Association of Pancreatic Adenocarcinoma Location With DNA Damage Response Status and Response to Platinum-Based Therapy.

Purpose: Pancreatic adenocarcinoma is an aggressive disease with poor clinical outcomes. Primary pancreatic tumors originating from the head of the pancreas (H) have different prognostic implications than tumors arising from the body and tail (BT). This is thought to be largely due to anatomic differences, as molecular underpinnings of survival have not been fully explored.

Effects of Oxytocin on Emotion Recognition in Schizophrenia: A Randomized Double-Blind Pilot Study.

Background: Schizophrenia (SCZ) is a neurodevelopmental disorder that leads to poor social function. Oxytocin (OXT), a neuropeptide involved in social cognition, is a potential therapeutic agent for alleviating social dysfunction. Therefore, we investigated the effects of intranasal oxytocin (IN-OXT) on emotional processes in experimental interactive social contexts in individuals with SCZ.

A virtual molecular tumor board to improve efficiency and scalability of delivering precision oncology to physicians and their patients.

Objectives: Scalable informatics solutions that provide molecularly tailored treatment recommendations to clinicians are needed to streamline precision oncology in care settings.

Materials And Methods: We developed a cloud-based virtual molecular tumor board (VMTB) platform that included a knowledgebase, scoring model, rules engine, an asynchronous virtual chat room and a reporting tool that generated a treatment plan for each of the 1725 patients based on their molecular profile, previous treatment history, structured trial eligibility criteria, clinically relevant cancer gene-variant assertions, biomarker-treatment associations, and current treatment guidelines. The VMTB systematically allows clinician users to combine expert-curated data and structured data from clinical charts along with molecular testing data to develop consensus on treatments, especially those that require off-label and clinical trial considerations.

Multi-omic molecular comparison of primary versus metastatic pancreatic tumours.

Background: Molecular profiling is increasingly used to match patients with metastatic cancer to targeted therapies, but obtaining a high-quality biopsy specimen from metastatic sites can be difficult.

Methods: Patient samples were received by Perthera to coordinate genomic, proteomic and/or phosphoproteomic testing, using a specimen from either the primary tumour or a metastatic site. The relative frequencies were compared across specimen sites to assess the potential limitations of using a primary tumour sample for clinical decision support.

Molecular Profiling of Patients with Pancreatic Cancer: Initial Results from the Know Your Tumor Initiative.

To broaden access to and implementation of precision medicine in the care of patients with pancreatic cancer, the Know Your Tumor (KYT) program was initiated using a turn-key precision medicine system. Patients undergo commercially available multiomic profiling to determine molecularly rationalized clinical trials and off-label therapies. Tumor samples were obtained for 640 patients from 287 academic and community practices covering 44 states.

Upregulation of IFN-Inducible and Damage-Response Pathways in Chronic Graft-versus-Host Disease.

Although chronic graft-versus-host disease (CGVHD) is the primary nonrelapse complication of allogeneic transplantation, understanding of its pathogenesis is limited. To identify the main operant pathways across the spectrum of CGVHD, we analyzed gene expression in circulating monocytes, chosen as in situ systemic reporter cells. Microarrays identified two interrelated pathways: 1) IFN-inducible genes, and 2) innate receptors for cellular damage.

Characterization and Risk Factor Analysis of Osteoporosis in a Large Cohort of Patients with Chronic Graft-versus-Host Disease.

The National Institutes of Health Chronic Graft-versus-Host Disease (cGVHD) Consensus Project Ancillary and Supportive Care Guidelines recommend annual assessment of bone mineral density (BMD) to monitor bone health. The study of osteoporosis in patients with cGVHD has been limited to small numbers of patients, and the guidelines are based on experience with other chronic diseases and expert opinion. We hypothesized that the prevalence of osteoporosis is high in a cohort of 258 patients with moderate to severe cGVHD because of prolonged exposure to risk factors for osteoporosis after allogeneic hematopoietic stem cell transplantation.

Allogeneic T Cells That Express an Anti-CD19 Chimeric Antigen Receptor Induce Remissions of B-Cell Malignancies That Progress After Allogeneic Hematopoietic Stem-Cell Transplantation Without Causing Graft-Versus-Host Disease.

Purpose: Progressive malignancy is the leading cause of death after allogeneic hematopoietic stem-cell transplantation (alloHSCT). After alloHSCT, B-cell malignancies often are treated with unmanipulated donor lymphocyte infusions (DLIs) from the transplant donor. DLIs frequently are not effective at eradicating malignancy and often cause graft-versus-host disease, a potentially lethal immune response against normal recipient tissues.

High-Dose Sirolimus and Immune-Selective Pentostatin plus Cyclophosphamide Conditioning Yields Stable Mixed Chimerism and Insufficient Graft-versus-Tumor Responses.

Purpose: We hypothesized that lymphoid-selective host conditioning and subsequent adoptive transfer of sirolimus-resistant allogeneic T cells (T-Rapa), when combined with high-dose sirolimus drug therapy in vivo, would safely achieve antitumor effects while avoiding GVHD.

Experimental Design: Patients (n = 10) with metastatic renal cell carcinoma (RCC) were accrued because this disease is relatively refractory to high-dose conditioning yet may respond to high-dose sirolimus. A 21-day outpatient regimen of weekly pentostatin (P; 4 mg/m(2)/dose) combined with daily, dose-adjusted cyclophosphamide (C; ≤200 mg/d) was designed to deplete and suppress host T cells.

Donor-derived CD19-targeted T cells cause regression of malignancy persisting after allogeneic hematopoietic stem cell transplantation.

New treatments are needed for B-cell malignancies persisting after allogeneic hematopoietic stem cell transplantation (alloHSCT). We conducted a clinical trial of allogeneic T cells genetically modified to express a chimeric antigen receptor (CAR) targeting the B-cell antigen CD19. T cells for genetic modification were obtained from each patient's alloHSCT donor.

Phase 2 clinical trial of rapamycin-resistant donor CD4+ Th2/Th1 (T-Rapa) cells after low-intensity allogeneic hematopoietic cell transplantation.

In experimental models, ex vivo induced T-cell rapamycin resistance occurred independent of T helper 1 (Th1)/T helper 2 (Th2) differentiation and yielded allogeneic CD4(+) T cells of increased in vivo efficacy that facilitated engraftment and permitted graft-versus-tumor effects while minimizing graft-versus-host disease (GVHD). To translate these findings, we performed a phase 2 multicenter clinical trial of rapamycin-resistant donor CD4(+) Th2/Th1 (T-Rapa) cells after allogeneic-matched sibling donor hematopoietic cell transplantation (HCT) for therapy of refractory hematologic malignancy. T-Rapa cell products, which expressed a balanced Th2/Th1 phenotype, were administered as a preemptive donor lymphocyte infusion at day 14 post-HCT.

Differential gene expression profile of first-generation and second-generation rapamycin-resistant allogeneic T cells.

Background Aims: We completed a phase II clinical trial evaluating rapamycin-resistant allogeneic T cells (T-rapa) and now have evaluated a T-rapa product manufactured in 6 days (T-rapa(6)) rather than 12 days (T-Rapa(12)).

Methods: Using gene expression microarrays, we addressed our hypothesis that the two products would express a similar phenotype. The products had similar phenotypes using conventional comparison methods of cytokine secretion and surface markers.