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

Synergistic growth-inhibitory effects of ponatinib and midostaurin (PKC412) on neoplastic mast cells carrying KIT D816V

Patients with advanced systemic mastocytosis, including mast cell leukemia, have a poor prognosis. In these patients, neoplastic mast cells usually harbor the KIT mutant D816V that confers resistance against tyrosine kinase inhibitors. We examined the effects of the multi-kinase blocker ponatinib on neoplastic mast cells and investigated whether ponatinib acts synergistically with other antineoplastic drugs. Ponatinib was found to inhibit the kinase activity of KIT G560V and KIT D816V in the human mast cell leukemia cell line HMC-1. In addition, ponatinib was found to block Lyn- and STAT5 activity in neoplastic mast cells. Ponatinib induced growth inhibition and apoptosis in HMC-1.1 cells (KIT G560V(+)) and HMC-1.2 cells (KIT G560V(+)/KIT D816V(+)) as well as in primary neoplastic mast cells. The effects of ponatinib were dose-dependent, but higher IC50-values were obtained in HMC-1 cells harboring KIT D816V than in those lacking KIT D816V. In drug combination experiments, ponatinib was found to synergize with midostaurin in producing growth inhibition and apoptosis in HMC-1 cells and primary neoplastic mast cells. The ponatinib+midostaurin combination induced substantial inhibition of KIT-, Lyn-, and STAT5 activity, but did not suppress Btk. We then applied a Btk short interfering RNA and found that Btk knockdown sensitizes HMC-1 cells against ponatinib. Finally, we were able to show that ponatinib synergizes with the Btk-targeting drug dasatinib to produce growth inhibition in HMC-1 cells. In conclusion, ponatinib exerts major growth-inhibitory effects on neoplastic mast cells in advanced systemic mastocytosis and synergizes with midostaurin and dasatinib in inducing growth arrest in neoplastic mast cells.</p

Proposed Diagnostic Criteria and Classification of Canine Mast Cell Neoplasms: A Consensus Proposal

Mast cell neoplasms are one of the most frequently diagnosed malignancies in dogs. The clinical picture, course, and prognosis vary substantially among patients, depending on the anatomic site, grade and stage of the disease. The most frequently involved organ is the skin, followed by hematopoietic organs (lymph nodes, spleen, liver, and bone marrow) and mucosal sites of the oral cavity and the gastrointestinal tract. In cutaneous mast cell tumors, several grading and staging systems have been introduced. However, no comprehensive classification and no widely accepted diagnostic criteria have been proposed to date. To address these open issues and points we organized a Working Conference on canine mast cell neoplasms in Vienna in 2019. The outcomes of this meeting are summarized in this article. The proposed classification includes cutaneous mast cell tumors and their sub-variants defined by grading- and staging results, mucosal mast cell tumors, extracutaneous/extramucosal mast cell tumors without skin involvement, and mast cell leukemia (MCL). For each of these entities, diagnostic criteria are proposed. Moreover, we have refined grading and staging criteria for mast cell neoplasms in dogs based on consensus discussion. The criteria and classification proposed in this article should greatly facilitate diagnostic evaluation and prognostication in dogs with mast cell neoplasms and should thereby support management of these patients in daily practice and the conduct of clinical trials

Identification of heat shock protein 32 (Hsp32) as a novel target in acute lymphoblastic leukemia

Heat shock proteins (Hsp) are increasingly employed as therapeutic targets in oncology. We have shown that Hsp32, also known as heme oxygenase-1 (HO-1), serves as survival factor and potential target in Ph+ chronic myeloid leukemia. We here report that primary cells and cell lines derived from patients with acute lymphoblastic leukemia (ALL) express Hsp32 mRNA and the Hsp32 protein in a constitutive manner. Highly enriched CD34+/CD38- ALL stem cells also expressed Hsp32. Two Hsp32-targeting drugs, pegylated zinc protoporphyrine (PEG-ZnPP) and styrene maleic acid-micelle-encapsulated ZnPP (SMA-ZnPP), induced apoptosis and growth arrest in the BCR/ABL1+ cell lines, in Ph- lymphoblastic cell lines and in primary Ph+ and Ph- ALL cells. The effects of PEG-ZnPP and SMA-ZnPP on growth of leukemic cells were dose-dependent. In Ph+ ALL, major growth-inhibitory effects of the Hsp32-targeting drugs were observed in imatinib-sensitive and imatinib-resistant cells. Hsp32-targeting drugs were found to synergize with imatinib, nilotinib, and bendamustine in producing growth inhibition and apoptosis in Ph+ ALL cells. A siRNA against Hsp32 was found to inhibit growth and survival of ALL cells and to synergize with imatinib in suppressing the growth of ALL cells. In conclusion, Hsp32 is an essential survival factor and potential new target in ALL.Sabine Cerny-Reiterer, Renata A. Meyer, Harald Herrmann, Barbara Peter, Karoline V. Gleixner, Gabriele Stefanzl, Emir Hadzijusufovic, Winfried F. Pickl, Wolfgang R. Sperr, Junia V. Melo, Hiroshi Maeda, Ulrich Jäger, Peter Valen

Minimally invasive esophagectomy: clinical evidence and surgical techniques

Background!#!Surgical esophagectomy plays a crucial role in the curative and palliative treatment of esophageal cancer. Thereby, minimally invasive esophagectomy (MIE) is increasingly applied all over the world. Combining minimal invasiveness with improved possibilities for meticulous dissection, robot-assisted minimal invasive esophagectomy (RAMIE) has been implemented in many centers.!##!Purpose!#!This review focuses on the development of MIE as well as RAMIE and their value based on evidence in current literature.!##!Conclusion!#!Although MIE and RAMIE are highly complex procedures, they can be performed safely with improved postoperative outcome and equal oncological results compared with open esophagectomy (OE). RAMIE offers additional advantages regarding surgical dissection, lymphadenectomy, and extended indications for advanced tumors

676 NECESSITY OF EXTENDED LOWER PARATRACHEAL LYMPH NODE RESECTION DURING ESOPHAGECTOMY FOR CANCER

Abstract Objective To evaluate the impact of lower paratracheal lymph node resection on oncological radicality and complication rate during esophagectomy for cancer. Backround The ideal extend of lymphadenectomy (LAD) in esophageal surgery is debated. Until today, there has been no proof for improved survival after standardized paratracheal lymph node resection performing oncological esophagectomy. Methods Lymph nodes from the lower paratracheal station are not standardly resected during 2-field Ivor-Lewis esophagectomy for esophageal cancer. Retrospectively, we identified 200 patients operated in our center for esophageal cancer from January 2017—December 2019. Histopathologically, 143 patients suffered from adenocarcinoma, 53 patients from squamous cell carcinoma, two patients from neuroendocrine carcinoma, and one from melanoma of the esophagus. Patients with and without lower paratracheal LAD were compared to patients regarding demographic data, tumor characteristics, operative details, postoperative complications, tumor recurrence and overall survival. Results 103 of 200 patients received lower paratracheal lymph node resection. On average, six lymph nodes were resected in the paratracheal region with histopathological cancer positivity in two patients. Those two patients suffered from neuroendocrine carcinoma and melanoma, none of the AC or SCC patients were positive. There was no significant difference between both groups regarding age, gender, BMI, or comorbidity. Harvesting of lower paratracheal lymph nodes was associated with less postoperative overall complications (p-value 0,029). Regarding overall survival and recurrence rate no difference could be detected between both groups (p-value 0,168, respectively 0,371). Conclusion The resection of lower paratracheal lymph nodes during esophagectomy seems not mandatory for distal squamous cell carcinoma or adenocarcinoma of the esophagus. It may be necessary in NEC, Melanoma of the esophagus or on demand if suspicious LN are detected in the CT scan. No increase of morbidity was caused by paratracheal dissection. </jats:sec