Prognostic stratification of feline triple-negative mammary carcinomas, spontaneous models of breast cancer

Les cancers du sein triple-négatifs (TN), négatifs pour le récepteur alpha aux œstrogènes, le récepteur à la progestérone et HER2, le récepteur de type 2 au facteur de croissance épidermique, représentent 15–20% des cancers du sein de la Femme. Il n’existe pas encore de thérapie ciblée spécifique de ce type tumoral agressif, de mauvais pronostic. Des études transcriptomiques montrent que les cancers du sein TN sont hétérogènes, comportant certains sous-types au pronostic particulier et pouvant relever d’une thérapie ciblée. Nous avons montré que 68% des carcinomes mammaires invasifs de chattes (FMC) sont TN, suggérant que les chattes sont des modèles animaux spontanés prometteurs pour de futurs essais de thérapie ciblée de ces cancers. L’hypothèse de la thèse est que les FMC-TN spontanés de la chatte comportent comme chez la Femme, différents sous-groupes au pronostic différent et aux possibilités thérapeutiques différentes. Une cohorte rétrospective de 180 chattes spontanément porteuses de FMC a été constituée et analysée par immunohistochimie mettant en évidence entre autres AR, le récepteur aux androgènes, des cytokératines basales et le marqueur de lymphocytes T régulateurs FoxP3. Les résultats de thèse montrent que la chatte développe spontanément l’équivalent des sous-groupes luminal-AR et basal immunosupprimé de cancer du sein TN humain. Ceci suggère qu’il sera possible d’évaluer dans l’espèce féline, avant leur application en cancérologie humaine, l’efficacité et la toxicité de stratégies thérapeutiques anti-androgènes ou d’immunothérapie, pressenties pour améliorer la prise en charge des patientes ayant un cancer du sein triple-négatif.Triple-negative (TN) breast cancers, negative for estrogen receptor, progesterone receptor and HER2, the epidermal growth factor receptor type 2, account for 15-20% of breast cancers in women. There exists yet no targeted therapy for this aggressive, poor-prognosis subtype of breast cancer. Gene expression studies have shown that TN breast cancers are heterogeneous, with certain subtypes associated with a particular prognosis, which may possibly benefit from targeted therapies. We have shown that 68% of invasive mammary carcinomas in cats are TN, suggesting that cats are promising spontaneous animal models for future targeted therapy trials of these aggressive cancers.The hypothesis of the PhD thesis is that spontaneous TN mammary carcinomas of the cat (FMC) comprise, as in women, different subgroups with different prognoses (associated with a more or less unfavorable patient outcome) and with different therapeutic possibilities.180 cats, diagnosed with spontaneous invasive mammary carcinoma, were included in a retrospective study and analyzed by immunohistochemistry, to identify among other markers, AR, the androgen receptor, basal cytokeratins and the regulatory T-cell marker FoxP3. The results obtained show that the cat spontaneously develops the equivalent of the "luminal-AR" and "basal immunosuppressed" subgroups of human TN breast cancers. This implies that future targeted therapies for triplenegative breast cancer could be tested for their efficacy and toxicity in the feline species, including antiandrogen therapeutic strategies or cancer immunotherapy, designed to improve the management of women with triple-negative breast cancer

Unfavorable Prognostic Effects of the Stem Cell Pluripotency Factor Sox2 in Feline Invasive Mammary Carcinomas

International audienceBackground: Sex-determining Region Y (SRY)-box transcription factor-2 (Sox2) belongs to the "Yamanaka's factors," necessary and sufficient to convert somatic cells into pluripotent stem cells. In breast cancers, Sox2 expression has been associated with poor prognosis, and resistance to therapy. The aims of this study were to determine the frequency of Sox2 positivity in feline invasive mammary carcinomas (FMCs), its relationships with other clinical-pathologic variables, and with patient outcomes. Materials and Methods: This study relies on a previously described retrospective cohort of 180 FMCs, diagnosed in female cats treated by mastectomy alone, with 2-year follow-up. Sox2 (clone SP76), Estrogen Receptor alpha (ER), Progesterone Receptor (PR), Ki-67, Human Epidermal growth factor Receptor 2 (HER2), Androgen Receptor (AR), Bcl-2, Forkhead box protein A1 (FOXA1), basal markers and FoxP3-positive regulatory T cells (Tregs) were detected by automated immunohistochemistry. Sox2 expression was quantitated as an index (percentage of neoplastic cells demonstrating a positive nuclear signal). The FMCs were considered Sox2-positive at threshold >42%. Results: Sox2 was not expressed in the normal mammary gland or in mammary hyperplasia without atypia, but was occasionally detected in atypical hyperplasia. In FMCs, the mean Sox2 index was 38 ± 30%, and 79/180 FMCs (44%) were Sox2-positive. Sox2 expression was associated with older age at diagnosis, lymphovascular invasion, high Ki-67 proliferation indexes, low PR and FOXA1 expression, and increased numbers of tumor-associated Tregs, but was not significantly associated with the clinical stage, histological types, and histological grade. By multivariate survival analysis, Sox2 was associated with poor cancer-specific survival (Hazard Ratio = 1.48, 95% confidence interval 1.04-2.11, p = 0.0292), independently of the pathologic tumor size, pathologic nodal stage, distant metastasis, and AR expression. A rare subgroup of FMCs characterized by an AR+Sox2-phenotype (19/180 cases, 11%) was associated with very favorable outcomes. Conclusion: Sox2 expression was associated with poor cancer-specific survival of female cats with invasive mammary carcinomas, as previously reported in human breast cancer, but was more commonly expressed in cats than reported in breast cancers. Sox2 showed complementarity with AR in FMC prognostication

An insidious presentation of thrombotic thrombocytopenic purpura: A case report and brief literature review

Thrombotic thrombocytopenic purpura (TTP) is a rare thrombotic microangiopathy with an estimated incidence of 11 cases/million population per year. Early treatment is essential and is curative in this disease where lack of treatment results in 90% mortality. We describe an atypical case of a patient with TTP who presented to the Emergency Department for headache, and was found to have thrombocytopenia but only mild anemia that was explained by another disease process. Case: A 44-year-old female presented to the Emergency Department for worsening headache and weakness over the last week. She had no fever and no focal neurological deficits but was pale and complained of severe headache. A blood test showed her to be anemic and thrombocytopenic. She explained that she had been having prolonged heavy menses over the last year. She was treated with blood and platelet transfusions, and seen by the Gynecology service who treated her for uterine fibroids after which she was discharged. She returned 1 week later with the same complaint, and was found to have a stable hemoglobin level but recurrence of thrombocytopenia. A TTP diagnosis was entertained and the workup confirmed it. The patient was treated with plasmapheresis and discharged home with no sequalae. Conclusion: Emergency physicians should keep TTP in mind when approaching cases of thrombocytopenia with mild anemia, even if an alternative diagnosis exists

Bone Lid Technique Using a Piezoelectric Device for the Treatment of a Mandibular Bony Lesion

Different techniques for the enucleation of jaw cyst lesion in the oral and maxillofacial regions have been proposed, including the bone lid technique. The purpose of this case report is to describe the case of a cystic lesion, approached with the bone lid technique performed using a piezoelectric device, with an 8-month clinical and radiographic follow-up. A 14-year-old male patient was treated for a suspicious lesion detected on a panoramic radiograph. The concerned area was surgically accessed, and a radiographically predetermined bony window was drawn, and the beveled bony lid was removed. The underlying lesion was enucleated and sent for pathology as a routine procedure, and the removed bony lid was repositioned in situ and secured with a collagen tape. Healing was uneventful with limited swelling and reduced pain. A complete radiographic bone healing at the previously diseased site was confirmed with an 8-month cone beam computed tomography (CBCT) scan with no buccal bone resorption nor ridge collapse. The bone lid technique with a piezoelectric device was noninvasive and atraumatic in this case. Further studies are needed and could lead to the adaptation of this approach as a possible standard of care

Feline Invasive Mammary Carcinomas: Prognostic Value of Histological Grading

International audienceFeline mammary carcinomas are highly malignant tumors usually associated with poor outcome. Nevertheless, survival times can differ significantly according to various prognostic factors. The Elston and Ellis (EE) histologic grading system, originally developed for human breast cancer, is commonly used to grade feline mammary carcinomas, although it is not really adapted for this species, hence the need of a more relevant grading system. Although few veterinary studies attempted to validate previously published results in an independent cohort, the aim of our study was to evaluate the prognostic value of different histologic grading systems in feline invasive mammary carcinomas, including the EE grading system applicable to human breast cancers and the modified and newly designed histologic grading systems recently proposed by Mills et al. Survey data and histologic features of 342 feline invasive mammary carcinomas were analyzed with respect to overall and cancer-specific survival. The histological grading system with best prognostic value was the mitotic-modified Elston and Ellis (MMEE) grading system: grade III carcinomas (P ¼ .04, hazard ratio [HR] ¼ 1.46, 95% CI, 1.01-2.11), grade II (P ¼ .03, HR ¼ 1.39, 95% CI, 1.03-1.88), and grade I carcinomas (HR ¼ 1.00, reference), with decreasing hazard ratios significantly were associated with a worse overall survival, independently from the pathologic tumor size (pT ! 20 mm: P ¼ .002, HR ¼ 1.45, 95% CI, 1.15-1.83) and positive nodal stage (P ¼ .001, HR ¼ 1.51, 95% CI, 1.18-1.94). This retrospective study validates Mills et al's proposal to adapt the thresholds for mitotic counts to better assess the histological grade of the highly proliferative mammary carcinomas encountered in the cat

Genome Size Evolution and Dynamics in Iris, with Special Focus on the Section Oncocyclus

Insights into genome size dynamics and its evolutionary impact remain limited by the lack of data for many plant groups. One of these is the genus Iris, of which only 53 out of c. 260 species have available genome sizes. In this study, we estimated the C-values for 41 species and subspecies of Iris mainly from the Eastern Mediterranean region. We constructed a phylogenetic framework to shed light on the distribution of genome sizes across subgenera and sections of Iris. Finally, we tested evolutionary models to explore the mode and tempo of genome size evolution during the radiation of section Oncocyclus. Iris as a whole displayed a great variety of C-values; however, they were unequally distributed across the subgenera and sections, suggesting that lineage-specific patterns of genome size diversification have taken place within the genus. The evolutionary model that best fitted our data was the speciational model, as changes in genome size appeared to be mainly associated with speciation events. These results suggest that genome size dynamics may have contributed to the radiation of Oncocyclus irises. In addition, our phylogenetic analysis provided evidence that supports the segregation of the Lebanese population currently attributed to Iris persica as a distinct species.This work was subsidised by the National Council for Scientific Research Lebanon under Grant [01-06-08] and the Research Council of Saint Joseph University under Grant FS 56. O.H. was supported by a Marie Skłodowska-Curie Action Individual Fellowship (grant agreement n°657918) and a Ramón y Cajal Fellowship (RYC-2016-21176).Peer reviewe

One‐year conditional survival of dogs and cats with invasive mammary carcinomas: A concept inspired from human breast cancer

International audienceNumerous studies have described the prognostic factors of canine and feline mammary carcinomas (MCs), that is, variables that predict patient survival after diagnosis. But how does survival estimation evolve in patients that escaped early death from their cancer? In human oncology, conditional survival (CS), the probability of surviving X further years when cancer patients have already survived Y years, is used to analyse cancer outcomes in a long-term perspective. In this cohort of 344 dogs and 342 cats with surgically removed stage I to III invasive MCs, with a minimal follow-up of 2 years, we calculated the 1-year CS, that is, the probability for patients that have survived 1 year, to survive or to die from cancer during the subsequent year. The 1-year conditional specific survival probabilities were 59% and 48% at diagnosis of invasive MC respectively in dogs and cats, and 80% and 52% in 1-year surviving dogs and cats respectively, suggesting that 1-year surviving dogs were relatively protected from cancer-related death, whereas feline MCs remained life-threatening cancers for longer periods of time. Among the most significant parameters associated with CS in surviving dogs and cats were the nodal stage and lymphovascular invasion, as well as patient age, cancer stage and margin status in surviving dogs. By comparison, tumour size and the histological grade did not significantly alter CS probabilities in surviving dogs and cats. Conditional survival may be considered a very interesting tool for veterinary practitioners to estimate the likely outcome of cancer survivors

Identification of an immune-suppressed subtype of feline triple-negative basal-like invasive mammary carcinomas, spontaneous models of breast cancer

International audienceFeline invasive mammary carcinomas are characterized by their high clinical aggressiveness, rare expression of hormone receptors, and pathological resemblance to human breast cancer, especially triple-negative breast cancer (negative to estrogen receptor, progesterone receptor, and epidermal growth factor receptor type 2). Recent gene expression studies of triple-negative breast cancers have highlighted their heterogeneity and the importance of immune responses in their biology and prognostic assessment. Indeed, regulatory T cells may play a crucial role in producing an immune-suppressed microenvironment, notably in triple-negative breast cancers. Feline invasive mammary carcinomas arise spontaneously in immune-competent animals, in which we hypothesized that the immune tumor microenvironment also plays a role. The aims of this study were to determine the quantity and prognostic value of forkhead box protein P3-positive peritumoral and intratumoral regulatory T cells in feline invasive mammary carcinomas, and to identify an immune-suppressed subgroup of triple-negative basal-like feline invasive mammary carcinomas. One hundred and eighty female cats with feline invasive mammary carcinomas, treated by surgery only, with 2-year follow-up post-mastectomy, were included in this study. Forkhead box protein P3, estrogen receptor, progesterone receptor, Ki-67, epidermal growth factor receptor type 2, and cytokeratin 14 expression were assessed by automated immunohistochemistry. Peritumoral regulatory T cells were over 300 times more abundant than intratumoral regulatory T cells in feline invasive mammary carcinomas. Peritumoral and intratumoral regulatory T cells were associated with shorter disease-free interval and overall survival in both triple-negative (ER-, PR-, HER2-, N = 123 out of 180) and luminal (ER+ and/or PR+, N = 57) feline invasive mammary carcinomas. In feline triple-negative basal-like (CK14+) mammary carcinomas, a regulatory T-cell-enriched subgroup was associated with significantly poorer disease-free interval, overall survival, and cancer-specific survival than regulatory T-cell-poor triple-negative basal-like feline invasive mammary carcinomas. High regulatory T-cell numbers had strong and negative prognostic value in feline invasive mammary carcinomas, especially in the triple-negative basal-like subgroup, which might contain a ''basal-like immune-suppressed'' subtype, as described in triple-negative breast cancer. Cats with feline invasive mammary carcinomas may thus be interesting spontaneous animal models to investigate new strategies of cancer immunotherapy in an immune-suppressed tumor microenvironment

Bcl-2 expression and prognostic significance in feline invasive mammary carcinomas: a retrospective observational study

Abstract Background Cats spontaneously develop invasive mammary carcinomas with high clinical aggressiveness, and are considered relevant animal models for human breast cancer. Bcl-2 is an anti-apoptotic pro-survival protein, whose expression is associated with a favorable outcome in human breast cancer. The aim of our study was to determine the frequency of Bcl-2 expression in feline invasive mammary carcinomas (FMCs), its relationship with other clinicopathologic variables, and its prognostic value. This retrospective study included 180 FMCs, diagnosed in female cats treated by surgery only, with a 2-year follow-up post-mastectomy. Bcl-2, ER, PR, Ki-67, HER2, and CK5/6 expression were determined by automated immunohistochemistry. A receiver-operating-characteristic curve was used to set the threshold for Bcl-2 positivity. Results The cohort comprises 32% (57/180) luminal FMCs defined by ER and/or PR positivity, and 68% (123/180) triple-negative FMCs (negative for ER, PR, and HER2). Bcl-2 expression was considered as positive when at least 65% of tumor cells were immunohistochemically stained. Thirty-one out of 180 FMCs (17%) were Bcl-2-positive. There was no significant association between Bcl-2 expression, and the tumor size, nodal stage, histological grade, or ER, PR, Ki-67, HER2, and CK5/6 expression. By multivariate survival analysis (Cox proportional-hazards regression), Bcl-2 positivity in FMCs was associated with longer disease-free interval (p = 0.005, HR = 0.38), overall survival (p = 0.028, HR = 0.61), and cancer-specific survival (p = 0.019, HR = 0.54) independently of other powerful prognostic factors such as pathologic tumor size, pathologic nodal stage, and distant metastasis. The positive prognostic value of Bcl-2 was confirmed in both luminal FMCs, of which 9/57 (16%) were Bcl-2-positive, and in basal-like triple-negative (ER–, PR–, HER2–, CK5/6+) FMCs, of which 14/76 (18%) were Bcl-2-positive. Conclusions Compared to human breast cancer, Bcl-2 positivity in feline invasive mammary carcinomas is also associated with better outcome, but is less common, and not associated with ER, PR, and HER2 expression. Cats with spontaneous Bcl-2-positive FMCs could be useful in preclinical trials evaluating anti-Bcl-2 strategies for chemoresistant luminal or triple-negative breast cancers

Sepsis in hemodialysis patients.

BACKGROUND: Bacterial infections are very common in End Stage Renal Disease (ESRD) patients. The diagnosis of sepsis in such patients is often challenging and requires a high index of suspicion. The aim of this study is to report on a series of patient with ESRD on hemodialysis (HD) diagnosed with sepsis. METHODS: Single center retrospective study looking at ESRD on HD who presented to our tertiary hospital were retrieved. Inclusion criteria included a discharge diagnosis of sepsis, septic shock or bacteremia. RESULTS: Our sample was composed of 41 females and 49 males, with a mean age of 70 ± 15 years. Infections from the HD catheters followed by lower respiratory tract infections were the most common cause of bacteremia. IV fluid replacement for the first 6 and 24 h were 0.58 and 1.27 l respectively. Vasopressors were used in 30 patients with norepinephrine, dopamine and dobutamine used in 22, nine and one patients respectively. Out of 90 subjects, 24 (26.6 %) were dead within the same hospital visit. the 28 days out of hospital mortality was 25.6 %. There was no significant difference in mortality in patients who presented with less than two SIRS or two or more SIRS criteria. CONCLUSION: This is the first study looking at an in depth analysis of sepsis in the specific dialysis population and examining the influence of fluid resuscitation, role of SIRS criteria and vasopressor use on their mortality