Wnt/ß-Catenin-Activated Nonpilomatrical Carcinoma of the Skin: A Case Series.

Among skin epithelial tumors, recurrent mutations in the APC/CTNNB1 genes resulting in activation of the Wnt/ß-catenin pathway have been reported predominantly in neoplasms with matrical differentiation. In the present study, we describe the morphologic, immunohistochemical, and genetic features of 16 primary cutaneous carcinomas harboring mutations activating the Wnt/ß-catenin pathway without evidence of matrical differentiation, as well as 4 combined tumors in which a similar Wnt/ß-catenin-activated carcinoma component was associated with Merkel cell carcinoma (MCC) or pilomatrical carcinoma. Among the pure tumor cases, 6 of 16 patients were women with a median age of 80 years (range, 58-98 years). Tumors were located on the head and neck (n = 7, 44%), upper limb (n = 4, 25%), trunk (n = 3, 18%), and leg (n = 2, 13%). Metastatic spread was observed in 4 cases resulting in death from disease in 1 patient. Microscopically, all cases were poorly differentiated neoplasms infiltrating the dermis and/or subcutaneous tissue. In 13 cases, solid "squamoid" areas were associated with a basophilic component characterized by rosette/pseudoglandular formation resulting in a biphasic appearance. Three specimens consisted only of poorly differentiated carcinoma lacking rosette formation. Immunohistochemical studies showed frequent expression of EMA (100%), BerEP4 (100%), cytokeratin 7 (94%), chromogranin A (44%), synaptophysin (82%), and cytokeratin 20 (69%). Complete loss of Rb expression was observed in all but 1 case. Nuclear ß-catenin and CDX2 expressions were detected in all cases. Recurrent pathogenic somatic mutations were observed in APC (60%), CTNNB1 (40%), and RB1 (n = 47%). Global methylation analysis confirmed that cases with rosette formation constituted a homogeneous tumor group distinct from established skin tumor entities (pilomatrical carcinoma, MCC, and squamous cell carcinoma), although the 3 other cases lacking such morphologic features did not. In addition, we identified 4 combined neoplasms in which there was a component showing a similar poorly differentiated rosette-forming carcinoma demonstrating Rb loss and ß-catenin activation associated with either MCC (n = 3) or pilomatrical carcinoma (n = 1). In conclusion, we describe a distinctive neoplasm, for which we propose the term "Wnt/ß-catenin-activated rosette-forming carcinoma," morphologically characterized by the association of rosette formation, squamous and/or neuroendocrine differentiation, diffuse CDX2 expression, Rb loss, and mutations in CTNNB1/APC genes.

Management of Pathogenic CDH1 Variant Carriers Within the FREGAT Network: A Multicentric Retrospective Study.

OBJECTIVE: To describe the management of pathogenic CDH1 variant carriers (pCDH1vc) within the FREGAT (FRench Eso-GAsTric tumor) network. Primary objective focused on clinical outcomes and pathological findings, Secondary objective was to identify risk factor predicting postoperative morbidity (POM). BACKGROUND: Prophylactic total gastrectomy (PTG) remains the recommended option for gastric cancer risk management in pCDH1vc with, however, endoscopic surveillance as an alternative. METHODS: A retrospective observational multicenter study was carried out between 2003 and 2021. Data were reported as median (interquartile range) or as counts (proportion). Usual tests were used for univariate analysis. Risk factors of overall and severe POM (ie, Clavien-Dindo grade 3 or more) were identified with a binary logistic regression. RESULTS: A total of 99 patients including 14 index cases were reported from 11 centers. Median survival among index cases was 12.0 (7.6-16.4) months with most of them having peritoneal carcinomatosis at diagnosis (71.4%). Among the remaining 85 patients, 77 underwent a PTG [median age=34.6 (23.7-46.2), American Society of Anesthesiologists score 1: 75%] mostly via a minimally invasive approach (51.9%). POM rate was 37.7% including 20.8% of severe POM, with age 40 years and above and low-volume centers as predictors ( P =0.030 and 0.038). After PTG, the cancer rate on specimen was 54.5% (n=42, all pT1a) of which 59.5% had no cancer detected on preoperative endoscopy (n=25). CONCLUSIONS: Among pCDH1vc, index cases carry a dismal prognosis. The risk of cancer among patients undergoing PTG remained high and unpredictable and has to be balanced with the morbidity and functional consequence of PTG.

Tissue cholesterol metabolism and prostate cancer aggressiveness: Ethno-geographic variations.

BACKGROUND: Prostate cancer (PCa) is more frequent and more aggressive in populations of African descent than in Caucasians. Since the fatty acid composition of peri-prostatic adipose tissue (PPAT) has been shown to differ according to the ethno-geographic origin and is involved in PCa aggressiveness, we aimed to analyze the cholesterol content of PPAT from Caucasian and African-Caribbean patients, in correlation with markers of disease aggressiveness and cholesterol metabolism in cancer tissues. METHODS: The quantification of cholesterol in PPAT was analyzed in 52 Caucasian and 52 African-Caribbean PCa patients, with in each group 26 indolent tumors (ISUP Group1 and pT2) and 26 potentially aggressive tumors (ISUP Group 3-5 and/or pT3). The expression of proteins involved in cholesterol metabolism was analyzed by immunohistochemistry on cancer tissue samples included in tissue microarrays. RESULTS: The amount of cholesterol esters was lower in PPAT from African-Caribbean patients compared with Caucasians, without any correlation with markers of disease aggressiveness. In cancer tissues from African-Caribbean patients, the expression of ABCA1 (involved in cholesterol efflux) was decreased, and that of SREBP-2 (involved in cholesterol uptake) was increased. In both groups of patients, SREBP-2 expression was strongly associated with that of Zeb1, a key player in the epithelial-to-mesenchymal transition (EMT) process. CONCLUSION: These results suggest that cholesterol metabolism differs according to the ethno-geographic origin, in both PPAT and cancer tissues. In African-Caribbeans, the orientation towards accumulation of cholesterol in cancer cells is associated with a more frequent state of EMT, which may promote PCa aggressiveness in this population.

Upfront immunohistochemistry improves specificity of Helicobacter pylori diagnosis. A French pathology laboratory point of view.

BACKGROUND: There is no consensus about the histopathologic methods to detect Helicobacter pylori in gastric biopsies to date. We aimed to question about the value of upfront anti-H. pylori immunohistochemistry in this field. MATERIAL AND METHODS: We led a retrospective study about the rate of H. pylori-positive gastric biopsies before and after the implementation of upfront immunohistochemistry, the inter-rater and intermethods agreements in H. pylori identification about Hematoxylin-Eosin Saffron (HES), Giemsa, and immunohistochemistry stains and the histopathologic features associated with low amounts of H. pylori. RESULTS: First, the rate of H. pylori-positive gastric biopsies significantly diminished after the implementation of upfront immunohistochemistry (from 21.15% to 12.56%, P<.0001), suggesting potential overdiagnosis of H. pylori infection before the use of immunohistochemistry. Secondly, immunohistochemistry was the most reproducible and performing stain (kappa values >0.80), but HES and Giemsa stains also presented good-to-very good agreements. Finally, less than 1% of gastric biopsies with inconspicuous H. pylori infection showed no mucosal injury pointing out that any HES-detected mucosal injury could help to preselect the gastric biopsies requiring ancillary stains for the detection of H. pylori. CONCLUSIONS: Albeit being considered as a gold standard in the detection of H. pylori, the interest of using immunohistochemistry as an upfront stain on gastric biopsies is still debated. In our opinion, its use in second line in case of ambiguous HE/HES-Giemsa result is more appropriate. Further effort is needed to optimize the inexpensive but feasible HE/HES-based detection of H. pylori.

B cells display an abnormal distribution and an impaired suppressive function in patients with chronic antibody-mediated rejection.

In kidney transplantation, the composition of the B-cell compartment is increasingly identified as an important determinant for graft outcome. Whereas naive and transitional B cells have been associated with long-term allograft survival and operational tolerance, memory B cells have been linked to graft rejection and graft loss. Chronic antibody-mediated rejection now represents a major complication in transplantation and is a challenge in current therapeutics. Here, we show that patients with chronic antibody-mediated rejection display a unique B-cell phenotype with a reduced ratio of activated to memory B cells associated with an impaired immunosuppressive activity. The regulatory functions of the B cells depended on their maturation status. Thus, phenotypic and functional analyses of the B-cell compartment may be indicated for appropriate follow-up after transplantation and drive therapy in the establishment of transplant tolerance processes.

Adult-onset eculizumab-resistant hemolytic uremic syndrome associated with cobalamin C deficiency.

A 20-year-old man was hospitalized for malignant hypertension, mechanical hemolysis, and kidney failure. Kidney biopsy confirmed glomerular and arteriolar thrombotic microangiopathy. Etiologic analyses, which included ADAMTS13 activity, stool culture, complement factor proteins (C3, C4, factor H, factor I, and MCP [membrane cofactor protein]), anti-factor H antibodies, HIV (human immunodeficiency virus) serology, and antinuclear and antiphospholipid antibodies, returned normal results. Malignant hypertension was diagnosed. Ten months later, we observed a relapse of acute kidney injury and mechanical hemolysis. Considering a diagnosis of complement dysregulation-related atypical hemolytic uremic syndrome (HUS), we began treatment with eculizumab. Despite the efficient complement blockade, the patient's kidney function continued to decline. We performed additional analyses and found that the patient's homocysteine levels were dramatically increased, with no vitamin B12 (cobalamin) or folate deficiencies. We observed very low plasma methionine levels associated with methylmalonic aciduria, which suggested cobalamin C disease. We stopped the eculizumab infusions and initiated specific treatment, which resulted in complete cessation of hemolysis. MMACHC (methylmalonic aciduria and homocystinuria type C protein) sequencing revealed compound heterozygosity for 2 causative mutations. To our knowledge, this is the first report of adult-onset cobalamin C-related HUS. Considering the wide availability and low cost of the homocysteine assay, we suggest that it be included in the diagnostic algorithm for adult patients who present with HUS.

Reproducibility in PD-L1 Immunohistochemistry Quantification through the Tumor Proportion Score and the Combined Positive Score: Could Dual Immunostaining Help Pathologists?

We studied the pathologists' agreements in quantifying PD-L1 expression through the tumor proportion score (TPS) and the combined positive score (CPS) using single PD-L1 immunohistochemistry (S-IHC) and double immunohistochemistry (D-IHC) combining PD-L1 staining and tumor cell markers. S-IHC and D-IHC were applied to 15 cancer samples to generate 60 digital IHC slides (30 whole slides images and 30 regions of interest of 1 mm2) for PD-L1 expression quantification using both TPS and CPS, twice by four pathologists. Agreements were estimated calculating intraclass correlation coefficients (ICC). Both S-IHC and D-IHC slides analyses resulted in excellent (for TPS, ICC > 0.9) to good (for CPS, ICC > 0.75) inter- and intra-pathologist agreements with slightly higher ICC with D-IHC than with S-IHC. S-IHC resulted in higher TPS and CPS than D-IHC (+5.6 and +6.1 mean differences, respectively). High reproducibility in the quantification of PD-L1 expression is attainable using S-IHC and D-IHC.

Optimal PSA density threshold and predictive factors for the detection of clinically significant prostate cancer in patient with a PI-RADS 3 lesion on MRI.

INTRODUCTION: While Prostate Imaging Reporting and Data System (PI-RADS) 4 and 5 lesions usually justify prostate biopsy (PBx), the management of a PI-RADS 3 lesion can be discussed. The aim of our study was to determine the optimal prostate-specific antigen density (PSAD) threshold and predictive factors of clinically significant prostate cancer (csPCa) in patients with a PI-RADS 3 lesion on MRI. PATIENTS AND METHODS: Using our prospectively maintained database, we conducted a monocentric retrospective study, including all patients with a clinical suspicious of prostate cancer (PCa), all of them had a PI-RADS 3 lesion on the mpMRI prior to PBx. Patients under active surveillance or displaying suspicious digital rectal examination were excluded. Clinically significant (csPCa) was defined as PCa with any ISUP grade group ≥ 2 (Gleason ≥ 3 + 4). RESULTS: We included 158 patients. The detection rate of csPCa was 22.2%. In case of PSAD ≤ 0.15 ng/ml/cm3, PBx would be omitted in 71.5% (113/158) of men at the cost of missing 15.0% (17/113) of csPCa. With a threshold of 0.15 ng/ml/cm3, the sensitivity and the specificity were 0.51 and 0.78 respectively. The positive predictive value was 0.40 and the negative predictive value was 0.85. According to multivariate analysis, age (OR = 1.10, CI95% 1.03-1.19, P = 0.007), and PSAD ≥ 0.15 ng/ml/cm3 (OR = 3.59, CI95% 1.41-9.47, P = 0.008) were independent predictive factors of csPCa. Previous negative PBx was negatively associated with csPCa (OR = 0.24, CI 95% 0.07-0.66, P = 0.01). CONCLUSION: Our result suggests that the optimal PSAD threshold was 0.15 ng/ml/cm3. However, in this case omitting PBx in 71.5% of cases would be at the cost of missing 15.0% of csPCa. PSAD should not be used alone, other predictive factors as age and PBx history should also be considered in the discussion with the patient, to avoid PBx while missing few csPCa.

Prognostic value of pre-therapeutic FDG-PET radiomic analysis in gastro-esophageal junction cancer.

The main aim of this study was to evaluate the prognostic value of radiomic approach in pre-therapeutic 18F-fluorodeoxyglucose positron-emission tomography (FDG-PET/CT) in a large cohort of patients with gastro-esophageal junction cancer (GEJC). This was a retrospective monocenter study including 97 consecutive patients with GEJC who underwent a pre-therapeutic FDG-PET and were followed up for 3 years. Standard first-order radiomic PET indices including SUVmax, SUVmean, SUVpeak, MTV and TLG and 32 textural features (TFs) were calculated using LIFEx software on PET imaging. Prognostic significance of these parameters was assessed in univariate and multivariate analysis. Relapse-free survival (RFS) and overall survival (OS) were respectively chosen as primary and secondary endpoints. An internal validation cohort was used by randomly drawing one-third of included patients. The main characteristics of this cohort were: median age of 65 years [41-88], sex ratio H/F = 83/14, 81.5% of patients with a histopathology of adenocarcinoma and 43.3% with a stage IV disease. The median follow-up was 28.5 months [4.2-108.5]. Seventy-seven (79.4%) patients had locoregional or distant progression or recurrence and 71 (73.2%) died. In univariate analysis, SUVmean, Histogram-Entropy and 2 TFs (GLCM-Homogeneity and GLCM-Energy) were significantly correlated with RFS and OS, as well as 2 others TFs (GLRLM-LRE and GLRLM-GLNU) with OS only. In multivariate analysis, Histogram-Entropy remained an independent prognostic factor of both RFS and OS whereas SUVmean was an independent prognostic factor of OS only. These results were partially confirmed in our internal validation cohort of 33 patients. Our results suggest that radiomic approach reveals independent prognostic factors for survival in patients with GEJC.

BCAR1 expression improves prediction of biochemical reccurence after radical prostatectomy.

BACKGROUND: Because prostate cancer exhibits a great variability in clinical outcome, biomarkers that can be used in daily practice are needed to better stratify patients into prognostic groups. Since steroid hormones play a central role in the development and progression of prostate cancer, we aimed to analyze in a matched nested case-control study the value of molecules involved in steroid signaling, to predict recurrence after radical prostatectomy, independently from standard prognostic tools. METHODS: Among 1,200 patients treated by radical prostatectomy with negative margins with at least 4 years follow-up, 121 prostate cancers with biochemical relapse were matched after pathological reassessment with 121 cancers with identical clinicopathological features but without relapse. Immunohistochemistry was performed on tissue microarrays, using antibodies directed against molecules involved in androgen and estrogen signaling, including hormone receptors, enzymes (such as the five alpha reductases 1,2 and 3, aromatase, alpha-keto reductase 1C3 and squalene epoxidase), the breast cancer antiestrogen resistance 1 (BCAR1), and the proliferation marker Ki67. RESULTS: The median follow-up for patients without recurrence was 7 years. Both cell proliferation and BCAR1 expression were significantly associated with biochemical relapse, in univariate and multivariate analysis. In subgroup analysis, the sole predictive marker in patients with well-differentiated prostate cancer was BCAR1 (P = 0.004), whereas only proliferation (P = 0.001) was significantly associated with relapse in less-differentiated prostate cancer patients. CONCLUSIONS: BCAR1 is an independent predictor of recurrence after radical prostatectomy for "low risk" prostate cancer. The use of this biomarker may enable more individualized treatment approaches.

Impact of Multiparametric MRI and PSA Density on the Initial Indication or the Maintaining in Active Surveillance During Follow-Up in low-Risk Prostate Cancer.

INTRODUCTION: A greater selection of candidates for active surveillance (AS) of prostate cancer (PCa) may decrease the rate of delayed treatment. We aimed to study: 1) the impact of MRI and PSA density (PSAd) at baseline on the final status, and 2) the impact of bio-clinical features during the follow-up on pursuing AS. MATERIALS AND METHODS: This retrospective, monocentric study between June 2013 and July 2020, included 99 patients in AS (median follow-up: 19 months [18-92]). All MRI were reviewed by a single radiologist. Lost to follow-up were 17 patients and 6 patients chose treatment by themselves. Treatment was proposed in case of upgrading (≥ GG2) or increasing PCa volume. RESULTS: Impact of MRI and PSAd at baseline:  Combining PSAd ≤ 0.15 and PIRADS ≤ 3, the probability to remain in AS was 72%. This rate reached 83% when PSAd ≤ 0.10 was associated to normal MRI.  During follow-up:  One hundred fifty-seven prostatic biopsies (PBx) were performed and 38 (24%) found PCa upgrading. The association between negative MRI and PSAd ≤ 0.10, during follow-up, had an excellent NPV to predict treatment (95%). This combination concerned 25% (37/151) of surveillance biopsies that could have been avoided at the cost of delaying upgrading in 3% (1/37). In multivariate analysis, only PIRADS ≥ 4 before PBx was associated to a risk of treatment during follow-up (OR, 10.4 [95% CI, 4.2-25.8]; P < .0001). CONCLUSION: Using PSAd and MRI at baseline to select patients showed excellent performances to predict the maintenance in AS. During follow-up, MRI PIRADS ≥ 4 was associated to an increased risk of treatment.

MiR-31-3p do not predict anti-EGFR efficacy in first-line therapy of RAS wild-type metastatic right-sided colon cancer.

BACKGROUND: Low miR-31-3p expression was identified as predictive of anti-EGFR efficacy in RAS-wt mCRC. Primary tumor side was also proposed as a predictive factor of anti-EGFR benefit. This retrospective multicentric study evaluated the predictive role of miR-31-3p in right-sided RAS-wt mCRC patients treated with first-line CT+anti-EGFR or CT+bevacizumab (Beva). METHODS: Seventy-two right-sided RAS-wt mCRC patients treated in first-line with CT+anti-EGFR (n = 43) or Beva (n = 29) were included. Overall survival (OS), progression-free survival (PFS) and response rate (RR) were analyzed and stratified according to tumor miR-31-3p expression level and targeted therapy (TT). RESULTS: BRAF V600E mutation was more frequent in high vs low miR-31-3p expressers (60.6% vs 15.4%, P < 0.001). PFS was significantly longer with CT+Beva than with CT+anti-EGFR (13 vs 7 months; P = 0.024). Among low miR-31-3p expressers, PFS, OS and RR were not significantly different between the two groups, while in high miR-31-3p expressers, only PFS was longer in the CT+Beva group (11 vs 6 months; P = 0.03). In patients treated with CT+anti-EGFR, low miR-31-3p expressers had a significantly longer OS (20 vs 13 months; P = 0.02) than high miR-31-3p expressers. ORR was not significantly different between the two groups of treatment, in both low and high miR-31-3p expressers. MiR-31-3p expression status was statistically correlated between primary tumors and corresponding metastases. CONCLUSION: In this study, miR-31-3p couldn't identify a subgroup of patients with right-sided RAS-wt mCRC who might benefit from anti-EGFR and suggest that Beva is the TT of choice in first-line treatment of these patients.

Fluorescent In Situ Hybridization Must be Preferred to pan-TRK Immunohistochemistry to Diagnose NTRK3-rearranged Gastrointestinal Stromal Tumors (GIST).

Tyrosine kinase inhibitors have revolutionized the treatment of patients with gastrointestinal stromal tumors (GISTs). Nevertheless, some GISTs do not contain any targetable KIT or PDGFRA mutations classically encountered in this field. Novel approved therapies targeting TRK chimeric proteins products of NTRK genes fusions consist in a promising approach to treat some patients with GISTs lacking any identified driver oncogenic mutation in KIT, PDGFRA or BRAF genes. Thus, an adequate testing strategy permitting to diagnose the rare NTRK-rearranged GISTs is required. In this work, we studied about the performances of pan-TRK immunohistochemistry (IHC) and NTRK1/2/3 fluorescent in situ hybridization in a series of 39 GISTs samples. Among 22 patients with GISTs lacking KIT or PDGFRA mutations, BRAFV600E IHC permitted to diagnose 2/22 (9%) BRAFV600E-mutated GISTs and, among the 20 KIT, PDGFRA, and BRAF wild type tumors, 1/20 (5%), NTRK3-rearranged tumor was diagnosed using NTRK3 fluorescent in situ hybridization. Pan-TRK IHC using EPR17341 and A7H6R clones was negative in this NTRK3-rearranged sample. Pan-TRK IHC was frequently positive in NTRK not rearranged tumors without (24 samples analyzed) or with (15 samples analyzed) KIT or PDGFRA mutations with major discrepancies between the 2 IHC clones (intraclass correlation coefficient of 0.3042). Given the new therapeutic opportunity offered by anti-TRK targeted therapies to treat patients with advanced cancers including GISTs, it is worth to extend molecular analysis to NTRK fusions testing in KIT, PDGFRA, and BRAF wild type GISTs. Pan-TRK IHC appears not relevant in this field but performing a simple NTRK3 fluorescent in situ hybridization test consists in a valuable approach to identify the rare NTRK3-rearranged GISTs treatable using anti-TRK therapies.

MSI-High RAS-BRAF wild-type colorectal adenocarcinomas with MLH1 loss have a high frequency of targetable oncogenic gene fusions whose diagnoses are feasible using methods easy-to-implement in pathology laboratories.

Targetable kinase fusions are extremely rare (<1%) in colorectal cancers (CRCs), making their diagnosis challenging and often underinvestigated. They have been shown particularly frequently among MSI-High, BRAF/KRAS/NRAS wild-type CRCs with MLH1 loss (MLH1loss MSI-High wild-type). We searched for NTRK1, NTRK2, NTRK3, ALK, ROS1, BRAF, RET, and NRG1 kinase fusions in CRCs using methods easy-to-implement in pathology laboratories: immunohistochemistry (IHC), fluorescent in situ hybridization (FISH), and fully automated real-time PCR targeted analyses. RNA-sequencing analyses were used for confirmation. Among 84 selected MLH1 deficient (IHC) CRCs cases, MLH1loss MSI-High wild-type CRCs consisted first in 19 cases after Idylla™ analyses and finally in 18 cases (21%) after RNA-sequencing (detection of one additional KRASG12D mutation). FISH (and when relevant, IHC) analyses concluded in 5 NTRK1, 3 NTRK3, 1 ALK, 2 BRAF, and 2 RET FISH positive tumors. ALK and NTRK1 rearranged tumors were IHC positive, but pan-TRK IHC was negative in the 3 NTRK3 FISH positive tumors. RNA-sequencing analyses confirmed 12 of 13 fusions with only one false positive RET FISH result. Finally, 12/18 (67%) of MLH1loss MSI-High wild-type CRCs contained targetable kinase fusions. Our study demonstrates the feasibility, but also the cost-effectiveness, of a multistep but rapid diagnostic strategy based on nonsequencing methods to identify rare and targetable kinase fusions in patients with advanced CRCs, as well as the high prevalence of these kinase fusions in MLH1loss MSI-High wild-type CRCs. Nevertheless, confirmatory RNA-sequencing analyses are necessary in case of low FISH positive nuclei percentage to rule out FISH false-positive results.

Development of a Radiomic-Based Model Predicting Lymph Node Involvement in Prostate Cancer Patients.

Significant advances in lymph node involvement (LNI) risk modeling in prostate cancer (PCa) have been achieved with the addition of visual interpretation of magnetic resonance imaging (MRI) data, but it is likely that quantitative analysis could further improve prediction models. In this study, we aimed to develop and internally validate a novel LNI risk prediction model based on radiomic features extracted from preoperative multimodal MRI. All patients who underwent a preoperative MRI and radical prostatectomy with extensive lymph node dissection were retrospectively included in a single institution. Patients were randomly divided into the training (60%) and testing (40%) sets. Radiomic features were extracted from the index tumor volumes, delineated on the apparent diffusion coefficient corrected map and the T2 sequences. A ComBat harmonization method was applied to account for inter-site heterogeneity. A prediction model was trained using a neural network approach (Multilayer Perceptron Network, SPSS v24.0©) combining clinical, radiomic and all features. It was then evaluated on the testing set and compared to the current available models using the Receiver Operative Characteristics and the C-Index. Two hundred and eighty patients were included, with a median age of 65.2 y (45.3-79.6), a mean PSA level of 9.5 ng/mL (1.04-63.0) and 79.6% of ISUP ≥ 2 tumors. LNI occurred in 51 patients (18.2%), with a median number of extracted nodes of 15 (10-19). In the testing set, with their respective cutoffs applied, the Partin, Roach, Yale, MSKCC, Briganti 2012 and 2017 models resulted in a C-Index of 0.71, 0.66, 0.55, 0.67, 0.65 and 0.73, respectively, while our proposed combined model resulted in a C-Index of 0.89 in the testing set. Radiomic features extracted from the preoperative MRI scans and combined with clinical features through a neural network seem to provide added predictive performance compared to state of the art models regarding LNI risk prediction in PCa.

Nationwide incidence of sarcomas and connective tissue tumors of intermediate malignancy over four years using an expert pathology review network.

BACKGROUND: Since 2010, nationwide networks of reference centers for sarcomas (RREPS/NETSARC/RESOS) collected and prospectively reviewed all cases of sarcomas and connective tumors of intermediate malignancy (TIM) in France. METHODS: The nationwide incidence of sarcoma or TIM (2013-2016) was measured using the 2013 WHO classification and confirmed by a second independent review by expert pathologists. Simple clinical characteristics, yearly variations and correlation of incidence with published clinical trials are presented and analyzed. RESULTS: Over 150 different histological subtypes are reported from the 25172 patients with sarcomas (n = 18712, 74,3%) or TIM (n = 6460, 25.7%), with n = 5838, n = 6153, n = 6654, and n = 6527 yearly cases from 2013 to 2016. Over these 4 years, the yearly incidence of sarcomas and TIM was therefore 70.7 and 24.4 respectively, with a combined incidence of 95.1/106/year, higher than previously reported. GIST, liposarcoma, leiomyosarcomas, undifferentiated sarcomas represented 13%, 13%, 11% and 11% of tumors. Only GIST, as a single entity had a yearly incidence above 10/106/year. There were respectively 30, 64 and 66 different histological subtypes of sarcomas or TIM with an incidence ranging from 10 to 1/106, 1-0.1/106, or < 0.1/106/year respectively. The 2 latter incidence groups represented 21% of the patients with 130 histotypes. Published phase III and phase II clinical trials (p<10-6) are significantly higher with sarcomas subtypes with an incidence above 1/106 per. CONCLUSIONS: This nationwide registry of sarcoma patients, with exhaustive histology review by sarcoma experts, shows that the incidence of sarcoma and TIM is higher than reported, and that tumors with a very low incidence (1<106/year) are less likely to be included in clinical trials.

Evaluation of KRAS, NRAS and BRAF mutational status and microsatellite instability in early colorectal carcinomas invading the submucosa (pT1): towards an in-house molecular prognostication for pathologists?

AIM: We aimed to study the prognostic value of KRAS, NRAS, BRAF mutations and microsatellite stable (MSS)/instable (MSI) in the field of colorectal cancer invading the submucosa (ie, pT1 colorectal cancer (CRC)). METHODS: We led a case-control study in tumour samples from 60 patients with pT1 CRC with (20 cases) and without (40 cases) metastatic evolution (5 years of follow-up) which were analysed for KRAS, NRAS, BRAF mutations (Idylla testing and next generation sequencing, NGS) and MSS/MSI status (Idylla testing and expression of mismatch repair (MMR) proteins using immunohistochemistry). RESULTS: KRAS mutations were encountered in 11/20 (55%) cases and 21/40 (52.5%) controls (OR=1.11 (0.38 to 3.25), p=0.8548), NRAS mutations in 1/20 (5%) cases and 3/40 (7.5%) controls (OR=3.08 (0.62 to 15.39), p=0.1698) and BRAF mutations in 3/20 (15%) cases and 6/40 (15%) controls (OR=1.00 (0.22 to 4.5), p=1.00). A MSI status was diagnosed in 3/20 (15%) cases and 5/40 (12.5%) controls (OR=1.2353 (0.26 to 5.79), p=0.7885). Beyond the absence of significant association between the metastatic evolution and any of the studied molecular parameters, we observed a very good agreement between methods analysing KRAS, NRAS and BRAF mutations (Kappa value of 0.849 (0.748 to 0.95) between Idylla and NGS) and MSS/MSI (Idylla)-proficient MMR/deficient MMR (immunohistochemistry) status (Kappa value of 1.00). CONCLUSION: Although being feasible using the fully automated Idylla method as well as NGS, the molecular testing of KRAS, NRAS, BRAF and MSS/MSI status does not seem useful for prognostic purpose in the field of pT1 CRC.