Explore the vast range of titles available.

Models that recapitulate the complexity of human tumors are urgently needed to develop more effective cancer therapies. We report a bank of human patient-derived xenografts (PDXs) and matched organoid cultures from tumors that represent the greatest unmet need: endocrine-resistant, treatment-refractory and metastatic breast cancers. We leverage matched PDXs and PDX-derived organoids (PDxO) for drug screening that is feasible and cost-effective with in vivo validation. Moreover, we demonstrate the feasibility of using these models for precision oncology in real time with clinical care in a case of triple-negative breast cancer (TNBC) with early metastatic recurrence. Our results uncovered a Food and Drug Administration (FDA)-approved drug with high efficacy against the models. Treatment with this therapy resulted in a complete response for the individual and a progression-free survival (PFS) period more than three times longer than their previous therapies. This work provides valuable methods and resources for functional precision medicine and drug development for human breast cancer.

Telepathology is a digital, microscope-independent method of diagnosing pathology from scanned slides. Frozen sections (FS) can be performed and read by a pathologist at any site. At our institution, telepathology is used for diagnosis of frozen sections of sentinel lymph nodes (SLN) in patients who have undergone neoadjuvant chemotherapy and are enrolled in a clinical trial. We investigated the accuracy of diagnosing SLN frozen sections in the neoadjuvant setting using telepathology. SLN were entirely submitted for frozen section. A pathology assistant prepared the frozen and scanned the slides using VisionTek M6 digital microscope ecosystem (East Dundee, IL). Cases were interpreted by trained, board-certified pathologists. All frozen sections remnants were submitted for formalin-fixed paraffin-embedded permanent sections. Frozen section diagnoses using telepathology were compared to final pathology. Turn-around time from specimen collection to frozen section diagnosis was recorded. 54 SLN from 22 breast neoadjuvant cases were diagnosed via telepathology from March 2017 to July 2019. 95% of SLNs interpreted as negative on frozen section and on permanents. A definitive diagnosis could not be rendered on six SLNs; diagnosed “atypical” at frozen. Sensitivity and specificity were 80% and 100% respectively with accuracy of 95.8%. The false-negative rate was 5%. There were no false positives. The average turn-around time was over an hour. Telepathology is an accurate method of diagnosing SLN frozen sections in the neoadjuvant setting, but lobular carcinomas and treatment effect pose diagnostic challenges and the time to report results is increased compared to standard microscopy.

Abstract Model systems that recapitulate the complexity of human tumors and the reality of variable treatment responses are urgently needed to better understand cancer biology and to develop more effective cancer therapies. Here we report development and characterization of a large bank of patient-derived xenografts (PDX) and matched organoid cultures from tumors that represent some of the greatest unmet needs in breast cancer research and treatment. These include endocrine-resistant, treatment-refractory, and metastatic breast cancers and, in some cases, multiple tumor collections from the same patients. The models can be grown long-term with high fidelity to the original tumors. We show that development of matched PDX and PDX-derived organoid (PDxO) models facilitates high-throughput drug screening that is feasible and cost-effective, while also allowing in vivo validation of results. Our data reveal consistency between drug screening results in organoids and drug responses in breast cancer PDX. Moreover, we demonstrate the feasibility of using these patient-derived models for precision oncology in real time with patient care, using a case of a triple negative breast cancer with early metastatic recurrence as an example. Our results uncovered an FDA-approved drug with high efficacy against the models. Treatment with the PDxO-directed therapy resulted in a complete response for the patient and a progression-free survival period more than three times longer than her previous therapies. This work provides valuable new methods and resources for functional precision medicine and drug development for human breast cancer. Figure1 Figure1 * Download figure * Open in new tab Competing Interest Statement University of Utah may license the models described herein to for-profit companies, which may result in tangible property royalties to members of the Welm labs who developed the models (K.P.G., M.F., A.J.B., S.D.S., Z.C., Y.S.D., L.Z., E.C-S., C-H.Y., J.T., G.W., A.L.W., B.E.W.) M.T.L. is a Manager in StemMed Holdings L.L.C., a limited partner in StemMed Ltd., and holds an equity stake in Tvardi Therapeutics. L.E.D. is a compensated employee of StemMed, Ltd. S.O. has received research support/reagents from AstraZeneca, Illumina, H3 Biomedicine and Blueprint Medicine. The other authors declare no conflicts. Footnotes * Figure 4a is updated with new data.

Anxiety is a common comorbidity of chronic obstructive pulmonary disease (COPD) that is associated with higher morbidity and mortality. We evaluated three anxiety screening questionnaires: the Generalized Anxiety Disorder 7-Item Scale (GAD-7), the Hospital Anxiety and Depression Scale Anxiety subscale (HADS-A), and the Anxiety Inventory for Respiratory Disease (AIR). To evaluate and compare the test performance characteristics of three anxiety screening questionnaires, using the Mini-International Neuropsychiatric Interview (MINI), version 7.0, as the \"gold standard.\" Individuals with COPD were recruited at 16 centers. The MINI and questionnaires were administered by trained research coordinators at an in-person visit and readministered by telephone 2-4 weeks later. A composite score for the presence of any , (DSM-V) anxiety disorder was computed, based on the MINI as the gold standard, compared with a participant screening positive on self-report measures for these analyses. Two hundred and twenty eligible individuals with COPD were enrolled; 219 completed the study. Eleven percent were identified as having a DSM-V anxiety disorder, based on the MINI. Elevated anxiety symptoms based on questionnaires were 38% for the AIR, 30% for the GAD-7, and 20% for the HADS-A. Area under the receiver operating characteristic curve (AUC) was highest for the GAD-7 (0.78; 95% confidence interval [CI], 0.69-0.87), followed by the HADS-A (0.74; 95% CI, 0.64-0.84) and the AIR (0.66; 95% CI, 0.56-0.76). The AUC for the GAD-7 was significantly greater than for the AIR (  = 0.014). Sensitivity was not statistically different among the questionnaires: 77% for the GAD-7, 63% for the HADS-A, and 66% for the AIR. The HADS-A had the highest specificity, 85%, which was significantly higher than that of the GAD-7 (77%;  < 0.001) and the AIR (65%;  < 0.001); GAD-7 specificity was higher than AIR specificity (  < 0.001). Symptoms of anxiety among patients with COPD as identified by screening questionnaires were common and significantly higher than the prevalence of anxiety disorder meeting DSM-V criteria. The GAD-7, the HADS-A and the AIR questionnaires had fair to moderate psychometric properties as screening tools for anxiety in individuals with COPD, indicating the need for improved measures for this patient population.