Microenvironment drives cell state, plasticity, and drug response in pancreatic cancer.

Prognostically relevant RNA expression states exist in pancreatic ductal adenocarcinoma (PDAC), but our understanding of their drivers, stability, and relationship to therapeutic response is limited. To examine these attributes systematically, we profiled metastatic biopsies and matched organoid models at single-cell resolution. In vivo, we identify a new intermediate PDAC transcriptional cell state and uncover distinct site- and state-specific tumor microenvironments (TMEs). Benchmarking models against this reference map, we reveal strong culture-specific biases in cancer cell transcriptional state representation driven by altered TME signals. We restore expression state heterogeneity by adding back in vivo-relevant factors and show plasticity in culture models. Further, we prove that non-genetic modulation of cell state can strongly influence drug responses, uncovering state-specific vulnerabilities. This work provides a broadly applicable framework for aligning cell states across in vivo and ex vivo settings, identifying drivers of transcriptional plasticity and manipulating cell state to target associated vulnerabilities.

Pembrolizumab alone and pembrolizumab plus chemotherapy in previously treated, extrapulmonary poorly differentiated neuroendocrine carcinomas.

BACKGROUND: To date, single-agent immune checkpoint inhibitor (CPI) therapy has proven to be ineffective against biomarker-unselected extrapulmonary poorly differentiated neuroendocrine carcinomas (EP-PDNECs). The efficacy of CPI in combination with chemotherapy remains under investigation. METHODS: Patients with advanced, progressive EP-PDNECs were enrolled in a two-part study of pembrolizumab-based therapy. In Part A, patients received pembrolizumab alone. In Part B, patients received pembrolizumab plus chemotherapy. PRIMARY ENDPOINT: objective response rate (ORR). Secondary endpoints: safety, progression-free survival (PFS) and overall survival (OS). Tumours were profiled for programmed death-ligand 1 expression, microsatellite-high/mismatch repair deficient status, mutational burden (TMB), genomic correlates. Tumour growth rate was evaluated. RESULTS: Part A (N = 14): ORR (pembrolizumab alone) 7% (95% CI, 0.2-33.9%), median PFS 1.8 months (95% CI, 1.7-21.4), median OS 7.8 months (95% CI, 3.1-not reached); 14% of patients (N = 2) had grade 3/4 treatment-related adverse events (TRAEs). Part B (N = 22): ORR (pembrolizumab plus chemotherapy) 5% (95% CI, 0-22.8%), median PFS 2.0 months (95% CI, 1.9-3.4), median OS 4.8 months (95% CI, 4.1-8.2); 45% of patients (N = 10) had grade 3/4 TRAEs. The two patients with objective response had high-TMB tumours. DISCUSSION: Treatment with pembrolizumab alone and pembrolizumab plus chemotherapy was ineffective in advanced, progressive EP-PDNECs. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov NCT03136055.

Genome-wide Enrichment of De Novo Coding Mutations in Orofacial Cleft Trios.

Although de novo mutations (DNMs) are known to increase an individual's risk of congenital defects, DNMs have not been fully explored regarding orofacial clefts (OFCs), one of the most common human birth defects. Therefore, whole-genome sequencing of 756 child-parent trios of European, Colombian, and Taiwanese ancestry was performed to determine the contributions of coding DNMs to an individual's OFC risk. Overall, we identified a significant excess of loss-of-function DNMs in genes highly expressed in craniofacial tissues, as well as genes associated with known autosomal dominant OFC syndromes. This analysis also revealed roles for zinc-finger homeobox domain and SOX2-interacting genes in OFC etiology.

Phase Ib and Expansion Study of Gemcitabine, Nab-Paclitaxel, and Ficlatuzumab in Patients With Metastatic Pancreatic Cancer.

BACKGROUND: In preclinical pancreatic ductal adenocarcinoma (PDAC) models, inhibition of hepatocyte growth factor (HGF) signaling using ficlatuzumab, a recombinant humanized anti-HGF antibody, and gemcitabine reduced tumor burden. METHODS: Patients with previously untreated metastatic PDAC enrolled in a phase Ib dose escalation study with 3 + 3 design of 2 dose cohorts of ficlatuzumab 10 and 20 mg/kg administered intravenously every other week with gemcitabine 1000 mg/m2 and albumin-bound paclitaxel 125 mg/m2 given 3 weeks on and 1 week off. This was followed by an expansion phase at the maximally tolerated dose of the combination. RESULTS: Twenty-six patients (sex, 12 male:14 female; median age, 68 years [range, 49-83 years]) were enrolled, 22 patients were evaluable. No dose-limiting toxicities were identified (N = 7 pts) and ficlatuzumab at 20 mg/kg was chosen as the maximum tolerated dose. Among the 21 patients treated at the MTD, best response by RECISTv1.1: 6 (29%) partial response, 12 (57%) stable disease, 1 (5%) progressive disease, and 2 (9%) not evaluable. Median progression-free survival and overall survival times were 11.0 months (95% CI, 7.6-11.4 months) and 16.2 months (95% CI, 9.1 months to not reached), respectively. Toxicities attributed to ficlatuzumab included hypoalbuminemia (grade 3, 16%; any grade, 52%) and edema (grade 3, 8%; any grade, 48%). Immunohistochemistry for c-Met pathway activation demonstrated higher tumor cell p-Met levels in patients who experienced response to therapy. CONCLUSION: In this phase Ib trial, ficlatuzumab, gemcitabine, and albumin-bound paclitaxel were associated with durable treatment responses and increased rates of hypoalbuminemia and edema.

Rare variants found in clinical gene panels illuminate the genetic and allelic architecture of orofacial clefting.

PURPOSE: Orofacial clefts (OFCs) are common birth defects including cleft lip, cleft lip and palate, and cleft palate. OFCs have heterogeneous etiologies, complicating clinical diagnostics because it is not always apparent if the cause is Mendelian, environmental, or multifactorial. Sequencing is not currently performed for isolated or sporadic OFCs; therefore, we estimated the diagnostic yield for 418 genes in 841 cases and 294 controls. METHODS: We evaluated 418 genes using genome sequencing and curated variants to assess their pathogenicity using American College of Medical Genetics criteria. RESULTS: 9.04% of cases and 1.02% of controls had "likely pathogenic" variants (P < .0001), which was almost exclusively driven by heterozygous variants in autosomal genes. Cleft palate (17.6%) and cleft lip and palate (9.09%) cases had the highest yield, whereas cleft lip cases had a 2.80% yield. Out of 39 genes with likely pathogenic variants, 9 genes, including CTNND1 and IRF6, accounted for more than half of the yield (4.64% of cases). Most variants (61.8%) were "variants of uncertain significance", occurring more frequently in cases (P = .004), but no individual gene showed a significant excess of variants of uncertain significance. CONCLUSION: These results underscore the etiological heterogeneity of OFCs and suggest sequencing could reduce the diagnostic gap in OFCs.

Rare variants found in multiplex families with orofacial clefts: Does expanding the phenotype make a difference?

Exome sequencing (ES) is now a relatively straightforward process to identify causal variants in Mendelian disorders. However, the same is not true for ES in families where the inheritance patterns are less clear, and a complex etiology is suspected. Orofacial clefts (OFCs) are highly heritable birth defects with both Mendelian and complex etiologies. The phenotypic spectrum of OFCs may include overt clefts and several subclinical phenotypes, such as discontinuities in the orbicularis oris muscle (OOM) in the upper lip, velopharyngeal insufficiency (VPI), microform clefts or bifid uvulas. We hypothesize that expanding the OFC phenotype to include these phenotypes can clarify inheritance patterns in multiplex families, making them appear more Mendelian. We performed exome sequencing to find rare, likely causal genetic variants in 31 multiplex OFC families, which included families with multiple individuals with OFCs and individuals with subclinical phenotypes. We identified likely causal variants in COL11A2, IRF6, SHROOM3, SMC3, TBX3, and TP63 in six families. Although we did not find clear evidence supporting the subclinical phenotype hypothesis, our findings support a role for rare variants in the etiology of OFCs.

Patterns of germline and somatic testing after universal tumor screening for Lynch syndrome: A clinical practice survey of active members of the Collaborative Group of the Americas on Inherited Gastrointestinal Cancer.

Clinical guidelines recommend universal tumor screening (UTS) of colorectal and endometrial cancers for Lynch syndrome (LS). There are limited guidelines for how to integrate germline testing and somatic tumor testing after a mismatch repair deficient (dMMR) tumor is identified. We sought to characterize current practice patterns and barriers to preferred practice among clinical providers in high-risk cancer programs. A clinical practice survey was sent to 423 active members of the Collaborative Group of the Americas on Inherited Gastrointestinal Cancer (CGA-IGC) with a follow-up survey sent to 103 clinician responders. The survey outlined clinical vignettes and asked respondents their preferred next test. The survey intended to assess: (1) the role of patient age and family history in risk assessment and (2) barriers to preferred genetic testing. Genetic test options included targeted germline testing based on dMMR expression, germline testing for LS, germline testing with a multigene cancer panel including LS, or paired tumor/germline testing including LS. In October 2020, 117 of 423 (28%) members completed the initial survey including 103 (88%) currently active clinicians. In April 2021, a follow-up survey was sent to active clinicians, with 45 (44%) completing this second survey. After selecting their preferred next germline or paired tumor/germline tumor test based on the clinical vignette, 39% of respondents reported wanting to make a different choice for the initial genetic test without any testing barriers. The proportion of respondents choosing a different initial genetic test was dependent on the proband's age at diagnosis and specified family history. The reported barriers included patient's lack of insurance coverage, patient unable/unwilling to self-pay for proposed testing, and inadequate tumor tissue. Responders reported insurance, financial constraints, and limited tumor tissue as influencing preferred genetic testing in high-risk clinics, thus resulting in possible under-diagnosis of LS and impacting potential surveillance and cascade testing of at-risk relatives.

Pancreatic acinar cell carcinoma: A multi-center series on clinical characteristics and treatment outcomes.

BACKGROUND: Acinar cell carcinoma (ACC) is a very rare tumor of the exocrine pancreas, representing less than 1% of all pancreatic malignancies. The majority of data regarding ACC are limited to small case series. METHODS: This is a retrospective study conducted at a large healthcare system from 1996 to 2019. Patients with pathologically confirmed ACC were included, and demographic data, tumor characteristics, and treatment outcomes were abstracted by chart review. Survival curves were obtained by using the Kaplan-Meier method and compared using the log-rank test. RESULTS: Sixty-six patients with ACC were identified. The median patient age at diagnosis was 64, and 42% presented with metastatic disease. The majority presented with abdominal pain or pancreatitis (69%), and laboratory parameters did not correlate with tumor size, metastatic disease, or survival. Several somatic abnormalities were noted in tumors (BRCA2, TP53, and mismatch-repair genes). In patients with localized disease that underwent resection, the median time to develop metastatic lesions was 13 months. The median overall survival (OS) was 24.7 months from diagnosis, with a survival difference based on metastatic disease at diagnosis (median 15 vs 38 mos). Surgery was associated with improved survival in non-metastatic cases (p = 0.006) but not metastatic cases (p = 0.22), and chemotherapy showed OS benefit in metastatic disease (p < 0.01). Patients with metastatic ACC treated after 2010 utilized more platinum-based agents, and there was a OS benefit to FOLFOX or FOLFIRINOX chemotherapy compared to gemcitabine or capecitabine-based regimens (p = 0.006). CONCLUSION: Pancreatic ACC patients often present with advanced disease. Surgery was associated with survival benefit among patients presenting with localized disease. The use of FOLFOX or FOLFIRINOX chemotherapy regimens was associated with improved OS in metastatic patients. These data add to our knowledge in this rare malignancy, and improves understanding about the genomic underpinnings, prognosis and treatment for acinar cancers.

Family history of cancer, Ashkenazi Jewish ancestry, and pancreatic cancer risk.

BACKGROUND: Individuals with a family history of cancer may be at increased risk of pancreatic cancer. Ashkenazi Jewish (AJ) individuals carry increased risk for pancreatic cancer and other cancer types. METHODS: We examined the association between family history of cancer, AJ heritage, and incident pancreatic cancer in 49 410 male participants of the prospective Health Professionals Follow-up Study. Hazard ratios (HRs) were estimated using multivariable-adjusted Cox proportional hazards models. RESULTS: During 1.1 million person-years (1986-2016), 452 participants developed pancreatic cancer. Increased risk of pancreatic cancer was observed in individuals with a family history of pancreatic (HR, 2.79; 95% confidence interval [CI], 1.28-6.07) or breast cancer (HR, 1.40; 95% CI, 1.01-1.94). There was a trend towards higher risk of pancreatic cancer in relation to a family history of colorectal cancer (HR, 1.21; 95% CI, 0.95-1.55) or AJ heritage (HR, 1.29; 95% CI, 0.94-1.77). The risk was highly elevated among AJ men with a family history of breast or colorectal cancer (HR, 2.61 [95% CI, 1.41-4.82] and 1.92 [95% CI, 1.05-3.49], respectively). CONCLUSION: Family history of pancreatic cancer was associated with increased risk of this malignancy. Family history of breast or colorectal cancer was associated with the increased risk among AJ men.

Germline cancer susceptibility gene variants, somatic second hits, and survival outcomes in patients with resected pancreatic cancer.

PURPOSE: Germline variants in double-strand DNA damage repair (dsDDR) genes (e.g., BRCA1/2) predispose to pancreatic adenocarcinoma (PDAC) and may predict sensitivity to platinum-based chemotherapy and poly(ADP) ribose polymerase (PARP) inhibitors. We sought to determine the prevalence and significance of germline cancer susceptibility gene variants in PDAC with paired somatic and survival analyses. METHODS: Using a customized next-generation sequencing panel, germline/somatic DNA was analyzed from 289 patients with resected PDAC ascertained without preselection for high-risk features (e.g., young age, personal/family history). All identified variants were assessed for pathogenicity. Outcomes were analyzed using multivariable-adjusted Cox proportional hazards regression. RESULTS: We found that 28/289 (9.7%; 95% confidence interval [CI] 6.5-13.7%) patients carried pathogenic/likely pathogenic germline variants, including 21 (7.3%) dsDDR gene variants (3 BRCA1, 4 BRCA2, 14 other dsDDR genes [ATM, BRIP1, CHEK2, NBN, PALB2, RAD50, RAD51C]), 3 Lynch syndrome, and 4 other genes (APC p.I1307K, CDKN2A, TP53). Somatic sequencing and immunohistochemistry identified second hits in the tumor in 12/27 (44.4%) patients with germline variants (1 failed sequencing). Compared with noncarriers, patients with germline dsDDR gene variants had superior overall survival (hazard ratio [HR] 0.54; 95% CI 0.30-0.99; P = 0.05). CONCLUSION: Nearly 10% of PDAC patients harbor germline variants, although the majority lack somatic second hits, the therapeutic significance of which warrants further study.

Survival of Staphylococcus epidermidis in Fibroblasts and Osteoblasts.

Staphylococcus epidermidis is a leading cause of infections associated with indwelling medical devices, including prosthetic joint infection. While biofilm formation is assumed to be the main mechanism underlying the chronic infections S. epidermidis causes, we hypothesized that S. epidermidis also evades immune killing, contributing to its pathogenesis. Here, we show that prosthetic joint-associated S. epidermidis isolates can persist intracellularly within human fibroblasts and inside human and mouse osteoblasts. We also show that the intracellularly persisting bacteria reside primarily within acidic phagolysosomes and that over the course of infection, small-colony variants are selected for. Moreover, upon eukaryotic cell death, these bacteria, which can outlive their host, can escape into the extracellular environment, providing them an opportunity to form biofilms on implant surfaces at delayed time points in implant-associated infection. In summary, the acidic phagolysosomes of fibroblasts and osteoblasts serve as reservoirs for chronic or delayed S. epidermidis infection.

Extracellular vesicle-mediated phenotype switching in malignant and non-malignant colon cells.

BACKGROUND: Extracellular vesicles (EVs) are secreted from many cells, carrying cargoes including proteins and nucleic acids. Research has shown that EVs play a role in a variety of biological processes including immunity, bone formation and recently they have been implicated in promotion of a metastatic phenotype. METHODS: EVs were isolated from HCT116 colon cancer cells, 1459 non-malignant colon fibroblast cells, and tumor and normal colon tissue from a patient sample. Co-cultures were performed with 1459 cells and malignant vesicles, as well as HCT116 cells and non-malignant vesicles. Malignant phenotype was measured using soft agar colony formation assay. Co-cultures were also analyzed for protein levels using mass spectrometry. The importance of 14-3-3 zeta/delta in transfer of malignant phenotype was explored using siRNA. Additionally, luciferase reporter assay was used to measure the transcriptional activity of NF-κB. RESULTS: This study demonstrates the ability of EVs derived from malignant colon cancer cell line and malignant patient tissue to induce the malignant phenotype in non-malignant colon cells. Similarly, EVs derived from non-malignant colon cell lines and normal patient tissue reversed the malignant phenotype of HCT116 cells. Cells expressing an EV-induced malignant phenotype showed increased transcriptional activity of NF-κB which was inhibited by the NF--κB inhibitor, BAY117082. We also demonstrate that knock down of 14-3-3 zeta/delta reduced anchorage-independent growth of HCT116 cells and 1459 cells co-cultured with HCT derived EVs. CONCLUSIONS: Evidence of EV-mediated induction of malignant phenotype, and reversal of malignant phenotype, provides rational basis for further study of the role of EVs in tumorigenesis. Identification of 14-3-3 zeta/delta as up-regulated in malignancy suggests its potential as a putative drug target for the treatment of colorectal cancer.

Transcriptionally Active Human Papillomavirus Infection in a Minority of Esophageal Squamous Cell Carcinomas in North America.

The role of Human papillomavirus (HPV) infection in esophageal squamous cell carcinoma (ESCC) is a topic of ongoing debate. This study used two screening approaches to look for evidence of HPV infection in esophageal squamous cell carcinoma. We initially checked for HPV infection in a randomly selected group of 53 ESCC cases. We did not detect any tumors positive for high-risk HPV. However, during clinical practice, we identified an HPV-positive ESCC in the distal esophagus, which tested positive for HPV16. This index case was TP53 wild-type, as determined by next-generation DNA sequencing (NGS). Since TP53 mutations are rare in other HPV-driven cancers, we improved our screening method by limiting our screen to a subset of ESCC cases without TP53 mutations. A second screen of 95 ESCCs (from 93 patients) sequenced by NGS revealed an additional 7 ESCCs with TP53 wild-type status (7.3% of the total). Of the 7 cases, 2 cases were found to be high-risk HPV positive. Both patients also tested positive for circulating cell-free HPV DNA and had a complete response to neoadjuvant chemoradiation. The index patient had microscopic residual tumor following neoadjuvant therapy. The patient underwent adjuvant immunotherapy and remained disease free after 22 months of surveillance. This study affirms the transcriptionally active status of high-risk HPV in a minority of ESCC patients in North America.

RAS/RAF Comutation and ERBB2 Copy Number Modulates HER2 Heterogeneity and Responsiveness to HER2-directed Therapy in Colorectal Cancer.

PURPOSE: ERBB2-amplified colorectal cancer is a distinct molecular subtype with expanding treatments. Implications of concurrent oncogenic RAS/RAF alterations are not known. EXPERIMENTAL DESIGN: Dana-Farber and Foundation Medicine Inc. Colorectal cancer cohorts with genomic profiling were used to identify ERBB2-amplified cases [Dana-Farber, n = 47/2,729 (1.7%); FMI, n = 1857/49,839 (3.7%)]. Outcomes of patients receiving HER2-directed therapies are reported (Dana-Farber, n = 9; Flatiron Health-Foundation Medicine clinicogenomic database, FH-FMI CGDB, n = 38). Multisite HER2 IHC and genomic profiling were performed to understand HER2 intratumoral and interlesional heterogeneity. The impact of concurrent RAS comutations on the effectiveness of HER2-directed therapies were studied in isogenic colorectal cancer cell lines and xenografts. RESULTS: ERBB2 amplifications are enriched in left-sided colorectal cancer. Twenty percent of ERBB2-amplified colorectal cancers have co-occurring oncogenic RAS/RAF alterations. While RAS/RAF WT colorectal cancers typically have clonal ERBB2 amplification, colorectal cancers with co-occurring RAS/RAF alterations have lower level ERRB2 amplification, higher intratumoral heterogeneity, and interlesional ERBB2 discordance. These distinct genomic patterns lead to differential responsiveness and patterns of resistance to HER2-directed therapy. ERBB2-amplified colorectal cancer with RAS/RAF alterations are resistant to trastuzumab-based combinations, such as trastuzumab/tucatinib, but retain sensitivity to trastuzumab deruxtecan in in vitro and murine models. Trastuzumab deruxtecan shows clinical efficacy in cases with high-level ERBB2-amplified RAS/RAF coaltered colorectal cancer. CONCLUSIONS: Co-occurring RAS/RAF alterations define a unique subtype of ERBB2-amplified colorectal cancer that has increased intratumoral heterogeneity, interlesional discordance, and resistance to trastuzumab-based combinations. Further examination of trastuzumab deruxtecan in this previously understudied cohort of ERBB2-amplified colorectal cancer is warranted.

RKIP phosphorylation and STAT3 activation is inhibited by oxaliplatin and camptothecin and are associated with poor prognosis in stage II colon cancer patients.

BACKGROUND: A major obstacle in treating colorectal cancer (CRC) is the acquired resistance to chemotherapeutic agents. An important protein in the regulation of cancer cell death and clinical outcome is Raf kinase inhibitor protein (RKIP). In contrast, activated signal transducer and activator of transcription 3 (STAT3) is a protein that promotes tumor cell survival by inhibiting apoptosis and has an important role in cancer progression in many of cancer types. The aim of this study was to evaluate the regulation of RKIP and STAT3 after treatment with clinically relevant chemotherapeutic agents (camptothecin (CPT) and oxaliplatin (OXP)) and the cytokine interleukin-6 (IL-6) in HCT116 colon cancer cells as well as evaluate the association between RKIP and STAT3 with clinical outcome of Stage II colon cancer patients. METHODS: HCT-116 colon cancer cells were treated with CPT, OXP, and IL-6 separately or in combination in a time and dose-dependent manner and examined for phosphorylated and non-phosphorylated RKIP and STAT3 via Western blot analysis. STAT3 transcriptional activity was measured via a luciferase reporter assay in HCT116 cells treated with CPT, IL-6 or transfected with JAK 1, 2 separately or in combination. We extended these observations and determined STAT3 and RKIP/ pRKIP in tumor microarrays (TMA) in stage II colon cancer patients. RESULTS: We demonstrate IL-6-mediated activation of STAT3 occurs in conjunction with the phosphorylation of RKIP in vitro in human colon cancer cells. OXP and CPT block IL-6 mediated STAT3 activation and RKIP phosphorylation via the inhibition of the interaction of STAT3 with gp130. We determined that STAT3 and nuclear pRKIP are significantly associated with poor patient prognosis in stage II colon cancer patients. CONCLUSIONS: In the analysis of tumor samples from stage II colon cancer patients and the human colon carcinoma cell line HCT116, pRKIP and STAT3, 2 proteins potentially involved in the resistance to conventional treatments were detected. The phosphorylation of pRKIP and STAT3 are induced by the cytokine IL-6 and suppressed by the chemotherapeutic drugs CPT and OXP. Therefore, these results suggest that STAT3 and pRKIP may serve as prognostic biomarkers in stage II colon cancer patients and may improve chemotherapy.

Optimization of Thromboprophylaxis Use in Hospitalized Pediatric Patients Through Implementation of a Venous Thromboembolism Risk Assessment Tool.

OBJECTIVE: Venous thromboembolism (VTE) is a leading cause of hospital-acquired morbidity for pediatric patients. Pharmacological thromboprophylaxis increases the risk of adverse events such as bleeding complications. There exists a need for a universal VTE risk assessment tool to aid in thromboprophylaxis prescribing while minimizing the risk of adverse events. The objective of this study is to investigate if implementation of a VTE risk assessment tool is associated with a change in the rate of thromboprophylaxis prescribing. METHODS: This retrospective study evaluated the change in thromboprophylaxis prescribing pre and post implementation of a VTE risk assessment tool. Patients were excluded if they were pregnant, diagnosed with VTE ≤48 hours of admission, presented with VTE symptoms, or if they were diagnosed with multisystem inflammatory syndrome in children (MIS-C) or coronavirus disease (COVID-19). RESULTS: A total of 186 pediatric patients were included in this study. Thromboprophylaxis was prescribed in 16/93 (17.12%) and 75/93 (80.6%) patients in the pre- and post-implementation group, respectively (95% CI, 0.523-0.745; p < 0.001). No VTE events occurred in either group. Bleeding complications occurred in 3.2% and 7.5% of patients in the pre- and post-implementation groups, respectively. The risk tool was used in 80.6% of patients; providers used the tool correctly in 48% of patients and incorrectly in 52% of patients. CONCLUSION: Implementation of a VTE risk assessment tool was associated with a statistically significant change in the rate of thromboprophylaxis prescribing. Incorrect use may be minimized by providing provider reeducation and making modifications to the order set.

Rare variants found in multiplex families with orofacial clefts: Does expanding the phenotype make a difference?

Whole-exome sequencing (WES) is now a relatively straightforward process to identify causal variants in Mendelian disorders. However, the same is not true for WES in families where the inheritance patterns are less clear, and a complex etiology is suspected. Orofacial clefts (OFCs) are highly heritable birth defects with both Mendelian and complex etiologies. The phenotypic spectrum of OFCs may include overt clefts and several subclinical phenotypes, such as discontinuities in the orbicularis oris muscle (OOM) in the upper lip, velopharyngeal insufficiency (VPI), microform clefts or bifid uvulas. We hypothesize that expanding the OFC phenotype to include these phenotypes can clarify inheritance patterns in multiplex families, making them appear more Mendelian. We performed whole-exome sequencing to find rare, likely causal genetic variants in 31 multiplex OFC families, which included families with multiple individuals with OFCs and individuals with subclinical phenotypes. We identified likely causal variants in COL11A2, IRF6, KLF4, SHROOM3, SMC3, TP63 , and TBX3 in seven families. Although we did not find clear evidence supporting the subclinical phenotype hypothesis, our findings support a role for rare variants in the etiology of OFCs.

Pancreatic cancer is associated with medication changes prior to clinical diagnosis.

Patients with pancreatic ductal adenocarcinoma (PDAC) commonly develop symptoms and signs in the 1-2 years before diagnosis that can result in changes to medications. We investigate recent medication changes and PDAC diagnosis in Nurses' Health Study (NHS; females) and Health Professionals Follow-up Study (HPFS; males), including up to 148,973 U.S. participants followed for 2,994,057 person-years and 991 incident PDAC cases. Here we show recent initiation of antidiabetic (NHS) or anticoagulant (NHS, HFS) medications and cessation of antihypertensive medications (NHS, HPFS) are associated with pancreatic cancer diagnosis in the next 2 years. Two-year PDAC risk increases as number of relevant medication changes increases (P-trend <1 × 10-5), with participants who recently start antidiabetic and stop antihypertensive medications having multivariable-adjusted hazard ratio of 4.86 (95%CI, 1.74-13.6). These changes are not associated with diagnosis of other digestive system cancers. Recent medication changes should be considered as candidate features in multi-factor risk models for PDAC, though they are not causally implicated in development of PDAC.

Current chemoprevention approaches in Lynch syndrome and Familial adenomatous polyposis: a global clinical practice survey.

Background: International chemoprevention preferences and approaches in Lynch syndrome (LS) and APC-associated polyposis, including Familial adenomatous polyposis (FAP) and attenuated FAP (AFAP) have not been previously explored. Aim: To describe current chemoprevention strategies for patients with LS or FAP/AFAP (referred to collectively as FAP) practiced by members of four international hereditary cancer societies through administration of a survey. Results: Ninety-six participants across four hereditary gastrointestinal cancer societies responded to the survey. Most respondents (91%, 87/96) completed information regarding their demographics and practice characteristics relating to hereditary gastrointestinal cancer and chemoprevention clinical practices. Sixty-nine percent (60/87) of respondents offer chemoprevention for FAP and/or LS as a part of their practice. Of the 75% (72/96) of survey respondents who were eligible to answer practice-based clinical vignettes based off of their responses to ten barrier questions regarding chemoprevention, 88% (63/72) of those participants completed at least one case vignette question to further characterize chemoprevention practices in FAP and/or LS. In FAP, 51% (32/63) would offer chemoprevention for rectal polyposis, with sulindac - 300 mg (18%, 10/56) and aspirin (16%, 9/56) being the most frequently selected options. In LS, 93% (55/59) of professionals discuss chemoprevention and 59% (35/59) frequently recommend chemoprevention. Close to half of the respondents (47%, 26/55) would recommend beginning aspirin at time of commencement of the patient's first screening colonoscopy (usually at age 25yrs). Ninety-four percent (47/50) of respondents would consider a patient's diagnosis of LS as an influential factor for aspirin use. There was no consensus on the dose of aspirin (≤100 mg, >100 mg - 325 mg or 600 mg) to offer patients with LS and there was no agreement on how other factors, such as BMI, hypertension, family history of colorectal cancer, and family history of heart disease, would affect the recommendation for aspirin use. Possible harm among older patients (>70 years) was identified as the most common reason to discourage aspirin use. Conclusion: Although chemoprevention is widely discussed and offered to patients with FAP and LS by an international group of hereditary gastrointestinal cancer experts, there is significant heterogeneity in how it is applied in clinical practice.