 μm away from blood vessels, and photodynamic activation resulted in substantial tumor necrosis, which was not elicited in T47D tumors (low EGFR) or when using untargeted constructs in both tumor types. Photodynamic activation of the Cet-PINs in the heterotypic desmoplastic tumors resulted in collagen photomodulation, with a 1.5-fold reduction in collagen density, suggesting that PDP may also hold potential for conquering desmoplasia. The in vivo safety profile of photodynamic activation of the Cet-PINs was also substantially improved, as compared to the untargeted constructs. While treatment using the Cet-PINs did not cause any detriment to the mice's health or to healthy proximal tissue, photodynamic activation of untargeted constructs induced severe acute cachexia and weight loss in all treated mice, with substantial peripheral skin necrosis, muscle necrosis, and bowel perforation. This study is the first report demonstrating the true value of molecular targeting for NIR-activable PINs. These constructs integrate high payload delivery, efficient photodestruction, molecular precision, and collagen photomodulation in desmoplastic PDAC tumors in a single treatment using a single construct. Such combined PIN platforms and heterocellular models open up an array of further multiplexed combination therapies to synergistically control desmoplastic tumor progression and extend PDAC patient survival.

Purpose: To evaluate safety and preliminary efficacy of metronomic 5-fluorouracil plus nab-paclitaxel, bevacizumab, leucovorin, and oxaliplatin (FABLOx) in patients with newly diagnosed metastatic pancreatic cancer (MPC). Methods: A total of 12 treatment-naive patients (aged 18–65 years, Eastern Cooperative Oncology Group performance status [ECOG PS] ≤1) with MPC received 5-fluorouracil 180 mg/m2 per day (days 1–14 continuous infusion); nab-paclitaxel 75 mg/m2, leucovorin 20 mg/m2, and oxaliplatin 40 mg/m2 (days 1, 8, and 15); and bevacizumab 5 mg/kg (days 1 and 15) administered intravenously in each 28-day cycle. The primary end-point was incidence of dose-limiting toxicities (DLTs) in cycle 1. Safety was further evaluated as a secondary end-point; preliminary efficacy was also examined. Results: Two DLTs (grade 3 anemia requiring transfusion and grade 3 mucositis unresponsive to treatment within 4 days of onset) were observed in one of six patients enrolled in dose cohort 1. Cohort 1 was expanded from 6 to 12 patients to further evaluate safety, per the investigators' recommendation. All patients discontinued treatment. The most common grade ≥3 adverse events were abdominal pain, fatigue, mucositis, and decreased neutrophil count. Objective response rate was 33% (four partial responses). Median progression-free survival (PFS) and overall survival (OS) were 5.6 (95% confidence interval [CI], 1.7–11.3) and 9.9 (95% CI, 4.4–13.2) months, respectively; 1-year PFS and OS rates were 12.2% (95% CI, 0.7–40.8) and 38.9% (95% CI, 12.6–65.0). Conclusion: FABLOx is feasible and tolerable in patients newly diagnosed with MPC. However, preliminary efficacy data are inconclusive for continued investigation in a phase II trial.

OBJECTIVES: Pancreatic cystic lesions (PCLs) may be precancerous. Those likely to harbor high-grade dysplasia (HGD) or pancreatic cancer (PC) are targets for surgical resection. Current algorithms to predict advanced neoplasia (HGD/PC) in PCLs lack diagnostic accuracy. In pancreatic tissue and cystfluid (CF) from PCLs, we sought to identify and validate novel methylated DNA markers (MDMs) that discriminate HGD/PC from low-grade dysplasia (LGD) or no dysplasia (ND). METHODS: From an unbiased whole-methylome discovery approach using predefined selection criteria followed by multistep validation on case (HGD or PC) and control (ND or LGD) tissues, we identified discriminant MDMs. Top candidate MDMs were then assayed by quantitative methylation-specific polymerase chain reaction on archival CF from surgically resected PCLs. RESULTS: Of 25 discriminant MDMs identified in tissue, 13 were selected for validation in 134 CF samples (21 cases [8 HGD, 13 PC], 113 controls [45 ND, 68 LGD]). A tree-based algorithm using 2 CF-MDMs (TBX15, BMP3) achieved sensitivity and specificity above 90%. Discrimination was significantly better by this CF-MDM panel than by mutant KRAS or carcinoembryonic antigen, with areas under the receiver operating characteristic curve of 0.93 (95% confidence interval: 0.86–0.99), 0.71 (0.57–0.85), and 0.72(0.60–0.84), respectively. Cutoffs for the MDM panel applied to an independent CF validation set (31 cases, 56 controls) yielded similarly high discrimination, areas under the receiver operating characteristic curve 5 0.86 (95% confidence interval: 0.77–0.94, P = 0.2). DISCUSSION: Novel MDMs discovered and validated in tissue accurately identify PCLs harboring HGD/PC. A panel of 2 MDMs assayed in CF yielded results with potential to enhance current risk prediction algorithms. Prospective studies are indicated to optimize and further evaluate CF-MDMs for clinical use.

OBJECTIVES: Current standard of care imaging, cytology, or cystic fluid analysis cannot reliably differentiate malignant from benign pancreatic cystic neoplasms. This study sought to determine if the metabolic profile of cystic fluid could distinguish benign and malignant lesions, as well as mucinous and non-mucinous lesions. Methods: Metabolic profiling by untargeted mass spectrometry and quantitative nuclear magnetic resonance was performed in 24 pancreatic cyst fluid from surgically resected samples with pathological diagnoses and clinicopathological correlation. Results: (Iso)-butyrylcarnitine distinguished malignant from benign pancreatic cysts, with a diagnostic accuracy of 89%. (Iso)-butyrylcarnitine was 28-fold more abundant in malignant cyst fluid compared with benign cyst fluid (P=.048). Furthermore, 5-oxoproline (P=.01) differentiated mucinous from non-mucinous cysts with a diagnostic accuracy of 90%, better than glucose (82% accuracy), a previously described metabolite that distinguishes mucinous from non-mucinous cysts. Combined analysis of glucose and 5-oxoproline did not improve the diagnostic accuracy. In comparison, standard of care cyst fluid carcinoembryonic antigen (CEA) and cytology had a diagnostic accuracy of 40% and 60% respectively for mucinous cysts. (Iso)-butyrylcarnitine and 5-oxoproline correlated with cyst fluid CEA levels (P 3 cm, ≥ 1 high-risk features, cyst fluid CEA, and cytology are 38%, 75%, 80%, and 75%, respectively. Conclusions: (Iso)-butyrylcarnitine has potential clinical application for accurately distinguishing malignant from benign pancreatic cysts, and 5-oxoproline for distinguishing mucinous from non-mucinous cysts.

Background Evidence on risk for adverse outcomes from coronavirus disease 2019 (COVID-19) among pregnant women is still emerging. We examined the association between COVID-19 at delivery and adverse pregnancy outcomes, maternal complications, and severe illness, and whether these associations differ by race/ethnicity, and describe discharge status by COVID-19 diagnosis and maternal complications. Methods Data from 703 hospitals in the Premier Healthcare Database during March–September 2020 were included. Adjusted risk ratios (aRRs) overall and stratified by race/ethnicity were estimated using Poisson regression with robust standard errors. Proportion not discharged home was calculated by maternal complications, stratified by COVID-19 diagnosis. Results Among 489 471 delivery hospitalizations, 6550 (1.3%) had a COVID-19 diagnosis. In adjusted models, COVID-19 was associated with increased risk for acute respiratory distress syndrome (aRR, 34.4), death (aRR, 17.0), sepsis (aRR, 13.6), mechanical ventilation (aRR, 12.7), shock (aRR, 5.1), intensive care unit admission (aRR, 3.6), acute renal failure (aRR, 3.5), thromboembolic disease (aRR, 2.7), adverse cardiac event/outcome (aRR, 2.2), and preterm labor with preterm delivery (aRR, 1.2). Risk for any maternal complications or for any severe illness did not significantly differ by race/ethnicity. Discharge status did not differ by COVID-19; however, among women with concurrent maternal complications, a greater proportion of those with (vs without) COVID-19 were not discharged home. Conclusions These findings emphasize the importance of implementing recommended prevention strategies to reduce risk for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and further inform counseling and clinical care for pregnant women during the COVID-19 pandemic.

Background: Changing practice guidelines and recommendations have important implications for cancer survivors. This study investigated genetic testing patterns and outcomes and reported family history of pancreatic cancer (FHPC) in a large registry population of breast cancer (BC) patients. Methods: Variables including clinical and demographic characteristics, FHPC in a first or second-degree relative, and genetic testing outcomes were analyzed for BC patients diagnosed between 2010-2018 in the NYU Langone Health Breast Cancer Database. Results: Among 3334 BC patients, 232 (7%) had a positive FHPC. BC patients with FHPC were 1.68 times more likely to have undergone genetic testing (pBRCA1/2 only and 44% had no genetic testing. Pathogenic germline variants (PGV) were identified in 15/129 (11.6%) BC patients with FHPC, and in 145/1315 (11.0%) BC patients without FHPC. Across both groups, updates in genetic testing criteria and recommendations could impact up to 80% of this cohort. Conclusions: Within a contemporary cohort of BC patients, 7% had a positive FHPC. The majority of these patients (56%) had no genetic testing, or incomplete testing by current standards, suggesting under-diagnosis of PC risk. This study supports recommendations for survivorship care that incorporate ongoing genetic risk assessment and counseling.

PurposeThe clinical utility of circulating tumor DNA (ctDNA) has been shown in advanced pancreatic ductal adenocarcinoma (PDA). However, diagnostic sensitivity of many ctDNA assays is low in resectable and locally advanced disease, where tumor burden is substantially lower. We have previously described Multiplex Enrichment using Droplet Pre-Amplification (MED-Amp), a multiplexed panel for the detection of the most common oncogenic KRAS mutations in PDA. In this study, we aimed to assess the diagnostic sensitivity of MED-Amp for detection of rare mutant alleles present in the plasma of patients with localized PDA.Experimental DesignWe retrospectively analyzed ninety-eight plasma samples from 51 patients with various stages of localized disease. For comparison, we measured ctDNA levels in 20 additional patients with metastatic PDA. The MED-Amp assay was used to measure the abundance of the four most common KRAS codon 12 mutations (G12C/D/R/V). We correlated the presence and quantity of ctDNA with overall survival (OS) as well as progression-free survival (PFS). Using serial plasma draws, we also assessed the relationship between changes in ctDNA allelic frequency and progression.ResultsKRAS-positive ctDNA was detected in 52.9% of localized PDA and 75% of metastatic samples tested using DNA inputs as low as 2 ng. As previously reported, the presence of KRAS mutant ctDNA was correlated with worse OS for all disease stages (p = 0.02). In patients with localized PDA high ctDNA levels also correlated with significantly worse median OS (533 days vs 1090 days) and PFS (192 days vs 787 days). We also studied a small cohort of serial plasma draws to observe the relationship between ctDNA fold change and PFS. We found 83% of patients with increased fold change in mutant KRAS experienced disease progression (n=6). In contrast, 75% (n=4) of patients with decreased fold change remained disease-free (p=0.03).ConclusionsMED-Amp is a flexible and cost-effective approach for measurement of ctDNA in patients with localized cancer. Though this study focused on KRAS mutation detection, this assay could be adapted for a number of common oncogenic alterations.Statement of translational relevanceOnly 25% of pancreatic ductal adenocarcinoma (PDA) patients with localized disease survive five years post-resection. It is hypothesized PDA undergoes dissemination at the earliest stages of tumor formation, driving formation of occult metastases which go undetected using conventional screening methods. Development of high specificity, high sensitivity biomarkers is critical to improving patient mortality. Circulating tumor DNA (ctDNA) has gained increasing acceptance as a non-invasive prognostic in metastatic disease. However, the sensitivity of most targeted ctDNA assays precludes reliable detection of localized and resected disease. Here, we present a digital droplet PCR assay for multiplexed enrichment and detection of KRAS mutations, the most commonly mutated oncogene in PDA. This assay preserves ctDNA allelic frequency in the original sample, while increasing the molecular signal over 50-fold. This study shows the ctDNA has potential diagnostic value in early-stage PDA, and that digital preenrichment of cell-free DNA increases overall assay sensitivity without sacrificing specificity.

Background and Aims Pancreatic ductal adenocarcinoma is an aggressive disease most often diagnosed after local progression or metastatic dissemination, precluding resection and resulting in a high mortality rate. For individuals with elevated personal risk of the development of pancreatic cancer, EUS is a frequently used advanced imaging and diagnostic modality. However, there is variability in the expertise and definition of EUS findings among gastroenterologists, as well as lack of standardized reporting of relevant findings at the time of examination. Adoption of standardized EUS reporting, using a universally accepted and agreed upon terminology, is needed. Methods A consensus statement designed to create a standardized reporting template was authored by a multidisciplinary group of experts in pancreatic diseases that includes gastroenterologists, radiologists, surgeons, oncologists, and geneticists. This statement was developed using a modified Delphi process as part of the Pancreatic Cancer Early Detection Consortium (PRECEDE) and >75% agreement was required to reach consensus. Results We identified reporting elements and present standardized reporting templates for EUS indications, procedural data, EUS image capture, and descriptors of findings, tissue sampling, and for postprocedural assessment of adequacy. Conclusions Adoption of this standardized EUS reporting template should improve consistency in clinical decision making for individuals with elevated risk of pancreatic cancer by providing complete and accurate reporting of pancreatic abnormalities. Standardization will also help to facilitate research and clinical trial design by using clearly defined and consistent imaging descriptions, thus allowing for comparison of results across different centers.

Background Early detection of pancreatic ductal adenocarcinoma (PDAC) is an important goal for improving survival. Individuals who meet published guidelines for surveillance may be underidentified, and family communication about risk represents a pathway to increasing participation in surveillance. We investigated the uptake of and barriers to surveillance in at-risk relatives of clinic patients. Methods We conducted a retrospective record review of patients with personal or family history of PDAC evaluated over 12 months. The first relative presenting to clinic (proband) reported surveillance status and reasons for nonparticipation for at-risk relatives. Descriptive analyses and Fisher's exact tests were conducted to evaluate differences in surveillance participation. Results Among 193 at-risk relatives, 21% were in surveillance. The primary reasons for nonparticipation were lack of awareness (36%) and lack of interest (24%). Neither the sex nor the cancer status of probands impacted surveillance. At-risk relatives with familial pancreatic cancer (FPC) who also carried relevant pathogenic germline variants (PGVs) were more likely to undergo surveillance than those with FPC or PGVs alone (P = .003). Among families with PGVs, 59% of relatives potentially eligible for surveillance had not completed genetic testing. Conclusion PDAC surveillance is underutilized in high-risk families. Communication interventions to address informational needs and decisional support could improve outcomes.

Needle-compatible miniaturized optoelectronic sensor may help pancreatic cancer diagnosis., Pancreatic cancer is one of the deadliest cancers, with a 5-year survival rate of

Immune checkpoint blockade (ICB) has demonstrated efficacy in multiple cancers, offering the potential of long-term disease control not achievable with cytotoxic or targeted therapies. However, the field has not yet achieved the crucial next steps - the expansion of the response rate and achievement of clinical efficacy in so-called "cold tumours". Mechanistic studies of tumour-type specific immunosuppressive pathways can reveal underlying biological hurdles to immunotherapy and offer new therapeutic insights. Our finding that tumour-derived IL-1β mediates immunosuppression in pancreatic cancer has precipitated a new clinical trial.

Background: Chaplain-led communication-board-guided spiritual care may reduce anxiety and stress during an intensive care unit (ICU) admission for nonvocal mechanically ventilated patients, but clinical pastoral education does not teach the assistive communication skills needed to provide communication-board-guided spiritual care. Objective: To evaluate a four-hour chaplain-led seminar to educate chaplains about ICU patients' psychoemotional distress, and train them in assistive communication skills for providing chaplain-led communication-board-guided spiritual care. Design: A survey immediately before and after the seminar, and one-year follow-up about use of communication-board-guided spiritual care. Subjects/Setting: Sixty-two chaplains from four U.S. medical centers. Measurements: Multiple-choice and 10-point integer scale questions about ICU patients' mental health and communication-board-guided spiritual care best practices. Results: Chaplain awareness of ICU sedation practices, signs of delirium, and depression, anxiety, and post-traumatic stress disorder in ICU survivors increased significantly (all p

Background In women with congenital heart defects (CHD), changes in blood volume, heart rate, respiration, and edema during pregnancy may lead to increased risk of adverse outcomes and conditions. The American Heart Association recommends providers of pregnant women with CHD assess cardiac health and discuss risks and benefits of cardiac-related medications. We described receipt of American Heart Association–recommended cardiac evaluations, filled potentially teratogenic or fetotoxic (Food and Drug Administration pregnancy category D/X) cardiac-related prescriptions, and adverse conditions among pregnant women with CHD compared with those without CHD. Methods and Results Using 2007 to 2014 US healthcare claims data, we ascertained a retrospective cohort of women with and without CHD aged 15 to 44 years with private insurance covering prescriptions during pregnancy. CHD was defined as ≥1 inpatient code or ≥2 outpatient CHD diagnosis codes >30 days apart documented outside of pregnancy and categorized as severe or nonsevere. Log-linear regression, accounting for multiple pregnancies per woman, generated adjusted prevalence ratios (aPRs) for associations between the presence/severity of CHD and stillbirth, preterm birth, and adverse conditions from the last menstrual period to 90 days postpartum. We identified 2056 women with CHD (2334 pregnancies) and 1 374 982 women without (1 524 077 pregnancies). During the last menstrual period to 90 days postpartum, 56% of women with CHD had comprehensive echocardiograms and, during pregnancy, 4% filled potentially teratogenic or fetotoxic cardiac-related prescriptions. Women with CHD, compared with those without, experienced more adverse conditions overall (aPR, 1.9 [95% CI, 1.7–2.1]) and, specifically, obstetric (aPR, 1.3 [95% CI, 1.2–1.4]) and cardiac conditions (aPR, 10.2 [95% CI, 9.1–11.4]), stillbirth (aPR, 1.6 [95% CI, 1.1–2.4]), and preterm delivery (aPR, 1.6 [95% CI, 1.4–1.8]). More women with severe CHD, compared with nonsevere, experienced adverse conditions overall (aPR, 1.5 [95% CI, 1.2–1.9]). Conclusions Women with CHD have elevated prevalence of adverse cardiac and obstetric conditions during pregnancy; 4 in 100 used potentially teratogenic or fetotoxic medications, and only half received an American Heart Association–recommended comprehensive echocardiogram.

Patients with cancer often confront the decision of whether to continue high-dose chemotherapy at the expense of cumulative toxicities. Reducing the dose of chemotherapy regimens while preserving efficacy is sorely needed to preserve the performance status of these vulnerable patients, yet has not been prioritized. Here, we introduce a dual pronged approach to modulate the microenvironment of desmoplastic pancreatic tumors and enable significant dose deescalation of the FDA-approved chemotherapeutic nanoliposomal irinotecan (nal-IRI) without compromising tumor control. We demonstrate that light-based photodynamic priming (PDP) coupled with vitamin D3 receptor (VDR) activation within fibroblasts increases intratumoral nal-IRI accumulation and suppresses protumorigenic CXCL12/CXCR7 crosstalk. Combined photodynamic and biochemical modulation of the tumor microenvironment enables a 75% dose reduction of nal-IRI while maintaining treatment efficacy, resulting in improved tolerability. Modifying the disease landscape to increase the susceptibility of cancer, via preferentially modulating fibroblasts, represents a promising and relatively underexplored strategy to enable dose deescalation. The approach presented here, using a combination of three clinically available therapies with nonoverlapping toxicities, can be rapidly translated with minimal modification to treatment workflow, and challenges the notion that significant improvements in chemotherapy efficacy can only be achieved at the expense of increased toxicity.

Despite tremendous gains in the molecular understanding of exocrine pancreatic cancer, the prognosis for this disease remains very poor, largely because of delayed disease detection and limited effectiveness of systemic therapies. Both incidence rates and mortality rates for pancreatic cancer have increased during the past decade, in contrast to most other solid tumor types. Recent improvements in multimodality care have substantially improved overall survival, local control, and metastasis-free survival for patients who have localized tumors that are amenable to surgical resection. The widening gap in prognosis between patients with resectable and unresectable or metastatic disease reinforces the importance of detecting pancreatic cancer sooner to improve outcomes. Furthermore, the developing use of therapies that target tumor-specific molecular vulnerabilities may offer improved disease control for patients with advanced disease. Finally, the substantial morbidity associated with pancreatic cancer, including wasting, fatigue, and pain, remains an under-addressed component of this disease, which powerfully affects quality of life and limits tolerance to aggressive therapies. In this article, the authors review the current multidisciplinary standards of care in pancreatic cancer with a focus on emerging concepts in pancreatic cancer detection, precision therapy, and survivorship.

Objective: Estimate the population attributable fraction (PAF) for a set of recognized risk factors for orofacial clefts. Design: We used data from the National Birth Defects Prevention Study. For recognized risk factors for which data were available, we estimated crude population attributable fractions (cPAFs) to account for potential confounding, average-adjusted population attributable fractions (aaPAFs). We assessed 11 modifiable and 3 nonmodifiable parental/maternal risk factors. The aaPAF for individual risk factors and the total aaPAF for the set of risk factors were calculated using a method described by Eide and Geffler. Setting: Population-based case–control study in 10 US states. Participants: Two thousand seven hundred seventy-nine cases with isolated cleft lip with or without cleft palate (CL±P), 1310 cases with isolated cleft palate (CP), and 11 692 controls with estimated dates of delivery between October 1, 1997, and December 31, 2011. Main Outcome Measures: Crude population attributable fraction and aaPAF. Results: The proportion of CL±P and CP cases attributable to the full set of examined risk factors was 50% and 43%, respectively. The modifiable factor with the largest aaPAF was smoking during the month before pregnancy or the first month of pregnancy (4.0% for CL±P and 3.4% for CP). Among nonmodifiable factors, the factor with the largest aaPAF for CL±P was male sex (27%) and for CP it was female sex (16%). Conclusions: Our results may inform research and prevention efforts. A large proportion of orofacial cleft risk is attributable to nonmodifiable factors; it is important to better understand the mechanisms involved for these factors.

Background: Drug development in PDAC has been disappointing with an extremely low trial success rate despite considerable effort. PrP is a transformative, adaptive clinical trial platform that attempts to correct this by continuously and rapidly evaluating novel therapeutic options while maximizing the probability of patient (pt) randomization to an experimental treatment and nurturing enhanced cooperation among groups representing pt advocacy, pharmaceuticals, translational/clinical academia, and the FDA. This patient-centric study represents a fundamental shift in drug development for PDAC in the United States and aims to become the largest Phase 2/3 registrational study ever launched in this disease. Methods: PrP (NCT04229004) is a clinical trial platform sponsored by the Pancreatic Cancer Action Network (PanCAN) and funded solely through non-government sources. The protocol was finalized based on the FDA 2020 guidance document regarding "complex innovative designs" in registration trials https://www.fda.gov/media/130897/download. It utilizes adaptive randomization along with several trial design and Bayesian statistical innovations provided by Berry Consultants LLC. All pts undergo pre-and on-treatment biopsies with state-of-the-art genomic, transcriptomic, and immune analysis, along with collection of blood samples for research purposes throughout the study. Pts are managed using novel standardized supportive care techniques, and PrP contains 3 sub-protocols involving quality of life, sarcopenia and actigraphy. PrP was launched in 2020, and currently includes 20 US sites. Focused on both 1st and 2nd line treatment of metastatic PDAC, PrP uses an adaptive platform design with 30% of pts randomized between one of the 2 standard of care control arms (gemcitabine + nab-paclitaxel and mFOLFIRINOX) and 70% to experimental arms, currently either SM-88, a cancer metabolism-based agent (Tyme Inc); or Pamrevlumab, an antibody inhibiting the activity of the connective tissue growth factor (Fibrogen Inc.) The study is ongoing with >100 pts enrolled to date. The Data and Safety Monitoring Committee regularly reviews the data and continues to recommend that the trial proceeds as planned. New study arms will be added after review by an Arm Selection Committee that assesses the validity of the treatment target and the adequacy of the preexisting pre-clinical and clinical data. An additional experimental arm is anticipated in 2021. Conclusion: Compared to traditional trial designs, PrP offers several advantages: multiple investigational treatments can be evaluated in parallel over time; only ~ 175 pts per experimental arm required to initiate a regulatory registration; and increased learning from every patient during the trial, altogether resulting in both time saving and a 30-50% cost saving. In effect, PrP has created an entirely new “learning community” and can substantially accelerate drug development for PDAC. Citation Format: Vincent J. Picozzi, Anne-Marie Duliege, Anirban Maitra, Manuel Hidalgo, Andrew Eugene Hendifar, Gregory L. Beatty, Sudheer Doss Doss, Regina Deck, Lynn M. Matrisian, Julie Fleshman, Diane M. Simeone. Precision Promise (PrP): An adaptive, multi-arm registration trial in metastatic pancreatic ductal adenocarcinoma (PDAC) [abstract]. In: Proceedings of the AACR Virtual Special Conference on Pancreatic Cancer; 2021 Sep 29-30. Philadelphia (PA): AACR; Cancer Res 2021;81(22 Suppl):Abstract nr PO-050.

BackgroundSolid tumors comprise >90% of cancers. Metastatic colorectal cancer, non-small cell lung cancer, and pancreatic cancer are among the leading causes of cancer-related mortality (5-year overall survival: 14%, 6%, and 3%, respectively).1Chimeric antigen receptor (CAR) T-cell therapy demonstrated clinical outcomes in hematologic malignancies.2 3 However, translating engineered T-cell therapies to solid tumors proves difficult due to a lack of tumor-specific targets that discriminate cancer cells from normal cells. In previous studies, the use of a carcinoembryonic antigen T-cell receptors and mesothelin CARs both resulted in dose-limiting on-target, off-tumor toxicities.4 5 TmodTM CAR T-cell therapy addresses these challenges by leveraging dual receptors to create a robust AND NOT signal integrator capable of killing tumor cells, while leaving healthy cells intact (figure 1).6 Tmod platform technology is a versatile system that may be applied to T cells and natural killer cells in autologous and allogeneic settings.HLA LOH offers a definitive tumor versus normal discriminator target for CAR T-cell therapy.6 7 The 2 receptors comprise an activator that recognizes an antigen present on the surface of normal and tumor cells and a blocker that recognizes a second surface antigen from an allele lost only in tumor cells. HLA LOH has been observed in ~13% across all solid tumors and up to 33% of pancreatic cancers.8 New technologies have shown higher HLA LOH rates; however, it is unclear whether patients with HLA LOH in their primary tumor tissues are at higher risk for recurrence. BASECAMP-1 is an observational study with key objectives: 1) To determine and identify patients with somatic HLA LOH eligible for Tmod CAR T-cell therapy, and 2) Subsequent leukapheresis and manufacturing feasibility for future Tmod CAR T-cell trials.MethodsBASECAMP-1 (NCT04981119) patient eligibility has 2 parts (figure 2): 1) Patients will be initially screened to identify germline HLA-A*02 heterozygosity by central next-generation sequencing (NGS). If HLA-A*02 heterozygosity is confirmed, primary archival tumor tissue will be analyzed by xT-Onco NGS testing9 to determine if somatic tumor HLA-A*02 LOH is present; 2) If the tumor demonstrates HLA-A*02 LOH and the patient screens eligible, the patient will undergo leukapheresis. Patients enrolled in the study who undergo leukapheresis will be evaluated for safety 7 days post-leukapheresis and followed for relapsed status. Banked T cells will be available for subsequent autologous Tmod CAR T-cell therapy at the time of relapse.Abstract 491 Figure 1Illustration of the Tmod T cell engaging with tumor cells with somatic loss of HLA-A*02 and with normal cellsAbstract 491 Figure 2Study schema. HLA, human leukocyte antigen; LOH, loss of heterozygosity; NGS, next generation sequencingTrial RegistrationNCT04981119ReferencesAmerican Cancer Society. Cancer Facts & Figures 2021. Atlanta: American Cancer Society; 2021.Neelapu S, Locke F, Bartlett N, et al. Axicabtagene ciloleucel CAR T-cell therapy in refractory large B-cell lymphoma. N Engl J Med 2017;377(26):2531–2544.Maude S, Laetsch T, Buechner J, et al. Tisagenlecleucel in children and young adults with B-cell lymphoblastic leukemia. N Engl J Med 2018;378(5):439–448.Parkhurst M, Yang J, Langan R, et al. T cells targeting carcinoembryonic antigen can mediate regression of metastatic colorectal cancer but induce severe transient colitis. Mol Ther 2011;19(3):620–626.Haas AR, Tanyi JL, O’Hara MH, et al. Phase I study of lentiviral-transduced chimeric antigen receptor-modified T cells recognizing mesothelin in advanced solid cancers. Mol Ther. 2019;27(11):1919–1929.Hamburger A, DiAndreth B, Cui J, et al. Engineered T cells directed at tumors with defined allelic loss. Mol Immunol 2020;128:298–310.Hwang M, Mog B, Douglass J, et al. Targeting loss of heterozygosity for cancer-specific immunotherapy. Proc Natl Acad Sci U S A 2021;118(12):e2022410118.The Cancer Genome Atlas (TCGA) Research Network. https://www.cancer.gov/tcga. Accessed June 2021.Perera J, Mapes B, Lau D, et al. Detection of human leukocyte antigen class I loss of heterozygosity in solid tumor types by next-generation DNA sequencing. J Immunother Cancer 2019;7(suppl 1):103.

Definitive chemoradiotherapy for unresectable pancreatic cancer has traditionally involved 5-fluorouracil-based chemotherapy. Our institution has a long history of combining gemcitabine and radiotherapy (RT), and performed a retrospective review of all patients treated in this manner. We reviewed the records of 180 patients treated from 1999 to 2012. Mean RT dose was 40.9 Gy in 2.2-Gy fractions, and targeted only radiographically apparent disease. Ninety-six percent of patients received full-dose gemcitabine-based chemotherapy with RT. Kaplan-Meier was used to analyze time-to-event endpoints, and Cox regression models were used to assess significant prognostic variables. Eighty-nine percent of patients completed RT without a toxicity-related treatment break. Median follow-up was 10.2 months. Twenty-nine percent of patients had a radiographic decrease in primary tumor size following treatment. Median overall survival was 11.8 months, time to distant metastasis (TDM) was 6.7 months, and time to local recurrence (TLR) was 8.3 months. On multivariate analysis, male sex, lower performance status, and higher posttreatment CA 19-9 level predicted for worse overall survival. Posttreatment, CA 19-9 was also associated with TDM and TLR, and radiographic tumor response was associated with better TLR. Definitive chemoradiation using full-dose gemcitabine is well tolerated and achieves survival outcomes comparable to reported trials in the literature.

In the United States, major structural or genetic birth defects affect approximately 3% of live births (1) and are responsible for 20% of infant deaths (2). Birth defects can affect persons across their lifespan and are the cause of significant lifelong disabilities. CDC used the Healthcare Cost and Utilization Project (HCUP) 2013 National Inpatient Sample (NIS), a 20% stratified sample of discharges from nonfederal community hospitals, to estimate the annual cost of birth defect-associated hospitalizations in the United States, both for persons of all ages and by age group. Birth defect-associated hospitalizations had disproportionately high costs, accounting for 3.0% of all hospitalizations and 5.2% of total hospital costs. The estimated annual cost of birth defect-associated hospitalizations in the United States in 2013 was $22.9 billion. Estimates of the cost of birth defect-associated hospitalizations offer important information about the impact of birth defects among persons of all ages on the overall health care system and can be used to prioritize prevention, early detection, and care.

BACKGROUND: Diabetes is associated with an increased risk for many birth defects and is likely to have an increasing impact on birth defect prevalence because of the rise in diabetes in the United States in recent decades. One of the first analyses in which specific birth defects were assessed for their relationship with both pregestational and gestational diabetes used data from the initial 6 years of the National Birth Defects Prevention Study. That analysis reported strong associations for pregestational diabetes with several birth defects, but few exposures among some of the less common birth defects led to unstable estimates with wide confidence intervals. Since that analysis, the study continued to collect data for another 8 years, including information on approximately 19,000 additional cases and 6900 additional controls. OBJECTIVE: Our objective was to use data from the National Birth Defects Prevention Study, the largest population-based birth defects case-control study in the United States, to provide updated and more precise estimates of the association between diabetes and birth defects, including some defects not previously assessed. STUDY DESIGN: We analyzed data on deliveries from October 1997 through December 2011. Mothers of case and control infants were interviewed about their health conditions and exposures during pregnancy, including diagnosis of pregestational (type 1 or type 2) diabetes before the index pregnancy or gestational diabetes during the index pregnancy. Using logistic regression, we separately assessed the association between pregestational and gestational diabetes with specific categories of structural birth defects for which there were at least 3 exposed case infants. For birth defect categories for which there were at least 5 exposed case infants, we calculated odds ratios adjusted for maternal body mass index, age, education, race/ethnicity, and study site; for defect categories with 3 or 4 exposed cases, we calculated crude odds ratios. RESULTS: Pregestational diabetes was reported by 0.6% of mothers of control infants (71 of 11,447) and 2.5% of mothers of case infants (775 of 31,007). Gestational diabetes during the index pregnancy was reported by 4.7% of mothers of control infants (536 of 11,447) and 5.3% of mothers of case infants (1,653 of 31,007). Pregestational diabetes was associated with strong, statistically significant odds ratios (range, 2.5–80.2) for 46 of 50 birth defects considered. The largest odds ratio was observed for sacral agenesis (adjusted odds ratio, 80.2; 95% confidence interval, 46.1–139.3). A greater than 10-fold increased risk was also observed for holoprosencephaly (adjusted odds ratio, 13.1; 95% confidence interval, 7.0–24.5), longitudinal limb deficiency (adjusted odds ratio, 10.1; 95% confidence interval, 6.2–16.5), heterotaxy (adjusted odds ratio, 12.3; 95% confidence interval, 7.3–20.5), truncus arteriosus (adjusted odds ratio, 14.9; 95% confidence interval, 7.6–29.3), atrioventricular septal defect (adjusted odds ratio, 10.5; 95% confidence interval, 6.2–17.9), and single ventricle complex (adjusted odds ratio, 14.7; 95% confidence interval, 8.9–24.3). For gestational diabetes, statistically significant odds ratios were fewer (12 of 56) and of smaller magnitude (range, 1.3– 2.1; 0.5 for gastroschisis). CONCLUSION: Pregestational diabetes is associated with a markedly increased risk for many specific births defects. Because glycemic control before pregnancy is associated with a reduced risk for birth defects, ongoing quality care for persons with diabetes is an important opportunity for prevention.

Continuing recalcitrance to therapy cements pancreatic cancer (PC) as the most lethal malignancy, which is set to become the second leading cause of cancer death in our society. We interrogated the transcriptome, genome, proteome and functional characteristics of 61 novel PC patient-derived cell lines to define novel therapeutic strategies targeting the DNA damage response (DDR) and replication stress. We show that patient-derived cell lines faithfully recapitulate the epithelial component of pancreatic tumors including previously described molecular subtypes. Biomarkers of DDR deficiency, including a novel signature of homologous recombination deficiency, co-segregates with response to platinum and PARP inhibitor therapy in vitro and in vivo. We generated a novel signature of replication stress with potential clinical utility in predicting response to ATR and WEE1 inhibitor treatment. Replication stress and DDR deficiency are independent of each other, creating opportunities for therapy in DDR proficient PC, and post-platinum therapy.Abstract FigureSTATEMENT OF SIGNIFICANCEWe define therapeutic strategies that target subgroups of PC using novel signatures of DNA damage response deficiency and replication stress. This potentially offers patients with DNA repair defects therapeutic options outside standard of care platinum chemotherapy and is being tested in clinical trials on the Precision-Panc platform.

Objective To describe how Zika virus (Zika) surveillance data informs and improves testing guidance, clinical evaluation and management of pregnant women and infants with possible Zika infection Introduction Little was known about the maternal and fetal/infant effects of Zika infection before the 2015 outbreak in the Americas, which made it challenging for public health practitioners and clinicians to care for pregnant women and infants exposed to Zika. In 2016, CDC implemented a rapid surveillance system, the US Zika Pregnancy and Infant Registry, to collect information about the impact of Zika infection during pregnancy and inform the CDC response and clinical guidance. In partnership with state, tribal, local, and territorial health departments, CDC disseminated information from this surveillance system, which served as the foundation for educational materials and clinical tools for healthcare providers. Methods Throughout the Zika response, CDC worked closely with health officers, epidemiologists, and clinical partners to seek expert input on the interpretation of emerging data and the evaluation and management of these vulnerable populations. In response to requests from clinical and public health partners, CDC created targeted educational materials and tools to facilitate the implementation of clinical guidance. These materials equipped healthcare providers with the information needed to care for pregnant women and infants with Zika infection. Examples of products developed included: 1) screening tools to identify pregnant women for whom testing is indicated; 2) an interactive web tool to assist with implementation and interpretation of Zika testing guidance (Pregnancy and Zika Testing Widget); 3) patient counseling scripts; and 4) videos to explain critical clinical concepts (e.g., measurement of infant head circumference). These tools were informally pre-tested with the target audiences prior to dissemination, specifically to assess usefulness in clinical settings. CDC disseminated these tools through the CDC website and through comprehensive outreach (e.g., webinars, calls, email alerts) to various audiences. Additionally, several professional organizations incorporated these tools into regular communication with their membership. Results The US Zika Pregnancy and Infant Registry is currently monitoring infants from approximately 7,300 pregnancies in the US states and territories with laboratory evidence of Zika. Surveillance data provided valuable information, including clues toward the pattern of defects and other neurologic disabilities associated with congenital Zika infection, estimates of the risks associated with congenital infection, and timeframes of greatest risk during pregnancy, to help clinicians counsel pregnant patients with potential Zika exposure. CDC used these data to inform their clinical tools, particularly in pretest counseling materials and educational factsheets for healthcare providers to use with pregnant women with potential Zika exposure. After informal testing among healthcare providers, the tools received positive feedback regarding usefulness and applicability in clinical settings. Collectively, CDC’s Zika clinical tools were downloaded more than 300,000 times from CDC’s website. The Pregnancy and Zika Testing Widget was accessed and followed to an endpoint (e.g., Zika testing recommended) more than 17,000 times, with more than 75% of users self-identifying as clinicians. Conclusions Rapid implementation of Zika surveillance captured evolving data about the impact of Zika on pregnant women and their infants. These data informed the development of clinical tools for healthcare providers caring for and counseling patients with Zika exposure. These tools ensured pregnant women and infants were adequately monitored during the Zika outbreak. Health education materials and clinical tools based on surveillance data should be considered in future emergency responses, particularly when knowledge is rapidly evolving. References CDC Zika Pregnancy Website: https://www.cdc.gov/pregnancy/zika/materials/index.html

Purpose The treatment of cancer is complex, which can overwhelm patients and lead to poor comprehension and recall of the specifics of the cancer stage, prognosis, and treatment plan. We hypothesized that an oncologist can feasibly record and deliver a custom video summary of the consultation that covers the diagnosis, recommended testing, treatment plan, and follow-up in < 5 minutes. The video summary allows the patient to review and share the most important part of a cancer consultation with family and caregivers. Methods At the conclusion of the office visit, oncologists recorded the most important points of the consultation, including the diagnosis and management plan as a short video summary. Patients were then e-mailed a link to a secure Website to view and share the video. Patients and invited guests were asked to respond to an optional survey of 15 multiple-choice and four open-ended questions after viewing the video online. Results Three physicians recorded and sent 58 video visit summaries to patients seen in multidisciplinary GI cancer clinics. Forty-one patients logged into the secure site, and 38 viewed their video. Fourteen patients shared their video and invited a total of 46 visitors, of whom 36 viewed the videos. Twenty-six patients completed the survey, with an average overall video satisfaction score of 9 on a scale of 1 to 10, with 10 being most positive. Conclusion Video visit summaries provide a personalized education tool that patients and caregivers find highly useful while navigating complex cancer care. We are exploring the incorporation of video visit summaries into the electronic medical record to enhance patient and caregiver understanding of their specific disease and treatment.

Background Health insurance claims are a rich data source to examine medication use in pregnancy. Our objective was to identify pregnant women, their pregnancy outcomes, and date of their last menstrual period (LMP), and to estimate antidepressant dispensations in pregnancy. Methods From a literature search, we identified diagnosis and procedure codes indicating the end of a pregnancy. Using Truven Health MarketScan® Commercial Claims and Encounters Databases, we identified all inpatient admissions and outpatient service claims with these codes. We developed an algorithm to assign: (1) pregnancy outcome (ectopic pregnancy, induced or spontaneous abortion, live birth, or stillbirth), and (2) estimated gestational age, to each inpatient or outpatient visit. For each pregnancy outcome, we estimated the LMP as the admission (for inpatient visits) or service (for outpatient visits) date minus the gestational age. To differentiate visits associated with separate pregnancies, we required ≥ 2 months between one pregnancy outcomes and the LMP of the next pregnancy. We used this algorithm to identify pregnancies in 2013 and to estimate the proportion of women who filled a prescription for an antidepressant from an outpatient pharmacy at various time points in pregnancy. Results We identified 488,887 pregnancies in 2013; 79% resulted in a live birth. A prescription for an antidepressant was filled in 6.2% of pregnancies. Dispensations varied throughout pregnancy and were lowest (3.1%) during the second trimester. Conclusion This work will inform future efforts to estimate medication dispensations during critical periods of preconception, interconception, and pregnancy using health insurance claims data. Birth Defects Research (Part A) 106:927–934, 2016. © 2016 Wiley Periodicals, Inc.

A modifiable spreadsheet tool will enable health officials to plan for these births., The marked increase in infants born with microcephaly in Brazil after a 2015 outbreak of Zika virus (Zika virus) disease suggests an association between maternal Zika virus infection and congenital microcephaly. To project the timing of delivery of infants born to mothers infected during early pregnancy in 1 city in Bahia State, Brazil, we incorporated data on reported Zika virus disease cases and microcephaly cases into a graphical schematic of weekly birth cohorts. We projected that these births would occur through February 2016. Applying similar projections to a hypothetical location at which Zika virus transmission started in November, we projected that full-term infants at risk for Zika virus infection would be born during April–September 2016. We also developed a modifiable spreadsheet tool that public health officials and researchers can use for their countries to plan for deliveries of infants to women who were infected with Zika virus during different pregnancy trimesters.

Background Little population-based data exist on limitations and health-related quality of life (HRQoL) in adults with congenital heart defects (CHD). Methods We used 2004 to 2012 Medical Expenditure Panel Survey data to identify a population-based sample of young adults ages 18 to 40 years reporting health symptoms or healthcare encounters in the previous year. Comparing adults reporting CHD to others, we examined the prevalence of cognitive, physical, and activity limitations, depressive symptoms, and physical and mental HRQoL. We used chi square tests to examine differences in demographic characteristics, logistic regression to generate adjusted prevalence ratios (aPR), and linear regression to examine HRQoL. Multivariable associations were adjusted for sex, age, race/ethnicity, and smoking status. All analyses were conducted in SUDAAN using weights to account for clustering within sampling units and nonresponse. Results Fifty-nine adults reported CHD (weighted prevalence = 0.1%; representing 700,000 U.S. adults from 2004 to 2012 or, on average, 80,000 per year) and 54,011 did not. No demographic characteristics differed significantly by CHD status except health insurance; 31.5% of adults with CHD, compared with 11.0% without, reported public insurance (p = 0.01). Compared with their counterparts, adults reporting CHD had a higher prevalence of cognitive (aPR = 2.7, 95% confidence interval (CI): 1.0, 7.2), physical (aPR = 4.0, 95% CI: 1.9, 8.2), and activity limitations (aPR = 4.8, 95% CI: 2.6, 9.1), and poorer physical HRQoL (p = 0.004). No differences were observed in depressive symptoms and mental HRQoL by CHD status. Conclusion Physical health and cognitive abilities of adults with CHD were compromised compared with adults without CHD. Birth Defects Research (Part A) 106:580–586, 2016. © 2016 Wiley Periodicals, Inc.

TPS789 Background: Patients with metastatic pancreatic cancer who have progressed on two prior lines of therapy have a poor prognosis with an overall survival in the range of 2-2.5 months. (Manax, et al. J Clin Oncol 37, 2019 suppl 4; abstr 226). There is currently no standard of care for these patients that has demonstrated improved outcomes. SM-88 (D,L-alpha-metyrosine; racemetyrosine [USAN]) is a proprietary dysfunctional tyrosine derivative and is the backbone of SM-88 used with MPS (Methoxsalen 10mg, Phenytoin 50mg and Sirolimus 0.5mg; all administered daily). SM-88 monotherapy was relatively well tolerated, with improvement in survival in select patients with heavily pretreated PDAC who achieved stable disease on therapy (HR 0.08, p = 0.02). Circulating tumor cells (CTC’s) were prognostic and decreased on therapy with SM-88 potentially identifying a subgroup of PDAC that may be most likely to benefit from therapy (Noel et al. Annal Oncol V30, Suppl 4, 2019). Preliminary radiomic analysis of the largest metastases at baseline suggested the same benefits including a correlation with baseline CTCs, changes in CTCs on therapy and OS (Ocean et al, Annal Oncol, V30, Suppl 5, 2019). Here, we describe a randomized, open-label, phase 2/3 trial evaluating the efficacy of SM-88 + MPS vs physician’s choice treatment as third line therapy for patients with metastatic PDAC. Methods: This is a multi-center Phase 3 study of patients ≥18 years with metastatic PDAC that progressed after 2 lines of chemotherapy (gemcitabine [gem] and 5-fluorouracil [5-FU] based) with an ECOG

Purpose An ASCO provisional clinical opinion (PCO) offers timely clinical direction to ASCO’s membership and other health care providers. This PCO addresses identification and management of patients and family members with possible predisposition to pancreatic adenocarcinoma. Methods ASCO convened an Expert Panel and conducted a systematic review of the literature published from January 1998 to June 2018. Results of the databases searched were supplemented with hand searching of the bibliographies of systematic reviews and selected seminal articles and contributions from Expert Panel members’ curated files. Provisional Clinical Opinion All patients diagnosed with pancreatic adenocarcinoma should undergo assessment of risk for hereditary syndromes known to be associated with an increased risk for pancreatic adenocarcinoma. Assessment of risk should include a comprehensive review of family history of cancer. Individuals with a family history of pancreatic cancer affecting two first-degree relatives meet criteria for familial pancreatic cancer (FPC). Individuals (cancer affected or unaffected) with a family history of pancreatic cancer meeting criteria for FPC, those with three or more diagnoses of pancreatic cancer in same side of the family, and individuals meeting criteria for other genetic syndromes associated with increased risk for pancreatic cancer have an increased risk for pancreatic cancer and are candidates for genetic testing. Germline genetic testing for cancer susceptibility may be discussed with individuals diagnosed with pancreatic cancer, even if family history is unremarkable. Benefits and limitations of pancreatic cancer screening should be discussed with individuals whose family history meets criteria for FPC and/or genetic susceptibility to pancreatic cancer. Additional information is available at www.asco.org/gastrointestinal-cancer-guidelines .

The tumor microenvironment plays a vital role in therapeutic resistance in pancreatic adenocarcinoma. We have created a 3D model to study the tumor microenvironment ex vivo that integrates tumor cells with tumor associated macrophages (TAMs) and cancer associated fibroblasts (CAFs). The microtumor model recreates the complex histology of a primary tumor and can be analyzed histologically or with viability assays for therapeutic testing. Microtumors demonstrate increased resistance to gemcitabine when compared to tumor cells alone in a 3D spheroid, highlighting the contribution of TAMs and CAFs when designing models for therapeutic testing.

Bladder cancer is a significant health problem. It is estimated that more than 16,000 people will die this year in the United States from bladder cancer. While 75% of bladder cancers are non-invasive and unlikely to metastasize, about 25% progress to an invasive growth pattern. Up to half of the patients with invasive cancers will develop lethal metastatic relapse. Thus, understanding the mechanism of invasive progression in bladder cancer is crucial to predict patient outcomes and prevent lethal metastases. In this article, we present a three-dimensional cancer invasion model which allows incorporation of tumor cells and stromal components to mimic in vivo conditions occurring in the bladder tumor microenvironment. This model provides the opportunity to observe the invasive process in real time using time-lapse imaging, interrogate the molecular pathways involved using confocal immunofluorescent imaging and screen compounds with the potential to block invasion. While this protocol focuses on bladder cancer, it is likely that similar methods could be used to examine invasion and motility in other tumor types as well.

The biological properties of pancreatic cancer stem cells (PCSCs) remain incompletely defined and the central regulators are unknown. By bioinformatic analysis of a human PCSC-enriched gene signature, we identified the transcription factor HNF1A as a putative central regulator of PCSC function. Levels of HNF1A and its target genes were found to be elevated in PCSCs and tumorspheres, and depletion of HNF1A resulted in growth inhibition, apoptosis, impaired tumorsphere formation, decreased PCSC marker expression, and downregulation of POU5F1/OCT4 expression. Conversely, HNF1A overexpression increased PCSC marker expression and tumorsphere formation in pancreatic cancer cells and drove pancreatic ductal adenocarcinoma (PDA) cell growth. Importantly, depletion of HNF1A in xenografts impaired tumor growth and depleted PCSC marker-positive cells in vivo. Finally, we established an HNF1A-dependent gene signature in PDA cells that significantly correlated with reduced survivability in patients. These findings identify HNF1A as a central transcriptional regulator of PCSC properties and novel oncogene in PDA., eLife digest Pancreatic ductal adenocarcinoma is the most common form of pancreatic cancer. It is also one of the deadliest types of cancer: fewer than one in ten patients live for five years after being diagnosed with the disease. Several reasons can explain this poor outcome including that the cancer is often diagnosed late, when tumor cells have already spread, and that there are not many effective treatments for it. Pancreatic tumors contain different types of cancer cells with different properties. Among these are the so-called pancreatic cancer stem cells. These aggressive cells produce copies of themselves, contributing to tumor growth and spread. They can also help tumors to resist chemotherapy and radiotherapy. New treatments that specifically target cancer stem cells could therefore prove important for treating pancreatic cancer. It is still not clear what makes pancreatic cancer stem cells so aggressive, or how they differ from the rest of the cells in a tumor. Abel et al. therefore looked for proteins that were more abundant in human pancreatic cancer stem cells than in other, less aggressive cancer cells with the idea that these proteins are likely to be important for the behavior of the pancreatic cancer stem cells. Abel et al. found that a protein called HNF1A is enriched in pancreatic cancer stem cells. Experimentally reducing the levels of HNF1A in cells taken from human pancreatic cancers caused the cells to grow less well and form smaller tumors when injected into the pancreases of mice. These tumors contained few cancer stem cells, suggesting that HNF1A is important for maintaining the stem cell state. Further experiments showed that HNF1A increases the amount of many other proteins inside cells, including one that controls the activity of normal stem cells. Given the importance of HNF1A to pancreatic cancer stem cells, finding ways to prevent this protein from working could lead to new treatments for pancreatic cancer. At the moment there are no drugs that target HNF1A. Further research is therefore needed to develop new drugs that work against HNF1A or one of the other proteins that it affects.

The ineffectiveness of chemotherapy in patients with pancreatic cancer highlights a critical unmet need in pancreatic cancer therapy. Two commonly mutated genes in pancreatic cancer, KRAS and CDKN2A, have an incidence exceeding 90%, supporting investigation of dual targeting of MEK and CDK4/6 as a potential therapeutic strategy for this patient population. An in vitro proliferation synergy screen was conducted to evaluate response of a panel of high passage and patient-derived pancreatic cancer models to the combination of trametinib and palbociclib to inhibit MEK and CDK4/6, respectively. Two adenosquamous carcinoma models, L3.6pl and UM59, stood out for their high synergy response. In vivo studies confirmed that this combination treatment approach was highly effective in subcutaneously implanted L3.6pl and UM59 tumor-bearing animals. Both models were refractory to single-agent treatment. Reverse-phase protein array analysis of L3.6pl tumors excised from treated animals revealed strong downregulation of COX-2 expression in response to combination treatment. Expression of COX-2 under a CMV-driven promoter and shRNA knockdown of COX-2 both led to resistance to combination treatment. Our findings suggest that COX-2 may be involved in the improved therapeutic outcome seen in some pancreatic tumors that fail to respond to MEK or CDK4/6 inhibitors alone but respond favorably to their combination.

Major birth defects (birth defects) are defined as structural abnormalities, present at birth, with surgical, medical, or cosmetic importance. Each year in the United States, 3% of live births (approximately 120,000 infants) have an identifiable structural birth defect. Examples of birth defects include neural tube defects, such as spina bifida; orofacial clefts; abdominal wall defects, such as gastroschisis; and congenital heart defects, such as hypoplastic left heart syndrome. Collectively, congenital heart defects are the most common birth defects (27%), followed by musculoskeletal defects (18%), genitourinary defects (15%), orofacial defects (5%), and neural tube defects (2%).

Background Individuals with congenital heart defects (CHDs) have high hospital resource use. We sought to identify factors associated with hospital costs and multiple hospitalizations among individuals with CHDs. Methods Data from the 2006 to 2011 Healthcare Cost and Utilization Project Arkansas State Inpatient Databases were linked across encrypted patient identifiers to develop a cohort of Arkansas residents aged 1 to 64 years who were hospitalized at least once with a CHD during this time period. Infants were excluded because patient identifiers were missing for 18 to 52% each year. CHDs were identified using principal and secondary International Classification of Diseases, Ninth Revision, Clinical Modification diagnoses codes. All hospitalizations of individuals ever admitted with a CHD were included. Mean and median patient-level costs were estimated; the association of hospital costs and patient readmissions were examined with linear and logistic regression. Results There were 1,185,868 inpatient hospitalizations of Arkansas residents aged 1 to 64 years between 2006 and 2011; these were accrued by 603,925 patients. Of those, 2542 patients (0.42%) had at least one hospitalization with a CHD diagnosis. Total costs for these 2542 patients were $126,999,837 and they accumulated 7898 hospitalizations. Factors associated with increased costs included patient age, CHD type, cardiac procedures, and comorbidities. Factors associated with hospital readmission within 1 year included age, CHD type, expected payer, and comorbidities. Conclusion Individuals with CHDs in Arkansas experience variation in hospital use and costs by patient characteristics. Future research should investigate factors associated with readmissions, cardiac procedures, and comorbidities, as these are strongly associated with hospital costs. Birth Defects Research (Part A) 103:589–596, 2015. © 2015 Wiley Periodicals, Inc.

Background Congenital heart defects (CHDs) are common birth defects and are associated with high hospital costs. The objectives of this study were to assess hospitalization costs, across the lifespan, of patients with CHDs in Arkansas. Methods Data from the 2006 to 2011 Healthcare Cost and Utilization Project Arkansas State Inpatient Databases were used. We included hospitalizations of patients whose admission occurred between January 1, 2006, and December 31, 2011, and included a principal or secondary CHD ICD-9-CM diagnosis code (745.0–747.49, except 747.0 and 745.5 for preterm infants). Hospitalizations were excluded if they involved out-of-state residents, normal newborn births, or if missing data included age at admission, state of residence, or hospital charges. Children were defined as those

Context Maternal pregestational diabetes (PGDM) is a risk factor for development of congenital heart defects (CHDs). Glycemic control before pregnancy reduces the risk of CHDs. A meta-analysis was used to estimate summary ORs and mathematical modeling was used to estimate population attributable fractions (PAFs) and the annual number of CHDs in the U.S. potentially preventable by establishing glycemic control before pregnancy. Evidence acquisition A systematic search of the literature through December 2012 was conducted in 2012 and 2013. Case−control or cohort studies were included. Data were abstracted from 12 studies for a meta-analysis of all CHDs. Evidence synthesis Summary estimates of the association between PGDM and CHDs and 95% credible intervals (95% CrIs) were developed using Bayesian random-effects meta-analyses for all CHDs and specific CHD subtypes. Posterior estimates of this association were combined with estimates of CHD prevalence to produce estimates of PAFs and annual prevented cases. Ninety-five percent uncertainty intervals (95% UIs) for estimates of the annual number of preventable cases were developed using Monte Carlo simulation. Analyses were conducted in 2013. The summary OR estimate for the association between PGDM and CHDs was 3.8 (95% CrI=3.0, 4.9). Approximately 2670 (95% UI=1795, 3795) cases of CHDs could potentially be prevented annually if all women in the U.S. with PGDM achieved glycemic control before pregnancy. Conclusions Estimates from this analysis suggest that preconception care of women with PGDM could have a measureable impact by reducing the number of infants born with CHDs.

In recent years, as the high burden of surgical disease and poor access to surgical care in low- and middle-income countries have gained recognition as major public health problems, interest in global health has surged among surgical trainees and faculty. Traditionally, clinical volunteerism was at the forefront of the high-income country response to the significant burden of surgical disease in low- and middle-income countries. However, sustainable strategies for providing surgical care in low- and middle-income countries increasingly depend on bilateral clinical, research, and education collaborations to ensure effective resource allocation and contextual relevance. Academic global surgery creates avenues for interested surgeons to combine scholarship and education with their clinical global surgery passions through incorporation of basic/translational, education, clinical outcomes, or health services research with global surgery. Training in global health, either within residency or through advanced degrees, can provide the necessary skills to develop and sustain such initiatives. We further propose that creating cross-continental, bidirectional collaborations can maximize funding opportunities. Academic institutions are uniquely positioned to lead longitudinal and, importantly, sustainable global surgery efforts. However, for the individual global surgeon, the career path forward may be unclear. This paper reviews the development of academic global surgery, delineates the framework and factors critical to training global surgeons, and proposes models for establishing an academic career in this field. Overall, with determination, the academic global surgeon will not only carve out a niche of expertise but will define this critical field for future generations.