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

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

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

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

Original Article Guidelines and diagnostic algorithm for patients with suspected systemic mastocytosis: a proposal of the Austrian competence network (AUCNM)

Abstract: Systemic mastocytosis (SM) is a hematopoietic neoplasm characterized by pathologic expansion of tissue mast cells in one or more extracutaneous organs. In most children and most adult patients, skin involvement is found. Childhood patients frequently suffer from cutaneous mastocytosis without systemic involvement, whereas most adult patients are diagnosed as suffering from SM. In a smaller subset of patients, SM without skin lesions develops which is a diagnostic challenge. In the current article, a diagnostic algorithm for patients with suspected SM is proposed. In adult patients with skin lesions and histologically confirmed mastocytosis in the skin (MIS), a bone marrow biopsy is recommended regardless of the serum tryptase level. In adult patients without skin lesions who are suffering from typical mediator-related symptoms, the basal serum tryptase level is an important diagnostic parameter. In those with slightly elevated tryptase (15-30 ng/ml), additional non-invasive investigations, including a KIT mutation analysis of peripheral blood cells and sonographic analysis, is performed. In adult patients in whom i) KIT D816V is detected or/and ii) the basal serum tryptase level is clearly elevated (> 30 ng/ml) or/and iii) other clinical or laboratory features are suggesting the presence of occult mastocytosis, a bone marrow biopsy should be performed. In the absence of KIT D816V and other indications of mastocytosis, no bone marrow investigation is required, but the patient's course and the serum tryptase levels are examined in the follow-up

Gebrauch von Antibiotika an der Universitätszahnklinik in Podgorica (Montenegro)

Ziel: Das Ziel dieser Studie ist es, mittels einer Fragebogenumfrage und anhand von Krankheitsgeschichten aus dem Jahr 2017, Daten zu erheben, welche Antibiotika auf der Universitätszahnklinik in Podgorica (Montenegro) am häufigsten verwendet werden. Weiter soll ermittelt werden, ob das Verschreiben von ausgewählten Antibiotika seine Berechtigung hat. Hintergrund: Antibiotika sind die am häufigsten verwendeten Medikamente in der Human- und Zahnheilkunde. Innerhalb der Zahnheilkunde und insbesondere bei Zahnärzten sollten eindeutige Indikationen vorhanden sein, bei denen Antibiotika eingesetzt werden. Durch die Auswertung der vorliegenden Daten sollen folgende Fragen beantwortet werden: Welche Antibiotika werden in welcher Menge, bei welchen Indikationen eingesetzt? Ist die Antibiotikaanwendung begründet oder nicht? Methode: Anhand von relevanter Literatur und bereits durchgeführten Studien aus verschiedenen Bereichen und Ländern wurde ein Fragebogen ausgearbeitet. Dieser Fragebogen wurde in die Landessprache der zu befragenden Zahnärzte übersetzt. Der Fragebogen wurde zusammen mit den befragten Zahnärzten ausgefüllt. Zusätzlich zu der durchgeführten Fragebogenuntersuchung wurden die Krankengeschichten aus dem Jahr 2017 zur Auswertung herangezogen. Diese wurden in eine vorgefertigte Tabelle übertragen. Die Ergebnisse beider Untersuchungen wurden mittels Microsoft Excel erfasst und in SPSS statistisch ausgewertet. Ergebnisse: Von den geplanten 30 Fragebogenbefragungen konnten 20 durchgeführt werden. Bei den Krankengeschichten aus dem Jahr 2017 wurden zwei Protokolle zur Verfügung gestellt, bei denen in Summe 444 Datensätze mit Antibiotikaverschreibung erfasst wurden. Es konnte festgestellt werden, dass die am häufigsten verschriebenen Antibiotika Amoxicillin, Amoxicillin + Clavulansäure und Metronidazol sind. Bei den Patienten, welche eine Penicillinallergie haben, wurden Clindamycin und Azithromycin verschrieben. Für 53,8% der Risikopatienten konnte eine richtlinienkonforme Antibiotikaverschreibung eindeutig identifiziert werden. Bei den restlichen 46,2% konnte kein eindeutiges Ergebnis identifiziert werden, da die Allgemeinerkrankungen dieser Patienten aus den Krankengeschichten nicht hervorgeht. Schlussfolgerung: Basierend auf Expertenmeinungen und aktuellen Studien, soll die Gabe von Antibiotika im zahnmedizinischen Bereich restriktiver erfolgen. Es ist jedoch ersichtlich, dass die Verschreibung dieser auf der Universitätszahnklinik in Podgorica nicht im Einklang mit den Expertenmeinungen steht. Diese Diskrepanzen zwischen der beobachteten und empfohlenen Praxis zeigt die Notwendigkeit von Bildungsinitiativen zur Förderung der rationellen Verschreibung von Antibiotika auf der Universitätszahnklinik in Podgorica.Aim: The aim of this study is to use a questionnaire survey and medical files from 2017 to collect data on which antibiotics are most commonly used at the University Dental Clinic in Podgorica (Montenegro). Furthermore, it should be determined whether the prescription of selected antibiotics is justified. Background: Antibiotics are the most commonly used drugs in medicine and dentistry. Within dentistry, and especially among dentists, there should be clear indications when antibiotics are used. By evaluating the available data, the following questions should be answered: Which antibiotics are used, in which quantities, in which indications? Is the antibiotic application justified or not? Method: A questionnaire has been prepared for the annex of relevant literature and studies already carried out in different fields and countries. This questionnaire was translated into the national language of the dentists to be interviewed. The questionnaire was filled in together with the questioned dentists. In addition to the questionnaire survey, the disease stories from 2017 were used for the evaluation. These were transferred to a ready-made table. The results of both examinations were recorded using Microsoft Excel and statistically evaluated in SPSS program. Results: Of the planned 30 questionnaire surveys, 20 could be conducted. In the medical files of 2017, two protocols were made available, in which a total of 444 data records based on a prescription of antibiotics were recorded. According to both methods, it has been found that the most commonly prescribed antibiotics are amoxicillin, amoxicillin + clavulanic acid and metronidazole. Patients with penicillin allergy were prescribed clindamycin and azithromycin. For 53,8% of the at-risk patients a policy-compliant antibiotic prescription was clearly identified. For the remaining 46,2%, no clear result could be identified because the general illnesses of these patients are not apparent from the medical files. Conclusion: Based on expert opinions and current studies, the administration of antibiotics in the dental field should be more restrictive. However, it can be seen that the prescription at the University Dental Clinic in Podgorica is not in line with the experts' opinions. These discrepancies between observed and recommended practice demonstrate the need for educational initiatives to promote the rational prescribing of antibiotics at the University Dental Clinic in Podgorica.Paralleltitel laut Übersetzung der VerfasserinMedizinische Universität Wien, Diplomarbeit, 2018(VLID)275269