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Abstract: Objectives:: Superficial bladder tumours are at high risk for recurrence, relapse after resection, escape to intravesical immunotherapy and they may become invasive. New therapeutics are therefore needed to achieve cure. Thus, gene therapy is an attractive new treatment modality for malignant bladder tumours. The purpose of this study was to evaluate the feasibility and the efficiency of retroviral mediated reporter gene transfer into malignant urothelial cells both in vitro and in vivo. Methods:: We evaluated the feasibility of the transfection of bladder tumour with direct intravesical instillation of a defective retrovirus. The vector was derived from LXSN. The efficiency of transduction with the Moloney Leukaemia Murine virus-based vector, amphotrophic retroviral vector, was monitored through the expression of two marker genes (nls-LacZ and NeoR). The canine animal was chosen since it can present with spontaneous bladder carcinomas mimicking human pathology. Primary cultures of two normal canine bladder urothelium and two canine primary bladder tumours were first studied. We then investigated in vivo, in two normal and two spontaneous tumour bearing dogs, the transduction of urothelial cells following direct intravesical instillation of 2·104 to 3·106 of the retroviral vector. Results:: Transduced cells were evidenced in all primary cultures of canine normal urothelium and transitional cell carcinoma. Bladder biopsies from sound dogs instilled with the viral solution showed long lasting transduction up to 60 days long. Bladder cryosections from tumour-bearing dogs displayed transduction of superficial layers of urothelial cancer cells without passing through lamina propria. In vivo transduction was evidenced in 1 to 15% (mean 5%) of the cells in the tumours and preferentially addressed malignant cells. Normal epithelium either originating from sound or tumour-bearing animals was not transduced. Conclusion:: These results demonstrate for the first time the feasibility of in vivo retroviral transduction of bladder cancer using a clinically relevant procedure. [Copyright &y& Elsevier]

Abstract: The aim of this study was to investigate the subcutaneous tissue response to administration of a single dose of multi-component vaccine in the cat. Three groups of 15 cats were injected with one of three vaccine products with saline as a negative control. Cats in group A received non-adjuvanted vaccine; cats in group B received vaccine with a lipid-based adjuvant; whilst those in group C were vaccinated with a product adjuvanted with an alum–Quil A mixture. The vaccine and saline injection sites were sampled on days 7, 21 and 62 post-vaccination. Biopsies of these vaccine sites were examined qualitatively and scored semi-quantitatively for a series of parameters related to aspects of the inflammatory and tissue repair responses. These data were analysed statistically, including by principal component analysis. At all three time points of the experiment, there was significantly less inflammation associated with administration of non-adjuvanted vaccine (p =0.000). Although there was evidence of tissue repair by day 62 in all groups, those cats receiving adjuvanted vaccines had evidence of residual adjuvant material accumulated within macrophages at this late time point. The severity of tissue reactions may vary significantly in response to vaccines which include adjuvants or are non-adjuvanted. [Copyright &y& Elsevier]

We tested the canarypox virus vector ALVAC and the genetically attenuated vaccinia virus vector NYVAC as vehicles for achieving local immunomodulation in domestic animals bearing spontaneous tumours. Following intratumoral administration of ALVAC-, or NYVAC-luciferase in dogs with melanoma, it was demonstrated that viral recombinants remained localized along the needle track, with no virus detectable in the periphery of the tumour. Given these distribution characteristics and their well-documented safety profile, ALVAC- or NYVAC-based recombinants expressing feline or human IL2, respectively, were administered to domestic cats, in order to prevent the recurrence of spontaneous fibrosarcomas. In the absence of immunotherapy, tumour recurrence was observed in 61% of animals within a 12-month follow-up period after treatment with surgery and iridium-based radiotherapy. In contrast, only 39 and 28% of cats receiving either NYVAC-human IL2 or ALVAC-feline IL2, respectively, exhibited tumour recurrences. Based on such results, and in the context of ongoing clinical studies conducted in humans, we discuss the utilization of ALVAC- or NYVAC-based recombinants as viable therapeutic modalities for local immunotherapy or therapeutic vaccination against cancer, both in humans and companion animals.Gene Therapy (2003) 10, 2126-2132. doi:10.1038/sj.gt.3302124 [ABSTRACT FROM AUTHOR]

This present study evaluates the potential of adenovirus-mediated gene transfer (AMGT) to the prostate of normal laboratory beagles. Many morphological and histological similarities can be noted between dog and human prostate. Moreover, dogs can spontaneously develop prostate cancer with a clinical and biological outcome identical to that in man. Firstly we showed the capacity of human adenovirus to infect canine prostatic cells in vitro. Secondly, we injected transrectally in the dogs’ prostates 2×109 plaque forming units of a first generation recombinant adenovirus vector harboring the reporter gene β-galactosidase (AdRSVβgal). Seven days after the adenoviral delivery, we observed expression of the transgene in both prostates, and exclusively in epithelial cells. Despite a cellular and a humoral immune response, the infusion appeared safe, since the dogs had no fever and presented no urinary symptoms. This study constitutes the first evaluation of AMGT in dog prostate and provides a basis for gene therapy treatment of prostate carcinoma-bearing patients. [ABSTRACT FROM AUTHOR]

Background & Aims: Major bleeding events during orthotopic liver transplantation (OLT) are associated with poor outcomes. The proportion of this risk related to portal hypertension is unclear. Hepatic venous pressure gradient (HVPG) is the gold standard for estimating portal hypertension. The aim of this study was to analyze the ability of HVPG to predict intraoperative major bleeding events during OLT in patients with cirrhosis., Methods: We retrospectively analyzed a prospective database including all patients with cirrhosis who underwent OLT between 2010 and 2020 and had liver and right heart catheterizations as part of their pre-transplant assessment. The primary endpoint was the occurrence of an intraoperative major bleeding event., Results: The 468 included patients had a median HVPG of 17 mmHg [interquartile range, 13-22] and a median MELD on the day of OLT of 16 [11-24]. Intraoperative red blood cell transfusion was required in 72% of the patients (median 2 units transfused), with a median blood loss of 1,000 ml [575-1,500]. Major intraoperative bleeding occurred in 156 patients (33%) and was associated with HVPG, preoperative hemoglobin level, severity of cirrhosis at the time of OLT (MELD score, ascites, encephalopathy), hemostasis impairment (thrombocytopenia, lower fibrinogen levels), and complications of cirrhosis (sepsis, acute-on-chronic liver failure). By multivariable regression analysis with backward elimination, HVPG, preoperative hemoglobin level, MELD score, and tranexamic acid infusion were associated with the primary endpoint. Three categories of patients were identified according to HVPG: low-risk (HVPG <16 mmHg), high-risk (HVGP ≥16 mmHg), and very high-risk (HVPG ≥20 mmHg)., Conclusions: HVPG predicted major bleeding events in patients with cirrhosis undergoing OLT. Including HVPG as part of pre-transplant assessment might enable better anticipation of the intraoperative course., Impact and Implications: Major bleeding events during orthotopic liver transplantation (OLT) are associated with poor outcomes but the proportion of this risk related to portal hypertension is unclear. Our work shows that hepatic venous pressure gradient (HVPG), the gold standard for estimating portal hypertension, is a strong predictor of major bleeding events and blood loss volume in patients with cirrhosis undergoing OLT. Three groups of patients can be identified according to their risk of major bleeding events: low-risk patients with HVPG <16 mmHg, high-risk patients with HVPG ≥16 mmHg, and very high-risk patients with HVPG ≥20 mmHg. HVPG could be systematically included in the pre-transplant assessment to anticipate intraoperative course and tailor patient management., Competing Interests: The authors of this study declare that they do not have any conflict of interest. Please refer to the accompanying ICMJE disclosure forms for further details., (© 2024 The Authors.)

Histiocytic sarcoma (HS) is a rare but aggressive cancer in both humans and dogs. The spontaneous canine model, which has clinical, epidemiological, and histological similarities with human HS and specific breed predispositions, provides a unique opportunity to unravel the genetic basis of this cancer. In this study, we aimed to identify germline risk factors associated with the development of HS in canine-predisposed breeds. We used a methodology that combined several genome-wide association studies in a multi-breed and multi-cancer approach as well as targeted next-generation sequencing, and imputation We combined several dog breeds (Bernese mountain dogs, Rottweilers, flat-coated retrievers, and golden retrievers), and three hematopoietic cancers (HS, lymphoma, and mast cell tumor). Results showed that we not only refined the previously identified HS risk CDKN2A locus, but also identified new loci on canine chromosomes 2, 5, 14, and 20. Capture and targeted sequencing of specific loci suggested the existence of regulatory variants in non-coding regions and methylation mechanisms linked to risk haplotypes, which lead to strong cancer predisposition in specific dog breeds. We also showed that these canine cancer predisposing loci appeared to be due to the additive effect of several risk haplotypes involved in other hematopoietic cancers such as lymphoma or mast cell tumors as well. This illustrates the pleiotropic nature of these canine cancer loci as observed in human oncology, thereby reinforcing the interest of predisposed dog breeds to study cancer initiation and progression., Competing Interests: The authors have declared that no competing interests exist.

Circulating tumor DNA (ctDNA) has become an attractive biomarker in human oncology, and its use may be informative in canine cancer. Thus, we used droplet digital PCR or PCR for antigen receptor rearrangement, to explore tumor-specific point mutations, copy number alterations, and chromosomal rearrangements in the plasma of cancer-affected dogs. We detected ctDNA in 21/23 (91.3%) of histiocytic sarcoma (HS), 2/8 (25%) of oral melanoma, and 12/13 (92.3%) of lymphoma cases. The utility of ctDNA in diagnosing HS was explored in 133 dogs, including 49 with HS, and the screening of recurrent PTPN11 mutations in plasma had a specificity of 98.8% and a sensitivity between 42.8 and 77% according to the clinical presentation of HS. Sensitivity was greater in visceral forms and especially related to pulmonary location. Follow-up of four dogs by targeting lymphoma-specific antigen receptor rearrangement in plasma showed that minimal residual disease detection was concordant with clinical evaluation and treatment response. Thus, our study shows that ctDNA is detectable in the plasma of cancer-affected dogs and is a promising biomarker for diagnosis and clinical follow-up. ctDNA detection appears to be useful in comparative oncology research due to growing interest in the study of natural canine tumors and exploration of new therapies.

In humans, histiocytic sarcoma (HS) is an aggressive cancer involving histiocytes. Its rarity and heterogeneity explain that treatment remains a challenge. Sharing high clinical and histopathological similarities with human HS, the canine HS is conversely frequent in specific breeds and thus constitutes a unique spontaneous model for human HS to decipher the genetic bases and to explore therapeutic options. We identified sequence alterations in the MAPK pathway in at least 63.9% (71/111) of HS cases with mutually exclusive BRAF (0.9%; 1/111), KRAS (7.2%; 8/111) and PTPN11 (56.75%; 63/111) mutations concentrated at hotspots common to human cancers. Recurrent PTPN11 mutations are associated to visceral disseminated HS subtype in dogs, the most aggressive clinical presentation. We then identified PTPN11 mutations in 3/19 (15.7%) human HS patients. Thus, we propose PTPN11 mutations as key events for a specific subset of human and canine HS: the visceral disseminated form. Finally, by testing drugs targeting the MAPK pathway in eight canine HS cell lines, we identified a better anti-proliferation activity of MEK inhibitors than PTPN11 inhibitors in canine HS neoplastic cells. In combination, these results illustrate the relevance of naturally affected dogs in deciphering genetic mechanisms and selecting efficient targeted therapies for such rare and aggressive cancers in humans., (© 2020 UICC.)

One of the main challenges in cell therapy for muscle diseases is to efficiently target the muscle. To address this issue and achieve better understanding of in vivo cell fate, we evaluated the relevance of a non-invasive cell tracking method in the Golden Retriever Muscular Dystrophy (GRMD) model, a well-recognised model of Duchenne Muscular Dystrophy (DMD). Mesoangioblasts were directly labelled with 111 In-oxine, and injected through one of the femoral arteries. The scintigraphy images obtained provided the first quantitative mapping of the immediate biodistribution of mesoangioblasts in a large animal model of DMD. The results revealed that cells were trapped by the first capillary filters: the injected limb and the lung. During the days following injection, radioactivity was redistributed to the liver. In vitro studies, performed with the same cells prepared for injecting the animal, revealed prominent cell death and 111 In release. In vivo, cell death resulted in 111 In release into the vasculature that was taken up by the liver, resulting in a non-specific and non-cell-bound radioactive signal. Indirect labelling methods would be an attractive alternative to track cells on the mid- and long-term.

Canine oral melanoma is the first malignancy of the oral cavity in dogs and is characterized by a local invasiveness and a high metastatic propensity. A better knowledge of genetic alterations is expected to improve management of this tumour. Copy number alterations are known characteristics of mucosal melanomas both in dogs and humans. The goal of this study was to explore the prognostic value of somatic focal amplifications on chromosomes (Canis Familiaris [CFA]) 10 and 30 in canine oral melanoma. The cohort included 73 dogs with oral melanoma confirmed by histology, removed surgically without adjuvant therapy and with a minimal follow-up of 6 months. Epidemiological, clinical and histological data were collected and quantitative-PCR were performed on formalin-fixed paraffin-embedded (FFPE) samples to identify specific focal amplifications. The 73 dogs included in the study had a median survival time of 220 days. Focal amplifications on CFA 10 and 30 were recurrent (49.3% and 50.7% of cases, respectively) and CFA 30 amplification was significantly associated with the amelanotic phenotype (P = .046) and high mitotic index (MI; P = .0039). CFA 30 amplification was also linked to poor prognosis (P = .0005). Other negative prognostic factors included gingiva location (P = .003), lymphadenomegaly (P = .026), tumour ulceration at diagnosis (P = .003), MI superior to 6 mitoses over 10 fields (P = .001) and amelanotic tumour (P = .029). In multivariate analyses using Cox proportional hazards regression, CFA 30 amplification (Hazard ratio [HR] = 2.08; P = .011), tumour location (HR = 2.20; P = .005) and histological pigmentation (HR = 1.87; P = .036) were significantly associated with shorter survival time. Focal amplification of CFA 30 is linked to an aggressive subset and constitutes a new prognostic factor., (© 2019 John Wiley & Sons Ltd.)

The experience of pain during a severe burn is multifactorial, both in the typology of the burn and in the circumstances of its occurrence. Third-degree burns are painless as the dermis and its nociception sensors are damaged. After a severe burn, from initial management, to home care, to a long hospital stay, pain evolves with its etiology and requires specific management., (Copyright © 2019 Elsevier Masson SAS. All rights reserved.)

Patients with extensive burns are an important group at risk for cutaneous mucormycosis. This study aimed to perform a systematic review of all reported mucormycosis cases in burn patients from 1990 onward. A Medline search yielded identification of 7 case series, 3 outbreaks, and 25 individual cases reports. The prevalence reached 0.04%⁻0.6%. The median age was 42⁻48 in the case series and outbreaks, except for the studies from military centers (23.5⁻32.5) and in individual reports (29.5). The median total body surface area reached 42.5%⁻65%. Various skin lesions were described, none being pathognomonic: the diagnosis was mainly reached because of extensive necrotic lesions sometimes associated with sepsis. Most patients were treated with systemic amphotericin B or liposomal amphotericin B, and all underwent debridement and/or amputation. Mortality reached 33%⁻100% in the case series, 29%⁻62% during outbreaks, and 40% in individual cases. Most patients were diagnosed using histopathology and/or culture. Mucorales qPCR showed detection of circulating DNA 2⁻24 days before the standard diagnosis. Species included the main clinically relevant mucorales (i.e., Mucor , Rhizopus , Absidia/Lichtheimia , Rhizomucor ) but also more uncommon mucorales such as Saksenaea or Apophysomyces . Contact with soil was reported in most individual cases. Bandages were identified as the source of contamination in two nosocomial outbreaks.

Purpose: Previous studies using FLASH radiotherapy (RT) in mice showed a marked increase of the differential effect between normal tissue and tumors. To stimulate clinical transfer, we evaluated whether this effect could also occur in higher mammals., Experimental Design: Pig skin was used to investigate a potential difference in toxicity between irradiation delivered at an ultrahigh dose rate called "FLASH-RT" and irradiation delivered at a conventional dose rate called "Conv-RT." A clinical, phase I, single-dose escalation trial (25-41 Gy) was performed in 6 cat patients with locally advanced T2/T3N0M0 squamous cell carcinoma of the nasal planum to determine the maximal tolerated dose and progression-free survival (PFS) of single-dose FLASH-RT., Results: Using, respectively, depilation and fibronecrosis as acute and late endpoints, a protective effect of FLASH-RT was observed (≥20% dose-equivalent difference vs. Conv-RT). Three cats experienced no acute toxicity, whereas 3 exhibited moderate/mild transient mucositis, and all cats had depilation. With a median follow-up of 13.5 months, the PFS at 16 months was 84%., Conclusions: Our results confirmed the potential advantage of FLASH-RT and provide a strong rationale for further evaluating FLASH-RT in human patients. See related commentary by Harrington, p. 3 ., (©2018 American Association for Cancer Research.)

Objectives Radioiodine ( 131 I) dose determination using radiotracer kinetic studies or scoring systems, and fixed relatively high 131 I dose (ie, 4 or 5 mCi) administration, are effective and associated with prolonged survival times for hyperthyroid cats. The latter method is less complicated but could expose patients and veterinary personnel to unnecessary levels of radiation. The aim of this study was to retrospectively evaluate the efficacy of a fixed 3.35 mCi 131 I dose for the treatment of 96 hyperthyroid cats with no length estimation for any palpated goitre ⩾20 mm, assess outcome and identify factors associated with survival. Methods Serum total thyroxine concentrations at diagnosis and at follow-up times, survival times and cause of death were recorded. Multivariable Cox regression analysis was used to identify factors associated with time to any cause of death from 131 I therapy initiation. Results Administration of a median (interquartile range) dose of 3.35 mCi (3.27-3.44 mCi) radioiodine was an effective treatment in 94/96 cats, but two cats remained hyperthyroid. No death related to hyperthyroidism was recorded. Median survival time was 3.0 years; the 1 and 2 year survival rates after 131 I therapy were 90% and 78%, respectively. Low body weight (⩽3.1 kg; adjusted hazard ratio [aHR] 5.88; 95% confidence interval [CI] 2.22-16.67; P <0.01) and male gender (aHR 2.63; 95% CI 1.01-7.14; P = 0.04) were independently associated with death, whereas age, prior treatment with antithyroid drugs, reason for treatment and pretreatment azotaemia were not. Conclusions and relevance This study suggests that a fixed 3.35 mCi 131 I dose treatment is effective for hyperthyroid cats with goitre(s) with a maximal length estimation <20 mm, that long-term survival can be achieved and that low body weight and male gender are significantly associated with shorter survival times.

Introduction: The peroperative management of liver transplantation is still associated with many cardiocirculatory complications in which diastolic dysfunction may play a contributive role. Transoesophageal echocardiography is a monitoring device commonly used in liver transplantation allowing diastolic function assessment., Methods: We prospectively analysed the peroperative transoesophageal echocardiography recordings of 40 patients undergoing liver transplantation in order to describe changes in diastolic function at different steps of the surgery. The diastolic function marker we used was the lateral mitral annulus motion (E' wave velocity) obtained by tissue-Doppler imaging. In addition, we also studied the left ventricular filling pressure indices and systolic function., Results: As a whole, there was no global change in E' wave velocity throughout the surgery. However, 11 patients (27.5%) presented a decrease in E' wave velocity up to 15% that identified an occurrence of diastolic function alteration. In this group, other peroperative data were not different from other patients (amount of bleeding, fluid administration or vasopressive support). Conversely, this group experienced lower preoperative E' wave velocity values (9cm·s -1 versus 12cm·s -1 , P=0.05) and an increased incidence of postoperative cardiorespiratory complications (OR=6 [1-56], P=0.02). Considering all patients, 18 patients had an E' wave velocity under 10cm·s -1 at unclamping, characterizing a diastolic dysfunction according to the usual criteria. This dysfunction was not associated with cardiorespiratory complications., Conclusion: This work investigated peroperative systematic echocardiographic evaluation of diastolic function during liver transplantation. Diastolic dysfunction occurs frequently during liver transplantation and could lead to postoperative cardiorespiratory complications., (Copyright © 2017 Société française d’anesthésie et de réanimation (Sfar). Published by Elsevier Masson SAS. All rights reserved.)

In this review, we present the synthesis of the newly acquired knowledge concerning high dose-rate irradiations and the hopes that these new radiotherapy modalities give rise to. The results were presented at a recent symposium on the subject., (Copyright © 2017. Published by Elsevier Masson SAS.)

Spontaneously occurring melanomas are frequent in dogs. They appear at the same localizations as in humans, i.e. skin, mucosal sites, nail matrix and eyes. They display variable behaviors: tumors at oral localizations are more frequent and aggressive than at other anatomical sites. Interestingly, dog melanomas are associated with strong breed predispositions and overrepresentation of black-coated dogs. Epidemiological analysis of 2350 affected dogs showed that poodles are at high risk of developing oral melanoma, while schnauzers or Beauce shepherds mostly developped cutaneous melanoma. Clinical and histopathological analyses were performed on a cohort of 153 cases with a 4-yr follow-up. Histopathological characterization showed that most canine tumors are intradermal and homologous to human rare morphological melanomas types - 'nevocytoid type' and 'animal type'-. Tumor cDNA sequencing data, obtained from 95 dogs for six genes, relevant to human melanoma classification, detected somatic mutations in oral melanoma, in NRAS and PTEN genes, at human hotspot sites, but not in BRAF. Altogether, these findings support the relevance of the dog model for comparative oncology of melanomas, especially for the elucidation of non-UV induced pathways., (© 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

The management of proctitis in patients who have undergone very-high-dose conformal radiotherapy is extremely challenging. The fibrosis-necrosis, fistulae, and hemorrhage induced by pelvic overirradiation have an impact on morbidity. Augmenting tissue repair by the use of mesenchymal stem cells (MSCs) may be an important advance in treating radiation-induced toxicity. Using a preclinical pig model, we investigated the effect of autologous bone marrow-derived MSCs on high-dose radiation-induced proctitis. Irradiated pigs received repeated intravenous administrations of autologous bone marrow-derived MSCs. Immunostaining and real-time polymerase chain reaction analysis were used to assess the MSCs' effect on inflammation, extracellular matrix remodeling, and angiogenesis, in radiation-induced anorectal and colon damages. In humans, as in pigs, rectal overexposure induces mucosal damage (crypt depletion, macrophage infiltration, and fibrosis). In a pig model, repeated administrations of MSCs controlled systemic inflammation, reduced in situ both expression of inflammatory cytokines and macrophage recruitment, and augmented interleukin-10 expression in rectal mucosa. MSC injections limited radiation-induced fibrosis by reducing collagen deposition and expression of col1a2/col3a1 and transforming growth factor-β/connective tissue growth factor, and by modifying the matrix metalloproteinase/TIMP balance. In a pig model of proctitis, repeated injections of MSCs effectively reduced inflammation and fibrosis. This treatment represents a promising therapy for radiation-induced severe rectal damage.

Background: Advantages offered by canine population substructure, combined with clinical presentations similar to human disorders, makes the dog an attractive system for studies of cancer genetics. Cancers that have been difficult to study in human families or populations are of particular interest. Histiocytic sarcoma is a rare and poorly understood neoplasm in humans that occurs in 15% to 25% of Bernese Mountain Dogs (BMD)., Methods: Genomic DNA was collected from affected and unaffected BMD in North America and Europe. Both independent and combined genome-wide association studies (GWAS) were used to identify cancer-associated loci. Fine mapping and sequencing narrowed the primary locus to a single gene region., Results: Both populations shared the same primary locus, which features a single haplotype spanning MTAP and part of CDKN2A and is present in 96% of affected BMD. The haplotype is within the region homologous to human chromosome 9p21, which has been implicated in several types of cancer., Conclusions: We present the first GWAS for histiocytic sarcoma in any species. The data identify an associated haplotype in the highly cited tumor suppressor locus near CDKN2A. These data show the power of studying distinctive malignancies in highly predisposed dog breeds., Impact: Here, we establish a naturally occurring model of cancer susceptibility due to CDKN2 dysregulation, thus providing insight about this cancer-associated, complex, and poorly understood genomic region., (©2012 AACR)

Regional citrate anticoagulation for continuous renal replacement therapy provides an efficient alternative to heparin as it reduces the likelihood of haemorrhage in critically ill patients with bleeding risk or coagulopathy and increases the haemofilter survival time. Liver failure is a classic contraindication of regional citrate anticoagulation since it carries the risk of citrate accumulation and its metabolic complications, although it could be attractive for this population of patients with high bleeding risk. We report three cases of continuous haemodialysis with regional citrate anticoagulation performed in patients with severe acute liver failure, without accumulation in two cases and with a suspected beginning of accumulation in the third case. For these patients, close monitoring of the total-to-ionized calcium ratio, pH and anion gap is particularly essential to control the safety of citrate infusion. Increasing effluent flow rate eliminates more calcium-bound citrate and therefore limits citrate accumulation and its consequences., (Copyright © 2012 Société française d’anesthésie et de réanimation (Sfar). Published by Elsevier SAS. All rights reserved.)

The cases of 7 adult dogs with generalized seizures managed by surgical excision and radiation therapy for frontal lobe meningiomas were reviewed. The neurological examination was unremarkable in 6 of the 7 dogs. Five dogs were operated on using a bilateral transfrontal sinus approach and 2 using a unilateral sinotemporal approach to the frontal lobe. One dog was euthanized 14 d after surgery; radiation therapy was initiated 3 wk after surgery in the remaining 6 dogs. Long-term follow-up consisted of neurological examination and magnetic resonance imaging (MRI) and/or computed tomography (CT) scan after radiation therapy. The mean survival time for dogs that had surgery and radiation therapy was 18 mo after surgery. Frontal lobe meningiomas have been associated with poor prognosis. However, the surgical approaches used in these cases, combined with radiation therapy, allow a survival rate for frontal lobe meningiomas similar to that for meningiomas located over the cerebral convexities.

Although most pituitary tumors are benign, some are invasive or aggressive. In the absence of specific markers of malignancy, only tumors with metastases are considered malignant. To identify markers of invasion and aggressiveness, we focused on prolactin (PRL) tumors in the human and rat. Using radiology and histological methods, we classified 25 human PRL tumors into three groups (non-invasive, invasive, and aggressive-invasive) and compared them with a model of transplantable rat PRL tumors with benign and malignant lineages. Combining histological(mitoses and labeling for Ki-67, P53, pituitary transforming tumor gene (PTTG), and polysialic acid neural cell adhesion molecule) and transcriptomic (microarrays and q-RTPCR) methods with clinical data (post-surgical outcome with case-control statistical analysis), we found nine genes implicated in invasion (ADAMTS6, CRMP1, and DCAMKL3) proliferation (PTTG, ASK, CCNB1, AURKB, and CENPE), or pituitary differentiation (PITX1) showing differential expression in the three groups of tumors (P = 0.015 to 0.0001). A case-control analysis, comparing patients in remission (9 controls) and patients with persistent or recurrent tumors (14 cases) revealed that eight out of the nine genes were differentially up- or downregulated (P = 0.05 to 0.002), with only PTTG showing no correlation with clinical course (P = 0.258). These combined histological and transcriptomic analyses improve the pathological diagnosis of PRL tumors, indicating a reliable procedure for predicting tumor aggressiveness and recurrence potential. The similar gene profiles found between non-invasive human and benign rat tumors, as well as between aggressive-invasive human and malignant rat tumors provide new insights into malignancy in human pituitary tumors.

The efficacy of low doses of radiotherapy for the treatment of pituitary corticotroph macrotumors in dogs is evaluated retrospectively. Twelve dogs with pituitary-dependent hyperadrenocorticism and a large pituitary tumor treated with 36 Gy of radiation were included. Radiation was delivered in 12 fractions of 3 Gy over a 4- to 6-week period. Effects of radiation therapy on tumor size were assessed by computed tomography scans; a decrease was observed in 11 dogs (decrease > 50% in 6 dogs). Three dogs were reirradiated due to major tumor regrowth or a lack of tumor decrease (mean total dose: 22 Gy given in 3-Gy fractions over 3 or 4 weeks). The mean and median survival times following the initiation of radiotherapy were 22.6 months (688 days) and 17.7 months (539 days), respectively. These data are consistent with previous findings, based on high-dose radiation, showing that radiotherapy is a useful option for treating pituitary corticotroph macrotumors in dogs. Furthermore, computed tomography follow-up of the treated dogs demonstrates objectively the efficacy of radiotherapy against corticotroph tumors in dogs.

Background: Dog prostate cancer is usually considered to be highly relevant to human prostate cancer. We report the isolation of a new canine prostate cancer epithelial cell line designated DPC-1., Methods: Primary cultures were established from a canine poorly differentiated prostatic adenocarcinoma. Population doubling time was determined by counting nuclei after cell lysis. Tumorigenicity was assessed in nude mice and in one adult immunodeficient dog. Immunoscintigraphy was performed in both models using a monoclonal antibody (mAb) raised against the [44-62] sequence of human PSMA., Results: DPC-1 cells have a rapid growth in vitro (doubling time, 27 hr) which is not stimulated by androgens. In addition, DPC-1 displays immunoreactivity to human PSA and PSMA. DPC-1 was found to be highly tumorigenic not only in nude mice but also for the first time after orthotopic seeding in an immunodeficient dog. This allograft mimicked, in a compressed form, the aggressive biological behavior of spontaneous dog prostate adenocarcinoma. Immunoscintigraphy using a (131)Iodine-labeled PSMA mAb clearly visualized induced tumors in nude mice and in the dog allograft., Conclusions: This study suggests that DPC-1 may constitute a powerful model for assessing new diagnostic and/or therapeutic tools in the management of prostate cancer., (Copyright 2001 Wiley-Liss, Inc.)

New strategies for cancer therapy must be developed, especially in severe neoplasms such as malignant pleural mesothelioma. Animal models of cancer, as close as possible to the human situation, are needed to investigate novel therapeutical approaches. Orthotopic transplantation of cancer cells is then relevant and efforts should be made to follow up tumour evolution in animals. In the present study, we developed a method for the orthotopic growth of mesothelioma cells in the pleural cavity of Fischer 344 and nude rats, along with a procedure for clinical survey. Two mesothelioma cell lines, of rat and human origin, were inoculated by transthoracic puncture. Body weight determination and chest X-ray analyses permitted the follow-up of tumour evolution by identifying different stages. Autopsies showed that tumours localized on the whole pleural cavity (diaphragm, parietal pleura), mediastinum and pericardium. Tumour morphology and antigenic characteristics were consistent with those of the inoculated cells and were similar in both types of rats inoculated with the same cell type. These results demonstrate that mesothelioma formation in rats can be followed up by clinical and radiographic survey after gentle intrathoracic inoculation of mesothelioma cells, thus allowing the definition of stages of interest for further experimental trials.

The production of human interleukin-2 (hIL-2) local to the tumor site by engineered histoincompatible cells has been shown in various murine models to promote a strong immune response leading to tumor growth inhibition or rejection. To assess whether this strategy would be similarly applicable for treatment of primary neoplastic cells, two naturally occurring tumors were used as preclinical models; the highly metastatic melanoma of the dog and the low metastatic fibrosarcoma of the cat. We demonstrate that both cats and dogs when treated by tumor surgery, radiotherapy and repeated local injections of xenogeneic Vero cells secreting high levels of hIL-2 relapse less frequently and survive longer than control animals treated by surgery and radiotherapy alone. Local secretion of hIL-2 by the xenogeneic cells is shown to be necessary for the induction of an optimal antitumor effect. Moreover, the safety of the procedure was demonstrated in both animal models and through extensive toxicological analysis performed in rats. These results confirm for the first time to our knowledge the safety and therapeutic potential of a gene transfer strategy in animals with spontaneous metastatic and nonmetastatic tumors.

Objective: We conducted the current study to evaluate the removal rate of air embolism from cerebral arteries after spontaneous breathing at a low FIO2 in comparison with mechanical ventilation at an FIO2 of 1.0., Design: Randomized, experimental trial., Setting: Neuroimaging department at a veterinary school hospital laboratory., Subjects: Nine anesthetized beagles undergoing mechanical ventilation with previous normal cranial computed tomography (CT) scan., Interventions: In each dog, after a control scan, air was infused at a constant flow rate, via a catheter inserted into the internal carotid artery. CT scan was repeated until typical bubbles appeared. Immediately after, the animals were randomly assigned to breathe room air (group A), or to be mechanically ventilated at an FIO2 of 1.0 (group B). CT scan was again repeated every minute until the removal of all bubbles. We compared the volume of air infused per kg of body and brain weights, the lowest density among bubbles (Hounsfield units), the duration of radiologic findings, and the ratio of volume/duration (mL/kg/min) between the two groups, using the Mann-Whitney test., Results: The volume of air infused per kg of body and brain weights and density were not significantly different between the two groups. The duration of radiologic findings was shorter (p < .02) in group B (7.0 +/- 4.7) than in group A (20.4 +/- 3.8), and the air removal rate from cerebral arteries (expressed as volume/duration of radiologic findings) was dramatically improved (p < .02) in group B (0.159 +/- 0.042) in comparison with group A (0.046 +/- 0.016)., Conclusions: These results suggest that the removal rate of air from cerebral arteries is dramatically increased by mechanical ventilation at an FIO2 of 1.0. Consequently, the time of cerebral ischemia may be decreased, but the result does not account for the effects of each factor separately. Further studies are required to evaluate the clinical benefits of high FIO2 administration and of mechanical ventilation separately. However, the prompt application of mechanical ventilation with an FIO2 of 1.0 may be recommended when air embolism is suspected.