Kit receptor tyrosine kinase dysregulations in feline splenic mast cell tumours

This study investigated Ki t receptor dysregulations (cytoplasmic immunohistochemical expression and/or c-KIT mutations) in cats a\ufb00ected with splenic mast cell tumours. Twenty-two cats were included. Median survival time was 780 days (range: 1\u20131219). An exclusive splenic involvement was signi\ufb01cantly (P = 0.042) associated with longer survival (807 versus 120 days). Eighteen tumours (85.7%) showed Kit cytoplasmic expression (Kit pattern 2, 3). Mutation analysis was successful in 20 cases. Fourteen missense mutations were detected in 13 out of 20 tumours (65%). Eleven (78.6%) were located in exon 8, and three (21.6%) in exon 9. No mutations were detected in exons 11 and 17. Seven mutations corresponded to the same internal tandem duplication in exon 8 (c.1245_1256dup). Although the association between Kit cytoplasmic expression and mutations was signi\ufb01cant, immunohistochemistry cannot be considered a surrogate marker for mutation analysis. No correlation was observed between c-Kit mutations and tumour di\ufb00erentiation, mitotic activity or survival

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

Extended lower paratracheal lymph node resection during esophagectomy for cancer : safety and necessity

Background The ideal extent of lymphadenectomy (LAD) in esophageal oncological surgery is debated. There is no evidence for improved survival after standardized paratracheal lymph node resection performing oncological esophagectomy. Lymph nodes from the lower paratracheal station are not standardly resected during 2-field Ivor-Lewis esophagectomy for esophageal cancer. The objective of this study was to evaluate the impact of lower paratracheal lymph node (LPL) resection on perioperative outcome during esophagectomy for cancer and analyze its relevance. Methods Retrospectively, we identified 200 consecutive patients operated in our center for esophageal cancer from January 2017 – December 2019. Patients with and without lower paratracheal LAD were compared regarding demographic data, tumor characteristics, operative details, postoperative complications, tumor recurrence and overall survival. Results 103 out of 200 patients received lower paratracheal lymph node resection. On average, five lymph nodes were resected in the paratracheal region and cancer infiltration was found in two patients. Those two patients suffered from neuroendocrine carcinoma and melanoma respectively. Cases with lower paratracheal lymph node yield had significantly less overall complicated procedures (p = 0.026). Regarding overall survival and recurrence rate no significant difference could be detected between both groups (p = 0.168 and 0.371 respectively). Conclusion The resection of lower paratracheal lymph nodes during esophagectomy remains debatable for distal squamous cell carcinoma or adenocarcinoma of the esophagus. Tumor infiltration was only found in rare cancer entities. Since resection can be performed safely, we recommend LPL resection on demand

Robot-assisted minimally invasive esophagectomy with intrathoracic anastomosis (Ivor Lewis) : promising results in 100 consecutive patients (the European experience)

BACKGROUND Robot-assisted minimally invasive esophagectomy (RAMIE) with intrathoracic anastomosis is gaining popularity as a treatment for esophageal cancer. The aim of this study was to describe postoperative complications and short-term oncologic outcomes for RAMIE procedures using the da Vinci Xi robotic system 4-arm technique. METHODS Data of 100 consecutive patients with esophageal or gastro-esophageal junction carcinoma undergoing modified Ivor Lewis esophagectomy were prospectively collected. All operations were performed by the same surgeon using an identical intrathoracic anastomotic reconstruction technique with the same perioperative management. Intraoperative and postoperative complications were graded according to Esophagectomy Complications Consensus Group (ECCG) definitions. RESULTS Mean duration was 416 min (±80); 70% of patients had an uncomplicated postoperative recovery. Pulmonary complications were observed in 17% of patients. Anastomotic leakage was observed in 8% of patients. Median ICU stay was 1 day and median overall postoperative hospital stay was 11 days. The 30-day mortality was 1%; 90-day mortality was 3%. A R0 resection was reached in 92% of patients with a median number of 29 dissected lymph nodes. All patients had at least 7 months of follow-up with a median follow-up of 17 months. Median overall survival was not reached yet. CONCLUSION RAMIE with intrathoracic anastomosis (Ivor Lewis) for esophageal or gastro-esophageal junction cancer was technically feasible and safe. Postoperative complications and short-term oncologic results were comparable to the highest international standards nowadays. Synopsis RAMIE with intrathoracic anastomosis (Ivor Lewis) for esophageal or gastro-esophageal junction cancer is technically feasible and safe. Postoperative complications and short-term oncologic results were comparable to the highest international standards nowadays

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

Robot-Assisted Minimally Invasive Esophagectomy with Intrathoracic Anastomosis (Ivor Lewis): Promising Results in 100 Consecutive Patients (the European Experience)

Background: Robot-assisted minimally invasive esophagectomy (RAMIE) with intrathoracic anastomosis is gaining popularity as a treatment for esophageal cancer. The aim of this study was to describe postoperative complications and short-term oncologic outcomes for RAMIE procedures using the da Vinci Xi robotic system 4-arm technique. Methods: Data of 100 consecutive patients with esophageal or gastro-esophageal junction carcinoma undergoing modified Ivor Lewis esophagectomy were prospectively collected. All operations were performed by the same surgeon using an identical intrathoracic anastomotic reconstruction technique with the same perioperative management. Intraoperative and postoperative complications were graded according to Esophagectomy Complications Consensus Group (ECCG) definitions. Results: Mean duration was 416 min (±80); 70% of patients had an uncomplicated postoperative recovery. Pulmonary complications were observed in 17% of patients. Anastomotic leakage was observed in 8% of patients. Median ICU stay was 1 day and median overall postoperative hospital stay was 11 days. The 30-day mortality was 1%; 90-day mortality was 3%. A R0 resection was reached in 92% of patients with a median number of 29 dissected lymph nodes. All patients had at least 7 months of follow-up with a median follow-up of 17 months. Median overall survival was not reached yet. Conclusion: RAMIE with intrathoracic anastomosis (Ivor Lewis) for esophageal or gastro-esophageal junction cancer was technically feasible and safe. Postoperative complications and short-term oncologic results were comparable to the highest international standards nowadays

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

Mast cells as a unique hematopoietic lineage and cell system:From Paul Ehrlich's visions to precision medicine concepts

The origin and functions of mast cells (MCs) have been debated since their description by Paul Ehrlich in 1879. MCs have long been considered 'reactive bystanders' and 'amplifiers' in inflammatory processes, allergic reactions, and host responses to infectious diseases. However, knowledge about the origin, phenotypes and functions of MCs has increased substantially over the past 50 years. MCs are now known to be derived from multipotent hematopoietic progenitors, which, through a process of differentiation and maturation, form a unique hematopoietic lineage residing in multiple organs. In particular, MCs are distinguishable from basophils and other hematopoietic cells by their unique phenotype, origin(s), and spectrum of functions, both in innate and adaptive immune responses and in other settings. The concept of a unique MC lineage is further supported by the development of a distinct group of neoplasms, collectively referred to as mastocytosis, in which MC precursors expand as clonal cells. The clinical consequences of the expansion and/or activation of MCs are best established in mastocytosis and in allergic inflammation. However, MCs have also been implicated as important participants in a number of additional pathologic conditions and physiological processes. In this article, we review concepts regarding MC development, factors controlling MC expansion and activation, and some of the fundamental roles MCs may play in both health and disease. We also discuss new concepts for suppressing MC expansion and/or activation using molecularly-targeted drugs