Characteristics of women concordant and discordant for urine drug screens for cannabis exposure and self-reported cannabis use during pregnancy.

BACKGROUND: Increasing cannabis use among pregnant people and equivocal evidence linking prenatal cannabis exposure to adverse outcomes in offspring highlights the need to understand its potential impact on pregnancy and child outcomes. Assessing cannabis use during pregnancy remains a major challenge with potential influences of stigma on self-report as well as detection limitations of easily collected biological matrices. OBJECTIVE: This descriptive study examined the concordance between self-reported (SR) cannabis use and urine drug screen (UDS) detection of cannabis exposure during the first trimester of pregnancy and characterized concordant and discordant groups for sociodemographic factors, modes of use, secondhand exposure to cannabis and tobacco, and alcohol use and cotinine positivity. STUDY DESIGN: The Cannabis Use During Development and Early Life (CUDDEL) Study is an ongoing longitudinal study that recruits pregnant individuals presenting for obstetric care, who report lifetime cannabis use as well as using (n = 289) or not using cannabis (n = 169) during pregnancy. During the first trimester pregnancy visit, SR of cannabis use and a UDS for cannabis, other illicit drugs and nicotine are acquired from eligible participants, of whom 333 as of 05/01/2023 had both. RESULTS: Using available CUDDEL Study data on both SR and UDS (n = 333; age 26.6 ± 4.7; 88.6% Black; 45.4% below federal poverty threshold; 56.5% with paid employment; 89% with high school education; 22% first pregnancy; 12.3 ± 3.6 weeks gestation), we classified pregnant individuals with SR and UDS data into 4 groups based on concordance (k = 0.49 [95% C.I. 0.40-0.58]) between SR cannabis use and UDS cannabis detection during the first trimester: 1) SR+/UDS+ (n = 107); 2) SR-/UDS- (n = 142); 3) SR+/UDS- (n = 44); 4) SR-/UDS+ (n = 40). Those who were SR+/UDS- reported less frequent cannabis use and fewer hours under the influence of cannabis during their pregnancy. Those who were SR-/UDS+ were more likely to have joined the study at a lower gestational age with 62.5% reporting cannabis use during their pregnancy prior to being aware that they were pregnant. Of the 40 SR-/UDS+ women, 14 (i.e., 35%) reported past month secondhand exposure, or blunt usage. In the subset of individuals with SR and UDS available at trimester 2 (N = 160) and 3 (N = 140), concordant groups were mostly stable and > 50% of those in the discordant groups became concordant by the second trimester. Classifying individuals as exposed or not exposed who were SR+ and/or UDS+ resulted in minor changes in group status based on self-report at screening. CONCLUSION: Overall, there was moderate concordance between SR and UDS for cannabis use/exposure during pregnancy. Instances of SR+/UDS- discordancy may partially be attributable to lower levels of use that are not detected on UDS. SR-/UDS+ discordancy may arise from recent use prior to knowledge of pregnancy, extreme secondhand exposure, deception, and challenges with completing questionnaires. Acquiring both self-report and biological detection of cannabis use/exposure allows for the examination of convergent evidence. Classifying those who are SR+ and/or UDS+ as individuals who used cannabis during their first trimester after being aware of their pregnancy resulted in only a minor change in exposure status; thus, relying on self-report screening, at least in this population and within this sociocultural context likely provides an adequate approximation of cannabis use during pregnancy.

A biobank of small cell lung cancer CDX models elucidates inter- and intratumoral phenotypic heterogeneity.

Although small cell lung cancer (SCLC) is treated as a homogeneous disease, biopsies and preclinical models reveal heterogeneity in transcriptomes and morphology. SCLC subtypes were recently defined by neuroendocrine transcription factor (NETF) expression. Circulating-tumor-cell-derived explant models (CDX) recapitulate donor patients' tumor morphology, diagnostic NE marker expression and chemotherapy responses. We describe a biobank of 38 CDX models, including six CDX pairs generated pretreatment and at disease progression revealing complex intra- and intertumoral heterogeneity. Transcriptomic analysis confirmed three of four previously described subtypes based on ASCL1, NEUROD1 and POU2F3 expression and identified a previously unreported subtype based on another NETF, ATOH1. We document evolution during disease progression exemplified by altered MYC and NOTCH gene expression, increased 'variant' cell morphology, and metastasis without strong evidence of epithelial to mesenchymal transition. This CDX biobank provides a research resource to facilitate SCLC personalized medicine.

Signaling pathway screening platforms are an efficient approach to identify therapeutic targets in cancers that lack known driver mutations: a case report for a cancer of unknown primary origin.

Precision medicine aims to tailor cancer therapies to target specific tumor-promoting aberrations. For tumors that lack actionable drivers, which occurs frequently in the clinic, extensive molecular characterization and pre-clinical drug efficacy studies will be required. A cell line maintained at low passage and a patient- derived xenograft model (PDX) were generated using a fresh biopsy from a patient with a poorly-differentiated neuroendocrine tumor of unknown primary origin. Next-generation sequencing, high throughput signaling network analysis, and drug efficacy trials were then conducted to identify actionable targets for therapeutic intervention. No actionable mutations were identified after whole exome sequencing of the patient's DNA. However, whole genome sequencing revealed amplification of the 3q and 5p chromosomal arms, that include the PIK3CA and RICTOR genes, respectively. We then conducted pathway analysis, which revealed activation of the AKT pathway. Based on this analysis, efficacy of PIK3CA and AKT inhibitors were evaluated in the tumor biopsy-derived cell culture and PDX, and response to the AKT inhibitor AZD5363 was observed both in vitro and in vivo indicating the patient would benefit from targeted therapies directed against the serine/threonine kinase AKT. In conclusion, our study demonstrates that high throughput signaling pathway analysis will significantly aid in identifying actionable alterations in rare tumors and guide patient stratification into early-phase clinical trials.

The Combination of the PARP Inhibitor Olaparib and the WEE1 Inhibitor AZD1775 as a New Therapeutic Option for Small Cell Lung Cancer.

Purpose: Introduced in 1987, platinum-based chemotherapy remains standard of care for small cell lung cancer (SCLC), a most aggressive, recalcitrant tumor. Prominent barriers to progress are paucity of tumor tissue to identify drug targets and patient-relevant models to interrogate novel therapies. Following our development of circulating tumor cell patient-derived explants (CDX) as models that faithfully mirror patient disease, here we exploit CDX to examine new therapeutic options for SCLC.Experimental Design: We investigated the efficacy of the PARP inhibitor olaparib alone or in combination with the WEE1 kinase inhibitor AZD1775 in 10 phenotypically distinct SCLC CDX in vivo and/or ex vivo These CDX represent chemosensitive and chemorefractory disease including the first reported paired CDX generated longitudinally before treatment and upon disease progression.Results: There was a heterogeneous depth and duration of response to olaparib/AZD1775 that diminished when tested at disease progression. However, efficacy of this combination consistently exceeded that of cisplatin/etoposide, with cures in one CDX model. Genomic and protein analyses revealed defects in homologous recombination repair genes and oncogenes that induce replication stress (such as MYC family members), predisposed CDX to combined olaparib/AZD1775 sensitivity, although universal predictors of response were not noted.Conclusions: These preclinical data provide a strong rationale to trial this combination in the clinic informed by prevalent, readily accessed circulating tumor cell-based biomarkers. New therapies will be evaluated in SCLC patients after first-line chemotherapy, and our data suggest that the combination of olaparib/AZD1775 should be used as early as possible and before disease relapse. Clin Cancer Res; 24(20); 5153-64. ©2018 AACR.

Vasculogenic mimicry in small cell lung cancer.

Small cell lung cancer (SCLC) is characterized by prevalent circulating tumour cells (CTCs), early metastasis and poor prognosis. We show that SCLC patients (37/38) have rare CTC subpopulations co-expressing vascular endothelial-cadherin (VE-cadherin) and cytokeratins consistent with vasculogenic mimicry (VM), a process whereby tumour cells form 'endothelial-like' vessels. Single-cell genomic analysis reveals characteristic SCLC genomic changes in both VE-cadherin-positive and -negative CTCs. Higher levels of VM are associated with worse overall survival in 41 limited-stage patients' biopsies (P<0.025). VM vessels are also observed in 9/10 CTC patient-derived explants (CDX), where molecular analysis of fractionated VE-cadherin-positive cells uncovered copy-number alterations and mutated TP53, confirming human tumour origin. VE-cadherin is required for VM in NCI-H446 SCLC xenografts, where VM decreases tumour latency and, despite increased cisplatin intra-tumour delivery, decreases cisplatin efficacy. The functional significance of VM in SCLC suggests VM regulation may provide new targets for therapeutic intervention.