Citations

Abstract Low dietary folate intake is associated with an increased risk for colon cancer; however, relevant genetic animal models are lacking. We therefore investigated the effect of targeted ablation of two folate transport genes, folate binding protein 1 (Folbp1) and reduced folate carrier 1 (RFC1), on folate homeostasis to elucidate the molecular mechanisms of folate action on colonocyte cell proliferation, gene expression, and colon carcinogenesis. Targeted deletion of Folbp1 (Folbp1+/− and Folbp1−/−) significantly reduced (P < 0.05) colonic Folbp1 mRNA, colonic mucosa, and plasma folate concentration. In contrast, subtle changes in folate homeostasis resulted from targeted deletion of RFC1 (RFC1+/−). These animals had reduced (P < 0.05) colonic RFC1 mRNA and exhibited a 2-fold reduction in the plasma S-adenosylmethionine/S-adenosylhomocysteine. Folbp1+/− and Folbp1−/− mice had larger crypts expressed as greater (P < 0.05) numbers of cells per crypt column relative to Folbp1+/+ mice. Colonic cell proliferation was increased in RFC1+/− mice relative to RFC1+/+ mice. Microarray analysis of colonic mucosa showed distinct changes in gene expression specific to Folbp1 or RFC1 ablation. The effect of folate transporter gene ablation on colon carcinogenesis was evaluated 8 and 38 weeks post-azoxymethane injection in wild-type and heterozygous mice. Relative to RFC1+/+ mice, RFC1+/− mice developed increased (P < 0.05) numbers of aberrant crypt foci at 8 weeks. At 38 weeks, RFC1+/− mice developed local inflammatory lesions with or without epithelial dysplasia as well as adenocarcinomas, which were larger relative to RFC1+/+ mice. In contrast, Folbp1+/− mice developed 4-fold (P < 0.05) more lesions relative to Folbp1+/+ mice. In conclusion, Folbp1 and RFC1 genetically modified mice exhibit distinct changes in colonocyte phenotype and therefore have utility as models to examine the role of folate homeostasis in colon cancer development.

Abstract Inflammatory myofibroblastic tumor (IMT) is a mesenchymal neoplasm of intermediate malignancy. We describe the largest cohort of IMT patients to date, aiming to further characterize this rare, poorly understood tumor. This is a multi‐institutional review of IMT patients ≤39 years, from 2000 to 2018, at 18 hospitals in the Pediatric Surgical Oncology Research Collaborative. One hundred and eighty‐two patients were identified with median age of 11 years. Thirty‐three percent of tumors were thoracic in origin. Presenting signs/symptoms included pain (29%), respiratory symptoms (25%) and constitutional symptoms (20%). Median tumor size was 3.9 cm. Anaplastic lymphoma kinase (ALK) overexpression was identified in 53% of patients. Seven percent of patients had distant disease at diagnosis. Ninety‐one percent of patients underwent resection: 14% received neoadjuvant treatment and 22% adjuvant treatment. Twelve percent of patients received an ALK inhibitor. Sixty‐six percent of surgical patients had complete resection, with 20% positive microscopic margins and 14% gross residual disease. Approximately 40% had en bloc resection of involved organs. Median follow‐up time was 36 months. Overall 5‐year survival was 95% and 5‐year event‐free survival was 80%. Predictors of recurrence included respiratory symptoms, tumor size and distant disease. Gross or microscopic margins were not associated with recurrence, suggesting that aggressive attempts at resection may not be warranted.

Background Patients with metastatic melanoma rely on PD-(L)1 immunotherapy, but only one-third of patients experience treatment response and all initial responders eventually develop resistance. Tumour-derived extracellular vesicles expressing Programmed death ligand 1 (evPD-L1) and soluble Programmed death ligand 1 (sPD-L1) in peripheral blood of patients with melanoma limit PD-(L)1 immunotherapy and correlate with poor survival. Therapeutic plasma exchange (TPE) removes immunosuppressive evPD-L1 and sPD-L1. We hypothesise that TPE may rescue and restore antimelanoma immunity. Methods In this two-arm study, 60 patients with metastatic melanoma progressing on checkpoint inhibition will be accrued. All patients will undergo radiotherapy on days 1–5 (at least one measurable lesion will not be irradiated) and ongoing checkpoint inhibition on day 8 and every 2–3 weeks per standard of care. Patients with baseline sPD-L1 level of ≥1.7 ng/mL and adequate clinical capacity will be enrolled in the TPE intervention arm and will undergo TPE on days 5–7, in addition to standard of care radiotherapy and immunotherapy. Other patients will remain in the standard of care arm. The primary endpoint of the study is to evaluate safety. Secondary endpoints include kinetics of sPD-L1 and evPD-L1 and clinical response by RECIST (Response Evaluation Criteria in Solid Tumors) criteria. Study registered at ClinicalTrials.gov ( NCT04581382 ). Ethics and dissemination This trial has been approved by the Mayo Clinic Institutional Review Board. It will assess the safety and feasibility of TPE in improving outcomes for PD-(L)1 inhibitor immunotherapy in melanoma. Data will be maintained on a secure database with deidentified patient information. Data will be shared on publication in a peer-reviewed journal without the aid of professional writers. If successful, this trial will lay the ground for phase II studies that will include cancer treated with PD-(L)1 inhibitors which may benefit from TPE such as renal, bladder and lung cancers. Trial registration number NCT04581382 .

Abstract Patients with metastatic breast cancer (MBC) typically have short survival times and their successful treatment represents one of most challenging aspects of patient care. This poor prognostic behavior is in part due to molecular features including increased tumor cell clonal heterogeneity, multiple drug resistance mechanisms, and alterations of the tumor microenvironment. The AURORA US Metastasis Project was established with the goal to identify molecular features specifically associated with metastasis. We therefore collected and molecularly characterized specimens from 55 metastatic breast cancer (BC) patients representing 51 primary cancers and 102 metastases. The 153 unique tumors were assayed using RNAseq, tumor/germline DNA exomes and low pass whole genome sequencing, and global DNA methylation microarrays. We found intrinsic molecular subtype differences between primary tumors and their matched metastases to be rare in triple negative breast cancer (TNBC)/Basal-like subtype tumors. Conversely, tumor subtype changes were relatively frequent in estrogen receptor positive (ER+) cancers where ~30% of Luminal A cases switched to Luminal B or HER2-enriched (HER2E) subtypes. Clonal evolution studies identified changes in expression subtype coincident with DNA clonality shifts, especially involving HER2 amplification and/or the HER2E expression subtype. We further found evidence for ER-mediated downregulation of genes involved in cell-cell adhesion in metastases. Microenvironment differences varied according to tumor subtype where ER+/Luminal metastases had lower fibroblast and endothelial cell content, while TNBC/Basal-like metastases showed a dramatic decrease in B cells and T cells. In 17% of metastatic tumors, we identified DNA hypermethylation and/or focal DNA deletions near HLA-A that were associated with its’ significantly reduced expression, and with lower immune cell infiltrates. We also identified low immune cell features in brain and liver metastases when compared to other metastatic sites, even within the same patient. These findings have direct implications for the treatment of metastatic breast cancer patients with immune- and HER2-targeting therapies and suggest potential novel therapeutic avenues for the improvement of outcomes for some patients with MBC.

Currently, there is no known clinical evidence that rituximab increases the rate of subsequent primary malignancies; however, some studies have raised the question of increased melanoma risk following rituximab treatment for non-Hodgkin lymphoma. We report three interesting cases of suspected rituximab-induced melanoma. We hypothesize that this association is secondary to rituximab-driven shifts in the immunologic balance. Based on these cases, it is possible that the number of post-rituximab melanoma cases is underreported. Further mechanistic research into individual cases and population-level studies are required to better define association and risk; however, given the increasing prevalence of oncologic and nononcologic rituximab use, awareness across all fields is essential.