Using Viscum album extracts (ISCADOR) for successful management of neoplasms of the skin in horses and cats in consideration of aspects relevant to human medicine.

Background: Mistletoe extracts (Viscum album extracts, VAE) such as ISCADOR, have been used successfully in human oncology for many years. In veterinary medicine, there have been reports of successful treatment, but scientific data on efficacy are lacking. Two studies were therefore conducted to assess whether VAE can serve as an adjunct to standard treatment in horses and cats. Methods: As part of a placebo-controlled double-blind study (study 1), 53 horses with equine sarcoid (a solitary or multifocal skin tumor) were treated with VAE pini (pine mistletoe) in progressively increasing doses (n=32) or with a sodium chloride solution (n=21). Three times a week for 15 weeks. All horses were observed over a period of 12 months for tumor recurrence and cure. In an observational study (study 2), 44 cats with fibrosarcoma, a very common skin tumor with a high rate of recurrence, were treated postoperatively with 0.1% (0.5ml per dose) oral VAE quercus (oak mistletoe) twice daily, and disease free survival was measured. Results: In study 1, treatment with ISCADOR led to significantly better results than placebo. Improvement was seen in 41% of the cases (placebo 14%), and cure was achieved in 28% of the cases (placebo 14%). In study 2, disease-free survival time in cats treated postoperatively with VAE quercus was 438 days compared with 365 to 475 days for conventional chemotherapies and 120 to 261 days for surgery alone, as seen in literature. Aggressive surgery combined with radiation and chemotherapy led to markedly superior results (661 to 986 days). Conclusion: The study 1 was able to demonstrate, for the first time, the efficacy of VAE compared to placebo control. This study also showed that the effect of VAE apparently extends considerably beyond the treatment period; unexpectedly, only very few recurrences were observed between the end of treatment and the 12th month of observation. The results of the study 2 show that oral administration of mistletoe preparations also yields satisfactory prophylactic effects. The discussion surrounding oral treatment and the question whether it can replace injection treatment must therefore be continued, even in human medicine

Postoperative adjuvante Therapie mit einem Mistelextrakt (Viscum album ssp. album) bei Hündinnen mit Mammatumoren

Canine Mammatumoren (CMT) sind wegen ihrer Häufigkeit und hohen Malignitätsrate eine Herausforderung für die Veterinärmedizin. Bisher ist noch keine postoperative adjuvante Therapie als wirksamer Standard etabliert und in den nächsten Jahren wohl auch nicht zu erwarten. Zusätzlich ist die Frage nach der Verträglichkeit einer adjuvanten Therapie mit Erhaltung oder Verbesserung der Lebensqualität (LQ) wichtig. Die Therapie mit Mistelextrakten (Viscum album L.; VAE) ist in der Humanonkologie nach adjuvanter Tumorbasistherapie (Chemotherapie und Bestrahlung) eine sehr häufig verwendete, zusätzliche adjuvante Behandlungsmethode. Auch bei verschiedenen Tierarten werden inzwischen Mistelpräparate in der Onkologie erfolgreich angewendet. Methoden: Überprüfung von Wirkung und Nutzen einer postoperativen, adjuvanten Misteltherapie beim CMT sowie Erfassung der LQ unter der VAE-Behandlung. Ausgewertet wurden 56 Hündinnen mit Mammaadenokarzinom, 33 ausschließlich operierte Kontrolltiere und 23 operierte Tiere, die adjuvant VAE erhielten. Ergebnisse: Die mediane Überlebenszeit (MST) aller Tiere (n= 56) betrug 32 Monate (Interquartilbereich 13–51 Monate). Im deskriptiven Vergleich der Überlebenszeiten (ST) nach Kaplan-Meier waren nach 12, 24, 36 bzw. 48 Monaten noch 24, 20, 15 bzw. 5 Hündinnen (entsprechend 72,7%, 60,6%, 45,1%, 12,4%) der Kontrollgruppe sowie 19, 14, 11 und 1 Hündin (82,6%, 60,9%, 47,8%, 4,3%) der VAE-Gruppe am Leben. Die VAE-Therapie führte zu einem geringeren Gesamtversterberisiko, das statistisch nicht signifikant war (Hazard Ratio (HR) 0,530, 95%-Konfidenzintervall (KI) 0,222–1,262; p = 0,15). Tendenziell (p = 0,07) zeigte sich eine Verringerung des tumorbedingten Sterberisikos auf 25% (HR 0,251, 95%-KI 0,056–1,122). Schlussfolgerungen: Es kann eine Tendenz zur Senkung des tumorbedingten Sterberisikos der VAEGruppe bei guter Verträglichkeit der Therapie angenommen werden. Die LQ der Tiere blieb über die gesamte Beobachtungszeit auf hohem Niveau stabil

Kombinierte Anwendung von Strahlentherapie und adjuvanter Therapie mit einem Mistelextrakt (Viscum album L.) zur Behandlung des oralen malignen Melanoms beim Hund: Eine retrospektive Studie

Hintergrund: Orale maligne Melanome (OMM) des Hundes zeichnen sich durch schnelles Wachstum, lokale Invasion und hohe Metastasierungsraten aus. Extrakte auf Basis von Viscum album L. (VAE) werden zunehmend in der Krebstherapie sowohl in der Human- als auch in der Veterinärmedizin eingesetzt. Ziel unserer Studie war es zu untersuchen, inwieweit die adjuvante Therapie mit VAE eine therapeutische Option zur Behandlung von OMM ist. Besonderes Augenmerk galt dabei der Überlebenszeit und möglichen Nebenwirkungen. Tiere und Methoden: 26 Hunde mit OMM, die in einem der größten veterinäronkologischen Zentren der Schweiz allesamt eine Strahlentherapie erhielten (teilweise nach operativer Tumorresektion) wurden in die retrospektive Studie eingeschlossen: 18 Hunde wurden mit VAE behandelt (1 ml VAE (Iscador®) in ansteigenden Konzentrationen von 0,1 bis 20 mg/ml subkutan 3-mal pro Woche (VAE-Gruppe), 8 erhielten keine adjuvante Behandlung (Vergleichsgruppe). Wir verglichen die Größenentwicklung der OMM sowie die Überlebenszeit. Ergebnisse: Patienten mit Bestrahlung und adjuvanter VAE-Therapie zeigten mit 236 Tagen eine signifikant längere mediane Überlebenszeit im Vergleich zu Patienten mit Bestrahlung, aber ohne adjuvante VAE-Therapie (49 Tage; Log-Rank-Test: p = 0,0047). Die VAE-Therapie verlängerte die Überlebenszeit um mehr als zwei Drittel (Hazard Ratio (HR) = 0,30, 95%-Konfidenzintervall (KI) 0,11-0,86; p = 0,024), während ein höheres Tumorstadium gemäß UICC (Union internationale contre le cancer) einen statistischen Trend zur Verdopplung des Sterberisikos zeigte (UICC-Stadium III/IV vs. I/II: HR = 2,12, 95%-KI 0,88-5,12; p = 0,095). Zwei Patienten zeigten milde Nebenwirkungen während der VAE-Behandlung. Einer der beiden zeigte 1 Tag lang ein selbstlimitiertes Fieber, bei dem anderen Patienten reduzierten wir die Dosis von einem konzentrierteren zu einem weniger konzentrierten VAE (Serie 0) aufgrund von Müdigkeit, die daraufhin verschwand. Schlussfolgerungen: VAE ist eine sichere, nebenwirkungsarme Behandlung und scheint sich positiv auf die Überlebenszeit von Hunden mit OMM auszuwirken. Somit ist dieser therapeutische Ansatz es wert, vermehrt bei der adjuvant zur Strahlentherapie eingesetzten Behandlung des OMM in Betracht gezogen zu werden. Die verglichenen Gruppen waren jedoch klein, divers und nicht konsistent hinsichtlich aller prognostischen Parameter. Eine prospektive Studie mit einer größeren Studienpopulation wäre daher von Interesse

Bcl3 Couples Cancer Stem Cell Enrichment With Pancreatic Cancer Molecular Subtypes

[Background & Aims]: The existence of different subtypes of pancreatic ductal adenocarcinoma (PDAC) and their correlation with patient outcome have shifted the emphasis on patient classification for better decision-making algorithms and personalized therapy. The contribution of mechanisms regulating the cancer stem cell (CSC) population in different subtypes remains unknown. [Methods]: Using RNA-seq, we identified B-cell CLL/lymphoma 3 (BCL3), an atypical nf-κb signaling member, as differing in pancreatic CSCs. To determine the biological consequences of BCL3 silencing in vivo and in vitro, we generated bcl3-deficient preclinical mouse models as well as murine cell lines and correlated our findings with human cell lines, PDX models, and 2 independent patient cohorts. We assessed the correlation of bcl3 expression pattern with clinical parameters and subtypes. [Results]: Bcl3 was significantly down-regulated in human CSCs. Recapitulating this phenotype in preclinical mouse models of PDAC via BCL3 genetic knockout enhanced tumor burden, metastasis, epithelial to mesenchymal transition, and reduced overall survival. Fluorescence-activated cell sorting analyses, together with oxygen consumption, sphere formation, and tumorigenicity assays, all indicated that BCL3 loss resulted in CSC compartment expansion promoting cellular dedifferentiation. Overexpression of BCL3 in human PDXs diminished tumor growth by significantly reducing the CSC population and promoting differentiation. Human PDACs with low BCL3 expression correlated with increased metastasis, and BCL3-negative tumors correlated with lower survival and nonclassical subtypes. [Conclusions]: We demonstrate that bcl3 impacts pancreatic carcinogenesis by restraining CSC expansion and by curtailing an aggressive and metastatic tumor burden in PDAC across species. Levels of BCL3 expression are a useful stratification marker for predicting subtype characterization in PDAC, thereby allowing for personalized therapeutic approaches.This work was supported by the Deutsche Forschungsgemeinschaft (grants AL 1174/4-1, AL1174/4-2, and Collaborative Research Center 1321 “Modeling and Targeting Pancreatic Cancer” to Hana Algül; SFB824 Z2 to Katja Steiger), the Deutsche Krebshilfe (grant 111646 to Hana Algül), a Ramon y Cajal Merit Award from the Ministerio de Economía y Competitividad, Spain (to Bruno Sainz Jr), a Coordinated Grant from Fundación Asociación Española Contra el Cáncer (GC16173694BARB to Bruno Sainz Jr), funding from The Fero Foundation (to Bruno Sainz Jr), and a Proyecto de Investigacion de Salud, ISCIII, Spain (no. PI18/00757 to Bruno Sainz Jr). Jiaoyu Ai is supported by the “China Scholarship Council” grant program

Phenotypic variation of larks along an aridity gradient:Are desert birds more flexible?

We investigated interindividual variation and intra-individual phenotypic flexibility in basal metabolic rate (BMR), total evaporative water loss (TEWL), body temperature (T-b), the minimum dry heat transfer coefficient (h), and organ and muscle size of five species of larks geographically distributed along an aridity gradient. We exposed all species to constant environments of 15degreesC or 35degreesC, and examined to what extent interspecific differences in physiology can be attributed to acclimation. We tested the hypothesis that birds from deserts display larger intra-individual phenotypic flexibility and smaller intern individual variation than species from mesic areas.Larks from arid areas had lower BMR, TEWL, and h, but did not have internal organ, sizes different from birds from mesic habitats. BMR of 15degreesC-acclimated birds was 18.0%, 29.1%, 12.2%, 25.3%, and 4.7% higher than of 35degreesC-acclimated Hoopoe Larks, Dunn's Larks, Spike-heeled Larks, Skylarks, and Woodlarks, respectively. TEWL of 15degreesC-acclimated Hoopoe Larks exceeded values for 35degreesC-acclimated individuals by 23% but did not differ between 15degreesC- and 35degreesC-acclimated individuals in the other species. The dry heat transfer coefficient was increased in 15degreesC-acclimated individuals of Skylarks and Dunn's Larks, but not in the. other species. Body temperature was on average 0.4degreesC +/- 0.15degreesC (mean +/- 1 SEM) lower in 15degreesC-acclimated individuals of all species. Increased food intake in 15degreesC-acclimated birds stimulated enlargement of intestine (26.9-38.6%), kidneys (9.8-24.4%), liver (16.5-27.2%), and. stomach (22.0-31.6%). The pectoral muscle increased in 15degreesC-acclimated Spike-heeled Larks and Skylarks, remained unchanged in Hoopoe Larks, and decreased in 15degreesC-acclimated Woodlarks and Dunn's Larks. We conclude that the degree of intra-individual flexibility varied between physiological traits and among species, but that acclimation does not account for interspecific differences in BMR, TEWL, and h in larks. We found no general support for the hypothesis that species from desert environments display larger intra-individual phenotypic flexibility than those from mesic areas.The coefficient of variation of larks acclimated to their natural environment was smaller in species from and areas than in species from mesic areas for mass-corrected BMR and surface-specific h, but not for mass-corrected TEWL. The high repeatabilities of BMR, TEWL, and h in several species indicated a within-individual consistency on which natural selection could operate.</p

Levels of the Autophagy-Related 5 Protein Affect Progression and Metastasis of Pancreatic Tumors in Mice

[Background and Aims]: Cells in pancreatic ductal adenocarcinoma (PDAC) undergo autophagy, but its effects vary with tumor stage and genetic factors. We investigated the consequences of varying levels of the autophagy related 5 (Atg5) protein on pancreatic tumor formation and progression. [Methods]: We generated mice that express oncogenic Kras in primary pancreatic cancer cells and have homozygous disruption of Atg5 (A5;Kras) or heterozygous disruption of Atg5 (A5+/–;Kras), and compared them with mice with only oncogenic Kras (controls). Pancreata were analyzed by histology and immunohistochemistry. Primary tumor cells were isolated and used to perform transcriptome, metabolome, intracellular calcium, extracellular cathepsin activity, and cell migration and invasion analyses. The cells were injected into wild-type littermates, and orthotopic tumor growth and metastasis were monitored. Atg5 was knocked down in pancreatic cancer cell lines using small hairpin RNAs; cell migration and invasion were measured, and cells were injected into wild-type littermates. PDAC samples were obtained from independent cohorts of patients and protein levels were measured on immunoblot and immunohistochemistry; we tested the correlation of protein levels with metastasis and patient survival times. [Results]: A5+/–;Kras mice, with reduced Atg5 levels, developed more tumors and metastases, than control mice, whereas A5;Kras mice did not develop any tumors. Cultured A5+/–;Kras primary tumor cells were resistant to induction and inhibition of autophagy, had altered mitochondrial morphology, compromised mitochondrial function, changes in intracellular Ca2+ oscillations, and increased activity of extracellular cathepsin L and D. The tumors that formed in A5+/–;Kras mice contained greater numbers of type 2 macrophages than control mice, and primary A5+/–;Kras tumor cells had up-regulated expression of cytokines that regulate macrophage chemoattraction and differentiation into M2 macrophage. Knockdown of Atg5 in pancreatic cancer cell lines increased their migratory and invasive capabilities, and formation of metastases following injection into mice. In human PDAC samples, lower levels of ATG5 associated with tumor metastasis and shorter survival time. [Conclusions]: In mice that express oncogenic Kras in pancreatic cells, heterozygous disruption of Atg5 and reduced protein levels promotes tumor development, whereas homozygous disruption of Atg5 blocks tumorigenesis. Therapeutic strategies to alter autophagy in PDAC should consider the effects of ATG5 levels to avoid the expansion of resistant and highly aggressive cells.This study was supported in part by the Mildred-Scheel-Professur der Deutschen Krebshilfe 111464, DFG AL 1174/6-1 to H.A., DFG DI 2299/1-1 to K.N.D., DFG SFB1321 (S01) to K.S. and W.W., and the German Federal Ministry of Education and Research to the German Center for Diabetes Research (DZD e.V.) to J.A

Ein Mistelextrakt (Viscum album) als ergänzendes Therapiekonzept beim felinen Fibrosarkom

Das feline Fibrosarkom (FFS) stellt durch seine Malignität und seine extrem hohe Rezidivrate ein großes Problem in der Kleintierpraxis dar. Nahezu alle betroffenen Katzen werden einer chirurgischen Entfernung des Tumors unterzogen, entwickeln aber zu einem hohen Prozentsatz innerhalb kurzer Zeit Rezidive. Unterstützende Misteltherapieprotokolle mit Injektionspräparaten werden kritisch beurteilt, da FFS im Verdacht stehen, durch mechanische Insulte (Spritzen, Verletzungen) zu entstehen. Die orale Anwendung von Viscum album erscheint daher als mögliche Alternative in der adjuvanten Tumortherapie. In einer prospektiven Anwendungsbeobachtung bei 44 Katzen soll die rezidiv prophylaktische Wirkung eines oralen Eichenmistelextraktes postoperativ geprüft werden. Alle Tiere erhielten zweimal täglich 0,5 ml einer wässrigen Viscum Quercus Lösung (Viscum Quercus praeparatum 0,1% Hiscia und Weleda, Arlesheim), Die mediane rezidivfreie Zeit (DFST, disease free survival time) betrug 447 Tage (31 bis 983 Tage). Verglichen mit Literaturdaten liegt dieses Ergebnis höher als in Patientenkollektiven ohne adjuvante Therapie (120 d – ca. 300 d Operationen ohne Amputation). Erstaunlicherweise zeigten die Katzen, die in einer Spezialklinik operiert worden waren, eine geringere DFST von 279 Tagen, verglichen mit 472 Tagen (nicht signifikant) der Tiere, die in einer allgemeinen Tierarztpraxis operiert worden waren. Weder die histologisch bestätigte komplette Exzision des Tumors, noch die Anzahl der vorausgegangenen Tumor- bzw. Rezidivoperationen zeigten einen signifikanten Effekt auf die Überlebenszeit. Zur Bestätigung bzw. Absicherung des als positiv zu wertenden therapeutischen Effektes sind weitere kontrollierte Studien notwendig

Clinical course of a malignant peripheral nerve sheath tumor in a Siberian tiger (Panthera tigris altaica)

A 14-year-old male Siberian tiger (Panthera tigris altaica) was admitted with an ulcerating mass on the right thoracic wall. Radiographic and computed tomographic evaluation indicated 2 isolated cutaneous masses without any signs of metastasis. Histology of a Tru-Cut biopsy revealed an anaplastic sarcoma with giant cells. Both tumors were resected with appropriate normal tissue margins. The size of the defect did not allow primary closure of the wound; therefore, a mesh expansion technique was attempted. Three months later, the tiger had to be euthanized due to extensive metastasis to the lungs. Histomorphological features and immunohistochemical results confirmed the diagnosis of malignant peripheral nerve sheath tumor. In contrast to domestic animal experience, the tumor had spread extensively to the lungs without local reccurrence in a short period of time. Correct diagnosis requires various immunohistochemical evaluations of the tumor tissue

Chemotherapy and radiation therapy in 4 dogs with muscle-invasive transitional cell carcinoma of the urinary tract

Four dogs with T(2)N(0)M(0) transitional cell carcinoma of the lower urinary tract underwent multimodal treatment consisting of neoadjuvant chemotherapy, external-beam radiotherapy, and adjuvant chemotherapy. No significant toxicity was documented. All dogs showed clinical improvement and reduction of tumor volume based on computed tomography (CT)