Common Spontaneous Tumors and Tumor-like Lesions in 70 Pet Rodents and Negative MMTV Detection in Mammary Tumors.

Compared to the number of studies on the neoplasms of laboratory rodents, fewer studies have focused on spontaneous neoplasms in pet rodents. Notably, the mouse mammary tumor virus (MMTV) is associated with mammary tumors in rodents. In this study, 77 tumors and tumor-like lesions of biopsy samples were collected from 70 pet rodents, including hamsters (n = 47), guinea pigs (n = 16), unknown species (n = 4), rats (n = 2), and a gerbil. Fifty tumors were collected from 47 hamsters, in which the most common tumors were mammary tumors (13/50), followed by fibrosarcoma (9/50), mast cell tumors (4/50), and squamous cell carcinoma (4/50). The collected subtypes of mammary tumors in hamsters included tubular carcinoma (n = 5), tubular adenoma (n = 4), carcinoma and malignant myoepithelioma (n = 1), simple tubular carcinoma (n = 1), adenosquamous carcinoma (n = 1), and tubulopapillary adenoma (n = 1). In addition, twenty tumors were collected from guinea pigs, in which the most common tumor was lipoma (6/20), followed by adenocarcinoma of the mammary gland (4/20), trichofolliculoma (2/20), and collagenous hamartomas (2/20). In guinea pigs, the subtypes of mammary gland tumors were tubular carcinoma (n = 2), tubular and solid carcinoma (n = 1), and tubulopapillary carcinoma (n = 1). In 20 cases of mammary tumors, MMTV was not detected, implicating no evidence of MMTV infection in mammary oncogenesis in pet rodents in Taiwan.

Gadolinium Neutron Capture Therapy for Cats and Dogs with Spontaneous Tumors Using Gd-DTPA.

We conducted a clinical veterinary study on neutron capture therapy (NCT) at a neutron-producing accelerator with seven incurable pets with spontaneous tumors and gadolinium as a neutron capture agent (gadolinium neutron capture therapy, or GdNCT). Gadolinium-containing dimeglumine gadopentetate, or Gd-DTPA (Magnevist®, 0.6 mL/kg b.w.), was used. We observed mild and reversible toxicity related to the treatment. However, no significant tumor regression in response to the treatment was observed. In most cases, there was continued tumor growth. Overall clinical improvement after treatment was only temporary. The use of Gd-DTPA for NCT had no significant effects on the life expectancy and quality of life of animals with spontaneous tumors. Further experiments using more advanced gadolinium compounds are needed to improve the effect of GdNCT so that it can become an alternative to boron neutron capture therapy. Such studies are also necessary for further NCT implementation in clinical practice as well as in veterinary medicine.

Complexes of ortho-Phthalic Acid in Spontaneous Animal Tumors.

The presence of diethyl-, dibutyl-, and 2-ethylhexyl phthalates in spontaneous animal tumors was determined for the first time. Small-cell breast cancer of the dog and Ehrlich ascites carcinoma with the cells are particularly rich of these compounds. It is assumed that the level of phthalates in these cells is due to the activity of expression of nuclear receptors for estrogens and progesterone, as well as the peculiarities of the metabolism of xenobiotics. The accumulation of these compounds in tumor cells can increase their malignancy. The data obtained can be used for development of new diagnostic and therapeutic technologies.

Granulocytosis, a Paraneoplastic Syndrome Associated With Non-Glandular Squamous Cell Carcinomas (NGSCC) in the Tg.rasH2 Studies.

Non-glandular squamous cell carcinoma (NGSCC) is an extremely rare tumor in Tg.raH2 mice. There have been 5 NGSCC in 1615 control male mice (0.31%) and 2 NGSCC in 1560 control female mice (0.13%) on 26-week carcinogenicity studies, with a range of 0 to 1 of per group per sex in each study without statistical significance in 52 male and 51 female studies conducted in Tg.rasH2 mice. Every case of NGSCC was accompanied by profound granulocytosis.

Spontaneous and Induced Tumors in Germ-Free Animals: A General Review.

Cancer, bacteria, and immunity relationships are much-debated topics in the last decade. Microbiome's importance for metabolic and immunologic modulation of the organism adaptation and responses has become progressively evident, and models to study these relationships, especially about carcinogenesis, have acquired primary importance. The availability of germ-free (GF) animals, i.e., animals born and maintained under completely sterile conditions avoiding the microbiome development offers a unique tool to investigate the role that bacteria can have in carcinogenesis and tumor development. The comparison between GF animals with the conventional (CV) counterpart with microbiome can help to evidence conditions and mechanisms directly involving bacterial activities in the modulation of carcinogenesis processes. Here, we review the literature about spontaneous cancer and cancer modeling in GF animals since the early studies, trying to offer a practical overview on the argument.

Beyond tradition and convention: benefits of non-traditional model organisms in cancer research.

Traditional laboratory model organisms are indispensable for cancer research and have provided insight into numerous mechanisms that contribute to cancer development and progression in humans. However, these models do have some limitations, most notably related to successful drug translation, because traditional model organisms are often short-lived, small-bodied, genetically homogeneous, often immunocompromised, are not exposed to natural environments shared with humans, and usually do not develop cancer spontaneously. We propose that assimilating information from a variety of long-lived, large, genetically diverse, and immunocompetent species that live in natural environments and do develop cancer spontaneously (or do not develop cancer at all) will lead to a more comprehensive understanding of human cancers. These non-traditional model organisms can also serve as sentinels for environmental risk factors that contribute to human cancers. Ultimately, expanding the range of animal models that can be used to study cancer will lead to improved insights into cancer development, progression and metastasis, tumor microenvironment, as well as improved therapies and diagnostics, and will consequently reduce the negative impacts of the wide variety of cancers afflicting humans overall.

Neoplasms in domestic hamsters in Southern Brazil: epidemiological and pathological aspects of 40 cases1 / Neoplasias em hamsters domésticos no Sul do Brasil: aspectos epidemiológicos e patológicos de 40 casos

Although neoplasms are commonly reported in domestic hamsters, retrospective studies approaching spontaneous tumors with data regarding epidemiological findings are scarce. The present study aimed to describe the epidemiological and pathological findings of 40 cases of tumors in domestic hamsters diagnosed in a veterinary pathology laboratory in Southern Brazil from 2002 to 2019. Chinese hamster (Cricetulus griseus) was the most commonly affected species (16/40), followed by Djungarian hamster (Phodopus sungorus, 11/40) and Syrian hamster (Mesocricetus auratus, 4/40). Among the cases, 57.5% were females (23/40), while 42.5% were males (17/40). The affected hamsters' median age was of 14-months old, with an age range of 8- to 36-months old. Twenty-four cases were assessed as anatomopathological samples (biopsies), while 16 were composed of carcasses submitted to postmortem examination, and, therefore, the neoplasm was related to the cause of death. The integumentary system was frequently affected (60%, 24/40), followed by the female reproductive tract (22.5%, 9/40), hematopoietic system (10%, 4/40), digestive tract (5%, 2/40), and endocrine system (2.5%, 1/40). The most frequent neoplasm was squamous cell carcinoma (35%, 14/40), mostly on the lip/nasal region (50%, 7/14). Other tumors included fibrosarcoma (10%, 4/40), lymphoma (10%, 4/40), mammary cystadenoma (10%, 4/40), apocrine sweat gland adenoma (7.5%, 3/40), hemangiosarcoma (5%, 2/40), leiomyosarcoma (5%, 2/40), and granulosa ovarian cell tumor (5%, 2/40). The five remaining cases occurred individually and were composed of hepatoid gland adenoma, solid thyroid carcinoma, cutaneous melanoma, ovarian teratoma, and cutaneous trichoblastoma. Neoplasms were identified as an important cause of death and major reason to perform biopsy in domestic hamsters in Southern Brazil.(AU)

Embora neoplasmas em hamsters domésticos sejam comumente relatados, estudos retrospectivos abordando neoplasias espontâneas e os dados epidemiológicos associados são escassos. O presente estudo teve o objetivo de descrever os principais achados epidemiológicos e patológicos de 40 casos de tumores em hamsters domésticos diagnosticados em um laboratório de patologia veterinária do Sul do Brasil de 2002 a 2019. A principal espécie acometida foi o hamster chinês (Cricetulus griseus, 16/40), seguido por hamster anão russo siberiano (Phodopus sungorus, 11/40) e hamster sírio (Mesocricetus auratus, 4/40). As fêmeas corresponderam a 57,5% dos casos (23/40), enquanto os machos representaram 42,5% (17/40). Foram afetados roedores com uma faixa etária de 8 a 36 meses de idade, e uma mediana de 14 meses. Do total de casos, 24 foram exames anatomopatológicos (biopsias) e 16 casos foram examinados através de necropsia e, portanto, relacionados com a causa da morte dos animais. O sistema tegumentar foi o mais frequentemente acometido (60%; 24/40), seguido pelo trato reprodutivo (22,5%; 9/40), sistema hematopoietico (10%; 4/40), trato digestório (5%; 2/40) e sistema endócrino (2,5%; 1/40). A neoplasia mais frequentemente diagnosticada foi o carcinoma de células escamosas (35%; 14/40), localizado principalmente em região labionasal (50%; 7/14). Outros tumores incluíram fibrossarcoma (10%; 4/40), linfoma (10%; 4/40), adenoma cístico de glândula mamária (10%; 4/40), adenoma de glândula sudorípara (7,5%; 3/40), hemangiossarcoma (5%; 2/40), leiomiossarcoma (5%; 2/40) e tumor de células da granulosa (5%; 2/40). Os outros cinco casos remanescentes ocorreram individualmente e eram compostos por adenoma de glândula hepatoide, carcinoma sólido de tireoide, melanoma cutâneo, teratoma ovariano e tricoblastoma cutâneo. Neoplasmas foram identificados como importantes causas de morte ou razões para realização de biopsia em hamsters domésticos no Sul do Brasil.(AU)

Comparison of longevity and common tumor profiles between Sprague-Dawley and Han Wistar rats.

The Sprague Dawley (SD) and Han Wistar (HW) are the two most commonly used rat strains in Europe and the US, with the Han Wistar increasing in popularity because of its greater longevity and lower tumor burden. This survey was undertaken at Covance CRS (Huntingdon and Eye) to compare in-house longevity and common spontaneous tumor profiles of the two strains with published data. Data were compiled from 104-week studies started between 2010 and 2017. Mean survival was greater for both sexes of HWs when compared with SDs. Pituitary tumors were the commonest in both strains, with slightly higher incidences and more malignant tumors in SDs of both sexes. Mammary tumors were the second most common tumor in both strains; the incidence being greater in SDs compared to HWs. Benign pheochromocytomas of the adrenal and fibromas of the skin/subcutis were commoner in male SDs than in HWs. Granular cell tumors of the uterine tract were recorded only in SDs, but uterine stromal and glandular tumors were more common in HWs, which also displayed a higher incidence of granulosa cell tumors of the ovaries. Vascular tumors of the mesenteric lymph nodes, thymomas and follicular cell tumors of the thyroids were recorded at a higher incidence in HWs than in SDs. Tumor profiles of other common tumors were broadly similar between the two strains. The results of this survey correlate closely with similar comparisons made at other laboratories, and with data compiled at our laboratories 10 years ago and published as a poster.

Preliminary safety and imaging efficacy of the near-infrared fluorescent contrast agent DA364 during fluorescence-guided surgery in dogs with spontaneous superficial tumors.

Tumor-targeting contrast agents may facilitate resection of solid neoplasms during fluorescence-guided surgery. Preliminary safety and imaging efficacy of the near-infrared fluorescent probe DA364 were evaluated during surgical resection of spontaneous solid tumors in 24 dogs. Intra-operative imaging was performed in situ and on excised specimens to evaluate fluorescence intensities of tumor and adjacent tissues. After standard-of-care tumor resection, the wound bed was imaged again, and additional tissue was excised if residual fluorescence was detected. DA364 was well tolerated after intravenous administration. The median tumor-to-background ratio in situ for mammary tumors, mast cell tumors and sarcomas was 1.8 (range 1.2-3.9), 2.2 (range 1.0-5.6), and 4.2 (range 2.0-4.3), respectively. Qualitative intra-operative tumor identification was feasible in half of the cases. Remaining fluorescence was detected in four wound beds that contained residual disease, and in11 tumor-free wound beds, confirmed by histopathology. Overall, DA364 did not raise safety concerns and showed accumulation in different types of spontaneous tumors, showing potential to pinpoint residual disease. Larger clinical trials are necessary to select accurate dosing and imaging protocols for specific indications to evaluate the sensitivity and specificity of the agent.

Preclinical murine tumor models: a structural and functional perspective.

The goal of this review is to pinpoint the specific features, including the weaknesses, of various tumor models, and to discuss the reasons why treatments that are efficient in murine tumor models often do not work in clinics. In a detailed comparison of transplanted and spontaneous tumor models, we focus on structure-function relationships in the tumor microenvironment. For instance, the architecture of the vascular tree, which depends on whether tumor cells have gone through epithelial-mesenchymal transition, is determinant for the extension of the spontaneous necrosis, and for the intratumoral localization of the immune infiltrate. Another key point is the model-dependent abundance of TGFß in the tumor, which controls the variable susceptibility of different tumor models to treatments. Grounded in a historical perspective, this review provides a rationale for checking factors that will be key for the transition between preclinical murine models and clinical applications.

Endogenous Avian Leukosis Virus in Combination with Serotype 2 Marek's Disease Virus Significantly Boosted the Incidence of Lymphoid Leukosis-Like Bursal Lymphomas in Susceptible Chickens.

In 2010, sporadic cases of avian leukosis virus (ALV)-like bursal lymphoma, also known as spontaneous lymphoid leukosis (LL)-like tumors, were identified in two commercial broiler breeder flocks in the absence of exogenous ALV infection. Two individual ALV subgroup E (ALV-E) field strains, designated AF227 and AF229, were isolated from two different breeder farms. The role of these ALV-E field isolates in development of and the potential joint impact in conjunction with a Marek's disease virus (MDV) vaccine (SB-1) were further characterized in chickens of an experimental line and commercial broiler breeders. The experimental line 0.TVB*S1, commonly known as the rapid feathering-susceptible (RFS) line, of chickens lacks all endogenous ALV and is fully susceptible to all subgroups of ALV, including ALV-E. Spontaneous LL-like tumors occurred following infection with AF227, AF229, and a reference ALV-E strain, RAV60, in RFS chickens. Vaccination with serotype 2 MDV, SB-1, in addition to AF227 or AF229 inoculation, significantly enhanced the spontaneous LL-like tumor incidence in the RFS chickens. The spontaneous LL-like tumor incidence jumped from 14% by AF227 alone to 42 to 43% by AF227 in combination with SB-1 in the RFS chickens under controlled conditions. RNA-sequencing analysis of the LL-like lymphomas and nonmalignant bursa tissues of the RFS line of birds identified hundreds of differentially expressed genes that are reportedly involved in key biological processes and pathways, including signaling and signal transduction pathways. The data from this study suggested that both ALV-E and MDV-2 play an important role in enhancement of the spontaneous LL-like tumors in susceptible chickens. The underlying mechanism may be complex and involved in many chicken genes and pathways, including signal transduction pathways and immune system processes, in addition to reported viral genes.IMPORTANCE Lymphoid leukosis (LL)-like lymphoma is a low-incidence yet costly and poorly understood disease of domestic chickens. The observed unique characteristics of LL-like lymphomas are that the incidence of the disease is chicken line dependent; pathologically, it appeared to mimic avian leukosis but is free of exogenous ALV infection; inoculation of the nonpathogenic ALV-E or MDV-2 (SB-1) boosts the incidence of the disease; and inoculation of both the nonpathogenic ALV-E and SB-1 escalates it to much higher levels. This study was designed to test the impact of two new ALV-E isolates, recently derived from commercial broiler breeder flocks, in combination with the nonpathogenic SB-1 on LL-like lymphoma incidences in both an experimental egg layer line of chickens and a commercial broiler breeder line of chickens under a controlled condition. Data from this study provided an additional piece of experimental evidence on the potency of nonpathogenic ALV-E, MDV-2, and ALV-E plus MDV-2 in boosting the incidence of LL-like lymphomas in susceptible chickens. This study also generated the first piece of genomic evidence that suggests host transcriptomic variation plays an important role in modulating LL-like lymphoma formation.

Mouse-Derived Isograft (MDI) In Vivo Tumor Models I. Spontaneous sMDI Models: Characterization and Cancer Therapeutic Approaches.

Syngeneic in vivo tumor models are valuable for the development and investigation of immune-modulating anti-cancer drugs. In the present study, we established a novel syngeneic in vivo model type named mouse-derived isografts (MDIs). Spontaneous MDIs (sMDIs) were obtained during a long-term observation period (more than one to two years) of naïve and untreated animals of various mouse strains (C3H/HeJ, CBA/J, DBA/2N, BALB/c, and C57BL/6N). Primary tumors or suspicious tissues were assessed macroscopically and re-transplanted in a PDX-like manner as small tumor pieces into sex-matched syngeneic animals. Nine outgrowing primary tumors were histologically characterized either as adenocarcinomas, histiocytic carcinomas, or lymphomas. Growth of the tumor pieces after re-transplantation displayed model heterogeneity. The adenocarcinoma sMDI model JA-0009 was further characterized by flow cytometry, RNA-sequencing, and efficacy studies. M2 macrophages were found to be the main tumor infiltrating leukocyte population, whereas only a few T cells were observed. JA-0009 showed limited sensitivity when treated with antibodies against inhibitory checkpoint molecules (anti-mPD-1 and anti-mCTLA-4), but high sensitivity to gemcitabine treatment. The generated sMDI are spontaneously occurring tumors of low passage number, propagated as tissue pieces in mice without any tissue culturing, and thus conserving the original tumor characteristics and intratumoral immune cell populations.

A Comparison of Spontaneous Tumors in Tg.rasH2 Mice in 26-week Carcinogenicity Studies Conducted at a Single Test Facility during 2004 to 2012 and 2013 to 2018.

This article presents the historical control data of spontaneous tumors in Tg.rasH2 published in 2013 (2004-2012) and compares and contrasts it to more recent data collected from 2013 to 2018, reporting differences in the average percentage incidences or incidence ranges as well as the incidence of new tumors. In 2013, we published a comprehensive review of spontaneous tumors in Tg.rasH2 mice used in 26-week carcinogenicity studies, which included data from control dose groups from 26 studies and a total of 710 mice per sex. The total database, now including the more recent data, has nearly doubled the number of animals, completing to date a total of 52 studies in males and 51 studies in females for a total of 1,615 male mice and 1,560 female mice, respectively. In this article, we compare the data collected from 2004 to 2012 against the data collected from 2013 to 2018 and the overall tumor incidence change.

High temperature hyperthermia treatment for canines exhibiting superficial tumors: A report of three cases.

High temperature hyperthermia (HTH) treatment has previously been demonstrated to suppress tumor growth in a tumor-bearing rat model. In the present study, the effects of HTH therapy for the treatment of spontaneous tumors in canines was evaluated. In case 1, an 18-year-old female Papillon presented with a right forelimb rhabdomyosarcoma. Case 2 was a 13-year-old male English Cocker Spaniel with a right external auditory canal ceruminous adenocarcinoma and case 3 was a 14-year-old male Golden Retriever that exhibited a perianal gland adenocarcinoma, which surrounded the anus. HTH treatment was performed in all three cases for 10 min at 45-65°C with or without the inhalation of isoflurane. In case 1, the tumor disappeared four weeks following HTH treatment. In case 2, the tumor volume had decreased by day 21, and in case 3, HTH was performed three times and the tumor disappeared following the third procedure. HTH is considered to be a simple procedure with no severe side effects. Consequently, this treatment modality is hypothesized to become a useful alternative therapy for superficial tumors in companion animals.

The chicken model of spontaneous ovarian cancer.

The chicken is a unique experimental model for studying the spontaneous onset and progression of ovarian cancer (OVC). The prevalence of OVC in chickens can range from 5 to 35% depending on age, genetic strain, reproductive history, and diet. Furthermore, the chicken presents epidemiological, morphological, and molecular traits that are similar to human OVC making it a relevant experimental model for translation research. Similarities to humans include associated increased risk of OVC with the number of ovulations, common histopathological subtypes including high-grade serous, and molecular-level markers or pathways such as CA-125 expression and p53 mutation frequency.  Collectively, the similarities between chicken and human OVC combined with a tightly controlled genetic background and predictable onset window provides an outstanding experimental model for studying the early events and progression of spontaneous OVC tumors under controlled environmental conditions. This review will cover the existing literature on OVC in the chicken and highlight potential opportunities for further exploitation (e.g. biomarkers, prevention, treatment, and genomics).

Magnetic resonance imaging-guided microdialysis cannula implantation in a spontaneous high-grade glioma murine model.

Cerebral microdialysis is used to study anticancer drug penetration in the central nervous system (CNS) and brain tumors in animal models. Genetically engineered murine models (GEMMs) have been recently used to study many aspects of CNS tumors since they represent a more relevant model than orthotopic brain tumor xenograft models. However, it is challenging to implant microdialysis cannula in these animals because T2-weighted magnetic resonance imaging (MRI) does not show the reference point (bregma) traditionally used to obtain stereotactic coordinates. Thus, an alternative reference point that can be visualized on MRI images is needed. In this study, a novel reference point, identified as the intersection between the olfactory bulb/frontal lobe border and the midline between cerebral hemispheres on T2-weighted MRI images, was used to calculate anterior-posterior and medial-lateral coordinates of brain tumors in a GEMM. This point overlies a visible crossover between the rostral rhinal vein and the midline suture on the mouse skull, allowing for the conversion of the MRI coordinates into surgical stereotactic coordinates. Postmortem MRI and histological examination confirmed accurate probe placement. This procedure will facilitate the accurate and precise implantation of microdialysis probes for the study of anticancer drug penetration in brain tumors of GEMMs.