Patient-derived xenografts (PDXs) are resected human tumors engrafted into mice for preclinical studies and therapeutic testing. It has been proposed that the mouse host affects tumor evolution during PDX engraftment and propagation, affecting the accuracy of PDX modeling of human cancer. Here, we exhaustively analyze copy number alterations (CNAs) in 1,451 PDX and matched patient tumor (PT) samples from 509 PDX models. CNA inferences based on DNA sequencing and microarray data displayed substantially higher resolution and dynamic range than gene expression-based inferences, and they also showed strong CNA conservation from PTs through late-passage PDXs. CNA recurrence analysis of 130 colorectal and breast PT/PDX-early/PDX-late trios confirmed high-resolution CNA retention. We observed no significant enrichment of cancer-related genes in PDX-specific CNAs across models. Moreover, CNA differences between patient and PDX tumors were comparable to variations in multiregion samples within patients. Our study demonstrates the lack of systematic copy number evolution driven by the PDX mouse host.

• Chronic thromboembolic pulmonary hypertension (CTEPH) is potentially curable by surgery. • The triage of patients with pulmonary hypertension currently relies on scintigraphy. • Dual-energy CT (DECT) can provide standard diagnostic information and lung perfusion from a single acquisition. • There is excellent agreement between DECT perfusion and scintigraphy in separating CTEPH and non-CTEPH patients.

• Depiction of chronic pulmonary embolism exclusively located on peripheral arteries is difficult. • The main differential diagnosis of pCTEPH is PAH. • The pattern of DECT perfusion changes can help differentiate PAH and pCETPH. • In PAH, almost all segments with abnormal perfusion showed patchy defects. • In pCTEPH, patchy and PE-type defects were the most frequent abnormalities.

Gastric cancer is the world's third leading cause of cancer mortality. In spite of significant therapeutic improvements, the clinical outcome for patients with advanced gastric cancer is poor; thus, the identification and validation of novel targets is extremely important from a clinical point of view. We generated a wide, multilevel platform of gastric cancer models, comprising 100 patient-derived xenografts (PDX), primary cell lines, and organoids. Samples were classified according to their histology, microsatellite stability, Epstein-Barr virus status, and molecular profile. This PDX platform is the widest in an academic institution, and it includes all the gastric cancer histologic and molecular types identified by The Cancer Genome Atlas. PDX histopathologic features were consistent with those of patients' primary tumors and were maintained throughout passages in mice. Factors modulating grafting rate were histology, TNM stage, copy number gain of tyrosine kinases/KRAS genes, and microsatellite stability status. PDX and PDX-derived cells/organoids demonstrated potential use-fulness to study targeted therapy response. Finally, PDX transcriptomic analysis identified a cancer cell-intrinsic microsatellite instability (MSI) signature, which was efficiently exported to gastric cancer, allowing the identification, among microsatellite stable (MSS) patients, of a subset of MSI-like tumors with common molecular aspects and significant better prognosis. In conclusion, we generated a wide gastric cancer PDX platform, whose exploitation will help identify and validate novel "druggable" targets and optimize therapeutic strategies. Moreover, transcriptomic analysis of gastric cancer PDXs allowed the identification of a cancer cell-intrinsic MSI signature, recognizing a subset of MSS patients with MSI transcriptional traits, endowed with better prognosis.Significance: This study reports a multilevel platform of gastric cancer PDXs and identifies a MSI gastric signature that could contribute to the advancement of precision medicine in gastric cancer.

Objective To explore associations between English proficiency, insurance status, outpatient rehabilitation service availability and travel time for children with traumatic brain injury (TBI). Design We used an ecologic cross-sectional design. Data were analyzed from a cohort of 82 children with moderate to severe TBI and rehabilitation providers in Washington State. Main measures included availability and travel time to services. Results Fewer than 20% of providers accepted children with Medicaid and provided language interpretation. Mental health services were most limited. Adjusted for median household income, multilingual service availability was lowest in counties with greater language diversity; for every 10% increase in persons >5 years old speaking a language other than English at home, there was a 34% decrease in availability of multilingual services (PR=0.66; 95%; CI:0.48-0.90). Adjusted for education and Medicaid status, children from Spanish-speaking families had significantly longer travel times to services (mean=16 additional minutes to mental health; 9 to other therapies). Conclusions Children in households with limited English proficiency and Medicaid faced significant barriers in availability and proximity of outpatient rehabilitation services. Innovative service strategies are needed to equitably improve availability of rehabilitation for children with TBI. Similar studies in other regions will inform our understanding of the scope of these disparities.

SummaryBackgroundThe transumbilical route began being clinically feasible with or without unique access devices.SettingThe setting for this study was a private practice at Clínica Las Condes, Santiago, Chile.ObjectiveThe objective was to describe our experience performing a laparoscopic sleeve gastrectomy (LSG) via transumbilical route using a single-port access device in addition to standard laparoscopic instruments.MethodA prospective nonrandomized protocol was applied to patients fulfilling the following inclusion criteria: to have been medically indicated for an LSG, to have a body mass index (BMI) of less than or equal to 40 kg/m2, and the distance between the xiphoid appendix and umbilicus should be less than 22 cm. All patients were female with a median (p50) age of 34.5 (ranging from 21 to 57) years, a median weight of 92 (ranging from 82.5 to 113) kg, and a median BMI of 35.1 (ranging from 30.5 to 40) kg/m2. The device insertion technique, the gastrectomy, and postoperative management are described.ResultsLSG via transumbilical route was successfully carried out in 19 of the 20 patients in whom the procedure was performed; one patient had to be converted to a conventional laparoscopic procedure. Mean operating time was 127 (ranging from 90 to 170) min. On the second postoperative day, all patients were assessed through an upper gastrointestinal barium-contrasted radiological series. There was neither morbidity nor mortality in this group. Excess weight loss at 25 months after surgery was 114 %.ConclusionsSingle-port LSG can be successfully performed in selected obese patients with a BMI of less than 40 kg/m2 using traditional laparoscopic instruments. The technique allows performing a safe and effective vertical gastrectomy.

41 a PDXNET consortium 42 b EurOPDX consortium 43 # These authors contributed equally to this work.44 § These authors jointly supervised this work. ABSTRACT 107Patient-derived xenografts (PDXs) are resected human tumors engrafted into mice for preclinical 108 studies and therapeutic testing. It has been proposed that the mouse host affects tumor evolution 109 during PDX engraftment and propagation, impacting the accuracy of PDX modeling of human 110 cancer. Here we exhaustively analyze copy number alterations (CNAs) in 1451 PDX and matched 111 patient tumor (PT) samples from 509 PDX models. CNA inferences based on DNA sequencing 112 and microarray data displayed substantially higher resolution and dynamic range than gene 113 expression-based inferences, and they also showed strong CNA conservation from PTs through 114 late-passage PDXs. CNA recurrence analysis of 130 colorectal and breast PT/PDX-early/PDX-115 late trios confirmed high-resolution CNA retention. We observed no significant enrichment of 116 cancer-related genes in PDX-specific CNAs across models. Moreover, CNA differences between 117 patient and PDX tumors were comparable to variations in multi-region samples within patients. 118Our study demonstrates the lack of systematic copy number evolution driven by the PDX mouse 119 host. 121 MAIN 122A variety of models of human cancer have been used to study basic biological processes and 123 predict responses to treatment. For example, mouse models with genetically engineered 124 mutations in oncogenes and tumor suppressor genes have clarified the genetic and molecular 125 basis of tumor initiation and progression 1,2 , though responses sometimes differ between human 126 and mouse 3 . Cell lines have also been widely used to study cancer cells, but they lack the 127 heterogeneity and microenvironment of in vivo tumors and have shown limitations for predicting 128 clinical response 4 . Human tumors engrafted into transplant-compliant recipient mice (patient-129 derived xenografts, PDX) have advantages over prior systems for preclinical drug efficacy studies 130 because they allow researchers to directly study human cells and tissues in vivo 5-8 . Comparisons131 of genome characteristics and histopathology of primary tumors and xenografts of human breast 132 cancer 9-13 , ovarian cancer 14 , colorectal cancer 15 and lung cancer 16-18 , have demonstrated that the 133 biological properties of patient-derived tumors are largely preserved in xenografts. A growing body 134 of literature supports their use in cancer drug discovery and development 19-21 . 135A caveat to PDX models is that intratumoral evolution can occur during engraftment and 136 passaging 11,22-25 . Such evolution could potentially modify treatment response of PDXs with 137 respect to the patient tumors 23,26,27 , particularly if the evolution were to systematically alter cancer-138 related genes. This issue is related to multi-region comparisons of patient tumors 28-31 , for which 139 local mutational and immune infiltration variations have sugg...

Objectives This study examined the family experience of critical care after pediatric traumatic brain injury in order to develop a model of specific factors associated with family-centered care. Design Qualitative methods with semi-structured interviews were utilized. Setting Two level 1 trauma centers. Participants Fifteen mothers of children who had an acute hospital stay after TBI within the last 5 years were interviewed about their experience of critical care and discharge planning. Participants who were primarily English, Spanish or Cantonese speaking were included. Interventions None Measurements and Main Results Content analysis was used to code the transcribed interviews and develop the family-centered care model. Three major themes emerged: 1) thorough, timely, compassionate communication, 2) capacity building for families, providers and facilities, and 3) coordination of care transitions. Participants reported valuing detailed, frequent communication that set realistic expectations and prepared them for decision-making and outcomes. Areas for capacity building included strategies to increase provider cultural humility, parent participation in care and institutional flexibility. Coordinated care transitions, including continuity of information and maintenance of partnerships with families and care teams were highlighted. Participants who were not primarily English speaking reported particular difficulty with communication, cultural understanding and coordinated transitions. Conclusions This study presents a family-centered traumatic brain injury care model based on family perspectives. In addition to communication and coordination strategies, the model offers methods to address cultural and structural barriers to meeting the needs of non-English speaking families. Given the stress experienced by families of children with TBI, careful consideration of the model themes identified here may assist in improving overall quality of care to families of hospitalized children with traumatic brain injury.