USP7 inactivation suppresses APC-mutant intestinal hyperproliferation and tumor development.

Adenomatous polyposis coli (APC) mutation is the hallmark of colorectal cancer (CRC), resulting in constitutive WNT activation. Despite decades of research, targeting WNT signaling in cancer remains challenging due to its on-target toxicity. We have previously shown that the deubiquitinating enzyme USP7 is a tumor-specific WNT activator in APC-truncated cells by deubiquitinating and stabilizing ß-catenin, but its role in gut tumorigenesis is unknown. Here, we show in vivo that deletion of Usp7 in Apc-truncated mice inhibits crypt hyperproliferation and intestinal tumor development. Loss of Usp7 prolongs the survival of the sporadic intestinal tumor model. Genetic deletion, but not pharmacological inhibition, of Usp7 in Apc+/- intestine induces colitis and enteritis. USP7 inhibitor treatment suppresses growth of patient-derived cancer organoids carrying APC truncations in vitro and in xenografts. Our findings provide direct evidence that USP7 inhibition may offer a safe and efficacious tumor-specific therapy for both sporadic and germline APC-mutated CRC.

[The effect of body mass index on outcome of body contouring surgeries]. / Influence de l'indice de masse corporelle sur les complications des chirurgies de séquelles d'amaigrissement.

BACKGROUND: The generalization of bariatric surgery interventions has led in recent years to an explosion in demand for body contouring surgeries. These operations can be followed by postoperative complications; and residual obesity, defined by a BMI≥30, is traditionally considered as a relative contraindication. The objective is to study the influence of a BMI≥30 on the risk of postoperative complications. METHODS: A retrospective study was conducted on all patients who underwent body contouring surgery between 2014 and 2020 at the Arras Hospital Center. Major complication rates were compared in obese and non-obese patients. RESULTS: Two hundred twenty-three patients were included, representing a total of 247 surgeries: 124 in the BMI<30 group and 123 in the BMI≥30 group. Sixteen surgeries were followed by at least one major complication, 6 in group I versus 10 in group II (RR=1.7 (0.6-4.5), NS, P=0.29). Therefore there were not significantly more major complications in obese patients. CONCLUSION: The incidence of major complications following body contouring surgeries is not modified by the presence of a BMI greater than 30, subject to a precautionary procedure adapted to each patient. BMI is therefore not a sufficient criterion to contraindicate this type of surgery.

Thermoregulation at birth differs between piglets from two genetic lines divergent for residual feed intake.

Thermoregulation is essential to piglets' neonatal survival. This study used infrared thermography (IRT) to assess thermoregulation abilities of piglets from two lines divergent for residual feed intake (RFI). At birth, morphology (weight, length, width and circumference), vigour (respiration, mobility and vocalisation), and rectal temperature were recorded from piglets of the 11th generation of the low RFI (LRFI, more efficient; n = 34) and the high RFI (HRFI, less efficient; n = 28) lines. Infrared thermography images were taken at 8, 15, 30 and 60 min post partum. Temperatures of the ear base and tip, and of the back (i.e. shoulders to rumps) were extracted (Thermacam Researcher Pro 2.0) and analysed with linear mixed models (SAS 9.4). Piglets had different average hourly weight gain (HRFI = 7.1 ±â€¯1.3 g/h, LRFI = 3.6 ±â€¯1.3 g/h; P < 0,001) but did not differ in morphology or vigour. All temperatures increased overtime. At birth, piglets' rectal temperature was correlated with the initial temperature of the ear base and the maximum back temperature (0.37 and 0.33, respectively; P < 0.05). High residual feed intake piglets had lower ear tip temperatures than LRFI piglets at 15 (24.7 ±â€¯0.37 °C vs. 26.3 ±â€¯0.36 °C, respectively; F1, 63.5 = 9.11, P < 0.005) and 30 min post partum (26.2 ±â€¯0.47 °C vs. 27.6 ±â€¯0.44 °C, respectively; F1, 66.9 = 4.52, P < 0.05). Moreover, thermal pattern of the ear tip differed between the two genetic lines. In conclusion, IRT allowed non-invasive assessment of piglets' thermoregulation abilities and indicated an influence of genetic selection for RFI on neonatal thermoregulation abilities.

Diagnosis and treatment of a caecal mucocoele in a dog.

An 11-year-old male intact Staffordshire Bull terrier was referred for diabetic ketoacidosis. Abdominal ultrasonographic examination revealed a 5 cm × 2 cm intraluminal caecal mass-like structure. Exploratory laparotomy and typhlectomy were subsequently performed. Histopathology of the caecal mass-like structure was consistent with a caecal mucocoele, defined as a cystic dilation of the caecal lumen with stasis of mucus. This lesion has been previously described in humans, where it is termed an appendiceal mucocoele. The patient was euthanased 58 days post-operatively due to unrelated diabetic complications.

Scent (Apocrine) Gland Adenocarcinoma in a Wedge-Capped Capuchin Monkey (Cebus olivaceus): Histological and Immunohistochemical Features.

In humans, apocrine gland tumours encompass a heterogeneous group of uncommon neoplasms with varied and unpredictable biological behaviour. They can be slow-growing lesions, recur after excision, produce lymph node metastasis in up to 50% of cases or lead to tumour-related death. We document a malignant scent adenocarcinoma in a wedge-capped capuchin monkey (Cebus olivaceus). Immunohistochemical labelling revealed complete absence of myoepithelial cells, a finding usually considered a hallmark of malignancy in humans; however, after a 2-year follow-up, the neoplasm had not recurred. This is the first detailed report of the pathology of a spontaneous scent (apocrine) gland adenocarcinoma in a non-human primate.

Aberrant Expression of Cell Cycle Regulator 14-3-3-σ and E-Cadherin in a Metastatic Cholangiocarcinoma in a Vervet Monkey (Chlorocebus pygerythrus).

We present a unique case of metastatic cholangiocarcinoma with concurrent abdominal cestodiasis in an African green monkey (Chlorocebus pygerythrus) that presented with respiratory insufficiency and abdominal discomfort. There were multiple white-grey masses in the liver and colonic serosa alongside intra-abdominal parasitic cysts. Histopathologically, the liver masses were composed of poorly-differentiated epithelial cells that formed densely cellular solid areas and trabeculae. The neoplastic cells were strongly immunopositive for CK7 but negative for Hep-Par1 antigen, which confirmed a diagnosis of cholangiocarcinoma. Interestingly, there was strong and diffuse neoexpression in the tumour of the cell cycle regulator 14-3-3σ, which is not constitutively expressed in normal liver. There was aberrantly strong expression of E-cadherin, a key cell-cell adhesion protein, in neoplastic cells with evidence of cytoplasmic internalization. This is the first immunohistochemical analysis of 14-3-3σ and E-cadherin in a liver neoplasm in an animal species and the use of these markers requires further investigation in animal liver neoplasms.

Primary Verocay Body-rich Epididymal Leiomyosarcoma in a Dog.

Leiomyosarcomas arising from paratesticular structures are rare. We report a case of epididymal sarcoma in an aged male Rottweiler that had histological features suggestive of neural origin but with muscular histogenesis confirmed by immunohistochemistry. Histologically, the lesion comprised a hypercellular neoplasm that had interlacing bundles of spindloid cells, prominent nuclear palisading and many Verocay bodies. Immunohistochemically, the neoplastic cells were strongly positive for smooth muscle markers but negative for neural markers, leading to the diagnosis of leiomyosarcoma. While the presence of nuclear palisading and Verocay bodies has been regarded as strong evidence for the diagnosis of schwannomas, the present report documents the presence of true Verocay bodies in a non-neuronal tumour. It also indicates that immunophenotyping is required for an accurate diagnosis when Verocay bodies are detected in sarcomatous or spindle cell tumours and provides prognostic information on this case. To the best of our knowledge, this is the first report of the presence of true Verocay bodies in a neoplasm other than a nerve sheath tumour in animals.

Avian Papilloma and Squamous Cell Carcinoma: a Histopathological, Immunohistochemical and Virological study.

In this retrospective study, we describe the histopathological findings in seven papillomas and 45 squamous cell carcinomas (SCCs) from psittacine birds, raptors and domestic fowl. The age of affected birds ranged from 3 to 40 years, with median age significantly higher in psittacines (P = 0.014). The majority of tumours were located in the skin (24/52, 46.2%) or uropygial gland (10/52, 19.2%). Thirty of the SCCs (66.7%) were well differentiated and 15 (33.3%) were poorly-differentiated. SCCs exhibited a significantly higher degree of nuclear pleomorphism (P = 0.005) and a greater proportion were ulcerated (P = 0.001) compared with papillomas; however, there was no significant difference in mitotic count (MC) or inflammation score. The expression of cyclo-oxygenase (COX)-2 and E-cadherin was investigated by immunohistochemistry. The COX-2 total score (TS) was significantly higher in SCCs compared with papillomas (P = 0.002), but the difference between COX-2 TS of well- and poorly-differentiated SCCs was not significant. COX-2 labelling was predominantly cytoplasmic, but some tumours had concurrent membranous and/or perinuclear labelling. SCCs with membranous labelling had a significantly higher MC (P = 0.028). A significantly higher proportion of SCCs were negative for E-cadherin compared with papillomas (P = 0.042), but there was no significant difference between well- and poorly-differentiated SCCs. Fourteen papillomas and SCCs from psittacines were also tested by polymerase chain reaction for the presence of Psittacus erithacus papillomavirus 1 and Psittacid herpesvirus 1, but all samples tested negative. We demonstrate for the first time the expression of COX-2 and E-cadherin in avian tissues, and suggest that these markers may be useful in differentiating papillomas from SCCs, particularly when sample size is small.

Pemphigus erythematosus and cutaneous epitheliotropic lymphoma in a Labrador Retriever dog.

BACKGROUND: Paraneoplastic pemphigus is an autoimmune blistering skin disease associated with concurrent neoplasia that is rarely observed in veterinary medicine. CASE DESCRIPTION: This case report presents a ten-year-old female Labrador Retriever dog with generalized seborrhea and alopecic, crusting and ulcerative lesions in the periocular and perioral regions, the lips and the groins. FINDINGS/TREATMENT AND OUTCOME: Hematology analysis showed a marked increase in the number of lymphocytes, while the rest of the values were normal. Skin biopsies were collected and the histological findings were consistent with pemphigus in association with an epitheliotropic lymphoma. Immunohistochemical analysis was performed. There was deposition of immunoglobulin G (IgG) in the basement membrane and in the intercellular space that corresponded with an immunostaining pattern characteristic of pemphigus erythematosus (PE). The lymphoma was positive to CD3 cells and was classified as a T-cell epitheliotropic lymphoma. CONCLUSION: To our knowledge, this is the first case of PE and cutaneous lymphoma coexisting in a dog, expanding the list of associations between immune-mediated diseases and cancer in dogs, and providing support to the eventual connection between autoimmunity and neoplasia in this species.

Detection of adult attention deficit hyperactivity disorder with cognitive complaint: Experience of a French memory center.

INTRODUCTION: Attention deficit hyperactivity disorder (ADHD) is a frequent neurodevelopmental mental disorder. It can persist in adulthood and be expressed as a cognitive complaint. METHODS: We conducted a descriptive study in a French memory center concerning patients seen over a period of two years. All patients for whom the final diagnosis was ADHD were included. All patients benefited from standard neuropsychological tests and a psychiatric specific consultation. RESULTS: Thirteen patients were included with an average age of 50.2±19 years. Main complaints related to memory, attention, focusing and organizational functioning. These difficulties had negative social, professional and academic consequences. ADHD history in descendants was noted in 46% of patients. More than 20% of subjects had motor, verbal or mental restlessness. Neuropsychological assessment highlighted impaired performances in executive functions (38%), sustained attention (67%), divided attention (45%), working memory (46%) and information processing speed (75%). A psychiatric history or comorbidities were present in 85% of patients, mostly of the anxio-depressive type. The more prevalent presentations of ADHD were the combined (38%) and inattentive (38%) types. DISCUSSION: Adult ADHD can masquerade as a cognitive impairment, including a stable cognitive complaint from infancy to old age. Inattentive, hyperactive and impulsive symptoms change with time and become more internalized (such as concentration difficulties or mental restlessness). No neuropsychological pattern has been reported but fluctuating deficits in sustained, divided attention, working memory and information processing speed are frequently observed in adult ADHD. A specific psychiatric expertise is essential in diagnosis and care for ADHD and its commonly associated psychiatric comorbidities.

Malignant Cutaneous Peripheral Nerve Sheath Tumour with Rhabdomyosarcomatous Differentiation (Triton Tumour) in a Domestic Cat.

Divergent differentiation is encountered frequently within human malignant peripheral nerve sheath tumours (MPNSTs). The new component is often a rhabdomyosarcoma, but in animals this specific form of divergent differentiation within MPNSTs has only been reported once (in a dog). Incisional wedge biopsy of a locally extensive, ventral abdominal wall mass, which extended from the dermis to the subcutis, from a 12-year-old female domestic shorthaired cat, was performed. The tissue was examined with routine haematoxylin and eosin staining and immunohistochemical methods. A malignant neoplasm with spindle and polygonal cell components and progression towards a rhabdomyosarcomatous phenotype was observed. Both neoplastic cell populations exhibited strong expression of vimentin and there was multifocal expression of S100 and desmin. There was strong cytoplasmic labelling for α-sarcomeric actin and muscle actin and weak labelling for myoglobin within the cells positive for desmin. There was multifocal positive nuclear labelling for myogenin. Glial fibrillary acidic protein, α-smooth muscle actin, microphthalmia-associated transcription factor and melanoma antigen recognized by T cells were not expressed. Microscopical features, aided by immunohistochemistry, identified a MPNST with progression towards a rhabdomyosarcomatous phenotype, a so-called 'triton tumour'. A Schwann cell component could account for the divergent patterns of growth, given the plasticity of the neural crest. Nerve sheath tumours have been reported in the skin and subcutis of cats and are a differential diagnosis of feline cutaneous spindle cell neoplasms.

Endocardial Peripheral Nerve Sheath Tumour with Features of a Benign Schwannoma in a Donkey.

A peripheral nerve sheath tumour, with features of a benign schwannoma and arising from the endocardium of the right ventricle, was found incidentally during routine post-mortem examination of a 28-year-old gelding donkey. Macroscopically, five round to oval, white to grey and red, firm masses, firmly attached to the endocardium were identified. Microscopically, the endocardium and adjacent subendocardium were infiltrated by a variably demarcated, non-encapsulated mesenchymal neoplasm with features of a benign schwannoma, including concurrent presence of Antoni A and Antoni B areas, nuclear palisading, neoplastic cells with enlarged bizarre nuclei ('ancient change') and the formation of Verocay-like bodies. Immunohistochemically, the tumour cells were variably strongly positive for expression of S100 and glial fibrillary acidic protein. This is the first cardiac tumour reported in a donkey and is macroscopically, histologically and immunohistochemically similar to endocardial schwannoma occurring in Wistar rats.

Benign Bilateral Adenomyoepithelioma of the Mammary Gland in a Ring-tailed Lemur (Lemur catta).

Naturally occurring mammary tumours are uncommon in prosimians. A 20-year-old female ring-tailed lemur (Lemur catta) developed bilateral enlargement of the mammary glands. Surgical removal revealed that both masses were comprised of multiple nodules and cystic areas that entirely replaced the normal glands. Histologically, a benign neoplastic biphasic cellular proliferation, composed of luminal-epithelial and basal-myoepithelial components, was identified. Immunohistochemical analysis for expression of cytokeratin (CK) AE1/AE3, CK7, CK5 + 8, CK14, vimentin, p63 and 14-3-3σ highlighted the biphasic nature of the neoplasm. A low mitotic count, low Ki67 labelling index, expression of oestrogen receptor-α, lack of expression of human epidermal growth factor receptor and a 3-year disease-free period without recurrence supported the benign nature of the tumour. Macroscopically, histologically and immunohistochemically this neoplasm resembled benign adenomyoepithelioma of the breast in women. This is the first complete report of a naturally occurring mammary tumour in a ring-tailed lemur.

Rapid Discovery of De Novo Deleterious Mutations in Cattle Enhances the Value of Livestock as Model Species.

In humans, the clinical and molecular characterization of sporadic syndromes is often hindered by the small number of patients and the difficulty in developing animal models for severe dominant conditions. Here we show that the availability of large data sets of whole-genome sequences, high-density SNP chip genotypes and extensive recording of phenotype offers an unprecedented opportunity to quickly dissect the genetic architecture of severe dominant conditions in livestock. We report on the identification of seven dominant de novo mutations in CHD7, COL1A1, COL2A1, COPA, and MITF and exploit the structure of cattle populations to describe their clinical consequences and map modifier loci. Moreover, we demonstrate that the emergence of recessive genetic defects can be monitored by detecting de novo deleterious mutations in the genome of bulls used for artificial insemination. These results demonstrate the attractiveness of cattle as a model species in the post genomic era, particularly to confirm the genetic aetiology of isolated clinical case reports in humans.

"De-novo" consultation: Evaluation of an outpatient's clinic dedicated to early diagnosis of parkinsonian syndromes.

INTRODUCTION: In the absence of specific clinical signs, imaging or biomarkers, the differential diagnosis of degenerative parkinsonian syndromes may be difficult at early stages of the disease. To reduce the risk of misdiagnosis or delayed diagnosis and referral to multiple medical centers at disease onset, easier access to expert centers should be available. To improve the initial care of parkinsonian patients, the Parkinson's disease Expert Center (PEC) at Pitié-Salpêtrière Academic Hospital has set up a specific outpatients clinic with short waiting times dedicated to the diagnosis of early Parkinson's disease and related disorders. METHODS: The PEC setup first identifies requests for diagnostic confirmation of parkinsonian syndromes, then specific outpatients clinic visits are scheduled weekly, with examinations carried out by neurologists at the PEC on a rotating schedule. Data from the first year of the new procedure were analyzed retrospectively through self-administered questionnaires sent to patients seen during this period. The main outcomes were to confirm the ability to keep to short delays for patients' examinations and to assess patients' satisfaction with the setup. RESULTS: Both study outcomes were achieved. The creation of an outpatients clinic dedicated to the early diagnosis of parkinsonian syndromes allowed shorter delays before the first examination of 5 weeks instead of several months. Keeping to the weekly schedule and limited time taken for each visit was also achieved. Following this initial outpatients visit, diagnosis of a parkinsonian syndrome was clinically confirmed or further specified in 80% of cases. A survey of patients' satisfaction showed a rate of over 91% in terms of the timing and course of clinical examinations at our PEC. DISCUSSION/CONCLUSION: This study of our quality-improvement program for Parkinson's disease management has shown that specific consultations with shorter waiting times aiming to allow early specialized assessment of parkinsonian syndromes is beneficial for patients and reduces the risk of delayed diagnoses.

Retrospective evaluation of COX-2 expression, histological and clinical factors as prognostic indicators in dogs with renal cell carcinomas undergoing nephrectomy.

Limited veterinary literature is available regarding prognostic markers for canine renal cell carcinoma (CRCC). We retrospectively evaluated COX-2 expression, histological and clinical features associated with prognosis of CRCC. Sixty-four cases post-nephrectomy were included, 54 had histopathological assessment and 30 had COX-2 immunostaining performed. Eight dogs (13%) had metastatic disease at initial diagnosis. Twenty-seven dogs (42%) received adjuvant therapy after nephrectomy. On univariate analysis, COX-2 expression, mitotic index (MI), histologic type, vascular invasion, neoplastic invasiveness and metastasis at diagnosis were significantly associated with overall median survival time (MST). COX-2 score (COX-2 score > 3 MST 420 days versus 1176 days if COX-2 score <3; P = 0.011) and MI (MI > 30 MST 120 days versus 540 days for MI < 30; P = 0.003) were the only variables associated with CRCC outcome on multivariate analysis. The addition of MI and COX-2 immunostaining to standard histopathological evaluation would help predicting outcome in CRCC patients.

The value of specialist care-infectious disease specialist referrals-why and for whom? A retrospective cohort study in a French tertiary hospital.

This study evaluated the impact of infectious disease (ID) specialist referrals on outcomes in a tertiary hospital in France. This study tackled methodological constraints (selection bias, endogeneity) using instrumental variables (IV) methods in order to obtain a quasi-experimental design. In addition, we investigated whether certain characteristics of patients have a bearing on the impact of the intervention. We used the payments database and ID department files to obtain data for adults admitted with an ID diagnosis in the North Hospital, Marseille from 2012 to 2014. Comparable cohorts were obtained using coarsened exact matching and analysed using IV models. Mortality, readmissions, cost (payer perspective) and length of stay (LoS) were analysed. We recorded 15,393 (85.97%) stays, of which 2,159 (14.03%) benefited from IDP consultations. The intervention was seen to significantly lower the risk of inpatient mortality (marginal effect (M.E) = -19.06%) and cost of stay (average treatment effect (ATE) = - €5,573.39). The intervention group was seen to have a longer LoS (ATE = +4.95 days). The intervention conferred a higher reduction in mortality and cost for stays that experienced ICU care (mortality: odds ratio (OR) =0.09, M.E cost = -8,328.84 €) or had a higher severity of illness (mortality: OR=0.35, M.E cost = -1,331.92 €) and for patients aged between 50 and 65 years (mortality: OR=0.28, M.E cost = -874.78 €). This study shows that ID referrals are associated with lower risk of inpatient mortality and cost of stay, especially when targeted to certain subgroups.

Clinical characteristics and prognostic factors of plasmablastic lymphoma patients: analysis of 135 patients from the LYSA group.

Background: Plasmablastic lymphoma (PBL), initially described in 1997 in the oral cavity of HIV positive patients, is now recognized as a distinct aggressive and rare entity of diffuse large B-cells lymphoma by the World Health Organization (WHO) classification. Since the original description, others cases have been reported. However, these are largely derived from case reports or small series limiting any definitive conclusions on clinical characteristics and outcome. Patients and methods: The clinical, biological, pathological features and outcome of a cohort including 135 patients with PBL, from LYSA centers in France and Belgium, were reported and analyzed. Results: The median age was 58 years, with a male predominance. The cohort was divided into 56 HIV-positive patients, 17 post-transplant patients and 62 HIV-negative/non-transplanted patients. Within HIV-negative/non-transplanted, a relative immunosuppression was found in most cases (systemic inflammatory disease, history of cancer, increased age associated with weakened immune system). We have also described a new subtype, PBL arising in a chronic localized inflammatory site, without any sign of immunosuppression. At presentation, 19% of patients showed oral involvement. Immunophenotype showed CD138 positivity in 88% of cases and CD20 negativity in 90% of cases. Chemotherapy was administered to 80% of patients, with a complete response (CR) rate of 55%. The median overall survival (OS) was 32 months. In univariate analysis, HIV positive status showed better OS when compared with HIV negative status. In multivariate analysis, International Prognostic Index score, chemotherapy and CR were associated with survival benefit. Conclusion(s): This cohort, the largest reported to date, increases the spectrum of knowledge on PBL, rarely described. However, specific guidelines to clarify treatment are lacking, and may improve the poor prognosis of this rare disease.

Multicentric Benign Epithelial Inclusions in a Free-ranging Risso's Dolphin (Grampus griseus).

This report describes the histological and immunohistochemical features of multicentric, benign, epithelial inclusions (BEIs) in a free-ranging, adult, female Risso's dolphin (Grampus griseus). The differential diagnoses included ectopic hamartomatous epithelial inclusions, non-Müllerian choristoma, Müllerian choristoma and low-grade metastatic carcinoma/mesothelioma. The most likely diagnosis of such BEIs was multicentric, embolic, reactive mesothelium, as suggested by cytomorphological and immunophenotypical features of the BEIs, the occurrence of focal pleural rupture and the immunophenotype of the pleural mesothelium. The former represents a pathological condition not previously reported in a marine mammal species, rarely described in animals, and relatively infrequently recognized in man.