Prediction of response to immune checkpoint blockade in patients with metastatic colorectal cancer with microsatellite instability.

BACKGROUND: Mismatch repair-deficient (dMMR) tumors displaying microsatellite instability (MSI) represent a paradigm for the success of immune checkpoint inhibitor (ICI)-based immunotherapy, particularly in patients with metastatic colorectal cancer (mCRC). However, a proportion of patients with dMMR/MSI mCRC exhibit resistance to ICI. Identification of tools predicting MSI mCRC patient response to ICI is required for the design of future strategies further improving this therapy. PATIENTS AND METHODS: We combined high-throughput DNA and RNA sequencing of tumors from 116 patients with MSI mCRC treated with anti-programmed cell death protein 1 ± anti-cytotoxic T-lymphocyte-associated protein 4 of the NIPICOL phase II trial (C1, NCT03350126, discovery set) and the ImmunoMSI prospective cohort (C2, validation set). The DNA/RNA predictors whose status was significantly associated with ICI status of response in C1 were subsequently validated in C2. Primary endpoint was progression-free survival by immune RECIST (iRECIST) (iPFS). RESULTS: Analyses showed no impact of previously suggested DNA/RNA indicators of resistance to ICI, e.g. MSIsensor score, tumor mutational burden, or specific cellular and molecular tumoral contingents. By contrast, iPFS under ICI was shown in C1 and C2 to depend both on a multiplex MSI signature involving the mutations of 19 microsatellites hazard ratio cohort C2 (HRC2) = 3.63; 95% confidence interval (CI) 1.65-7.99; P = 1.4 × 10-3] and the expression of a set of 182 RNA markers with a non-epithelial transforming growth factor beta (TGFB)-related desmoplastic orientation (HRC2 = 1.75; 95% CI 1.03-2.98; P = 0.035). Both DNA and RNA signatures were independently predictive of iPFS. CONCLUSIONS: iPFS in patients with MSI mCRC can be predicted by simply analyzing the mutational status of DNA microsatellite-containing genes in epithelial tumor cells together with non-epithelial TGFB-related desmoplastic RNA markers.

Tumor budding is an independent prognostic factor in stage III colon cancer patients: a post-hoc analysis of the IDEA-France phase III trial (PRODIGE-GERCOR).

BACKGROUND: Histological characteristics at the invasive front may reflect tumor aggressiveness; specifically, tumor budding (Bd) is an emerging prognostic biomarker in colon cancer (CC). We explored further the significance of Bd for risk stratification by evaluating survival of stage III CC patients included in the IDEA-France phase III trial. PATIENTS AND METHODS: This post-hoc study was conducted on tissue slides from 1048 stage III CC patients. Bd was scored by central review by the Bd criteria of the 2016 International Tumor Budding Consensus Conference (ITBCC 2016) and classified as Bd1 (0-4 buds/0.785 mm2), Bd2 (5-9 buds), and Bd3 (≥10 buds) categories. Disease-free survival (DFS) and overall survival (OS) were analyzed by the log-rank test. Clinicopathological features and Immunoscore® were correlated with Bd. RESULTS: Overall, Bd1, Bd2, and Bd3 were observed in 39%, 28%, and 33% of CC, respectively. Bd2 and Bd3 were associated with vascular (P = 0.002) and perineural invasions (P = 0.0009). The 3-year DFS and the 5-year OS rates for Bd (1 versus 2-3) were 79.4% versus 67.2% (P = 0.001) and 89.2% versus 80.8% (P = 0.001), respectively. This was confirmed after adjustment for relevant clinicopathological features for DFS [hazard ratio (HR) 1.41, 95% confidence interval (CI) 1.12-1.77, P = 0.003] and OS (HR 1.65, 95% CI 1.22-2.22, P = 0.001). When combined with pTN stage and Immunoscore® subgroups, Bd significantly improved disease prognostication. CONCLUSIONS: Bd demonstrated its independent prognostic value for DFS and OS. Given these findings, Bd as per the ITBCC 2016 should be mandatory in every pathology report in stage III CC patients. Bd and Immunoscore® could play a complementary role in personalized health care in this setting.

Combining tumor deposits with the number of lymph node metastases to improve the prognostic accuracy in stage III colon cancer: a post hoc analysis of the CALGB/SWOG 80702 phase III study (Alliance)☆.

BACKGROUND: In colon cancer, tumor deposits (TD) are considered in assigning prognosis and staging only in the absence of lymph node metastasis (i.e. stage III pN1c tumors). We aimed to evaluate the prognostic value of the presence and the number of TD in patients with stage III, node-positive colon cancer. PATIENTS AND METHODS: All participants from the CALGB/SWOG 80702 phase III trial were included in this post hoc analysis. Pathology reports were reviewed for the presence and the number of TD, lymphovascular and perineural invasion. Associations with disease-free survival (DFS) and overall survival (OS) were evaluated by multivariable Cox models adjusting for sex, treatment arm, T-stage, N-stage, lymphovascular invasion, perineural invasion and lymph node ratio. RESULTS: Overall, 2028 patients were included with 524 (26%) TD-positive and 1504 (74%) TD-negative tumors. Of the TD-positive patients, 80 (15.4%) were node negative (i.e. pN1c), 239 (46.1%) were pN1a/b (<4 positive lymph nodes) and 200 (38.5%) were pN2 (≥4 positive lymph nodes). The presence of TD was associated with poorer DFS [adjusted hazard ratio (aHR) = 1.63, 95% CI 1.33-1.98] and OS (aHR = 1.59, 95% CI 1.24-2.04). The negative effect of TD was observed for both pN1a/b and pN2 groups. Among TD-positive patients, the number of TD had a linear negative effect on DFS and OS. Combining TD and the number of lymph node metastases, 104 of 1470 (7.1%) pN1 patients were re-staged as pN2, with worse outcomes than patients confirmed as pN1 (3-year DFS rate: 65.4% versus 80.5%, P = 0.0003; 5-year OS rate: 87.9% versus 69.1%, P = <0.0001). DFS was not different between patients re-staged as pN2 and those initially staged as pN2 (3-year DFS rate: 65.4% versus 62.3%, P = 0.4895). CONCLUSION: Combining the number of TD and the number of lymph node metastases improved the prognostication accuracy of tumor-node-metastasis (TNM) staging.

A transcriptomic signature to predict adjuvant gemcitabine sensitivity in pancreatic adenocarcinoma.

BACKGROUND: Chemotherapy is the only systemic treatment approved for pancreatic ductal adenocarcinoma (PDAC), with a selection of regimens based on patients' performance status and expected efficacy. The establishment of a potent stratification associated with chemotherapeutic efficacy could potentially improve prognosis by tailoring treatments. PATIENTS AND METHODS: Concomitant chemosensitivity and genome-wide RNA profiles were carried out on preclinical models (primary cell cultures and patient-derived xenografts) derived from patients with PDAC included in the PaCaOmics program (NCT01692873). The RNA-based stratification was tested in a monocentric cohort and validated in a multicentric cohort, both retrospectively collected from resected PDAC samples (67 and 368 patients, respectively). Forty-three (65%) and 203 (55%) patients received adjuvant gemcitabine in the monocentric and the multicentric cohorts, respectively. The relationships between predicted gemcitabine sensitivity and patients' overall survival (OS) and disease-free survival were investigated. RESULTS: The GemPred RNA signature was derived from preclinical models, defining gemcitabine sensitive PDAC as GemPred+. Among the patients who received gemcitabine in the test and validation cohorts, the GemPred+ patients had a higher OS than GemPred- (P = 0.046 and P = 0.00216). In both cohorts, the GemPred stratification was not associated with OS among patients who did not receive gemcitabine. Among gemcitabine-treated patients, GemPred+ patients had significantly higher OS than the GemPred-: 91.3 months [95% confidence interval (CI): 61.2-not reached] versus 33 months (95% CI: 24-35.2); hazard ratio 0.403 (95% CI: 0.221-0.735, P = 0.00216). The interaction test for gemcitabine and GemPred+ stratification was significant (P = 0.0245). Multivariate analysis in the gemcitabine-treated population retained an independent predictive value. CONCLUSION: The RNA-based GemPred stratification predicts the benefit of adjuvant gemcitabine in PDAC patients.

Prognostic and predictive value of the Immunoscore in stage III colon cancer patients treated with oxaliplatin in the prospective IDEA France PRODIGE-GERCOR cohort study.

BACKGROUND: The Immunoscore (IS), which prognostically classifies stage I-III colon cancer (CC) patients, was evaluated in the International Duration Evaluation of Adjuvant Therapy (IDEA) France cohort study investigating 3 versus 6 months of oxaliplatin-based adjuvant chemotherapy in stage III CC patients. PATIENTS AND METHODS: Densities of CD3+ and CD8+ T cells in the tumor and invasive margin were determined by immunohistochemistry, quantified by digital pathology, and converted to IS. Mismatch repair status was determined by immunohistochemistry or by pentaplex PCR. Prediction of disease-free survival (DFS) by IS was analyzed by a multivariable Cox regression model in each study arm. Harrell's C-statistics were used to investigate the IS performance. RESULTS: Samples of 1322 patients were available. IS Low, Intermediate (Int), and High were observed in 43.6%, 47.0%, and 9.4% of patients, respectively. IS Low identified patients at higher risk of relapse or death compared with Int + High [hazard ratio (HR) = 1.54; 95% confidence interval (CI) 1.24-1.93, P = 0.0001]. The 3-year DFS was 66.80% (95% CI 62.23-70.94) for IS Low and 77.14% (95% CI 73.50-80.35) for IS Int + High. In multivariable analysis, IS remained significantly independently associated with DFS (P = 0.003) when adjusted for sex, histological grade, T/N stage, and microsatellite instability. For mFOLFOX6-treated patients (91.6% of the cohort), a statistical significant interaction was observed for the predictive value of IS for treatment duration (3 versus 6 months) in terms of DFS (P = 0.057). IS Int + High significantly predicted benefit of 6 months of treatment (HR = 0.53; 95% CI 0.37-0.75; P = 0.0004), including clinically low- and high-risk stage III CC (all P < 0.001). Conversely, patients with IS Low (46.4%) did not significantly benefit from the 6-month mFOLFOX6 versus the 3-month mFOLFOX6. CONCLUSIONS: The prognostic value of IS for DFS was confirmed in patients with stage III CC treated with oxaliplatin-based chemotherapy. Its predictive value for DFS benefit of longer duration of mFOLFOX6 adjuvant treatment was found in IS Int + High. These results will be validated in an external independent cohort. CLINICALTRIALS. GOV REGISTRATION: NCT03422601; EudraCT Number: 2009-010384-16.

Prognostic value and characteristics of N1c colorectal cancer.

AIM: The presence of tumour deposits (TDs) in colorectal cancer (CRC) is associated with poor prognosis. The seventh edition of TNM subclassified a new nodal stage, N1c, characterized by the presence of TDs without any concurrent positive lymph node (LN). It is not clear if the N1c category is or is not equal to LN metastasis. We aimed to examine the prevalence, characteristics and prognostic significance of this new subcategory. METHOD: Consecutive patients who underwent surgery for CRC in two centres (2011-2014) were analysed. N1 cM0 patients were matched against non-N1 cM0 (N0, N1a and N1b) patients for 3-year overall survival (OS) and disease-free survival (DFS). RESULTS: We identified 1122 patients with 648 (57.8%) colonic cancers. In 57 patients (5.1%), N1c status was associated with rectal cancers [rectum = 33/57 (57.9%) vs colon = 24/57 (42.1%); P = 0.029], a higher pathological tumour stage [pT3-T4 N1c = 55/843 (6.5% vspT3-T4 non-N1c = 2/279 (0.7%); P < 0.0001] and vascular emboli [n = 35 (61.4%) vs n = 552 (51.8%); P = 0.0305]. Synchronous metastasis was observed in 23 cases (40%). After a mean follow-up of 31 months, 3-year OS for M0 patients, was 89.4%, 89.1%, 86.6% and 81.8% for N0, N1a, N1b and N1c tumours, respectively. DFS was significantly worse for N1c than for N0 (P = 0.0169), with N1c status having a significant effect on DFS in colonic cancers (P = 0.014). The presence of more than one TD was associated with a significantly worse DFS (P = 0.021). CONCLUSION: Our results indicate that N1c CRC patients should be included among high-risk patients for whom it is widely accepted that adjuvant chemotherapy should be considered.

Is the assessment of submucosal invasion still useful in the management of early rectal cancer? A study of 91 consecutive patients.

AIM: The only studies on the prognosis of T1 tumours are old and investigate colic and rectal cancers. Very few studies use Kikuchi's classification (of dividing submucosa into three strata) to evaluate the depth of the submucosal invasion. This study aimed to assess the pathological risk factors for lymph node metastasis (LNM), and the pathological and oncological results of patients with early rectal cancer (ERC, pT1 tumour). METHOD: Between 2000 and 2014, 91 consecutive patients undergoing surgery [primary total mesorectal excision (TME) or local excision (LE) alone, or LE followed by TME] for ERC were included. RESULTS: Eighteen patients underwent LE, 22 underwent LE followed by TME and 51 underwent primary total TME. After TME (n = 73), 16 (23%) patients had LNM. The LNM rate was 15% for Sm1 tumours, 14% for Sm2 tumours and 30% for Sm3 tumours. In multivariate analysis, lymphovascular invasion (P = 0.027) and high tumour budding (P = 0.037) were the only independent factors predictive of LNM. The depth of submucosal invasion was not associated with an increased risk of LNM. After a mean follow up of 56 ± 46 months, 5-year overall survival, specific survival and disease-free survival were, respectively, 82%, 93% and 75%. No significant difference of survival was found according to the depth of submucosal invasion or to the surgical management. CONCLUSION: Histological features seem to be stronger risk factors for LNM than depth of submucosal invasion. Considering the LNM rate, TME should be discussed after LE in terms of one of these pathological criteria.

Para-aortic lymph node sampling in pancreatic head adenocarcinoma.

BACKGROUND: The significance of positive para-aortic nodes in patients with resectable pancreatic carcinoma is unclear. This study sought to evaluate the accuracy of intraoperative detection and prognostic significance of these lymph nodes in patients with resected adenocarcinoma of the pancreatic head. METHODS: From 2000 to 2010, para-aortic node sampling was performed prospectively in all patients before pancreatoduodenectomy. Frozen sections were created and nodes categorized as positive or negative for metastases. Surgeons were blinded to the frozen-section results. This was followed by standard histopathological assessment of corresponding paraffin-embedded, haematoxylin and eosin-stained material. Nodes considered uninvolved by this analysis were examined immunohistochemically for micrometastases. RESULTS: A total of 111 consecutive patients were included, with a median follow-up of 20·8 (range 1·5-126) months. The 1-, 2- and 5-year overall survival (OS) and disease-free survival (DFS) rates were 73·6, 54·0 and 24·7 per cent, and 51·8, 28·1 and 18·8 per cent respectively. Para-aortic node involvement was always associated with peripancreatic lymph node metastasis, and was detected by frozen-section analysis in 12 patients and by haematoxylin and eosin staining in 17. Sensitivity and specificity of frozen-section examination for detecting para-aortic lymph node metastases were 71 and 100 per cent respectively. Median OS for patients with and without para-aortic node involvement on frozen-section analysis was 9·7 versus 28·5 months respectively (P = 0·012), and 15·7 versus 27·2 months (P = 0·050) when assessed by haematoxylin and eosin staining. Median DFS for patients with and without para-aortic node involvement on frozen-section examination was 5·6 versus 12·9 months respectively (P = 0·041), and 8·4 versus 12·9 months (P = 0·038) for haematoxylin and eosin analysis. The presence of micrometastases in para-aortic nodes was not significantly associated with altered OS or DFS. CONCLUSION: Para-aortic node sampling with frozen-section examination detects distant lymphatic involvement reliably. It should be performed systematically. When metastases are found, they should be considered a contraindication to pancreatic resection.

Tumour-infiltrating CD68+ and CD57+ cells predict patient outcome in stage II-III colorectal cancer.

BACKGROUND: The aim of our study was to evaluate the prognostic role of immunological microenvironnement in stage II-III CRC patients. METHODS: We constructed a tissue microarray from 196 consecutive patients with stage II-III CRC and compared CD3, CD4, CD8, CD57, CD68, CXCL9/MIG, CXCL13, and PPARγ immunoreactivity in tumour samples and their matched non-tumour tissue. We assessed their association with relapse-free survival (RFS; primary endpoint) and overall survival (OS) in multivariate Cox models. RESULTS: Low densities of CD57+ and CD68+ tumour-infiltrating cells (TIC) independently predicted worse outcomes. A prognostic score combining CD57 (+, > vs -, ≤2 cells per spot) and CD68 (+, >0 vs -, =0 cells per spot) TIC density discriminated CRC patients at low (CD68+/CD57+), intermediate (CD68+/CD57-), or high (CD68-/CD57-) risk, with hazard ratios for the intermediate-risk and high-risk groups of 2.7 (95% confidence interval (CI): 1.3-5.8) and 9.0 (3.2-25.4) for RFS, and 2.5 (1.2-5.1) and 10.6 (3.8-29.2) for OS, respectively, as compared with the low-risk group. Corresponding 5-year survival rates (95% CI) in the low-, moderate- and high-risk groups were 84% (71-91), 65% (54-74), and 12% (2-47), respectively, for RFS, and 91% (80-96), 76% (66-84), and 25% (7-59), respectively, for OS. CONCLUSION: Tumour CD57+ and CD68+ TIC density assessment independently predicts survival in patients with stage II-III CRC. If validated, our score based on a quick, inexpensive, and well-established method such as point counting on diagnostic tissue sections could be used routinely as a prognostic tool in CRC patients.

Small bowel adenocarcinoma phenotyping, a clinicobiological prognostic study.

BACKGROUND: Small bowel adenocarcinoma (SBA) is a rare tumour with a poor prognosis. Molecular biology data on SBA carcinogenesis are lacking. METHODS: Expression of HER2, ß-catenin, p53 and mismatch repair (MMR) protein was assessed by immunohistochemistry. KRAS, V600E BRAF mutations and microsatellite instability were investigated. RESULTS: We obtained samples from 63 SBA patients (tumour stages: I-II: 30%; III: 35%; IV: 32%; locally advanced: 3%). HER2 overexpression (3+) was observed in 2 out of 62 patients, overexpression of p53 in 26 out of 62, abnormal expression of ß-catenin in 12 out of 61, KRAS mutation in 21 out of 49, BRAF V600E mutation in 1 out of 40 patients, MMR deficiency (dMMR) in 14 out of 61 and was consistent with Lynch syndrome in 9 out of 14 patients. All of the dMMR tumours were in the duodenum or jejunum and only one was stage IV. Median overall survival (OS) was 36.6 months (95% CI, 26.9-72.2). For all patients, in univariate analysis, stages I-II (P<0.001), WHO PS 0-1 (P=0.01) and dMMR phenotype (P=0.02) were significantly associated with longer OS. In multivariate analysis, disease stage (P=0.01) and WHO PS 0-1 (P=0.001) independently predicted longer OS. For stage IV patients, median OS was 20.5 months (95% CI: 14.6; 36.6 months). In multivariate analysis, WHO PS 0-1 (P=0.0001) and mutated KRAS status (P=0.02) independently predicted longer OS. CONCLUSION: This large study suggests that molecular alterations in SBA are closer to those in colorectal cancer (CRC) than those in gastric cancer, with low levels of HER 2 overexpression and high frequencies of KRAS mutations. The seemingly higher frequency of dMMR than in CRC may be explained by the higher frequency of Lynch syndrome in SBA patients. A dMMR phenotype was significantly associated with a non-metastatic tumour (P=0.02). A trend for a good prognosis and a duodenum or jejunum primary site was associated with dMMR.

Trop-2 is a ubiquitous and promising target in pancreatic adenocarcinoma.

BACKGROUND: Trop-2 is overexpressed in tumor cells of various cancers, including pancreatic ductal adenocarcinoma (PDAC), and has emerged as a potent therapeutic target. We evaluated Trop-2 expression both at the transcriptomic and protein levels, and its correlation with tumor features and patients' outcomes in a large cohort of PDAC. METHODS: We included patients undergoing pancreatic resection for PDAC in 5 academic hospitals in France and Belgium. Transcriptomic profiles were obtained from FFPE tissue samples, with paired primary -25and metastatic lesions when available. Protein expression was evaluated by immunohistochemistry (IHC) using tissue micro-arrays. RESULTS: 495 patients (male 54%, median age 63 years) were included between 1996 and 2012. Trop-2 mRNA expression was significantly associated to tumor cellularity, but no association with survival nor with any clinical or pathological features was observed, with tumor cells showing an overall high expression among every subgroup. Trop-2 mRNA expression was maintained between primary and metastatic lesion in all 26 paired samples evaluated. In 50 tumors assessed by IHC, 30%, 68% and 2% harbored a high, medium, or low Trop-2 expression score, respectively. Trop-2 staining was significantly associated to mRNA expression, but not to survival or any pathological features. CONCLUSIONS: Our results suggest Trop-2 overexpression as a ubiquitous marker of PDAC tumor cells and thus a promising therapeutic target to evaluate in these patients.

Contribution of CXCR4 and SMAD4 in predicting disease progression pattern and benefit from adjuvant chemotherapy in resected pancreatic adenocarcinoma.

BACKGROUND: Prognosis of patients with pancreatic adenocarcinoma is poor. Many prognostic biomarkers have been tested, but most studies included heterogeneous patients. We aimed to investigate the prognostic and/or predictive values of four relevant biomarkers in a multicentric cohort of patients. PATIENTS AND METHODS: A total of 471 patients who had resected pancreatic adenocarcinoma were included. Using tissue microarray, we assessed the relationship of biomarker expressions with the overall survival: Smad4, type II TGF-ß receptor, CXCR4, and LKB1. RESULTS: High CXCR4 expression was found to be the only independent negative prognostic biomarker [hazard ratio (HR) = 1.74; P < 0.0001]. In addition, it was significantly associated with a distant relapse pattern (HR = 2.19; P < 0.0001) and was the strongest prognostic factor compared with clinicopathological factors. In patients who did not received adjuvant treatment, there was a trend toward decrease in the overall survival for negative Smad4 expression. Loss of Smad4 expression was not correlated with recurrence pattern but was shown to be predictive for adjuvant chemotherapy (CT) benefit (HR = 0.59; P = 0.002). CONCLUSIONS: CXCR4 is a strong independent prognostic biomarker associated with distant metastatic recurrence and appears as an attractive target to be evaluated in pancreatic adenocarcinoma. Negative SMAD4 expression should be considered as a potential predictor of adjuvant CT benefit.

Unexplained polyposis: a challenge for geneticists, pathologists and gastroenterologists.

Two main colorectal polyposis syndromes have been described, familial adenomatous polyposis and MUTYH-associated polyposis syndromes. Some polyposis remains unexplained: 20% of adenomatous polyposis and serrated polyposis. The aim of this study was to evaluate in a cohort of patients with unexplained polyposis whether a genetic defect could be detected. Individuals presenting polyposis with more than 40 adenomas or more than 20 serrated polyps (hyperplastic, sessile serrated and mixed), without causative mutation identified, were included. Complementary explorations on APC or MUTYH were performed: search for APC mosaicism, splicing-affecting mutations, large genomic rearrangement of MUTYH. Four genes of Wnt pathway (AXIN2, PPP2R1B, WIF1, SFRP1) and two genes of transforming growth factor-ß (TGF-ß) pathway (SMAD4, BMPR1A) were screened for germline mutation. Twenty-five patients had an unexplained adenomatous polyposis (familial or sporadic). Five pathogenic mutations were found: four in APC gene (with one case of mosaicism) and one in BMPR1A gene. The exploration of APC mosaicism was better performed from adenoma DNA with high-resolution melting. The screening of the candidate genes did not find any causative mutation. Thirteen individuals had an unexplained serrated polyposis and a frameshift on SMAD4 gene was identified. All mutations were identified in familial cases of polyposis. After new pathological examination, both BMPR1A and SMAD4 cases were found to be associated with a juvenile polyposis while the polyposis was initially described as adenomatous or undetermined. In 17% (6/38) of the patients the causative mutation of the polyposis was identified. Genetic causes were heterogeneous. Sporadic polyposis patients must be considered as potential APC mosaicism. The histological classification of polyposis is strongly important in direct genetic exploration.

ECCO Position on Harmonisation of Crohn's Disease Mucosal Histopathology.

In inflammatory bowel disease [IBD], mucosal healing is a major therapeutic target and a reliable predictor of clinical course. However, endoscopic mucosal healing is not synonymous with histological healing, and the additional benefits of including histological remission as a target are unclear. In Crohn´s disease [CD], there are few studies highlighting the value of histological remission as a therapeutic target. Histological activity can persist in CD patients who are in endoscopic remission, and the absence of histological activity may be associated with lower relapse rates. Therefore, standardisation of procedures to evaluate CD histological activity is desirable. Topics that would benefit from standardisation and harmonisation include biopsy procedures, biopsy processing techniques, the content of histological scores, and the definitions of histological remission, histological response, and histological activity. In line with these needs, the European Crohn's and Colitis Organisation [ECCO] assembled a consensus group with the objective of developing position statements on CD histology based on published evidence and expert consensus. There was agreement that definitions of histological remission should include absence of erosion, ulceration, and mucosal neutrophils; that the absence of neutrophilic inflammation is an appropriate histological target in CD; that CD histological scores, such as the Global Histological Disease Activity Score, lack formal validation; and that histological scoring systems for ulcerative colitis, including the Geboes Score, Robarts Histopathology Index, and Nancy Histological Index, can be used for scoring intestinal biopsies in CD patients.

Relevance of biopsy-derived pancreatic organoids in the development of efficient transcriptomic signatures to predict adjuvant chemosensitivity in pancreatic cancer.

Pancreatic ductal adenocarcinoma (PDAC) patients are frequently treated by chemotherapy. Even if personalized therapy based on molecular analysis can be performed for some tumors, PDAC regimens selection is still mainly based on patients' performance status and expected efficacy. Therefore, the establishment of molecular predictors of chemotherapeutic efficacy could potentially improve prognosis by tailoring treatments. We have recently developed an RNA-based signature that predicts the efficacy of adjuvant gemcitabine using 38 PDAC primary cell cultures. While demonstrated its efficiency, a significant association with the classical/basal-like PDAC spectrum was observed. We hypothesized that this flaw was due to the basal-like biased phenotype of cellular models used in our strategy. To overcome this limitation, we generated a prospective cohort of 27 consecutive biopsied derived pancreatic organoids (BDPO) and include them in the signature identification strategy. As BDPO's do not have the same biased phenotype as primary cell cultures we expect they can compensate one with each other and cover a broader range of molecular phenotypes. We then obtained an improved signature predicting gemcitabine sensibility that was validated in a cohort of 300 resected PDAC patients that have or have not received adjuvant gemcitabine. We demonstrated a significant association between the improved signature and the overall and disease-free survival in patients predicted as sensitive and treated with adjuvant gemcitabine. We propose then that including BDPO along primary cell cultures represent a powerful strategy that helps to overcome primary cell cultures limitations producing unbiased RNA-based signatures predictive of adjuvant treatments in PDAC.

Discordance between immunochemistry of mismatch repair proteins and molecular testing of microsatellite instability in colorectal cancer.

BACKGROUND: DNA mismatch repair system deficiency (dMMR) is found in 15% of colorectal cancers (CRCs). Two methods are used to determine dMMR, immunohistochemistry (IHC) of MMR proteins and molecular testing of microsatellite instability (MSI). Only studies with a low number of patients have reported rates of discordance between these two methods, ranging from 1% to 10%. MATERIALS AND METHODS: Overall, 3228 consecutive patients with CRCs from two centers were included. Molecular testing was carried out using the Pentaplex panel and IHC evaluated four (MLH1, MSH2, MSH6, and PMS2; cohort 1; n = 1085) or two MMR proteins (MLH1 and MSH2; cohort 2; n = 2143). The primary endpoint was the rate of discordance between MSI and MMR IHC tests. RESULTS: Fifty-one discordant cases (1.6%) were initially observed. Twenty-nine out of 51 discordant cases were related to IHC misclassifications. In cohort 1, after re-reading IHC and/or carrying out new IHC, 16 discordant cases were reclassified as nondiscordant. In cohort 2, after the addition of MSH6/PMS2 IHC and re-examination, 13 were reclassified as nondiscordant. In addition, 10 misclassifications of molecular tests were identified. Finally, only 12 discordant cases (0.4%) remained: 5 were proficient MMR/MSI and 7 were dMMR/microsatellite stable. CONCLUSIONS: Our study confirmed the high degree of concordance between MSI and MMR IHC tests. Discordant cases must be reviewed, and if needed, tests must be repeated and analyzed by an expert team.

[Hereditary gastric cancer]. / Hereditäres Magenkarzinom.

Hereditary diffuse gastric cancer is an autosomal dominant cancer syndrome with approximately 70%-80% penetrance. The cumulative lifetime risk of clinically detected gastric cancer is 63%-83% for women and 40%-67% for men. The average age at diagnosis is 40 years. Approximately 25%-40% of patients carry a germline mutation of the CDH1 gene. This gene encodes the transmembrane protein E-cadherin which plays a central role in cell adhesion and signal transduction. Classified according to Laurén, patients develop multifocal diffuse signet-ring cell carcinoma and, in late stages, linitis plastica. In the foveolar neck region, the site of gastric stem cells, in situ signet-ring cell carcinoma has been identified as a precursor lesion of invasive cancer. Therein, pagetoid spread of tumour cells below the preserved epithelium within the basal membrane represents the characteristic morphology. PAS staining may facilitate detection of tiny lesions.The present article provides detailed information on this cancer syndrome from the point of view of the pathologist as well as the human geneticist, focussing on the multidisciplinary management of affected patients.

Oxaliplatin, 5-Fluorouracil and Nab-paclitaxel as perioperative regimen in patients with resectable gastric adenocarcinoma: A GERCOR phase II study (FOXAGAST).

BACKGROUND: 5-Fluorouracil (5-FU) and platinum-based perioperative chemotherapy is standard of care for resectable gastric adenocarcinoma (RGA). Nanoparticle albumin-bound (Nab-) paclitaxel is active in advanced disease but has never been evaluated in the perioperative setting. The objective was to evaluate the efficacy of Nab-paclitaxel in combination with FOLFOX for RGA patients. METHODS: We performed a non-randomised, open-label, phase II study. RGA patients were assigned to receive neoadjuvant Nab-paclitaxel (150 mg/m2) and FOLFOX q2w for six cycles. Six additional post-operative cycles were kept at the investigator's discretion. The primary end-point was complete pathological response (tumour regression grade [TRG1]) rate. According to Fleming design, 49 patients were required to test H0 (10% TRG1) and H1 (25% TRG1). To reject H0, TRG1 had to be achieved in 8 patients. RESULTS: Forty-nine patients were included. Median number of neoadjuvant chemotherapy cycles was 6 (range, 3-6). Median dose intensity for Nab-paclitaxel, oxaliplatin and 5-FU was 96% (38-103%), 97% (47-103%) and 99% (50-112%), respectively. Surgery could not be performed in 5 (10.2%) patients. Tumour resection was R0 for 42 of 44 (95.5%) patients. Pathological review classified tumours as TRG1 to TRG5 for 8 (16.3%), 11 (22.5%), 4 (8.2%), 18 (36.7%) and 3 (6.1%) patients, respectively. Grade 3 or worse toxicities during neoadjuvant chemotherapy were non-febrile neutropenia (20.4%), nausea (8.2%), diarrhoea (8.2%) and neuropathy (6.1%). Of 44 patients, 14 (31.8%) experienced surgery-related complications and three (6.8%) died of surgical complications. CONCLUSION: This regimen shows promising activity. Toxicity is manageable but a meaningful rate of surgical complications was observed. This strategy deserves investigation in phase III studies.

National multicentric evaluation of quality of pathology reports for rectal cancer in France in 2016.

The quality of pathologic assessment of rectal cancer specimens is crucial for treatment efficiency and survival. The Royal College of Pathologists (RCP) recommends evaluating the quality of the pathology report in routine practice using three quality indicators (QIs): the number of lymph nodes (LNs) analyzed (≥ 12), the rate of venous invasion (VI ≥ 30%), and peritoneal involvement (pT4a ≥ 10%). In this study, we evaluated the three QIs of the French national pathology reports and compared them with British guidelines and assessed the influence of neoadjuvant radiochemotherapy on QIs. From January 1 to December 31, 2016, all pathology reports for rectal adenocarcinoma were collected from French departments. Neoadjuvant radiochemotherapy included long-course radiotherapy with concomitant 5-FU-based chemotherapy. A total of 983 rectal cancer pathology reports were evaluated. A median of 15 LNs were analyzed and 81% of centers had ≥ 12 LNs. The rate of VI was 30% and 41% of centers had ≥ 30% VI. The rate of pT4a was 4% and 18% of centers reported ≥ 10% pT4a. None of the centers reached the threshold for the three QIs. All three QIs were lower after radiochemotherapy compared to surgery alone. In conclusion, in French routine practice, the values of two of the three QIs (LNs analyzed and VI) were globally in line with RCP guidelines. However, the rate of pT4a was very low, particularly after radiochemotherapy, suggesting its low value in rectal cancer.