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PDF file - 317K, List of EMT- and autophagy-related differentially expressed genes in SNAI1- and SNAI1-6SA-expressing MCF-7 cells

PDF file - 204K, Cancer stem cell properties of EMTed and autophagic cell lines

PDF file - 10396K, Human breast cancer biopsies were stained for SNAI2 and LC3B expression by immunohistochemistry on serial tumor sections

PDF file - 72K, SNAI1-6SA cells were sorted by flow cytometry (MoFlo� Astrios� - Beckman Coulter, Inc) based on their ALDH activity

PDF file - 160K, Data mining of microarray data showing the connections between EMT and autophagy-related genes

We provide a unique case of haemorrhagic shock complicating a corticosteroid-resistant diffuse ulcerative enteritis in a patient treated with a combination of an anti CTLA-4 and an anti PD-1 for metastatic melanoma. Immunotherapy has changed the perspective for the management of patients with metastatic melanoma but are also responsible for digestive complications mainly represented by immunomediated colitis. Digestive bleeding is common in patients with extensive colonic lesions but has never been described in enteritis independent of colitis. The patient with acute intestinal obstruction related ileitis without evidence of stricture on imaging and then had a gastro-intestinal bleed. In the absence of haemorrhagic lesions on upper gastrointestinal endoscopy, colonoscopy and CT angiography, a surgical exploration with enteroscopy was performed. This revealed an extensive ulcerated jejunoileitis, with active bleeding, within a Meckel's diverticulum. Management included resection of the Meckel diverticulum with a transient double barrel ileostomy. Two infliximab infusions were given due to persistent bleeding. We observed a dramatic improvement after infliximab treatment with complete cessation of bleeding and no further need for transfusions. A complete mucosal healing has been achieved on enteroscopy at 3 months with disappearance of histological inflammatory lesions. This observation suggests that infliximab represents a therapeutic option in severe enteritis and may be as effective as in more moderate immune-mediated enterocolitis.

The French Society of Pathology (SFP) organized its first data challenge in 2020 with the help of the Health Data Hub (HDH). The organization of this event first consisted of recruiting nearly 5000 cervical biopsy slides obtained from 20 pathology centers. After ensuring that patients did not refuse to include their slides in the project, the slides were anonymized, digitized, and annotated by expert pathologists, and finally uploaded to a data challenge platform for competitors from around the world. Competing teams had to develop algorithms that could distinguish 4 diagnostic classes in cervical epithelial lesions. Among the many submissions from competitors, the best algorithms achieved an overall score close to 95%. The final part of the competition lasted only 6 weeks, and the goal of SFP and HDH is now to allow for the collection to be published in open access for the scientific community. In this report, we have performed a "post-competition analysis" of the results. We first described the algorithmic pipelines of 3 top competitors. We then analyzed several difficult cases that even the top competitors could not predict correctly. A medical committee of several expert pathologists looked for possible explanations for these erroneous results by reviewing the images, and we present their findings here targeted for a large audience of pathologists and data scientists in the field of digital pathology.

Massive Open Online Courses (MOOCs) are gaining popularity in education while classroom lectures are being deserted, especially after COVID-19 pandemic. Their added value in teaching undergraduate medical students remains to be confirmed. This study evaluated a MOOC devoted to undergraduate medical students in a blended oncology-teaching university program. It was the first to target undergraduate medical students in oncology at its beginning. Students were asked to participate in a survey before and after MOOC to explore interactions between their characteristics and final grades, 65% of the participating students belonged to the rich class. 70% of the students completed the MOOC. Grades distributions were similar before and after MOOC implementation, so MOOC doesn't alter overall results. In addition, there was a positive effect of the MOOC on median grades on the immediate test. The univariate and multivariate analysis showed that socioeconomic status and student's willingness to participate interacted significantly with final results. Particularly, students' motivation and satisfaction were associated with better results; Almost 70% of students asked for blended learning. E-learning is reliable to teach oncology to undergraduate medical students. The success is directly linked to students' willingness to participate, and can be improved using blended methods including tutorials.

Resume Le type de colite le plus frequemment observe sous immunotherapie anti-PD-1 est celui d’une colite aigue active a polynucleaires neutrophiles. A l’inverse, la colite collagene, qui appartient a la famille des colites microscopiques, est exceptionnelle. Nous rapportons un cas de colite collagene chez un homme de 76 ans, traite par pembrolizumab pour un melanome cutane multimetastatique. Quatorze mois apres l’introduction du pembrolizumab, le patient a developpe une diarrhee de grade 3 (jusqu’a 9 selles liquides non glairo-sanglantes/j), associee a une profonde hypokaliemie. Aucun agent infectieux n’a ete identifie. La rectosigmoidoscopie a mis en evidence une congestion colique diffuse, sans ulceration. Les biopsies coliques systematiques ont revele un epaississement de la bande collagene sous-epitheliale, mesurant entre 20 et 30 μm d’epaisseur, associe a une augmentation moderee de la cellularite inflammatoire du chorion, avec presence de lymphocytes et plasmocytes. Le patient a ete efficacement traite par un arret temporaire du pembrolizumab et la mise en place d’une corticotherapie (prednisone) a la dose de 0,8 mg/kg/j, d’abord intraveineuse, puis par voie orale, avec decroissance progressive sur 6 semaines. Lors de la decroissance de la prednisone, une recidive des diarrhees a ete observee. Il a donc ete propose un relais par budesonide 9 mg/j permettant une resolution complete et definitive des diarrhees. Le budesonide a depuis ete stoppe. Le pembrolizumab n’a pour l’instant pas ete repris. Il existe actuellement une progression osseuse localisee du melanome, traitee par radiotherapie seule. En cas de reprise evolutive plus importante, un nouveau traitement systemique pourra etre discute.

Resume La ganglioneuromatose du tube digestif est une affection rare pouvant etre isolee ou syndromique. Une neoplasie endocrinienne multiple de type 2 est le syndrome le plus frequemment associe. De plus rares cas d’association avec la neurofibromatose de type 1 ont egalement ete decrits. Nous rapportons un patient ayant une neurofibromatose de type 1 et une ganglioneuromatose du colon decouverte fortuitement a la suite de troubles digestifs.

The french society of pathology (SFP) organized in 2020 its first data challenge with the help of Health Data Hub (HDH). The organisation of this event first consisted in recruiting almost 5000 slides of uterus cervical biopsies obtained in 20 pathology centers. After having made sure that patients did not refuse to include their slides in the project, the slides were anonymised, digitized and annotated by expert pathologists, and were finally uploaded on a data challenge platform for competitors all around the world. Competitors teams had to develop algorithms that could distinguish among four diagnostic classes in epithelial lesions of uterine cervix. Among many submissions by competitors, the best algorithms obtained an overall score close to 95%. The best 3 teams shared 25k€ prizes during a special session organised during the national congress of the SFP. The final part of the competition lasted only 6 weeks and the goal of SFP and HDH is now to allow for the collection to be published in open access. This final step will allow data scientists and pathologists to further develop artificial intelligence algorithms in this medical area.

Resume La reconnaissance des metastases mammaires par le pathologiste est fondamentale car leur pronostic et leur traitement sont differents de ceux des carcinomes mammaires primitifs. Nous rapportons l’observation d’une patiente de 54 ans presentant sur sa mammographie de depistage un nodule du sein gauche connu depuis 5 ans ayant discretement augmente de taille. L’echographie mammaire montrait une formation nodulaire hypoechogene reguliere de 1,2 cm. Une microbiopsie a ete effectuee. A l’examen microscopique, on observait une proliferation tumorale realisant des massifs au sein d’un stroma peu abondant richement vascularise. Les cellules tumorales avaient un cytoplasme moyennement abondant, eosinophile, granuleux et un noyau arrondi, legerement atypique. Une mitose a ete retrouvee en moyenne pour 10 champs au grossissement × 400. Les cellules tumorales n’exprimaient pas les recepteurs hormonaux mais la chromogranine A, la synaptophysine, le TTF1 et la thyrocalcitonine. L’index de proliferation etabli par l’anticorps anti-Ki67 etait de 5 %. Le diagnostic retenu etait celui de localisation secondaire d’une tumeur neuroendocrine bien differenciee, dont le profil immunohistochimique oriente en premier lieu vers une origine thyroidienne. Nous avons appris, ulterieurement, que la patiente avait un antecedent de thyroidectomie totale 13 ans auparavant. Il s’agissait d’un carcinome medullaire de la thyroide sporadique. Dans le cadre du bilan d’extension, la scintigraphie osseuse a mis en evidence une lesion lacunaire de la partie posterieure de l’aile iliaque droite suspecte de localisation secondaire. Cette lesion iliaque droite a ete biopsiee. Il s’agissait egalement d’une localisation du carcinome medullaire thyroidien connu. Le diagnostic final est celui de carcinome medullaire thyroidien metastatique, lentement evolutif, la metastase mammaire existant probablement depuis 5 ans.

601 Background: Triple negative breast cancer (TNBC) is a biologically and clinically heterogenous disease, associated with poorer outcomes when compared with other subtypes of breast cancer. In early-stage TNBC, surgery with curative intent remains the mainstay of therapy. Neoadjuvant chemotherapy is often given prior to surgery and achieving pathological complete response (pCR) has been associated with improved long-term outcomes in terms of progression-free survival (PFS) and overall survival (OS). There is thus high clinical interest in the ability to accurately predict pCR status using baseline data. Methods: A retrospective cohort of 57 patients with early-stage TNBC treated with neoadjuvant chemotherapy was analyzed to develop a machine learning-based algorithm predictive of pCR likelihood at the individual patient level. Multimodal baseline data were collected including clinical, biological (e.g., histology, genomic profile including CDC2, CDC20, KPNA2, MYBL2, complete blood count, Ki67), imaging data (baseline PET/CT scan), the radiology report and clinical outcomes data (pCR, PFS, OS). For each patient, tumors were segmented in 3D by an experimented nuclear physician using the SOPHiA Radiomics platform. Radiomics features were then extracted following the IBSI standards and then combined with the other data modalities. A filter-based variable selection method was applied before training several machine learning algorithms. The optimization criterion was the Area Under the ROC Curve (AUC). Due to the small size of the cohort, a nested leave-pair-out cross-validation approach was used to properly estimate the model performance. Results: The best result was obtained with the SVM algorithm with a linear kernel, reaching an AUC of 0.82, a precision of 71%, a sensitivity of 71% and a specificity of 70%. The features with highest weight in the algorithm were a mix of radiological, radiomics, biological and clinical features, highlighting the importance of a truly multimodal analysis. Indeed, withdrawing a specific data modality (e.g., radiomics features or biological features), led to a decrease of ̃10% of the AUC. Patients were then stratified into two groups based upon their predicted pCR status. These two groups displayed a statistically significant difference in PFS (p

Liver blood test anomalies are common after allogeneic hematopoietic stem cell transplantation (allo-HSCT), but their cause often remains difficult to identify. Our objective was to evaluate the safety and utility of liver biopsies in patients who underwent allo-HSCT. In a retrospective single-center cohort study, we reviewed all cases of patients who underwent liver biopsy between June 2005 and July 2017. During this period, 54 biopsies were performed in 45 patients, in which 38 patients underwent allo-HSCT for malignant and 7 for nonmalignant hematological disorders. Median time between allo-HSCT and liver biopsy was 213 days. Seven biopsies were percutaneous, and 47 were transjugular. No adverse event related to the biopsy procedure occurred; 94.5% biopsies (51 of 54) led to a histological diagnosis. Cholestatic graft-versus-host disease was histologically demonstrated in 16 biopsies (30%); hepatitis-like graft-versus-host disease in 9 biopsies (17%); nonalcoholic steatohepatitis in 6 biopsies (9%); regenerative nodular hyperplasia in 4 biopsies (5%); and drug-induced liver injury, sinusoidal obstruction syndrome, and viral hepatitis each in 3 biopsies (5%). Association between clinical, laboratory, imaging and pathological features was poor. Only 34% of physicians' prebiopsy hypotheses were confirmed by pathological findings. Patient management was influenced by liver biopsy results in 65% of cases, allowing us to identify a new diagnosis (n = 13), rule out a differential diagnosis (n = 14), or confirm the main hypothesis (n = 6). In conclusion, liver biopsy is a safe and useful technique to investigate liver blood test anomalies following allo-HSCT.

Background The prevalence and prognosis association of microsatellite instability (MSI) in oesogastric junction and gastric adenocarcinoma (OGC) have been reported with conflicting results. Methods Patients with OGC from 2010 to 2015 were enrolled in this retrospective multicenter study. MSI was determined by genotyping. MLH1 promoter methylation and BRAF V600E mutation were screened in the MSI tumors. Results Among 315 tumors analyzed, 39 (12.4%) were of the MSI phenotype. Compared to MSS tumors, MSI tumors were more frequent in patients > 70 years (17% vs 9%, p = 0.048) and in gastric antral primary (20% versus 5% in junction tumor and 12% in fundus tumor. Among 29 MSI tumors analyzed, 28 had a loss of MLH1 protein expression and 27 had MLH1 promotor hypermethylation. None had a BRAF V600E mutation. The 4-year cumulative incidence of recurrence for patients with resected tumor was significantly lower in dMMR tumors versus pMMR tumors (17% versus 47%, p = 0.01). For the patients with unresectable tumor the median overall survival was 11 months in MSS group and 14 months in MSI group (p = 0.24). Conclusion MSI prevalence in OGC was 12.4%, associated with antral localization and advanced age. Patients with MSI tumors had a lower cumulative incidence of recurrence after surgery. MSI phenotype was mainly associated with loss of MLH1 protein expression, MLH1 promotor hypermethylation and had no BRAF V600E mutation.

Background: The efficacy of neoadjuvant chemotherapy regimens in advanced luminal breast cancer patients is difficult to predict. Intrinsic properties of breast tumors, including altered gene expression profile and dynamic evaluation of metabolic properties of tumor cells using positron emission tomography/computed tomography (PET/CT) of tumor cells, have been identified to guide patient's prognosis. The aim of this study is to determine if both analyses may improve the prediction of response to neoadjuvant chemotherapy in ER-positive / HER2-negative breast cancers (BCs) patients. Methods: We used metabolic PET parameters, at diagnosis and after two cycles of chemotherapy and proliferation gene expression profile on biopsy at diagnosis, in particular, the genomic grade index (GGI) analyzed by reverse transcription and quantitative polymerase chain reaction (RT-qPCR). The pathological response was the surrogate endpoint. Results: The change of FDG uptake between baseline PET and interim PET after 2 cycles of neoadjuvant chemotherapy (ΔSUVmax) was highly associated with pCR (p=0.008). We also observed an ability of P53 mutated status (p=0.042), in addition to histological grade (p=0. 0004), and PR expression (p=0.01) to predict pCR in ERpositive BCs, whereas no proliferation marker predicted pCR (P=0.39 for GGI). Finally, only ΔSUVmax was significantly associated with event free survival (p=0.047). Conclusions: Our results confirm the predictive and prognostic value of tumor ΔSUVmax in ER-positive /HER2-negative advanced BCs patients. These findings can be helpful to select high-risk patients within trials investigating novel treatment strategies., SCOPUS: ar.j, info:eu-repo/semantics/published

International audience; Background: Patients treated with chemotherapy for microsatellite unstable (MSI) and/or mismatch repair deficient (dMMR) cancer metastatic colorectal cancer (mCRC) exhibit poor prognosis. We aimed to evaluate the relevance of distinguishing sporadic from Lynch syndrome (LS)-like mCRCs.Patients and methods: MSI/dMMR mCRC patients were retrospectively identified in six French hospitals. Tumour samples were screened for MSI, dMMR, RAS/RAF mutations and MLH1 methylation. Sporadic cases were molecularly defined as those displaying MLH1/PMS2 loss of expression with BRAFV600E and/or MLH1 hypermethylation and no MMR germline mutation.Results: Among 129 MSI/dMMR mCRC patients, 81 (63%) were LS-like and 48 (31%) had sporadic tumours; 22% of MLH1/PMS2-negative mCRCs would have been misclassified using an algorithm based on local medical records (age, Amsterdam II criteria, BRAF and MMR statuses when locally tested), compared to a systematical assessment of MMR, BRAF and MLH1 methylation statuses. In univariate analysis, parameters associated with better overall survival were age (P < 0.0001), metastatic resection (P = 0.001) and LS-like mCRC (P = 0.01), but not BRAFV600E. In multivariate analysis, age (hazard ratio (HR) = 3.19, P = 0.01) and metastatic resection (HR = 4.2, P = 0.001) were associated with overall survival, but not LS. LS-like patients were associated with more frequent liver involvement, metastatic resection and better disease-free survival after metastasectomy (HR = 0.28, P = 0.01). Median progression-free survival of first-line chemotherapy was similar between the two groups (4.2 and 4.2 months; P = 0.44).Conclusions: LS-like and sporadic MSI/dMMR mCRCs display distinct natural histories. MMR, BRAF mutation and MLH1 methylation testing should be mandatory to differentiate LS-like and sporadic MSI/dMMR mCRC, to determine in particular whether immune checkpoint inhibitors efficacy differs in these two populations.

The adrenal primary epithelioid angiosarcoma (ASE) is a rare malignant tumor which can be histologically confused with other neoplasms. We report one case in a 79-year-old man who underwent adrenal tumor surgery for a mass fortuitly discovered by imaging for examination of an inflammatory syndrome associated with anemia. The histological diagnosis was difficult because of the undifferentiated and epithelioid appearance of tumor cells, whose immunohistochemical epithelial markers positivity led to frequent confusion with a metastatic carcinoma. Careful research for vascular differentiation at histopathological study and expression of immunohistochimical endothelial markers, are crucial to confirm the diagnosis.

The Massive Open Online Course (or MOOC) "Diagnostic Strategies Cancers", was hosted in autumn 2016 on the platform "France Universite Numerique" and had two levels of learners: students in the field of health and biology and the general public. Of the 5285 learners in 81 different countries, 1237 (23%) were successfully certified. This MOOC was also integrated into the teaching program of medical students of Paris Diderot University and Paris 13 University. Using anonymous questionnaires before and after MOOC, it has been shown that pathology is less known than other medical specialties. Participation in this MOOC led to a marked improvement in participants' knowledge of the place and role of the pathologist in the diagnosis of cancers. Regarding the students who have followed the MOOC as part of their university course, their comments were very positive, but it is necessary to make substantial adjustments in the amounts and contents of the campus-based courses.

The most commonly reported pattern of anti-PD-1 induced colitis is an active colitis characterized by neutrophilic inflammation and prominent apoptosis. On the other hand, reports of collagenous colitis (which is a microscopic colitis) are exceptional. In this report, we describe an unusual case of anti-PD1-associated collagenous colitis in a 76-year-old man, treated with pembrolizumab for a stage IV cutaneous melanoma. Fourteen months after the start of pembrolizumab, the patient developed a grade 3 diarrhea (up to 9 stools per day) associated with profound hypokalemia. No bacterial, viral or parasitological infectious agents were found from stool analysis. The rectosigmoidoscopy showed colonic diffuse congestion with no ulceration. Systematic biopsies were performed during endoscopy. Histologically, the fragments analyzed revealed a moderately thickened subepithelial collagen layer (20-30μm thick) associated with a mild mixed inflammatory infiltrate within the lamina propria. There were no granuloma lesions, ulcerations or viral inclusion bodies. The patient was initially successfully treated with corticosteroids (prednisone) and temporary interruption of pembrolizumab. However, during corticosteroids tapering, a relapse was observed. The treatment was switched to budesonide, leading to a complete and definitive resolution of diarrhea. To date, budesonide has been stopped and pembrolizumab has not been restarted. Currently, there is a bone progression treated by radiotherapy alone. In case of a more important progression, a systemic treatment will be secondarily discussed.

Gastrointestinal toxicities of MEK inhibitors in melanoma patients are frequent. In clinical trials, the most common digestive adverse events were nausea, vomiting, and diarrhoea. However, severe toxicities such as colitis and gastrointestinal perforation, some with fatal outcomes, have been reported. These rare but severe adverse events are not well described. We performed a retrospective analysis of all patients with stage IV and unresectable stage III melanoma treated with a MEK inhibitors at Saint-Louis Hospital, Paris, between 1 August 2013 and 15 October 2018. Among 119 patients exposed to MEK inhibitors, 78 were treated with trametinib, 19 with cobimetinib, four with binimetinib, and 18 patients with two different MEK inhibitors at separate times. All grade digestive adverse events were observed in 39 (32.7%) patients. Grade 3 and 4 adverse events occurred in 6 (5%) patients: 2 (1.7%) developed perforations, 3 (2.5%) had colitis and 1 (0.8%) had grade 4 diarrhoea. These adverse events were all reversible following a permanent discontinuation of the MEK inhibitors, or a temporary interruption followed by resumption at a dose lower than conventional posology. There were no fatal outcomes; however one patient had a permanent ileostomy. The mechanism underlying these toxicities is not well known. Clinicians should be aware of such toxicities.

Resume L’enseignement de l’anatomie et cytologie pathologiques (ACP), au meme titre que l’enseignement des autres disciplines medicales, est a un tournant de son evolution. Face a une augmentation du champ des connaissances et de la complexite des diagnostics, l’epoque est a une mutualisation des ressources pedagogiques a une echelle regionale voire nationale. Nous presentons, ici, les outils en ligne permettant a des communautes d’etudiants de plus en plus larges d’acceder a des contenus d’apprentissage, a des auto-evaluations et a des outils d’evaluation de leurs competences. Les plateformes de e-learning et de MOOC (« Massive open online courses »), sont au centre de ces modalites pedagogiques, avec une mention particuliere pour la plateforme nationale des disciplines dediee a l’enseignement des 50 000 internes en medecine de France. Ces enseignements jouent aussi sur l’attractivite avec notamment les serious games, et on parlera de la place essentielle des images et des lames virtuelles dans l’enseignement de l’ACP. La pedagogie a grande echelle ne doit, bien sur, pas se concevoir comme un remplacement des enseignements utilises auparavant, mais comme l’etape initiale d’acquisition des connaissances, devant deboucher sur des enseignements presentiels renoves, centres sur l’interactivite et les competences.

Gastrointestinal tract ganglioneuromatosis is a rare condition, which is isolated or included in a syndromique disease. Multiple endocrine neoplasia type 2 is the most frequently associated syndrome. Association with type 1 neurofibromatosis has also been established, but much rarely. We report the case of large bowel ganglioneuromatosis found incidentally in a patient with type 1 neurofibromatosis.

Medical education is currently facing great changes that affect all medical specialties, including anatomical pathology. Due to rapidly increasing medical knowledge and diagnostic complexity, we are living an era of teaching resources mutualization. We present different tools that allow large numbers of students to access courses, self-evaluations, and competencies assessments. MOOC platforms and e-learning platforms are central to these new online tools, which include the French National Platform of Medical Specialties, dedicated to the teaching of 50,000 medical residents in France. We also discuss "serious games" and the use of images and virtual slides in anatomical pathology teaching. These new modalities can deliver essential knowledge to large student populations, but they must be used in conjunction with adapted teacher-led courses focusing on competencies and professional skills in order to be fully effective.

Resume Le cours en ligne ouvert et massif (Massive Open Online Course ou MOOC) est une nouvelle modalite pedagogique en ligne s’adressant a une audience dont la taille est sans precedent par rapport aux autres strategies d’enseignement tout en permettant des interactions avec une equipe pedagogique. Ces cours universitaires, le plus souvent encore gratuits, donnent lieu a la remise d’une attestation de suivi et pourraient rapidement etre diplomants. Le MOOC « Strategies diagnostiques des cancers » sera dispense a l’automne 2016 sur la plateforme France universite numerique et aura deux niveaux d’apprenants : les etudiants de premier cycle dans le domaine de la sante et de la biologie et le grand public. Il sera egalement integre a des unites d’enseignement pour des etudiants en medecine des universites Paris Diderot et Paris 13. L’objectif pedagogique de ce MOOC est de transmettre a l’ensemble des apprenants une vision globale des etapes diagnostiques du cancer et des differentes specialites medicales impliquees dans ce diagnostic. La deuxieme semaine d’enseignement de ce MOOC, intitulee « le prelevement tumoral, son analyse macroscopique et microscopique », presente la specialite d’anatomie et cytologie pathologiques avec la prise en charge technique des echantillons tissulaires ou cellulaires et les elements basiques du raisonnement anatomopathologique. A l’issue de ce MOOC, il est prevu de realiser une evaluation de l’impact de cette nouvelle modalite d’enseignement sur la perception de l’anatomie et cytologie pathologiques par le grand public.

Resume Objectif Depuis les dernieres recommandations nationales elaborees par l’Institut national du cancer (INCa) et la Societe francaise de senologie et de pathologie mammaire (SFSPM) sur l’ensemble de la prise en charge diagnostique et therapeutique des carcinomes canalaires in situ (CCIS), de nouvelles publications ont fait emerger des interrogations en termes de bonnes pratiques et sur les possibilites de desescalade therapeutique dans la prise en charge des CCIS. L’actualisation de ces recommandations intervient dans un contexte de questionnement sur le surdiagnostic et son corollaire le surtraitement. Elle met a la disposition des professionnels des informations sur les bonnes pratiques correspondant a l’etat le plus recent des connaissances scientifiques et etudie notamment les possibilites de desescalade therapeutique. Methode Le processus d’elaboration est base sur une revue systematique de la litterature et sur le jugement argumente d’experts cliniciens au sein d’un groupe de travail multidisciplinaire. Avant publication, les recommandations sont revues par plus de cent experts cliniciens independants du groupe de travail. Resultats Cet article presente les recommandations nationales relatives a l’indication de l’IRM, la place de la macrobiopsie en cas de microcalcifications et la conduite a tenir en cas de CCIS de bas grade identifie par biopsie, dans le diagnostic des CCIS.

Targeted immunotherapy has markedly improved the survival of melanoma patients. We report the case of a melanoma patient who developed a collagenous colitis under an anti-PD1 regimen. A 68-year-old woman was treated for a stage IV melanoma. An anti-PD1, pembrolizumab, was introduced after the failure of a first-line therapy with an anti-CTLA4. At cycle 14, pembrolizumab was interrupted because of grade 3 diarrhea. Histologic analysis of colon mucosa showed a thickened apical subepithelial collagen layer with irregular collagen deposition of more than 25 µm thickness. Budesonide 9 mg/day and cholestyramin 8 g/day were then introduced, leading to a decrease in the number of stools to grade 2. Because of the prognosis of the disease, the efficacy of pembrolizumab in this patient and the lack of other efficient treatments, pembrolizumab was restarted, with no worsening of the diarrhea after a follow-up of 8 weeks. In the era of immunotherapy, a new type of drug-induced colitis has emerged because of monoclonal antibodies targeting immune checkpoints such as CTLA-4 and PD1. Gastrointestinal tract immune-mediated adverse effects are now well described with ipilimumab. To the best of our knowledge, this is the first report of a collagenous colitis in a patient treated with pembrolizumab, thus suggesting a new mechanism of toxicity. Classically, collagenous colitis first-line treatment is based on discontinuation of the suspected treatment. However, there may be a strong benefit to maintaining an anti-PD1 regimen in our patients. In this case, symptomatic management associated with budesonide and cholestyramin enabled continuation of pembrolizumab.

BACKGROUND The prognostic and predictive role of cyclo-oxygenase-2 (COX2) in breast cancer is still debated, and in particular, its role as a target of COX2 inhibitor (celecoxib) in neoadjuvant setting. MATERIALS AND METHODS We analyzed a series of 156 breast cancer samples from patients of the COX2 inhibitor-treated arm included in the REMAGUS-02 randomized phase II trial. COX2 gene expression was assessed by reverse transcription and quantitative polymerase chain reaction using ribonucleic acid from frozen biopsies. Pathological complete response (pCR) was the surrogate end-point. RESULTS Significantly higher rates of grade 3, and estrogen and progesterone receptor negativity were observed in tumors with the highest expression of COX2. pCR rates were significantly higher in COX2-overexpressing tumors in patients receiving celecoxib. The test for interaction between COX2 gene expression and the celecoxib effect was statistically significant (p

Recognition of mammary metastases by pathologists is fundamental because their prognosis and treatment are different from those of primary mammary carcinomas. We report the case of a 54-year-old woman presenting on her mammography a left breast nodule known for 5 years, having discreetly increased in size. Breast ultrasound showed a regular 1.2cm hypoechogenic nodular formation. A microbiopsy was performed. On microscopic examination, we observed a tumor proliferation realizing nests within a small, richly vascularized stroma. The tumor cells had a moderately abundant, eosinophilic, granular cytoplasm and a rounded, slightly atypical nucleus. One mitosis was found for 10 fields at×400 magnification. Tumor cells did not express hormone receptors but chromogranin A, synaptophysin, TTF1 and thyrocalcitonin. The proliferation index established by the anti-Ki67 antibody was 5 %. The diagnosis was a secondary localization of a well-differentiated neuroendocrine tumor which immunohistochemical profile firstly suggests a thyroid origin. We later learned that the patient had a history of total thyroidectomy 13 years ago. It was a sporadic medullary carcinoma of the thyroid. Bone scintigraphy revealed a lacunar lesion of the posterior part of the right iliac wing suspicious of secondary location. This right iliac lesion was biopsied. It was also a localization of the medullary thyroid carcinoma. The final diagnosis is a metastatic medullary thyroid carcinoma, slowly progressive, the mammary metastasis having probably existed for 5 years.

Survival is increased when pathological complete response (pCR) is reached after neoadjuvant chemotherapy (NAC), especially in triple-negative breast cancer (TNBC) patients. Positron emission tomography/computed tomography (PET/CT) with 18F-fluorodeoxyglucose (FDG) and the genomic grade index (GGI), each separately, showed good potential to predict pCR. Our study was designed to evaluate the predictive value for the therapeutic response of a combination of parameters based on FDG-PET, histoclinical features and molecular markers of proliferation. Molecular parameters were measured on pre-treatment biopsy. Tumor metabolic activity was measured using two PET/CT scans, one before and one after 2 cycles of NAC. The pCR was determined on specimen after NAC. Event-free survival (EFS) was estimated using the Kaplan Meier method. Of 55 TNBC patients, 19 (35%) reached pCR after NAC. Tumor grade and Ki67 were not associated with pCR whereas GGI (P = 0.04) and its component KPNA2 (P = 0.04) showed a predictive value. The change of FDG uptake between PET1 and PET2 (ΔSUVmax) was highly associated with pCR (P = 0.0001) but the absolute value of baseline SUVmax was not (P = 0.11). However, the AUC of pCR prediction increased from 0.63 to 0.76 when baseline SUVmax was combined with the GGI (P = 0.016). The only two parameters associated with EFS were ΔSUVmax (P = 0.048) and pathological response (P = 0.014). The early tumor metabolic change during NAC is a powerful parameter to predict pCR and outcome in TNBC patients. The GGI, determined on pretreatment biopsy, is also predictive of pCR and the combination GGI and baseline SUVmax improves the prediction.

Introduction Les inhibiteurs de MEK (MEKi) ont une toxicite digestive (TD) dose dependante exceptionnellement de grade 3. La frequence de la diarrhee est estimee a 40 % dans les essais cliniques, celle des vomissements a 10 %. Recemment des colites et des perforations digestives ont ete declarees a la pharmacovigilance, cependant la litterature sur ces complications est pauvre. Nous avons revu les TD de grades 3–4 survenues sous MEKi chez tous patients traites pour melanome stades III avance et IV dans notre centre. Materiel et methodes Analyse monocentrique a travers la base de donnees MelBase des dossiers des patients traites par MEKi seuls ou en association entre aout 2013 et mai 2018 et ayant developpe une ou plusieurs TD en utilisant les mots-cles : nausees, vomissements, diarrhee, douleur abdominale, colite, occlusion, perforation. Seules les TD gradees CTCAE 3 et 4 ont ete retenues. Resultats Parmi les 84 patients chez qui un MEKi avait ete introduit sur la periode analysee, 5 âges entre 41 et 76 ans developpaient des TD de grades 3 et 4 : 2 cas de perforation intestinale, 2 cas de colite et 1 cas de diarrhee febrile grade 4. Ces TD etaient notees sous cobimetinib (n = 2), trametinib (n = 2) et binimetinib (n = 1), et etaient apparues dans des delais allant d’une semaine a 5,5 mois de l’initiation du MEKi (mediane = 18 jours). Une des perforations survenait 5,5 mois apres introduction de cobimetinib. L’histologie montrait une reactivation d’une rectocolite hemorragique, qui etait quiescente depuis 15 ans sous mesalazine. L’autre perforation survenait une semaine apres initiation de trametinib ; l’histologie montrait une diverticulite sigmoidienne perforee avec peritonite aigue. Les 2 patients etaient operes en urgence avec realisation d’une derivation digestive. Les 2 cas de colite sous MEKi se declaraient par des diarrhees liquidiennes persistantes. La coloscopie montrait des ulcerations d’etendue variable. L’histologie montrait une colite ulceree possiblement medicamenteuse chez une patiente, et des remaniements inflammatoires vasculo-exsudatifs non granulomateux chez l’autre. L’evolution etait rapidement favorable a l’arret du traitement. Une des 2 patientes avait un antecedent de colite sous ipilimumab 17 mois auparavant. Enfin, une patiente developpait une reaction inflammatoire systemique severe avec diarrhee profuse 3 semaines apres initiation de trametinib. L’enquete infectieuse etait negative. L’evolution etait favorable apres un court sejour en reanimation, antibiotherapie et arret de la therapie ciblee. Les MEKi n’etaient pas repris ( Tableau 1 ). Conclusion Les MEKi sont connus pour avoir des TD, cependant celles de grades 3 et 4 sont mal decrites dans la litterature. Ces TD peuvent se declarer dans les quelques jours a quelques mois suivant l’introduction du traitement. Elles peuvent avoir des presentations variables allant d’une simple diarrhee a des perforations digestives.

Introduction Les syndromes auto-inflammatoires (SAI) PAPASH, PsAPASH et PASS associent respectivement une spondylarthrite (Sp) peripherique, un rhumatisme psoriasique (RP) ou une Sp axiale a un pyoderma gangrenosum (PG), une acne, et une hidradenite suppuree (HS). Notre etude vise a preciser les phenotypes cutaneo-articulaires et les caracteristiques biologiques et therapeutiques de ces syndromes de description recente. Materiel et methodes Dans 2 centres experts, etude de cas sur les caracteristiques cliniques et biologiques incluant la recherche d’anticorps anti-saccharomyces cerevisiae (ASCA) ainsi que la reponse aux traitements. Une recherche de mutation des genes du complexe gamma-secretase (GS) APH1, NCSTN, PSENEN, PSTPIP1 et de NOD2 etait realisee. Resultats Neuf patients (4 hommes, 5 femmes) dont 2 PAPASH, 3 PASS, 1 PsAPASH et 3 patients avec une Sp mixte. L’âge moyen de debut de l’atteinte cutanee et/ou articulaire etait de 24,4 ans (14–40). L’HS etait constamment severe (Hurley III dans 8 cas), inaugurale (7), avec atteinte inguino-perineale et axillaire (9), ainsi qu’une acne cheloidienne de la nuque (3). La dermatose neutrophilique etait un PG (2), des pustules aseptiques disseminees (7), et/ou des abces aseptiques sous cutanes (2). L’asthenie constante etait parfois accompagnee de fievre (3). Le taux initial moyen de CRP etait de 82 mg/L, avec hypergammaglobulinemie (5/7) et SAA elevee (4/5). Les ASCA etaient positifs (7/8), sans signe endoscopique de maladie inflammatoire chronique intestinale (MICI) mais avec presence histologique d’abces ou d’infiltrat neutrophilique gastrique ou colique (3/5). Un patient presentait un RP, 3 une Sp axiale et peripherique, 3 une Sp axiale pure et 2 une atteinte peripherique seronegative. Aucune destruction articulaire n’etait observee. Aucune mutation n’etait trouvee. Les elements cutanes du syndrome dont l’HS resistaient a l’antibiotherapie, necessitant le recours aux immunomodulateurs (methotrexate, corticoides oraux, azathioprine, ciclosporine), tous en echec en monotherapie. Une reponse partielle a complete etait obtenue sous infliximab (jusqu’a 10 mg/kg/4 semaines) ou adalimumab (40 mg/semaine) combines a un autre immunomodulateur, avec des taux plasmatiques residuels d’anti-TNF souvent eleves. Discussion Les SAI PAPASH, PsAPASH et PASS sont severes par leur atteinte cutaneo-articulaire et systemique et partagent les ASCA comme biomarqueur commun, suggestif d’une dysbiose. Leur controle optimal est le plus souvent obtenu sous anti-TNF associe a un autre immunomodulateur, permettant parfois la chirurgie de l’HS. Conclusion Les SAI cutaneo-articulaires derives de l’HS, heterogenes sur le plan rhumatologique, sont particuliers par leur severite, par des marqueurs immunobiologiques communs et par la necessite d’un traitement immunosuppresseur intensif incluant un anti-TNF. Leur substratum genetique, inconnu, semble different de ceux de l’HS et d’autres SAI.

Introduction La necrolyse epidermique toxique (NET) est une toxidermie grave pouvant mettre en jeu le pronostic vital. L’atteinte cutaneomuqueuse est au premier plan, mais d’autres manifestations peuvent s’y associer. Observations Un patient de 26 ans etait suivi pour une epilepsie frontale focale non controlee pour laquelle un traitement par carbamazepine etait introduit. Dix jours plus tard apparaissait une eruption maculopapuleuse d’extension rapide avec secondairement decollement cutane et odynophagie. Au tableau cutane s’associaient simultanement des diarrhees glaireuses. Le patient etait transfere en reanimation devant une suspicion de NET a la carbamazepine, avec un score SCORTEN a 1. L’histologie cutanee et l’immunofluorescence directe negative confirmaient le diagnostic. L’evolution sur le plan cutaneomuqueux etait favorable apres arret de la carbamazepine et soins de support, mais les diarrhees devenaient glairo-sanglantes et plus frequentes (plus de 20 selles par jour). Le scanner abdominal montrait une ileite et une pancolite. Le bilan microbiologique etait negatif. La rectosigmoidoscopie trouvait une rectocolite ulceree sans intervalle de muqueuse saine. L’analyse histologique montrait d’importants remaniements inflammatoires de la muqueuse sigmoidienne compatibles avec des lesions de rectocolite hemorragique (RCH). Devant cette colite aigue grave, une corticotherapie systemique etait debutee a la dose de 1 mg/kg/j, sans efficacite ; apres une menace de perforation digestive, deux perfusion d’infliximab etaient effectuees a une semaine d’intervalle, respectivement de 5, et 10 mg/kg, permettant une remission clinique quasi complete en quelques jours, confirmee endoscopiquement. La cicatrisation cutanee et muqueuse etait complete ( Fig. 1 et 2 ). Discussion Une diarrhee chez un patient atteint de NET doit faire eliminer une cause infectieuse, mais une atteinte muqueuse colique specifique doit etre evoquee en cas de negativite des prelevements microbiologiques. Des atteintes coliques dans le cadre de NET sont parfois decrites comme evocatrices de RCH. Un cas similaire au cours d’un NET a la dapsone a precedemment ete decrit dans la litterature. Chez cette patiente, l’evolution sous soins de support nutritionnels avait ete defavorable (deces par perforation digestive). Chez notre patient, deux hypotheses sont possibles : une atteinte specifique de la NET « RCH-like » ou une poussee de RCH declenchee par la NET. Conclusion Nous rapportons le premier cas de colite aigue grave evocatrice de RCH concomitante a une NET a la carbamazepine d’evolution favorable apres deux perfusions d’anti-TNFα (infliximab). Devant une colite non infectieuse au cours d’une NET, la realisation d’une endoscopie digestive pour en preciser la nature doit etre discutee.

Research states that the success of a specific innovation cannot be predicted. As a consequence, the value of such an innovation can only be stated very late in the development process, or even in retrospect. Based on C-K design-theory, our empirical research shows that professionals directly engaged in the design process are able to perform an early and complete valuation. The cognitive process of this valuation is extremely similar to the overall process of innovative design. Also, this process has tangible outputs, in particular local, dedicated management tools used as proofs of concepts., La recherche en gestion a établi l'imprévisibilité du succès d'une innovation. Un corollaire largement accepté veut que la détermination de la valeur de cette innovation ne puisse être que tardive, voire rétrospective. Nous observons dans cette recherche que les acteurs directs de l'innovation sont à même de procéder à une détermination de la valeur précoce, complète et révisable. Nous appuyant sur la théorie C-K, nous montrons que ces équipes appliquent à la détermination de la valeur le même type de raisonnement qu'à l'innovation elle-même. Nous montrons également que ce travail de conception innovante passe par la génération d'outils de gestion locaux, souvent à l'usage exclusif du projet et utilisés pour mettre à l'épreuve les différents concepts de valeur.

Summary Background Survival of metastatic colon cancer (mCC) patients has considerably improved with optimization of new drugs regimen. Inactivation of TP53 pathway by TP53 mutations is observed in nearly half of colorectal tumors. The impact of such mutations has been poorly studied in the metastatic setting. Methods The files of 254 mCC treated in a single institution at Saint-Louis hospital between January 1999 and April 2011 were retrospectively reviewed. Tissue samples for analysis of TP53 mutations were available for 68 patients, performed using FASAY. The prognostic value of TP53 status was evaluated by comparing progression free survival (PFS) and overall survival (OS) in the group of TP53-mutated and wild type patients. Results PFS was 6.9 months and OS 21.7 months in the whole population. There was no statistical difference in TP53- mutated and wild type groups in term of PFS (HR = 1.04; IC9 5% = 0.6–1.79) and OS (HR = 0.99; IC 95% = 0.53–1.55) whatever the chemotherapy regimen (oxaliplatin- or irinotecan-based). Only BRAF V600 mutation was demonstrated to be a poor prognostic factor for PFS and OS, and CEA level for OS. Conclusions Routine determination of TP53 mutations, even with a highly sensitive method, cannot be recommended to predict chemotherapy response in mCC.

// Guilhem Bousquet 1, 2, 3, 4 , Morad El Bouchtaoui 2 , Tan Sophie 2 , Christophe Leboeuf 1, 2 , Cedric de Bazelaire 1, 2, 5 , Philippe Ratajczak 1, 2 , Sylvie Giacchetti 6 , Anne de Roquancourt 1, 2, 7 , Philippe Bertheau 1, 2, 7 , Laurence Verneuil 1, 2 , Jean-Paul Feugeas 8 , Marc Espie 1, 6 , Anne Janin 1, 2, 7 1 Universite Paris Diderot, Sorbonne Paris Cite, Laboratoire Pathologie, Paris, France 2 INSERM, Paris, France 3 Universite Paris 13, Villetaneuse, France 4 AP, HP, Avicenne, Service Oncologie, Paris, France 5 AP HP Hopital Saint-Louis, Service Radiologie, Paris, France 6 AP HP Hopital Saint-Louis, Centre Maladies Sein, Paris, France 7 AP HP Hopital Saint-Louis, Service Pathologie, Paris, France 8 INSERM, Paris, France Correspondence to: Guilhem Bousquet, email: guilhem.bousquet@aphp.fr Anne Janin, email: anne.janin1165@gmail.com Keywords: breast cancer stem cells, TNBC, chemoresistance, autophagy, hypoxia Received: March 21, 2017 Accepted: March 29, 2017 Published: April 07, 2017 ABSTRACT There is growing evidence for the role of cancer stem-cells in drug resistance, but with few in situ studies on human tumor samples to decipher the mechanisms by which they resist anticancer agents. Triple negative breast cancer (TNBC) is the most severe sub-type of breast cancer, occurring in younger women and associated with poor prognosis even when treated at a localized stage. We investigated here the relationship between complete pathological response after chemotherapy and breast cancer stem-cell characteristics in pre-treatment biopsies of 78 women with triple negative breast carcinoma (TNBC). We found that chemoresistance was associated with large numbers of breast cancer stem-cells, and that these cancer stem-cells were neither proliferative nor apoptotic, but in an autophagic state related to hypoxia. Using relevant pharmacological models of patient-derived TNBC xenografts, we further investigated the role of autophagy in chemoresistance of breast cancer stem-cells. We demonstrated that hypoxia increased drug resistance of autophagic TNBC stem-cells, and showed that molecular or chemical inhibition of autophagic pathway was able to reverse chemoresistance. Our results support breast cancer stem-cell evaluation in pre-treatment biopsies of TNBC patients, and the need for further research on autophagy inhibition to reverse resistance to chemotherapy.

The Massive Open Online Course (or MOOC) "Diagnostic Strategies Cancers", was hosted in autumn 2016 on the platform "France Université Numérique" and had two levels of learners: students in the field of health and biology and the general public. Of the 5285 learners in 81 different countries, 1237 (23%) were successfully certified. This MOOC was also integrated into the teaching program of medical students of Paris Diderot University and Paris 13 University. Using anonymous questionnaires before and after MOOC, it has been shown that pathology is less known than other medical specialties. Participation in this MOOC led to a marked improvement in participants' knowledge of the place and role of the pathologist in the diagnosis of cancers. Regarding the students who have followed the MOOC as part of their university course, their comments were very positive, but it is necessary to make substantial adjustments in the amounts and contents of the campus-based courses.

Background The REMAGUS-02 multicenter randomised phase II trial showed that the addition to neoadjuvant chemotherapy (NAC) of trastuzumab in patients with localised HER2-positive breast cancer (BC) increased the pathological complete response (pCR) rate and that the addition of celecoxib in HER2-negative cases did not increase the pCR rate. We report here the long-term follow-up results for disease-free survival (DFS) and overall survival (OS). Patients and methods From 2004 to 2007, 340 stage II–III BC patients were randomly assigned to receive neoadjuvant EC-T (four cycles of epirubicin–cyclophosphamide followed by four cycles of docetaxel) +/− celecoxib in HER2-negative cases (n = 220) and ± trastuzumab in HER2-positive cases (n = 120). From September 2005, all patients with HER2-positive BC received adjuvant T (n = 106). Results Median follow-up was nearly 8 years (94.4 months, 20–127 m). In the HER2-negative subgroup, addition of celecoxib was not associated with a DFS benefit. Favourable factors were smaller tumour size, expression of progesterone receptor status (PgR) and pCR. In the HER2-positive population, neoadjuvant trastuzumab was not associated with a DFS benefit. Axillary pCR was the only prognostic factor associated with DFS in this group [HR = 0.44, 95% CI = 0.2–0.97], p = 0.035]. To note, DFS and OS were significantly higher in the HER2-positive than in HER2-negative BC patients (HR = 0.58 [0.36–0.92], p = 0.021). Conclusion Celecoxib combined with NAC provided neither pCR nor survival benefit in patients with HER2-negative BC. Absence of PgR is a major prognostic factor. Neoadjuvant trastuzumab increased pCR rates without translation into a DFS or OS benefit compared with adjuvant trastuzumab only. Axillary pCR could be a more relevant surrogate of survival than in the breast in HER2-positive population. A retrospective comparison shows that patients with HER2-positive tumours have a better outcome than HER2-negative BC patients showing the impact of trastuzumab on the natural history of BC.

Resume La creation et la mise en ligne de materiel pedagogique demandent beaucoup de temps et d’energie, et restent difficile a organiser pour les enseignants d’une seule universite. Sous l’egide du College des pathologistes, nous avons initie la mise en place d’un reseau national inter-universitaire ayant pour objectif de creer et de mutualiser un enseignement en ligne en pathologie, reposant sur des cas anatomocliniques, des tests et d’autres contenus pedagogiques multimedias. Dix-neuf universites francaises sont associees a ce projet initialement soutenu par l’UNF3S ( http://www.unf3s.org/ ). Le contenu pedagogique en ligne repose sur une plate-forme utilisant le logiciel Moodle ( http://virtual-slides.univ-paris7.fr/moodle/ ), contenant du texte, differents medias et des liens vers des lames virtuelles decentralisees. Les enseignants ont appris a maitriser l’interface Moodle a l’aide de conferences Web avec partage d’ecran. A ce jour, 20 cas anatomocliniques ont ete crees, ainsi que plusieurs tests contenant des questions a choix multiples ou a reponses courtes, et des videos de macroscopie. Une enquete realisee aupres de 16 enseignants et etudiants a montre un taux de satisfaction de 94 %, la plupart souhaitant que ce type d’enseignement en ligne se developpe en complement de l’enseignement presentiel. Les developpements du site concerneront l’ensemble des niveaux d’etude, du L2–L3 jusqu’aux internes en pathologie et le developpement professionnel continu, en passant par la preparation aux ECN. En conclusion, ces nouveaux outils offrent de tres interessantes perspectives pour l’enseignement de la pathologie. L’organisation d’un reseau national inter-universitaire est un moyen efficace de creer et de mutualiser des ressources pedagogiques nombreuses et de qualite.