Search

© 2022 The Authors; Published by the American Association for Cancer Research. This open access article is distributed under Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 International (CC BY-NC-ND), Purpose: Cetuximab is an EGFR-targeted therapy approved for the treatment of RAS wild-type (WT) metastatic colorectal cancer (mCRC). However, about 60% of these patients show innate resistance to cetuximab. To increase cetuximab efficacy, it is crucial to successfully identify responder patients, as well as to develop new therapeutic approaches to overcome cetuximab resistance. Experimental design: We evaluated the value of EGFR effector phospholipase C gamma 1 (PLCγ1) in predicting cetuximab responses, by analyzing progression-free survival (PFS) of a multicentric retrospective cohort of 94 treated patients with mCRC (log-rank test and Cox regression model). Furthermore, we used in vitro and zebrafish xenotransplant models to identify and target the mechanism behind PLCγ1-mediated resistance to cetuximab. Results: In this study, levels of PLCγ1 were found increased in RAS WT tumors and were able to predict cetuximab responses in clinical samples and in vitro and in vivo models. Mechanistically, PLCγ1 expression was found to bypass cetuximab-dependent EGFR inhibition by activating ERK and AKT pathways. This novel resistance mechanism involves a noncatalytic role of PLCγ1 SH2 tandem domains in the propagation of downstream signaling via SH2-containing protein tyrosine phosphatase 2 (SHP2). Accordingly, SHP2 inhibition sensitizes PLCγ1-resistant cells to cetuximab. Conclusions: Our discoveries reveal the potential of PLCγ1 as a predictive biomarker for cetuximab responses and suggest an alternative therapeutic approach to circumvent PLCγ1-mediated resistance to cetuximab in patients with RAS WT mCRC. In this way, this work contributes to the development of novel strategies in the medical management and treatment of patients with mCRC., M. Martins' research was supported by Liga Portuguesa Contra o Cancro (LPCC): Terry Fox Fundation; Investigador FCT- Fundação para a Ciência e Technologia (IF/00409/2014) and IMM Bridge grant; RC-D research was supported by Fundação para a Ciência e Technologia (SFRH/BD/139138/2018). A. Fernandes was supported by LPCC-IMM BIOBANK; R. Fior was supported by Champalimaud Foundation and L. Costa was supported by Merck Serono.

Introduction Many diseases can imitate inflammatory bowel disease [IBD] clinically and pathologically. This review outlines the differential diagnosis of IBD and discusses morphological pointers and ancillary techniques that assist with the distinction between IBD and its mimics. Methods European Crohn’s and Colitis Organisation [ECCO] Topical Reviews are the result of an expert consensus. For this review, ECCO announced an open call to its members and formed three working groups [WGs] to study clinical aspects, pathological considerations, and the value of ancillary techniques. All WGs performed a systematic literature search. Results Each WG produced a draft text and drew up provisional Current Practice Position [CPP] statements that highlighted the most important conclusions. Discussions and a preliminary voting round took place, with subsequent revision of CPP statements and text and a further meeting to agree on final statements. Conclusions Clinicians and pathologists encounter a wide variety of mimics of IBD, including infection, drug-induced disease, vascular disorders, diverticular disease, diversion proctocolitis, radiation damage, and immune disorders. Reliable distinction requires a multidisciplinary approach.

Purpose:Cetuximab is an EGFR-targeted therapy approved for the treatment of RAS wild-type (WT) metastatic colorectal cancer (mCRC). However, about 60% of these patients show innate resistance to cetuximab. To increase cetuximab efficacy, it is crucial to successfully identify responder patients, as well as to develop new therapeutic approaches to overcome cetuximab resistance.Experimental Design:We evaluated the value of EGFR effector phospholipase C gamma 1 (PLCγ1) in predicting cetuximab responses, by analyzing progression-free survival (PFS) of a multicentric retrospective cohort of 94 treated patients with mCRC (log-rank test and Cox regression model). Furthermore, we used in vitro and zebrafish xenotransplant models to identify and target the mechanism behind PLCγ1-mediated resistance to cetuximab.Results:In this study, levels of PLCγ1 were found increased in RAS WT tumors and were able to predict cetuximab responses in clinical samples and in vitro and in vivo models. Mechanistically, PLCγ1 expression was found to bypass cetuximab-dependent EGFR inhibition by activating ERK and AKT pathways. This novel resistance mechanism involves a noncatalytic role of PLCγ1 SH2 tandem domains in the propagation of downstream signaling via SH2-containing protein tyrosine phosphatase 2 (SHP2). Accordingly, SHP2 inhibition sensitizes PLCγ1-resistant cells to cetuximab.Conclusions:Our discoveries reveal the potential of PLCγ1 as a predictive biomarker for cetuximab responses and suggest an alternative therapeutic approach to circumvent PLCγ1-mediated resistance to cetuximab in patients with RAS WT mCRC. In this way, this work contributes to the development of novel strategies in the medical management and treatment of patients with mCRC.

Supplementary Figure from Predictive and Therapeutic Implications of a Novel PLCγ1/SHP2-Driven Mechanism of Cetuximab Resistance in Metastatic Colorectal Cancer

Supplementary Data from Predictive and Therapeutic Implications of a Novel PLCγ1/SHP2-Driven Mechanism of Cetuximab Resistance in Metastatic Colorectal Cancer

project LA/P/0140/2020 of the Associate Laboratory Institute for Health and Bioeconomy—i4HB. Publisher Copyright: © 2023 by the authors. Triple-negative breast cancer (TNBC) encompasses multiple entities and is generally highly aggressive and metastatic. We aimed to determine the clinical and biological relevance of Sialyl-Lewis X and A (sLeX/A)—a fucosylated glycan involved in metastasis—in TNBC. Here, we studied tissues from 50 TNBC patients, transcripts from a TNBC dataset from The Cancer Genome Atlas (TCGA) database, and a primary breast cancer cell line. All 50 TNBC tissue samples analysed expressed sLeX/A. Patients with high expression of sLeX/A had 3 years less disease-free survival than patients with lower expression. In tissue, sLeX/A negatively correlated with cytokeratins 5/6 (CK5/6, which was corroborated by the inverse correlation between fucosyltransferases and CK5/6 genes. Our observations were confirmed in vitro when inhibition of sLeX/A remarkably increased expression of CK5/6, followed by a decreased proliferation and invasion capacity. Among the reported glycoproteins bearing sLeX/A and based on the STRING tool, α6 integrin showed the highest interaction score with CK5/6. This is the first report on the sLeX/A expression in TNBC, highlighting its association with lower disease-free survival and its inverse crosstalk with CK5/6 with α6 integrin as a mediator. All in all, sLeX/A is critical for TNBC malignancy and a potential prognosis biomarker and therapeutic target. publishersversion published

The tumor microenvironment is crucial in tumourigenesis, response to therapy, and elimination of tumor cells. Tumor-infiltrating lymphocytes (TILs) promote the host immune response and are associated with a better prognosis in colorectal cancer (CRC). This multicentric retrospective study evaluated the relationship between the presence and intensity of TILs and survival outcomes. A total of 651 patients from four Portuguese oncological centers who underwent surgical resection for stages II or III colorectal adenocarcinoma between 2016 and 2019 were included in this study. The mean age of the study population was 70 years; 58.2% were males. The median overall survival was 58.03 ± 1.29 months (95% confidence interval (CI) 55.50 - 60.56), and the median disease-free survival (DFS) was 53.02 ± 1.39 months (95% CI 50.29 - 55.74). Patients with high infiltrate (including those with moderate, abundant, or Crohn-like infiltrate) had significantly longer DFS i.e., 58.48 ± 1.84 months (95% CI 54.87 - 62.09 months) vs 49.22 ± 1.75 months (95% CI 45.79 - 52.64 months) in the group with absent or minimal infiltrate; p = 0.003. Assessing the side of the tumor, high infiltrate was associated with higher DFS (59.86 ± 2.36 months (95% CI 55.23 - 64.50 months) vs 49.60 ± 2.40 months (95% CI 44.90 - 54.29 months), p = 0.011). This work reinforces the importance of research into possible prognostic and predictive factors in patients with CRC.

Funding Information: R.M. is supported by Fundação para a Ciência e a Tecnologia (CEEC position, 2019–2025 investigator). This article is a result of the projects (iNOVA4Health—UIDB/04462/2020), supported by Lisboa Portugal Regional Operational Programme (Lisboa2020), under the PORTUGAL 2020 Partnership Agreement, through the European Regional Development Fund (ERDF). This work is also funded by FEDER funds through the COMPETE 2020 Programme and National Funds through FCT—Portuguese Foundation for Science and Technology under the projects number PTDC/BTM-TEC/30087/2017 and PTDC/BTM-TEC/30088/2017. Publisher Copyright: © 2022 by the authors. Background: Pleural effusion (PE) is common in advanced-stage lung cancer patients and is related to poor prognosis. Identification of cancer cells is the standard method for the diagnosis of a malignant PE (MPE). However, it only has moderate sensitivity. Thus, more sensitive diagnostic tools are urgently needed. Methods: The present study aimed to discover potential protein targets to distinguish malignant pleural effusion (MPE) from other non-malignant pathologies. We have collected PE from 97 patients to explore PE proteomes by applying state-of-the-art liquid chromatography-mass spectrometry (LC-MS) to identify potential biomarkers that correlate with immunohistochemistry assessment of tumor biopsy or with survival data. Functional analyses were performed to elucidate functional differences in PE proteins in malignant and benign samples. Results were integrated into a clinical risk prediction model to identify likely malignant cases. Sensitivity, specificity, and negative predictive value were calculated. Results: In total, 1689 individual proteins were identified by MS-based proteomics analysis of the 97 PE samples, of which 35 were diagnosed as malignant. A comparison between MPE and benign PE (BPE) identified 58 differential regulated proteins after correction of the p-values for multiple testing. Furthermore, functional analysis revealed an up-regulation of matrix intermediate filaments and cellular movement-related proteins. Additionally, gene ontology analysis identified the involvement of metabolic pathways such as glycolysis/gluconeogenesis, pyruvate metabolism and cysteine and methionine metabolism. Conclusion: This study demonstrated a partial least squares regression model with an area under the curve of 98 and an accuracy of 0.92 when evaluated on the holdout test data set. Furthermore, highly significant survival markers were identified (e.g., PSME1 with a log-rank of 1.68 × 10−6). publishersversion published

ObjectiveEffective medical therapy and validated trial outcomes are lacking for small bowel Crohn’s disease (CD) strictures. Histopathology of surgically resected specimens is the gold standard for correlation with imaging techniques. However, no validated histopathological scoring systems are currently available for small bowel stricturing disease. We convened an expert panel to evaluate the appropriateness of histopathology scoring systems and items generated based on panel opinion.DesignModified RAND/University of California Los Angeles methodology was used to determine the appropriateness of 313 candidate items related to assessment of CD small bowel strictures.ResultsIn this exercise, diagnosis of naïve and anastomotic strictures required increased bowel wall thickness, decreased luminal diameter or internal circumference, and fibrosis of the submucosa. Specific definitions for stricture features and technical sampling parameters were also identified. Histopathologically, a stricture was defined as increased thickness of all layers of the bowel wall, fibrosis of the submucosa and bowel wall, and muscularisation of the submucosa. Active mucosal inflammatory disease was defined as neutrophilic inflammation in the lamina propria and any crypt or intact surface epithelium, erosion, ulcer and fistula. Chronic mucosal inflammatory disease was defined as crypt architectural distortion and loss, pyloric gland metaplasia, Paneth cell hyperplasia, basal lymphoplasmacytosis, plasmacytosis and fibrosis, or prominent lymphoid aggregates at the mucosa/submucosa interface. None of the scoring systems used to assess CD strictures were considered appropriate for clinical trials.ConclusionStandardised assessment of gross pathology and histopathology of CD small bowel strictures will improve clinical trial efficiency and aid drug development.

Background Targeting histological remission or response in Crohn's disease (CD) is not recommended in clinical practice guidelines or as an outcome in clinical trials due to uncertainties regarding index validity and prognostic relevance. Aims To conduct a modified RAND/University of California Los Angeles appropriateness process with the goal of producing a framework to standardise histological assessment of CD activity in clinical trials. Methods A total of 115 statements generated from literature review and expert opinion were rated on a scale of 1-9 by a panel of 11 histopathologists and 6 gastroenterologists. Statements were classified as inappropriate, uncertain or appropriate based upon the median panel rating and degree of disagreement. Results The panellists considered it important to measure histological activity in clinical trials to determine efficacy and that absence of neutrophilic inflammation is an appropriate histological target. They were uncertain whether the Global Histological Activity Score was an appropriate instrument for measuring histological activity. The Geboes Score and Robarts Histopathology Index were considered appropriate. Two biopsies from five segments should be biopsied, and the colon and the ileum should be analysed separately for all indices. Endoscopic mucosal appearance should guide biopsy procurement site with biopsies taken from the ulcer edge, or the most macroscopically inflamed area in the absence of ulcers. Conclusion We evaluated the appropriateness of items for assessing histological disease activity in CD clinical trials. These items will be used to develop a novel histological index.

© The Author(s) 2021. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/., Colorectal cancer (CRC) is one of the most lethal malignancies. The extreme heterogeneity in survival rate is driving the need for new prognostic biomarkers. Human endogenous retroviruses (hERVs) have been suggested to influence tumor progression, oncogenesis and elicit an immune response. We examined multiple next-generation sequencing (NGS)-derived biomarkers in 114 CRC patients with paired whole-exome and whole-transcriptome sequencing (WES and WTS, respectively). First, we demonstrate that the median expression of hERVs can serve as a potential biomarker for prognosis, relapse, and resistance to chemotherapy in stage II and III CRC. We show that hERV expression and CD8+ tumor-infiltrating T-lymphocytes (TILs) synergistically stratify overall and relapse-free survival (OS and RFS): the median OS of the CD8-/hERV+ subgroup was 29.8 months compared with 37.5 months for other subgroups (HR = 4.4, log-rank P < 0.001). Combing NGS-based biomarkers (hERV/CD8 status) with clinicopathological factors provided a better prediction of patient survival compared to clinicopathological factors alone. Moreover, we explored the association between genomic and transcriptomic features of tumors with high hERV expression and establish this subtype as distinct from previously described consensus molecular subtypes of CRC. Overall, our results underscore a previously unknown role for hERVs in leading to a more aggressive subtype of CRC., The biobanking of CRC from Hospital Santa Maria, Lisbon, Portugal, was supported by a grant from the Official Portuguese Funding Agency for Science and Technology (FCT: PIC/IC/82821/2007).

Next-generation sequencing (NGS) has been implemented in clinical oncology for diagnosis, prognosis, and therapeutic guidance. Among the various NGS applications in molecular oncology, we focused on the following topics: laboratory standards for targeted gene panels (somatic mutations) and therapeutic guidance based on NGS of lung cancer and rare cancers, namely sarcomas and cancers of unknown primary. Multiple quality control checkpoints should be addressed in the pre-analytical phase for good quality and interpretation of the NGS results. It includes tumor size and cellularity, tissue processing and decalcification, tumor fraction, tumor viability, fixatives, and staining. Communication between clinicians and laboratory support is also essential. In lung cancer, all patients with non-squamous non-small cell lung cancer should be tested with a NGS panel, and it should include not only genes with approved targeted therapies (ALK, BRAF, EGFR, MET, NTRK, RET, and ROS1) but also genes with potentially actionable genomic alterations (HER2 and KRAS). Since there is a lack of extensive knowledge regarding the use of NGS in rare tumors performing comprehensive genomic profiling, NGS panels to better manage the disease are recommended. Moreover, other patients with other incurable solid tumors may benefit from being included in biomarker-driven clinical trials. Multidisciplinary tumor boards with the participation of experts with the ability to integrate genomic profiling data are essential to tailor the best strategy for each patient. Considering that there are no national guidelines, this article aims to guide laboratory and clinical practice for the use of NGS in the context of lung cancer, rare tumors, and cancer of unknown primary in Portugal.Na área da oncologia clínica, a sequenciação de nova geração (NGS) foi implementada com o objetivo de contribuir para o diagnóstico, prognóstico e orientação terapêutica. A utilização de NGS em oncologia molecular é vasta, focalizando-se estas recomendações nas: normas laboratoriais para painéis genéticos direcionados (mutações somáticas) e na orientação terapêutica baseada em NGS de cancro do pulmão e cancros raros, nomeadamente sarcomas e cancros de origem desconhecida. Para que sejam obtidos resultados de NGS com a qualidade que permita a sua correta interpretação, devem ser abordados múltiplos controlos de qualidade na fase pré-analítica que disponibilizem informação sobre o tamanho e celularidade do tumor, processamento e descalcificação de tecidos, fração tumoral, viabilidade do tumor, fixadores e coloração utilizados. A comunicação entre os diferentes intervenientes no processo, em particular entre os clínicos e o laboratório também contribui, de forma inequívoca, para a interpretação dos resultados de NGS. Todos os doentes com cancro do pulmão de não pequenas células não escamoso devem ser testados com um painel de NGS, que deve incluir não só genes com terapias dirigidas aprovadas (ALK, BRAF, EGFR, MET, NTRK, RET e ROS1), mas também genes com alterações genómicas identificadas como potenciais alvos terapêuticos (HER2 e KRAS). Dada a escassez de evidência científica sobre a utilização de NGS em tumores raros, recomenda-se a realização de painéis genómicos abrangentes que poderão contribuir para uma melhor gestão da doença. Adicionalmente, outros doentes, com outros tumores sólidos incuráveis, podem beneficiar da inclusão em ensaios clínicos orientados por biomarcadores. A realização de reuniões multidisciplinares com a participação de diferentes especialistas capazes de integrar dados dos perfis genómicos são fundamentais para a escolha da melhor estratégia para cada doente. Considerando que não existem recomendações nacionais, este artigo visa orientar a prática laboratorial e clínica para a utilização de NGS em tumores do pulmão, raros e cancros de origem primária desconhecida em Portugal.

TPS435 Background: Testicular germ cell tumors (TGCT) are the most common solid malignancy in men aged 15 to 35, and Seminoma histology can account for up to half of the cases. Since the latest edition of the American Joint Committee on Cancer (AJCC) staging manual (8th edition, 2018), it is recommended that, only in pure Seminoma, the pT1 category should be subdivided according to tumor size: pT1a for tumors < 3 cm or T1b for tumors ≥ 3 cm. This change was based on large retrospective data that suggested almost a doubling of the risk of relapse at 3-years in pT1b versus pT1a, with a Hazard Ratio of 1.87, 95% confidence interval (CI) 1.15-3.06. So far, there has been no prospective validation for these staging changes and there are no known implications of its use in clinical practice. Furthermore, these changes are exclusive for AJCC since the Union for International Cancer Control (UICC), another widely used staging system, did not change from previous editions (i.e., no pT1 subdivision in pure Seminoma). Tumor size was already recognized as a risk factor for relapse (if tumor size > 4 cm) but not formally used for staging before. Of concern, these are mostly young patients, and despite exceptionally good long-term survival rates, in stage I Seminoma, the general estimation of relapse is about 15% but can surpass 30% — therefore accurate prognostic information is particularly important. This study aims to validate the 3 cm cut-off in stage I Seminoma introduced by AJCC 8th edition. Additionally, the study will allow for the evaluation for current trends of adjuvant options (namely surveillance vs active treatment). Methods: S3MI-PT, or Seminoma 3 cm cut-off Prospective Trial, is a multicenter prospective observational validation study that aims to include at least 300 patients (the estimate includes a 10% loss to follow-up rate as TGCT studies are historically difficult to accrue). Eligibility criteria: male patients ≥ 18 years old diagnosed with clinical stage I pure Seminoma histology (pT1N0M0S0), whose orchiectomy must have occurred after January 2018, the AJCC 8th ed. implementation date, who are willing to sign the informed consent. Demographic and clinical data will be collected, that includes, age at diagnosis, tumor size, rete testis invasion, values for TGCT markers, adjuvant treatment options (surveillance or active treatment) and relapse, if applicable. Exclusion criteria: non-pure Seminoma TGCT staged pT2-T4, pN1-N3, M1, S1-3. Primary endpoint is relapse-free survival at 3 years in pT1a versus pT1b, with two-sided P < 0.05 used to determine statistical significance with a 95% CI, by Kaplan-Meier method. S3MI-PT has been approved by the Ethics Committee. The study is actively enrolling, and all individuals and institutions interested in collaborating can do so by request.

Background and Aims Evidence has been supporting that histological activity of ulcerative colitis [UC] has relevance for the prediction of clinical outcomes in UC patients, such as clinical relapse. In this study, we aimed to compare two histological indexes—the continuous Geboes score [GS] and the Nancy index [NI] —regarding their definitions of histological remission and response, and to determine the ability of faecal calprotectin [FC] levels to discriminate between these histological statuses according to the NI. Methods A large cohort of UC patients [N = 422] who were previously enrolled in other studies was analysed. Results GS and NI were shown to be strongly correlated [correlation coefficient: 0.882, p 0 {area under the curve (AUC) 0.667 (95% confidence interval [CI] 0.609–0.724)}, and were good predictors of the absence of histological response defined by NI >1 (AUC 0.825 [95% CI 0.777–0.872]). The optimal FC cut-offs determined to predict the NI-defined histological remission and response were 91 μg/g and 106 μg/g, when maximising the negative predictive value [NPV]. Conclusions Due to the higher applicability of the NI, this study encourages the systematic use of this histological index to assess histological remission and response in UC patients.

Simple Summary More than 50% of breast cancer (BC) patients selected for neoadjuvant chemotherapy (NACT) are subjected to at least a 6-month regimen of this treatment without a clear benefit, probably delaying more effective therapeutic strategies and being exposed to potential treatment-associated toxicity. Thus, it is urgent to implement reliable predictive biomarkers, as well as novel treatments for NACT non-responder patients. This study validates that the HLA-DR level in cytotoxic T lymphocytes (CTLs) is an independent and robust predictive factor of BC patients’ response to NACT, as previously proposed. Hence, a predictive probability model of response was developed as a new tool to improve treatment decisions. HLA-DR level in CTLs also have a general prognostic value, which might be relevant for long-term BC management. In addition, our results suggest that increasing the expression of HLA-DR in CTLs of non-responders could be a promising therapeutic strategy to ameliorate BC response to NACT. Abstract Neoadjuvant chemotherapy (NACT) is common in breast cancer (BC) treatment, though more than half of the patients lack an effective response. Therefore, new predictive biomarkers and alternative therapies are crucial. Previously, we proposed HLA-DR-expressing cytotoxic T lymphocytes (CTLs) as a potential biomarker of the response to NACT. To validate this observation and further investigate these cells, 202 BC patients were enrolled. Flow cytometry analyses were performed in 61 biopsies and 41 blood samples pre-NACT and 100 non-NACT tumor samples. All the patients were followed up for 34 months. Blood-isolated immune cells were cultured with BC cell lines in a 3D system. We confirmed that HLA-DR level in CTLs is a highly sensitive, specific, and independent biomarker to predict response to NACT and developed a predictive probability model. This biomarker was also associated with progression-free survival, regardless of the treatment. The clinical observations are substantiated by the anti-tumor properties of HLA-DR-expressing CTLs. Intriguingly, HLA-DR level in CTLs can be modulated ex vivo, boosting their capacity to kill tumor cells synergistically with doxorubicin. Thus, HLA-DR expression in CTLs is a validated tool to select patients that will actually benefit from NACT, and its stimulation might be a novel therapeutic approach for BC.

BackgroundNeoadjuvant chemotherapy (NACT) is the usual treatment for locally-advanced breast cancer (BC). However, more than half of the patients lack an effective response to this treatment. Thus, it’s urgent to find predictive biomarkers. Recently, we proposed the HLA-DR expression level in cytotoxic T lymphocytes (CTLs) as a robust biomarker to select, in advance, patients that will actually benefit from NACT.Patients and MethodsA total of 202 BC patients, 102 of which submitted to NACT, were enrolled in this study. 61 biopsies and 41 blood samples collected pre-NACT and 100 non-NACT tumor samples were immunophenotyped by flow cytometry. Both NACT and non-NACT patients were followed up for 34 months. Blood-isolated immune cells were cultured with BC cell lines in a 3D system.ResultsHere we confirmed that HLA-DR level in CTLs is a highly sensitive and specific biomarker to predict BC response to NACT, reflected in circulation and independent of the patients’ age, BC subtype and other tumor-immunological features. Therefore, we developed a predictive probability model, based on the determination of HLA-DR level in tumor-infiltrating CTLs, that could be used to guide therapeutic decisions. Interestingly, this biomarker was also associated with progression-free survival, regardless the treatment. Contrary to HLA-DRnegative CTLs, HLA-DR+ CTLs were able to reduce the viability of tumor cells, in culture, in agreement with their higher expression of activation, proliferation and cytotoxicity-related molecules. Tissue-residency and memory markers were also increased in HLA-DR+ CTLs. These anti-tumor features of HLA-DR+ CTLs may justify the clinical observations.ConclusionHLA-DR level in CTLs is a validated and independent biomarker to predict response to NACT which allow the establishment of a clinical meaningful tool to select in advance patients that will truly benefit from this treatment. Intriguingly, it may be further used as a biomarker of BC patients’ general prognosis.Highlights- HLA-DR level in cytotoxic T cells is an independent predictive factor of breast cancer response to NACT- A predictive probability model based on this biomarker was developed as a new tool to improve treatment decisions- HLA-DR level in cytotoxic T cells is also reflected systemically- HLA-DR level in cytotoxic T cells is also a prognostic factor, associated with progression-free survival- HLA-DR+ cytotoxic T cells exhibit several phenotypic and functional anti-tumor characteristics

Background The Montreal classification categorizes patients with ulcerative colitis (UC) based on their macroscopic disease extent. Independent of endoscopic extent, biopsies through all colonic segments should be retrieved during index colonoscopy. However, the prognostic value of histological inflammation at diagnosis in the inflamed and uninflamed regions of the colon has never been assessed. Methods This was a multicenter retrospective cohort study of newly diagnosed patients with treatment-naïve proctitis and left-sided UC. Biopsies from at least 2 colonic segments (endoscopically inflamed and uninflamed mucosa) were retrieved and reviewed by 2 pathologists. Histological features in the endoscopically inflamed and uninflamed mucosa were scored using the Nancy score. The primary outcomes were disease complications (proximal disease extension, need for hospitalization or colectomy) and higher therapeutic requirements (need for steroids or for therapy escalation). Results Overall, 93 treatment-naïve patients were included, with a median follow-up of 44 months (range, 2-329). The prevalence of any histological inflammation above the endoscopic margin was 71%. Proximal disease extension was more frequent in patients with histological inflammation in the endoscopically uninflamed mucosa at diagnosis (21.5% vs 3.4%, P = 0.04). Histological involvement above the endoscopic margin was the only predictor associated with an earlier need for therapy escalation (adjusted hazard ratio, 3.69; 95% confidence interval, 1.05-13.0); P = 0.04) and disease complications (adjusted hazard ratio, 4.79; 95% confidence interval, 1.10-20.9; P = 0.04). Conclusions The presence of histological inflammation in the endoscopically uninflamed mucosa at the time of diagnosis was associated with worse outcomes in limited UC.

ispartof: JOURNAL OF CROHNS & COLITIS vol:13 issue:2 pages:144-+ ispartof: location:England status: published

Background & Aims In addition to findings from endoscopy, histologic features of colon biopsies have been associated with outcomes of patients with ulcerative colitis (UC). We investigated associations between Geboes scores (a system to quantify structural changes and inflammatory activity in colon biopsies) and UC progression, and the time period over which this association is valid. Methods We analyzed data from 399 asymptomatic patients with UC enrolled in the ACERTIVE study, followed at 13 inflammatory bowel disease (IBD) centers in Portugal through 31 December 2019. Blood and stool samples were collected and analyzed, and all patients underwent sigmoidoscopy within 24 h of sample collection. We assessed baseline endoscopic status (Mayo endoscopic subscore), histologic features of 2 sigmoid and 2 rectal biopsies (Geboes score), and concentration of fecal calprotectin (FC). The primary outcome was UC progression (surgical, pharmacologic, and clinical events). We generated survival curves for 36 months or less and more than 36 months after biopsy according to Geboes score using the Kaplan-Meier method and compared findings with those from a log rank test. Cox regression was adjusted for Mayo endoscopic subscore, Geboes score, and level of FC; results were expressed as adjusted hazard ratios (HR) with 95% CIs. Results Patients with Geboes scores >2B.0, Geboes scores >3.0, or Geboes scores >4.0 had a higher frequency of, and a shorter time to UC progression, than patients with Geboes scores ≤2B.0, Geboes scores ≤3.0, or Geboes score ≤4.0 (P 2B.0, Geboes scores >3.0, or Geboes scores >4.0 compared with patients with Geboes scores ≤2B.0 (HR, 2.021; 95% CI, 1.158–3.526), Geboes scores ≤3.0 (HR, 2.007; 95% CI, 1.139–3.534), or Geboes scores ≤4.0 (HR, 2.349; 95% CI, 1.269–4.349), respectively, in the first 36 months after biopsy. Similar results were found for patients with concentrations of FC below 150 μg/g. Conclusions We found histologic features of colon biopsies (Geboes score) to be an independent risk factor for progression of UC in the first 36 months after biopsy.

© The Author(s) 2020. Published by Oxford University Press on behalf of European Crohn’s and Colitis Organisation. All rights reserved. This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model)., Currently, the main targets of drug therapy for ulcerative colitis [UC] are endoscopic and clinical remission. However, there is active discussion about the additional advantages of including histological remission as a target. Accumulating evidence indicates that microscopic activity persists in endoscopically quiescent UC, that histological changes may lag behind clinical remission after treatment, and that absence of histological activity predicts lower rates of relapse, hospitalization, surgery and subsequent neoplasia. Obtaining useful information from mucosal biopsies in this setting depends on accurate and consistent evaluation of histological features. However, there is no standardization of biopsy procedures, histological sample processing technique or histological scoring systems, and there is no agreement on the definitions of histological remission, response or activity. Accordingly, a consensus expert panel convened by the European Crohn's and Colitis Organisation [ECCO] reviewed the literature and agreed a number of position statements regarding harmonization of UC histopathology. The objective was to provide evidence-based guidance for the standardization and harmonization of procedures, definitions and scoring systems for histology in UC, and to reach expert consensus where possible. We propose the absence of intraepithelial neutrophils, erosion and ulceration as a minimum requirement for the definition of histological remission. For randomized control trials we recommend the use of the Robarts histopathology index [RHI] or the Nancy index [NI]. For observational studies or in clinical practice we recommend the use of the NI. To predict the risk of future neoplasia in UC, cumulative histological scores over time are more useful than single scores.

Background and Aims The histological status of ulcerative colitis [UC] patients in clinical and endoscopic remission has gained space as an important prognostic marker and a key component of disease monitoring. Our main aims were to compare two histological indexes—the continuous Geboes score [GS] and the Robarts Histopathology index [RHI]—regarding their definitions of histological remission and response, and the ability of faecal calprotectin [FC] levels to discriminate between these statuses. Methods This was an analysis of three prospective cohorts including 422 patients previously enrolled in other studies. Results The two continuous scores [GS and RHI] were shown to be significantly correlated [correlation coefficient of 0.806, p < 0.001] and particularly close regarding their definition of histological response: 95% and 88% of all patients classified as having/not having [respectively] histological response according to RHI also did so according to GS. Moreover, median FC levels in patients with histological response were lower than those in patients without histological response [GS: 73.00 vs 525.00, p < 0.001; RHI: 73.50 vs 510.00, p < 0.001]; a similar trend was observed when FC levels of patients in histological remission were compared to those of patients with histological activity [GS: 76.00 vs 228.00, p < 0.001; RHI: 73.50 vs 467.00, p < 0.001]. FC levels allowed us to exclude the absence of histological remission [according to RHI] and absence of histological response [according to RHI and GS], with negative predictive values varying from 82% to 96%. However, optimization of the FC cut-off to exclude the absence of histological remission, as for the continuous GS, falls within values that resemble those of the healthy population. Conclusion The continuous GS and RHI histological scores are strongly correlated in their definitions of histological response. An absence of histological remission could only be excluded at physiological levels of FC.