Comparative oncology: The paradigmatic example of canine and human mast cell neoplasms

In humans, advanced mast cell (MC) neoplasms are rare malignancies with a poor prognosis. Only a few preclinical models are available, and current treatment options are limited. In dogs, MC neoplasms are the most frequent malignant skin tumours. Unlike low-grade MC neoplasms, high-grade MC disorders usually have a poor prognosis with short survival. In both species, neoplastic MCs display activating KIT mutations, which are considered to contribute to disease evolution. Therefore, tyrosine kinase inhibitors against KIT have been developed. Unfortunately, clinical responses are unpredictable and often transient, which remains a clinical challenge in both species. Therefore, current efforts focus on the development of new improved treatment strategies. The field of comparative oncology may assist in these efforts and accelerate human and canine research regarding diagnosis, prognostication, and novel therapies. In this article, we review the current status of comparative oncology approaches and perspectives in the field of MC neoplasms

Sedimentology, stratigraphic context, and implications of Miocene intrashelf bottomset deposits, offshore New Jersey

Drilling of intrashelf Miocene clinothems onshore and offshore New Jersey has provided better understanding of their topset and foreset deposits, but the sedimentology and stratigraphy of their bottomset deposits have not been documented in detail. Three coreholes (Sites M27–M29), collected during Integrated Ocean Drilling Program (IODP) Expedition 313, intersect multiple bottomset deposits, and their analysis helps to refine sequence stratigraphic interpretations and process response models for intrashelf clinothems. At Site M29, the most downdip location, chronostratigraphically well-constrained bottomset deposits follow a repeated stratigraphic motif. Coarse-grained glauconitic quartz sand packages abruptly overlie deeply burrowed surfaces. Typically, these packages coarsen then fine upwards and pass upward into bioturbated siltstones. These coarse sand beds are amalgamated and poorly sorted and contain thin-walled shells, benthic foraminifera, and extrabasinal clasts, consistent with an interpretation of debrites. The sedimentology and mounded seismic character of these packages support interpretation as debrite-dominated lobe complexes. Farther updip, at Site M28, the same chronostratigraphic units are amalgamated, with the absence of bioturbated silts pointing to more erosion in proximal locations. Graded sandstones and dune-scale cross-bedding in the younger sequences in Site M28 indicate deposition from turbidity currents and channelization. The sharp base of each package is interpreted as a sequence boundary, with a period of erosion and sediment bypass evidenced by the burrowed surface, and the coarse-grained debritic and turbiditic deposits representing the lowstand systems tract. The overlying fine-grained deposits are interpreted as the combined transgressive and highstand systems tract deposits and contain the deepwater equivalent of the maximum flooding surface. The variety in thickness and grain-size trends in the coarse-grained bottomset packages point to an autogenic control, through compensational stacking of lobes and lobe complexes. However, the large-scale stratigraphic organization of the bottomset deposits and the coarse-grained immature extrabasinal and reworked glauconitic detritus point to external controls, likely a combination of relative sea-level fall and waxing-and-waning cycles of sediment supply. This study demonstrates that large amounts of sediment gravity-flow deposits can be generated in relatively shallow (~100–200 m deep) and low-gradient (~1°–4°) clinothems that prograded across a deep continental shelf. This physiography likely led to the dominance of debris flow deposits due to the short transport distance limiting transformation to low-concentration turbidity currents

Pulse‐Administered Toceranib Phosphate Plus Lomustine for Treatment of Unresectable Mast Cell Tumors in Dogs

BACKGROUND: Nonresectable mast cell tumors (MCT) in dogs remain a therapeutic challenge, and investigation of novel combination therapies is warranted. Intermittent administration of tyrosine kinase inhibitors (TKI) combined with cytotoxic chemotherapy may effectively chemosensitize canine MCT while decreasing cost and adverse effects associated with either agent administered as monotherapy. HYPOTHESIS/OBJECTIVES: The primary study objectives were to (1) identify the maximally tolerated dose (MTD), (2) determine the objective response rate (ORR) and (3) describe the adverse event profile of pulse‐administered toceranib phosphate (TOC) combined with lomustine. ANIMALS: Forty‐seven client‐owned dogs with measurable MCT. METHODS: Toceranib phosphate was given PO on days 1, 3 and 5 of a 21‐day cycle at a target dosage of 2.75 mg/kg. Lomustine was given PO on day 3 of each cycle at a starting dosage of 50 mg/m(2). All dogs were concurrently treated with diphenhydramine, omeprazole, and prednisone. RESULTS: The MTD of lomustine was established at 50 mg/m(2) when combined with pulse‐administered TOC; the dose‐limiting toxicity was neutropenia. Forty‐one dogs treated at the MTD were evaluable for outcome assessment. The ORR was 46% (4 complete response, 15 partial response) and the overall median progression‐free survival (PFS) was 53 days (1 to >752 days). On multivariate analysis, variables significantly associated with improved PFS included response to treatment, absence of metastasis, and no previous chemotherapy. CONCLUSIONS AND CLINICAL IMPORTANCE: Combined treatment with pulse‐administered TOC and lomustine generally is well tolerated and may be a reasonable treatment option for dogs with unresectable or metastatic MCT