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Introduction Interstitial inflammation and peritubular capillaritis are observed in many diseases on native and transplant kidney biopsies. A precise and automated evaluation of these histological criteria could help stratify patients’ kidney prognoses and facilitate therapeutic management. Methods We used a convolutional neural network to evaluate those criteria on kidney biopsies. 423 kidney samples from various diseases were included. 83 kidney samples were used for the neural network training, 106 for comparing manual annotations on limited areas to automated predictions, and 234 to compare automated and visual gradings. Results The Precision, the Recall, and the F-score for leukocyte detection were respectively 81%, 71% and 76%. Regarding peritubular capillaries detection the Precision, the Recall, and the F-score were respectively 82%, 83%, and 82%. There was a strong correlation between the predicted and observed grading of total inflammation, as for the grading of capillaritis (r = 0.89 and r = 0.82 respectively, all p Conclusion We developed a tool using deep learning that scores the total inflammation and capillaritis, demonstrating the potential of artificial intelligence in kidney pathology.

BACKGROUND AND OBJECTIVES: The prognosis of patients undergoing kidney tumor resection or kidney donation is linked to many histologic criteria. These criteria notably include glomerular density, glomerular volume, vascular luminal stenosis, and severity of interstitial fibrosis/tubular atrophy. Automated measurements through a deep-learning approach could save time and provide more precise data. This work aimed to develop a free tool to automatically obtain kidney histologic prognostic features. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: In total, 241 samples of healthy kidney tissue were split into three independent cohorts. The “Training” cohort (n=65) was used to train two convolutional neural networks: one to detect the cortex and a second to segment the kidney structures. The “Test” cohort (n=50) assessed their performance by comparing manually outlined regions of interest to predicted ones. The “Application” cohort (n=126) compared prognostic histologic data obtained manually or through the algorithm on the basis of the combination of the two convolutional neural networks. RESULTS: In the Test cohort, the networks isolated the cortex and segmented the elements of interest with good performances (>90% of the cortex, healthy tubules, glomeruli, and even globally sclerotic glomeruli were detected). In the Application cohort, the expected and predicted prognostic data were significantly correlated. The correlation coefficients r were 0.85 for glomerular volume, 0.51 for glomerular density, 0.75 for interstitial fibrosis, 0.71 for tubular atrophy, and 0.73 for vascular intimal thickness, respectively. The algorithm had a good ability to predict significant (>25%) tubular atrophy and interstitial fibrosis level (receiver operator characteristic curve with an area under the curve, 0.92 and 0.91, respectively) or a significant vascular luminal stenosis (>50%) (area under the curve, 0.85). CONCLUSION: This freely available tool enables the automated segmentation of kidney tissue to obtain prognostic histologic data in a fast, objective, reliable, and reproducible way.

Supplementary Table 1 from Hypermethylator Phenotype in Sporadic Colon Cancer: Study on a Population-Based Series of 582 Cases

Supplementary Table 2 from Hypermethylator Phenotype in Sporadic Colon Cancer: Study on a Population-Based Series of 582 Cases

Background Although the MEST-C classification is among the best prognostic tools in immunoglobulin A nephropathy (IgAN), it has a wide interobserver variability between specialized pathologists and others. Therefore we trained and evaluated a tool using a neural network to automate the MEST-C grading. Methods Biopsies of patients with IgAN were divided into three independent groups: the Training cohort (n = 42) to train the network, the Test cohort (n = 66) to compare its pixel segmentation to that made by pathologists and the Application cohort (n = 88) to compare the MEST-C scores computed by the network or by pathologists. Results In the Test cohort, >73% of pixels were correctly identified by the network as M, E, S or C. In the Application cohort, the neural network area under the receiver operating characteristics curves were 0.88, 0.91, 0.88, 0.94, 0.96, 0.96 and 0.92 to predict M1, E1, S1, T1, T2, C1 and C2, respectively. The kappa coefficients between pathologists and the network assessments were substantial for E, S, T and C scores (kappa scores of 0.68, 0.79, 0.73 and 0.70, respectively) and moderate for M score (kappa score of 0.52). Network S and T scores were associated with the occurrence of the composite survival endpoint (death, dialysis, transplantation or doubling of serum creatinine) [hazard ratios 9.67 (P = .006) and 7.67 (P Conclusions This work highlights the possibility of automated recognition and quantification of each element of the MEST-C classification using deep learning methods.

Resume Introduction Afin de valider notre strategie d’amelioration continue et chercher d’eventuelles nouvelles pistes pour une performance accrue, nous avons audite l’ensemble des processus du service en utilisant les principes du lean management. Materiel et methodes L’application de la methodologie Lean-6-sigma (Gemba Walk, Value Stream Mapping, diagramme spaghetti, atelier Kaizen et matrice de priorisation) a permis d’analyser les processus des secteurs conventionnels et moleculaires, de definir les goulets d’etranglement, d’evaluer les actions sans valeur ajoutee et de proposer des solutions. Resultats L’audit a identifie les principaux goulets d’etranglement qui interessaient les secteurs pre-analytique (enregistrement), analytique (cytologie, immunohistochimie, sequencage, pathologistes) et post-analytique (absence de secretaire et diffusion du courrier). Il a souligne une marche en avant insuffisante, l’impact important de l’augmentation de la charge de travail (8 %/an) sur la reception et la microscopie malgre l’externalisation et une maquette de postes techniques souvent critique qui ne permettait pas de realiser des taches sans valeur ajoutee (qualite, validation de methodes, protocoles) et parfois quotidiennes (coupes, immunohistochimie). Au terme des 72 tâches du plan d’action pour gerer la surproduction, l’amelioration des conditions de travail et le developpement de nouvelles activites, les delais de reponse sont partiellement maitrises et notre demarche d’automatisation bien avancee. Discussion et conclusion L’audit a valide notre strategie d’amelioration et mieux standardise nos conditions de travail. Meme s’il n’a permis qu’une maitrise partielle des delais de reponse, il a initie une dynamique medicale et technique positive vertueuse pour continuer a avancer vers les prochaines etapes de notre reorganisation (automatisation, agrandissement du service).

Background The recent COVID-19 pandemic has raised concerns about patient diagnosis and follow-up of chronically ill patients. Patients suffering from chronic illnesses, concomitantly infected by SARS-CoV-2, globally tend to have a worse prognosis and poor outcomes. Renal tropism and acute kidney injury following SARS-CoV-2 infection has recently been described in the literature, with elevated mortality rates. Furthermore, patients with pre-existing chronic kidney disease, infected by SARS-CoV-2, should be monitored carefully. Here, we report the case of a 69-year-old patient with splenic marginal zone lymphoma, suffering from longstanding chronic kidney disease following SARS-CoV-2 infection. Case presentation A 69-year-old male patient previously diagnosed with pulmonary embolism and splenic marginal zone lymphoma (Splenomegaly, Matutes 2/5, CD5 negative and CD23 positive), was admitted to the hospital with shortness of breath, fever and asthenia. A nasopharyngeal swab test was performed in addition to a CT-scan, which confirmed SARS-CoV-2 infection. Blood creatinine increased following SARS-CoV-2 infection at 130 μmol/l, with usual values at 95 μmol/l. The patient was discharged at home with rest and symptomatic medical treatment (paracetamol and hydration), then readmitted to the hospital in August 2020. A kidney biopsy was therefore conducted as blood creatinine levels were abnormally elevated. Immunodetection performed in a renal biopsy specimen confirmed co-localization of SARS-CoV2 nucleocapsid and protease 3C proteins with ACE2, Lewis x and sialyl-Lewis x antigens in proximal convoluted tubules and podocytes. Co-localization of structural and non-structural viral proteins clearly demonstrated viral replication in proximal convoluted tubules in this chronically ill patient. Additionally, we observed the co-localization of sialyl-Lewis x and ACE2 receptors in the same proximal convoluted tubules. Reverse Transcriptase-Polymerase Chain Reaction test performed on the kidney biopsy was negative, with very low Ct levels (above 40). The patient was finally readmitted to the haematology department for initiation of chemotherapy, including CHOP protocol and Rituximab. Conclusions Our case emphasizes on the importance of monitoring kidney function in immunosuppressed patients and patients suffering from cancer following SARS-CoV-2 infection, through histological screening. Further studies will be required to decipher the mechanisms underlying chronic kidney disease and the putative role of sialyl-Lewis x and HBGA during SARS-CoV-2 infection.

Systemic sclerosis (SSc) is a multisystem autoimmune fibrosing disease affecting the connective tissue. It particularly affects the skin, notably with skin thickening, but SSc is also characterized by the involvement of many other organs, such as the lungs, the gastrointestinal tract, or the musculoskeletal tissues. One of the most life-threatening situations associated with SSc is scleroderma renal crisis (SRC), which classically associates a hypertensive crisis with oliguric acute kidney injury due to an acute thrombotic microangiopathy.1, 2 In some cases, the diagnosis of this disease can be delayed by atypical presentation such as systemic sclerosis sine scleroderma and/or the presence of rare antibodies. Here we report a case of a histologically confirmed SRC in a patient with systemic sclerosis sine scleroderma and anti-PM/Scl antibodies (Table 1). Table 1 Teaching points

Background The limitations of the assessment of tumor aggressiveness by Prostate Imaging Reporting and Data System (PI-RADS) and biopsies suggest that the diagnostic algorithm could be improved by quantitative measurements in some chosen indications. We assessed the tumor high-risk predictive performance of 3.0 Tesla (3.0T) multiparametric magnetic resonance imaging (mp-MRI) combined with nuclear magnetic resonance spectroscopic sequences (NMR-S) in order to show that the metabolic analysis could bring out an evocative result for the aggressive form of prostate cancer. Methods We conducted a retrospective study of 26 patients (mean age, 62.4 years) who had surgery for prostate cancer between 2009 and 2016 after pre-therapeutic assessment with 3.0T mp-MRI and NMR-S. Groups within the intermediate range of the D'Amico risk classification were divided into two categories, low risk (n=20) and high risk (n=6), according to the International Society of Urological Pathology (ISUP) 2-3 limit. Histoprognostic discordances within various risk groups were compared with the corresponding predictive MRI values. The performance of predictive models was assessed based on sensitivity, specificity, and the area under the curve (AUC) of receiver operating characteristic (ROC) curves. Results After prostatectomy, histological analysis reclassified 18 patients as high-risk, including 16 who were T3 MRI grade, of whom 13 (81.3%) were found to be pT3. Among the patients who had cT1 or cT2 digital rectal examinations, the T3 MRI factor multiplied by 8.7 [odds ratio (OR), 8.7; 95% confidence interval (CI), 1.3-56.2; P=0.024] the relative risk of being pT3 and by 5.8 (OR, 5.8; 95% CI, 0.95-35.7; P=0.05) the relative risk of being pGleason (pGS) > GS-prostate biopsy. Spectroscopic data showed that the choline concentration was significantly higher (P=0.001) in aggressive disease. Conclusions The predictive model of tumor aggressiveness combining mp-MRI plus NMR-S was better than the mp-MRI model alone (AUC, 0.95 vs. 0.86). Information obtained by mp-MRI coupled with spectroscopy may improve the detection of occult aggressive disease, helping in the discrimination of intermediate risks.

In order to validate our strategy of continuous improvement and to identify new ways to increase performance, an evaluation of all the procedures was conducted in our department using the principles of lean management.Lean-6-sigma methodology (Gemba Walk, Value StreamMapping, spaghetti diagram, Kaizen workshop and priorization matrix) was used to analyze the procedures of the conventional and molecular sectors, and to identify bottlenecks, actions without added value and solutions.The audit identified bottlenecks in pre-analytical (registration), analytical (cytology, immunohistochemistry, sequencing, pathologists) and post-analytical processes (absence of secretaries, delivery of reports by mail). It underlined a suboptimal flow of people and materials, the heavy impact of an increasing work load (8%/year) in reception and microscopy even though we had outsourced, and an often critical work place schedule for technicians which prevent them from achieving tasks without added value (quality control, validation of methods and protocols) or even daily tasks (cutting, immunohistochemistry). After completing the 72 actions aimed at managing overproduction, improving working conditions and developing new activities, turn-around time was partially under control and the automation process was well advanced.The audit validated our strategy of continuous improvement and advanced the standardization of our working conditions. Even if the turn-around time for reports was shortened, the audit initiated a positive medical and technical dynamic that should help us to implement the next steps of our reorganization (automation and extension of the department).

Because radical prostatectomy with robot-assisted surgery can lead to unwanted prostatic capsular incisions, capsular incision in normal prostatic tissue (CINPT) is not rare. To study the relationship between positive surgical margins (PSM) and CINPT after robot-assisted radical prostatectomy. From September 2009 to January 2013, 203 consecutive robot-assisted prostatectomies were carried out by the same surgeon. A transperitoneal Montsouris technique was used for all cases, but modified to suit the use of the four-arm DaVinci device. The data were recorded prospectively in our database. Preoperative data were patient’s age, body mass index, prostate-specific antigen level, prostate weight, percentage of positive biopsy, clinical stage, and Gleason score. Postoperative data were preservation of the bladder neck and neurovascular bundles (NVB), the presence of extended pelvic lymph-node dissection (ePLND), pathological stage, Gleason score, margin status, blood loss, and operative room times. The CINPT and no-CINPT groups were analysed and compared retrospectively. The CINPT rates were 23.2 versus 18.2 % for PSM. CINPT contrary to PSM seemed to be more frequent in low-risk prostate cancer. NVB preservation led to more CINPT (p = 0.01). At the multivariate analysis, only the absence of ePLND significantly affected the CINPT status (p = 0.03) and the absence of CINPT positively affected the PSM rate (p = 0.03). Capsular incision in normal prostatic tissue is not a predictive factor of PSM but reflected risk-taking during surgery especially when NVB preservation is indicated in low-risk prostate cancer. It can therefore only be considered a means to evaluate a surgical technique, but not a real predictor of PSM.

Resume La pathologie metastatique de l’estomac est rare. Nous rapportons un cas de metastase gastrique d’un cancer ovarien revelee par une perforation gastro-splenique. La tumeur gastrique secondaire etait apparue 17 ans apres le diagnostic du cancer primitif.

Surgical ligation of a patent ductus arteriosus (PDA) in small premature infants may be performed with open thoracotomy or video-assisted thoracoscopic surgery (VATS). The LigaSure vessel sealing system (Valleylab/Tyco Healthcare, Boulder, CO) is increasingly being used because of its effectiveness in promoting coagulation. Moreover, for PDA ligation using VATS, the LigaSure system seems more practical than vascular clips. Among 81 children, including 43 premature infants weighing less than 1000 grams operated on for PDA in our institution, one 9-month-old boy weighing 7600 grams underwent PDA ligation using a LigaSure grasp. The perioperative aspect of the closed ductus was satisfactory. The following day, however, ultrasound control revealed recanalization of the ductus, and the child had to undergo a second operation. At operation, the ductus wall adventia and media appeared to have retracted to both extremities, leaving the intima exposed and pulsating under the blood pressure. The PDA ligation was repeated, but in conditions of severe hemorrhage. The LigaSure system works by fusing collagen in the tissue. However, because the ductus wall has less collagen than any other vessels in the body, the LigaSure vessel sealing system is not reliable for PDA ligation.

GASTROINTESTINAL STROMAL TUMORS (GISTS) are the most common mesenchymal tumors of the gastrointestinal tract. Type 1 neurofibromatosis (von Recklinghausen disease) is known to be associated with GIST. A 56-year-old man with no previous medical history presented with epigastric pain and anemia. The clinical examination showed multiple subcutaneous nodes in the trunk. The upper gastrointestinal endoscopy revealed two submucosal tumors of 20 and 8 mm in the second part of the duodenum, whichnarrowed the lumen andwas associatedwith 2 additional lesions of less than 1 cm in the third part of the duodenum. Endoscopic ultrasonography confirmed these multiple submucosal duodenal tumorswithout involvement of themucosa.Multiple nonspecific lymph nodes surrounded the duodenum.At biopsy, fusiformcells, suggestingGIST, were found. The colonoscopy was unremarkable, as was the thoracoabdominal CT scan.

International audience; Abstract PURPOSE: To determine whether a relationship exists between the tumor volume (TV) or relative choline content determined using magnetic resonance spectroscopy imaging (MRSI) at 3T and the clinical prognostic parameters for patients with localized prostate cancer (PCa). METHODS AND MATERIALS: A total of 72 men (mean age, 67.8 ± 6.2 years) were stratified as having low-risk (n = 26), intermediate-risk (n = 24), or high-risk (n = 22) PCa. MRSI was performed at 3T using a phased-array coil. Spectra are expressed as the total choline/citrate, total choline plus creatine/citrate, and total choline plus polyamines plus creatine/citrate ratios. The mean ratio of the most pathologic voxels and the MRSI-based TV were also determined. RESULTS: The mean values of the total choline/citrate, total choline plus creatine/citrate, and total choline plus polyamine plus creatine/citrate ratios were greater for Stage T2b or greater tumors vs. Stage T2a or less tumors: 7.53 ± 13.60 vs. 2.31 ± 5.65 (p = .018), 8.98 ± 14.58 vs. 2.56 ± 5.70 (p = .016), and 10.32 ± 15.47 vs. 3.55 ± 6.16 (p = .014), respectively. The mean MRSI-based TV for Stage T2b or greater and Stage T2a or less tumors was significantly different (2.23 ± 2.62 cm(3) vs. 1.26 ± 2.06 cm(3), respectively; p = .030). This TV correlated with increased prostate-specific antigen levels (odds ratio, 1.293; p = .012). Patients with high-risk PCa had a larger TV than did the patients with intermediate-risk PCa. A similar result was found for the intermediate-risk group compared with the low-risk group (odds ratio, 1.225; p = .041). CONCLUSION: Biomarkers expressing the relative choline content and TV were significant parameters for the localization of PCa and could be helpful for determining the prognosis more accurately.

In order to look for a relationship between humoral mechanisms of rejection and chronic allograft dysfunction, plasma cells, C4d deposits and donor-specific antibodies (DSA) were simultaneously sought on serial biopsies of kidney allograft recipients.Ten recipients with chronic dysfunction (G1) and 8 recipients with long-term normal graft function (G2) were included. Biopsies and serums were sampled at early graft dysfunction (T1), between 8months and 2years (T2) and after the third year following transplantation (T3).In G1, plasma cells represented 12.3% (T1), 8.2% (T2) and 14.1% (T3) of mononuclear cells. The mean percentage of plasma cells was 11.6% in G1 versus 0.4% in G2 (p0.05). A progressive rise in C4d deposits was seen in G1, from 25% at T1 to 80% at T3. Donor-specific antibodies were identified in at least one serum sample of 60% of the patients in G1 and 12.5% of the patients in G2 (p=0.012), whereas donor-specific antibodies were eluted from at least one biopsy of 50% of the patients in G1 and 12.5% of the patients in G2 (p=0.03). In G1, C4d deposits were significantly associated with plasma cells (p=0.0012) and anti-HLA Abs in serum samples and/or eluates (p=0.026).This study shows that plasma cells, DSA and C4d are associated in renal transplants developing chronic rejection.

The CpG island methylator phenotype (CIMP) is a distinct phenotype in colorectal cancer, associated with specific clinical, pathologic, and molecular features. However, most of the studies stratified methylation according to two subgroups (CIMP-High versus No-CIMP/CIMP-Low). In our study, we defined three different subgroups of methylation (No-CIMP, CIMP-Low, and CIMP-High) and evaluated the prognostic significance of methylation status on a population-based series of sporadic colon cancers. A total of 582 colon adenocarcinomas were evaluated using methylation-specific PCR for 5 markers (hMLH1, P16, MINT1, MINT2, and MINT31). No-CIMP status was defined as no methylated locus, CIMP-Low status as one to three methylated loci, and CIMP-High status as four or five methylated loci. Clinicopathologic and molecular characteristics were correlated to the methylation status. Crude and relative survival was compared according to methylation status. In the microsatellite-stable (MSS) group, CIMP-High was significantly associated with proximal location (P = 0.011) and BRAF mutation (P < 0.001). KRAS mutations were more associated with CIMP-High and CIMP-Low status (P = 0.008). A shorter 5-year survival was observed in MSS cancer patients with CIMP-Low or CIMP-High status. These results remained significant in multivariate analysis adjusted for age, stage, and BRAF and KRAS mutational status [CIMP-Low: hazard ratio (HR), 1.85; 95% confidence interval (95% CI), 1.37–2.51; CIMP-High, HR, 2.90; 95% CI, 1.53–5.49 compared with No-CIMP]. Within the high-level microsatellite instability group, no difference in survival was observed between the different CIMP groups. Our results show the interest of defining three subgroups of patients according to their methylation status (No-CIMP/CIMP-Low/CIMP-High). Methylation is an independent prognostic factor in MSS colon cancer. [Cancer Res 2008;68(20):8541–6]

Background Emerging data suggest that donor-specific HLA antibodies should be more frequently found onto the transplant itself than in the bloodstream. It is now possible to detect such antibodies in kidney transplant needle biopsy samples by flow cytometry. In order to know if the detection of antibodies into such blind biopsy samples depends of the site of the biopsy, we have studied the distribution of antibodies in both the cortex and medulla of 12 transplants removed after graft loss due to chronic allograft nephropathy, and in 10 controls. Methods Donor-specific HLA antibodies were extracted from the cortex and the medulla of each removed transplant by an acid elution and characterized by Luminex® assays. Results They were found in 58.3% of transplants with chronic allograft nephropathy and never in other kidney samples. The same antibodies were found in the bloodstream at the time of transplantectomy in only 16.6% of the recipients. The distribution between the cortex and medulla was concordant in 75% of cases. However, we observed 2 discrepancies: one in favor of the cortex and one in favor of the medulla. A majority (5/7) transplants with CAN and intra-graft donor-specific antibodies had also C4d deposits along peritubular capillaries. Conclusion Testing for donor-specific HLA antibodies in kidney transplant needle biopsies can be of value provided the biopsy includes both the cortex and the medulla.

Metastatic disease involving the stomach is unusual. We report the case of a gastric metastasis from ovarian cancer revealed by gastro-splenic perforation. The gastric metastasis was diagnosed 17 years after the diagnosis of primary cancer.