RESUMO
BACKGROUND: Despite high expression of PD-L1, around half of advanced non-small cell lung cancer (NSCLC) will not experience tumor response with pembrolizumab. There is an need for a better understanding of the resistance mechanisms in this setting. METHODS: This bi-centric retrospective study included all consecutive patients with PDL1 ≥ 50% advanced NSCLC treated with pembrolizumab in first-line treatment between 2016 and 2020. We compared the clinical characteristics of patients with early progression (refractory) vs others. We performed a comprehensive gene expression profile screening by RNAseq capture on tumor samples. RESULTS: We included 46 patients. Twenty-two patients were refractory to pembrolizumab, mainly women, with poor performance status and lower albumin concentration. RNAseq analysis was performed on 19 samples. Hierarchical clustering allowed the identification of 3 clusters with various proportion of refractory tumors: intermediate (C1: 57%), high (C2: 71%) and low proportion (C3: 40%). Comparative analysis between C2 and C3 allowed the identification of overexpressed (n = 137) and underexpressed (n = 40) genes. Among the genes of interest, C2 exhibits higher activation of pathways associated with stemness phenotype (Hedgehog, Notch and Hippo pathways) and pathways associated with loss of PTEN and JAK2. In C2, genes associated with PD-1, toll-like receptor-9 (TLR-9), major histocompatibility complex (MHC) and interferon-γ pathways were underexpressed. CONCLUSION: This study gives an overview of activated and downregulated pathways in high PD-L1 NSCLC refractory to pembrolizumab. These tumors showed activation of pathways associated with cancer stem cells, loss of PTEN and JAK2, and inhibition of both priming and effector phases of the immune response.
Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Albuminas/uso terapêutico , Anticorpos Monoclonais Humanizados , Antígeno B7-H1/metabolismo , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Resistencia a Medicamentos Antineoplásicos , Feminino , Humanos , Interferon gama/uso terapêutico , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Masculino , Receptor de Morte Celular Programada 1 , Estudos Retrospectivos , Receptor Toll-Like 9/metabolismo , TranscriptomaRESUMO
Glomus tumors (GTs) are perivascular tumors mostly occurring in the distal extremities. Rare cases arise in the digestive tract and may be misdiagnosed with neuroendocrine or gastrointestinal stromal tumors. We aimed to specify the features of GT of the upper digestive tract. Clinical, histological, phenotypic, and molecular features of 16 digestive GTs were analyzed, of whom two underwent whole exome and RNA sequencing to search for gene alterations. RNA-sequencing disclosed a t(1:5)(p13;q32) translocation, which resulted in the fusion of CARMN and NOTCH2 in two GTs. The fusion gene encoded a protein sequence corresponding to the NOTCH2 intracellular domain that functions as transcription factor. These finding was supported by high expression of genes targeted by NOTCH. The CARMN-NOTCH2 translocation was detected in 14 out of 16 (88%) GTs of the upper digestive tract; but in only in two out of six cutaneous GTs (33%). Most digestive GT arose from the stomach (n = 13), and the others from duodenal (2) or oesophagous (1). Nuclear expression of NOTCH2 was detected in the 14 cases containing the fusion transcripts. The CARMN-NOTCH2 fusion transcript may contribute to activation of the NOTCH2 pathway in GT and drive tumor development. The high frequency of this translocation in GT of the upper digestive track suggest that detection of nuclear NOTCH2 expression may be useful diagnostic biomarker of these tumors.
Assuntos
Biomarcadores Tumorais/genética , Neoplasias Gastrointestinais/genética , Fusão Gênica , Tumor Glômico/genética , MicroRNAs/genética , Receptor Notch2/genética , Neoplasias Gastrointestinais/metabolismo , Neoplasias Gastrointestinais/patologia , Tumor Glômico/metabolismo , Tumor Glômico/patologia , HumanosRESUMO
In colorectal cancer (CRC), T-cell checkpoint blockade is only effective in patients diagnosed with mismatch repair-deficient (MMR-d) cancers. However, defects in Human Leukocyte Antigen (HLA) class I expression were reported to occur in most MMR-d CRCs, which would preclude antigen presentation in these tumours, considered essential for the clinical activity of this immunotherapeutic modality. We revisited this paradox by characterising HLA class I expression in two independent cohorts of CRC. We determined that loss of HLA class I expression occurred in the majority (73-78%) of MMR-d cases. This phenotype was rare in CRC liver metastases, irrespective of MMR status, whereas weak, inducible expression of HLA class I molecules was frequent in liver lesions. We propose that HLA class I is an important determinant of metastatic homing in CRCs. This observation is paramount to understand CRC carcinogenesis and for the application of immunotherapies in the metastatic setting.
Assuntos
Neoplasias Colorretais/terapia , Genes MHC Classe I/genética , Imunoterapia , Linfócitos T/imunologia , Apresentação de Antígeno/imunologia , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/imunologia , Carcinogênese/genética , Carcinogênese/imunologia , Neoplasias Colorretais/genética , Neoplasias Colorretais/imunologia , Neoplasias Colorretais/patologia , Feminino , Regulação Neoplásica da Expressão Gênica/imunologia , Genes cdc/efeitos dos fármacos , Genes cdc/imunologia , Humanos , Fígado/metabolismo , Fígado/patologia , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Síndromes Neoplásicas Hereditárias/genética , Síndromes Neoplásicas Hereditárias/imunologiaRESUMO
OBJECTIVE: The primary endpoint was to analyze the predictive factors of lymph node involvement (LN+). BACKGROUND: Indications for additional right hemicolectomy (RHC) with lymph node (LN) resection after appendectomy for appendix neuroendocrine tumor (A-NET) remain controversial, especially for tumors between 1 and 2âcm in size. METHODS: National study including all patients with nonmetastatic A-NET diagnosed after January, 2010 in France. RESULTS: In all, 403 patients were included. A-NETs were: within tip (67%), body (24%) or base (9%) of the appendix; tumor size was <â1âcm (62%), 1 to 2âcm (30%), or >2âcm (8%); grade 1 (91%); mesoappendix involvement 3âmm (5%); lymphovascular (15%) or perineural (24%) invasion; and positive resection margin (8%). According to the European NeuroEndocrine Tumor Society (ENETS) recommendations, 85 patients (21%) should have undergone RHC. The agreement between ENETS guidelines and the multidisciplinary tumor board for complementary RHC was 89%. In all, 100 (25%) patients underwent RHC with LN resection, 26 of whom had LN+. Tumor size (best cut-off at 1.95âcm), lymphovascular and perineural invasion, and pT classifications were associated with LN+. Among the 44 patients who underwent RHC for a tumor of 1 to 2âcm in size, 8 (18%) had LN+. No predictive factor of LN+ (base, resection margins, grade, mesoappendix, lymphovascular, perineural involvement) was found in this subgroup of patients. CONCLUSIONS: In the largest study using the latest pathological criteria for completion RHC in A-NET, a quarter of patients had residual tumor. Further studies are warranted to demonstrate the survival impact of RHC in this setting.
Assuntos
Apendicectomia , Neoplasias do Apêndice/patologia , Neoplasias do Apêndice/cirurgia , Colectomia , Linfonodos/patologia , Tumores Neuroendócrinos/patologia , Tumores Neuroendócrinos/cirurgia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Feminino , Seguimentos , Humanos , Metástase Linfática , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Fatores de Risco , Adulto JovemRESUMO
IL-1 family cytokines play a dual role in the gut, with different family members contributing either protective or pathogenic effects. IL-36γ is an IL-1 family cytokine involved in polarizing type-1 immune responses. However, its function in the gut, including in colorectal cancer pathogenesis, is not well appreciated. In a murine model of colon carcinoma, IL-36γ controls tertiary lymphoid structure formation and promotes a type-1 immune response concurrently with a decrease in expression of immune checkpoint molecules in the tumor microenvironment. Here, we demonstrate that IL-36γ plays a similar role in driving a pro-inflammatory phenotype in human colorectal cancer. We analyzed a cohort of 33 primary colorectal carcinoma tumors using imaging, flow cytometry, and transcriptomics to determine the pattern and role of IL-36γ expression in this disease. In the colorectal tumor microenvironment, we observed IL-36γ to be predominantly expressed by M1 macrophages and cells of the vasculature, including smooth muscle cells and high endothelial venules. This pattern of IL-36γ expression is associated with a CD4+ central memory T cell infiltrate and an increased density of B cells in tertiary lymphoid structures, as well as with markers of fibrosis. Conversely, expression of the antagonist to IL-36 signaling, IL-1F5, was associated with intratumoral expression of checkpoint molecules, including PD-1, PD-L1, and CTLA4, which can suppress the immune response. These data support a role for IL-36γ in the physiologic immune response to colorectal cancer by sustaining inflammation within the tumor microenvironment.
Assuntos
Neoplasias Colorretais/imunologia , Inflamação/imunologia , Interleucina-1/imunologia , Estruturas Linfoides Terciárias/imunologia , Idoso , Idoso de 80 Anos ou mais , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/metabolismo , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Feminino , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica/imunologia , Humanos , Interleucina-1/metabolismo , Masculino , Pessoa de Meia-Idade , Microambiente Tumoral/genética , Microambiente Tumoral/imunologiaRESUMO
BACKGROUND: Radiofrequency ablation (RFA) is a valid treatment for liver metastases from colorectal cancer (CRLM) smaller than 25 mm and unsuitable for surgical resection. Tumor size is predictive for local tumor progression (LTP). The aim of this study was to evaluate whether RFA is indicated for lesions >25 mm at presentation but <25 mm after chemotherapy. METHOD: Patients who underwent RFA for CRLM after chemotherapy (January 2004-December 2012) were reviewed. Metastases were classified according to their size. Group 1: ≤25 mm before and after chemotherapy. Group 2A: >25 mm before but ≤25 mm after chemotherapy. Group 2B: >25 mm before and after chemotherapy. RESULTS: 133 CRLM were ablated in 83 patients (median follow-up 56 months). At 1-year, the LTP rate was higher in group 2A than in group 1 (32% vs. 16%, p ≤ 0.001). The highest rate of 1-year LTP was 64% in group 2B. Time to LTP (TLTP) was shorter in group 2A than in group 1 (HR: 2.89; 95% CI [1.04-8.01]; p = 0.004). Following multivariate analysis, the group type was the only predictive factor for TLTP (p < 0.001). CONCLUSIONS: RFA is not the optimal treatment for CRLM > 25 mm at presentation.
Assuntos
Antineoplásicos/uso terapêutico , Neoplasias Colorretais/patologia , Neoplasias Hepáticas/secundário , Neoplasias Hepáticas/terapia , Terapia Neoadjuvante , Ablação por Radiofrequência , Adulto , Idoso , Idoso de 80 Anos ou mais , Quimioterapia Adjuvante , Neoplasias Colorretais/terapia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Estudos Retrospectivos , Resultado do Tratamento , Carga TumoralRESUMO
BACKGROUND: Patients with ypN0 rectal cancer who have received preoperative chemoradiotherapy can be divided into those who initially were node negative and those whose positive nodes have been sterilized by preoperative therapy. The long-term prognosis for ypN0 patients with sterilized lymph nodes (LNS) is unknown. This study aimed to assess the prognostic value of LNS after preoperative chemoradiotherapy for patients with ypN0 rectal cancer. METHODS: From January 2007 to March 2014, 206 patients with ypN0 tumors of the mid or lower rectum treated by chemoradiotherapy and radical surgery were enrolled in the study. Of these 206 patients, 49 had ypN0 tumors with LNS (LNS+ group), and 157 had ypN0 tumors without LNS (LNS- group). The patients in both groups were comparable in terms of tumor characteristics, type of chemoradiotherapy, type of surgery, R0 resection rate, and postoperative complication rate. RESULTS: The mean follow-up period was 40.5 ± 27 months. The 1- and 3-year OS rates in the LNS+ group were respectively 100 and 95.5% versus 99.4 and 91.6% in the LNS- group (P = 0.549). The 1- and 3-year DFS rates in the LNS+ group were respectively 100 and 94.2% versus 94.7 and 87.1% in the LNS- group (P = 0.117). The multivariate analysis showed that the presence of LNS did not affect OS (P = 0.918) or DFS (P = 0.209). CONCLUSIONS: The prognosis is excellent for patients with ypN0 rectal cancer who have LNS after preoperative chemoradiotherapy. The presence of LNS in ypN0 rectal cancer patients after chemoradiotherapy should not be considered a factor for a poor prognosis.
Assuntos
Linfonodos/patologia , Neoplasias Retais/patologia , Neoplasias Retais/terapia , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Quimiorradioterapia Adjuvante , Intervalo Livre de Doença , Fracionamento da Dose de Radiação , Feminino , Fluoruracila/administração & dosagem , Humanos , Metástase Linfática , Masculino , Pessoa de Meia-Idade , Terapia Neoadjuvante , Neoplasia Residual , Cuidados Pré-Operatórios , Estudos Retrospectivos , Taxa de SobrevidaRESUMO
This work aims at three goals: first, to define a set of statistical parameters and plan structures for a 3D pretreatment thoracic and prostate intensity-modulated radiation therapy (IMRT) quality assurance (QA) protocol; secondly, to test if the 3D QA protocol is able to detect certain clinical errors; and third, to compare the 3D QA method with QA performed with single ion chamber and 2D gamma test in detecting those errors. The 3D QA protocol measurements were performed on 13 prostate and 25 thoracic IMRT patients using IBA's COMPASS system. For each treatment planning structure included in the protocol, the following statistical parameters were evaluated: average absolute dose difference (AADD), percent structure volume with absolute dose difference greater than 6% (ADD6), and 3D gamma test. To test the 3D QA protocol error sensitivity, two prostate and two thoracic step-and-shoot IMRT patients were investigated. Errors introduced to each of the treatment plans included energy switched from 6 MV to 10 MV, multileaf collimator (MLC) leaf errors, linac jaws errors, monitor unit (MU) errors, MLC and gantry angle errors, and detector shift errors. QA was performed on each plan using a single ion chamber and 2D array of ion chambers for 2D and 3D QA. Based on the measurements performed, we established a uniform set of tolerance levels to determine if QA passes for each IMRT treatment plan structure: maximum allowed AADD is 6%; maximum 4% of any structure volume can be with ADD6 greater than 6%, and maximum 4% of any structure volume may fail 3D gamma test with test parameters 3%/3 mm DTA. Out of the three QA methods tested the single ion chamber performed the worst by detecting 4 out of 18 introduced errors, 2D QA detected 11 out of 18 errors, and 3D QA detected 14 out of 18 errors.
Assuntos
Neoplasias da Próstata/radioterapia , Garantia da Qualidade dos Cuidados de Saúde/normas , Planejamento da Radioterapia Assistida por Computador/normas , Erros de Configuração em Radioterapia/prevenção & controle , Radioterapia de Intensidade Modulada/normas , Neoplasias Torácicas/radioterapia , Braquiterapia , Calibragem , Humanos , Masculino , Prognóstico , Dosagem RadioterapêuticaRESUMO
Gastric cancer (GC) is a major cause of cancer-related mortality worldwide. It is often associated with a bad prognosis because of its asymptomatic phenotype until advanced stages, highlighting the need for its prevention and early detection. GC development is preceded by the emergence of gastric preneoplasia lesions (GPNLs), namely atrophic gastritis (AG), intestinal metaplasia (IM), and dysplasia (DYS). GC is currently diagnosed by endoscopy, which is invasive and costly and has limited effectiveness for the detection of GPNLs. Therefore, the discovery of non-invasive biomarkers in liquid biopsies, such as blood samples, in order to identify the presence of gastric preneoplasia and/or cancer lesions at asymptomatic stages is of paramount interest. This comprehensive review provides an overview of recently identified plasma/serum proteins and their diagnostic performance for the prediction of GPNLs and early cancer lesions. Autoantibodies appear to be promising biomarkers for AG, IM and early gastric cancer detection, along with inflammation and immunity-related proteins and antibodies against H. pylori virulence factors. There is a lack of specific protein biomarkers with which to detect DYS. Despite the need for further investigation and validation, some emerging candidates could pave the way for the development of reliable, non-invasive diagnostic tests for the detection and prevention of GC.
RESUMO
The identification of biomarkers related to treatment in patients with non-small cell lung cancer (NSCLC) treated with immune checkpoint inhibitors (ICIs) represents a significant challenge. The aim of this study was to determine the predictive value of macrophage-related markers assessed in plasma and tissue samples of patients with NSCLC undergoing ICI treatment. This bicentric study included a prospective cohort of 88 patients with advanced NSCLC who received first-line therapy with ICI (either as monotherapy or in combination with chemotherapy) or chemotherapy alone (CT). Samples were collected from the patients at baseline and during follow-up. Plasma levels of CSF-1 and IL-34 were measured using ELISA, while expression levels of the macrophage receptors CD163 and CSF-1-R were evaluated using immunohistochemistry on lung biopsies. At baseline, the median plasma CSF-1 expression was higher in patients who did not respond to immunotherapy compared to those who responded (8898 pg/mL vs. 14031 pg/mL, p = 0.0005). Importantly, high CSF-1 levels at the initial assessment were associated with disease progression regardless of the treatment received. Furthermore, high CSF-1 levels were associated with shorter progression-free survival (PFS) and overall survival (OS) in patients receiving ICI therapy, but not in those treated with chemotherapy. There was no correlation between IL-34, CSF-1R, CD163 and therapeutic response. We observed in vitro that the activation of lymphocytes mediated by pembrolizumab was hindered by the treatment of PBMC with recombinant CSF-1, suggesting that CSF-1 creates a systemic immunosuppressive state that interferes with ICI treatment. In conclusion, baseline CSF-1 levels represent a potential predictive marker to ICI treatment in NSCLC.
Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Humanos , Inibidores de Checkpoint Imunológico/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Leucócitos Mononucleares , Fator Estimulador de Colônias de Macrófagos , Estudos Prospectivos , Neoplasias Pulmonares/tratamento farmacológicoRESUMO
INTRODUCTION: Duodenal neuroendocrine tumours (D-NETs) have a low incidence; however, their diagnosis has been increasing. Features such as tumour location, size, type, histological grade, and stage were used to adapt the treatment to either endoscopic (ER) or surgical (SR) resections. There is no consensus regarding the definitive treatment. The authors' study aimed to describe the management of non-metastatic, well-differentiated D-NETs in France and its impact on patient survival. METHODS: A registry-based multicenter study using prospectively collected data between 2000 and 2019, including all patients managed for non-metastatic G1 and G2 D-NETs, was conducted in the GTE group. RESULTS: A total of 153 patients were included. Fifty-eight benefited from an ER, and 95 had an SR. No difference in recurrence-free survival (RFS) was observed regardless of treatment type. There was no significant difference between the two groups (ER vs. SR) in terms of location, size, grade, or lymphadenopathy, regardless of the type of incomplete resection performed or regarding the pre-therapeutic assessment of lymph node invasion in imaging. The surgery allowed for significantly more complete resection (patients with R1 resection in the SR group: 9 vs. 14 in the ER group, P <0.001). Among the 51 patients with positive lymph node dissection after SR, tumour size was less than or equal to 1 cm in 25 cases. Surgical complications were more numerous ( P =0.001). In the sub-group analysis of G1-G2 D-NETs between 11 and 19 mm, there was no significant difference in grade ( P =0.977) and location ( P =0.617) between the two groups (ER vs. SR). No significant difference was found in both morphological and functional imaging, focusing on the pre-therapeutic assessment of lymph node invasion ( P =0.387). CONCLUSION: Regardless of the resection type (ER or SR) of G1-G2 non-metastatic D-NETs, as well as the type of management of incomplete resection, which was greater in the ER group, long-term survival results were similar between ER and SR. Organ preservation seems to be the best choice owing to the slow evolution of these tumours.
Assuntos
Neoplasias Duodenais , Tumores Neuroendócrinos , Humanos , Feminino , Masculino , França , Tumores Neuroendócrinos/mortalidade , Tumores Neuroendócrinos/patologia , Tumores Neuroendócrinos/cirurgia , Tumores Neuroendócrinos/terapia , Pessoa de Meia-Idade , Neoplasias Duodenais/cirurgia , Neoplasias Duodenais/patologia , Neoplasias Duodenais/mortalidade , Idoso , Adulto , Estudos de Coortes , Sistema de RegistrosRESUMO
It is unclear if AGEs are involved in the bone fragility of type 1 diabetes (T1D). We evaluated whether skin AGEs by skin autofluorescence and serum AGEs (pentosidine, carboxymethyl-lysine [CML]) are independently associated with BMD by DXA (lumbar spine, hip, distal radius), trabecular bone score (TBS), serum bone turnover markers (BTMs: CTX; P1NP; osteocalcin), and sclerostin in participants with and without T1D. Linear regression models were used, with interaction terms to test effect modification by T1D status. In participants with T1D, correlations between skin and serum AGEs as well as between AGEs and 3-year HbA1C were evaluated using Spearman's correlations. Data are mean ± SD or median (interquartile range). We included individuals who participated in a cross-sectional study and had BMD and TBS assessment (106 T1D/65 controls, 53.2% women, age 43 ± 15 yr, BMI 26.6 ± 5.5 kg/m2). Participants with T1D had diabetes for 27.6 ± 12.3 yr, a mean 3-yr HbA1C of 7.5 ± 0.9% and skin AGEs of 2.15 ± 0.54 arbitrary units. A subgroup of 65 T1D/57 controls had BTMs and sclerostin measurements, and those with T1D also had serum pentosidine (16.8[8.2-32.0] ng/mL) and CML [48.0 ± 16.8] ng/mL) measured. Femoral neck BMD, TBS, and BTMs were lower, while sclerostin levels were similar in participants with T1D vs controls. T1D status did not modify the associations between AGEs and bone outcomes. Skin AGEs were significantly associated with total hip and femoral neck BMD, TBS, BTMs, and sclerostin before, but not after, adjustment for confounders. Serum AGEs were not associated with any bone outcome. There were no significant correlations between skin and serum AGEs or between AGEs and 3-yr HbA1C. In conclusion, skin and serum AGEs are not independently associated with BMD, TBS, BTMs, and sclerostin in participants with relatively well-controlled T1D and participants without diabetes.
RESUMO
BACKGROUND: To validate pathologic markers of response to preoperative chemotherapy as predictors of disease-free survival (DFS) after resection of colorectal liver metastases (CLM). METHODS: One hundred seventy-one patients who underwent resection of CLM after preoperative chemotherapy at 4 centers were studied. Pathologic response-defined as the proportion of tumor cells remaining (complete, 0%; major, <50%; minor, ≥50%) and tumor thickness at the tumor-normal liver interface (TNI) (<0.5 mm, 0.5 to <5 mm, ≥5 mm)-was assessed by a central pathology reviewer and local pathologists. RESULTS: Pathologic response was complete in 8% of patients, major in 49% of patients, and minor in 43% of patients. Tumor thickness at the TNI was <0.5 mm in 21% of patients, 0.5 to <5 mm in 56% of patients, and ≥5 mm in 23% of patients. On multivariate analyses, using either pathologic response or tumor thickness at TNI, pathologic response (P = .002, .009), tumor thickness at TNI (P = 0.015, <.001), duration of preoperative chemotherapy (P = .028, .043), number of CLM (P = .038, . 037), and margin (P = .011, .016) were associated with DFS. In a multivariate analysis using both parameters, tumor thickness at TNI (P = .004, .015), duration of preoperative chemotherapy (P = .025), number of nodules (P = .027), and margin (P = .014) were associated with DFS. Tumor size by pathology examination was the predictor of pathologic response. Predictors of tumor thickness at the TNI were tumor size and chemotherapy regimen. There was near perfect agreement for pathologic response (κ = .82) and substantial agreement (κ = .76) for tumor thickness between the central reviewer and local pathologists. CONCLUSIONS: Pathologic response and tumor thickness at the TNI are valid predictors of DFS after preoperative chemotherapy and surgery for CLM.
Assuntos
Neoplasias Colorretais/patologia , Neoplasias Colorretais/terapia , Neoplasias Hepáticas/secundário , Neoplasias Hepáticas/terapia , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/cirurgia , Terapia Combinada , Intervalo Livre de Doença , Feminino , Humanos , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/cirurgia , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Estudos RetrospectivosAssuntos
Calcinose/patologia , Neoplasias de Tecido Conjuntivo/patologia , Neoplasias Císticas, Mucinosas e Serosas/patologia , Neoplasias de Células Epitelioides Perivasculares/patologia , Ligamentos Redondos/patologia , Idoso , Biópsia , Calcinose/diagnóstico por imagem , Calcinose/cirurgia , Feminino , Fibrose , Humanos , Laparoscopia , Neoplasias de Tecido Conjuntivo/diagnóstico por imagem , Neoplasias de Tecido Conjuntivo/cirurgia , Neoplasias Císticas, Mucinosas e Serosas/diagnóstico por imagem , Neoplasias Císticas, Mucinosas e Serosas/cirurgia , Neoplasias de Células Epitelioides Perivasculares/diagnóstico por imagem , Neoplasias de Células Epitelioides Perivasculares/cirurgia , Ligamentos Redondos/diagnóstico por imagem , Ligamentos Redondos/cirurgia , Tomografia Computadorizada por Raios XRESUMO
Background: Tumour apparent diffusion coefficient (ADC) from diffusion-weighted magnetic resonance imaging (MRI) is a putative pharmacodynamic/response biomarker but the relationship between drug-induced effects on the ADC and on the underlying pathology has not been adequately defined. Hypothesis: Changes in ADC during early chemotherapy reflect underlying histological markers of tumour response as measured by tumour regression grade (TRG). Methods: Twenty-six patients were enrolled in the study. Baseline, 14 days, and pre-surgery MRI were performed per study protocol. Surgical resection was performed in 23 of the enrolled patients; imaging-pathological correlation was obtained from 39 lesions from 21 patients. Results: There was no evidence of correlation between TRG and ADC changes at day 14 (study primary endpoint), and no significant correlation with other ADC metrics. In scans acquired one week prior to surgery, there was no significant correlation between ADC metrics and percentage of viable tumour, percentage necrosis, percentage fibrosis, or Ki67 index. Conclusions: Our hypothesis was not supported by the data. The lack of meaningful correlation between change in ADC and TRG is a robust finding which is not explained by variability or small sample size. Change in ADC is not a proxy for TRG in metastatic colorectal cancer.
RESUMO
The optimal strategy for identifying patients with Lynch syndrome among patients with newly diagnosed colorectal cancer (CRC) is still debated. Several predictive models (e.g., MMRpredict, PREMM1,2 and MMRpro) combining personal and familial data have recently been developed to quantify the risk that a given patient with CRC carries a Lynch syndrome-causing mutation. Their clinical applicability to patients with CRC from the general population requires evaluation. We studied a consecutive series of 214 patients with newly diagnosed CRC characterized for tumor microsatellite instability (MSI), somatic BRAF mutation, MLH1 promoter methylation and mismatch repair (MMR) gene germline mutation status. The performances of the models for identifying MMR mutation carriers (8/214, 3.7%) were evaluated and compared to the revised Bethesda guidelines and a molecular strategy based on MSI testing in all patients followed by the exclusion of MSI-positive sporadic cases from mutational testing by screening for BRAF mutation and MLH1 promoter methylation. The sensitivities of the three models, at the lowest thresholds proposed, were identical (75%), with similar numbers of probands eligible for further MSI testing (almost half the patients). In our dataset, the prediction models gave no better discrimination than the revised Bethesda guidelines. Both approaches failed to identify two of the eight mutation carriers (the same two patients, aged 67 and 81 years, both with no family history). Thus, like the revised Bethesda guidelines, predictive models did not identify all patients with Lynch syndrome in our series of consecutive CRC. Our results support systematic screening for MMR deficiency in all new CRC cases.
Assuntos
Neoplasias Colorretais Hereditárias sem Polipose/diagnóstico , Neoplasias Colorretais Hereditárias sem Polipose/genética , Neoplasias Colorretais/diagnóstico , Neoplasias Colorretais/genética , Proteínas Adaptadoras de Transdução de Sinal/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Metilação de DNA , Reparo de Erro de Pareamento de DNA , Feminino , Predisposição Genética para Doença , Testes Genéticos/métodos , Mutação em Linhagem Germinativa , Humanos , Masculino , Instabilidade de Microssatélites , Pessoa de Meia-Idade , Proteína 1 Homóloga a MutL , Proteínas Nucleares/genética , Regiões Promotoras Genéticas/genética , Proteínas Proto-Oncogênicas B-raf/genéticaRESUMO
BACKGROUND & AIMS: Oxaliplatin-based chemotherapy for colorectal liver metastases (CRLM) can result in vascular liver lesions such as sinusoidal dilatations. Physiopathology remains unclear and variability between patients suggests that there is individual susceptibility. A better understanding of the molecular mechanisms of oxaliplatin liver toxicity may allow the identification of biomarkers and adaptation of chemotherapy delivery. METHODS: Between 1998 and 2009, 83 non-tumor frozen liver samples were obtained from patients operated on for CRLM after an exclusive oxaliplatin-based chemotherapy. Gene-expression profiles were first analyzed by microarray on a selected population of 19 patients: 9 patients with severe sinusoidal dilatation after a short period of chemotherapy and 10 patients without any sinusoidal dilatation after a long period of chemotherapy. These were compared with a control group of 5 patients without any chemotherapy and lesions. Twenty-two differentially-expressed (at least 1.5-fold difference in expression) genes were selected. These were validated using microfluidic quantitative RT-PCR in an independent set of 58 patients (28 with sinusoidal dilatation and 30 without sinusoidal dilatation). RESULTS: Among the 22 selected genes, 12 were validated as being up-regulated in samples from patients with sinusoidal dilatation compared to patients without sinusoidal dilatation. Genes involved in angiogenesis (VEGFD, THY-1, GPNMB) and cellular adhesion (VWF, CDH13, THBS2), and extracellular matrix components (COL1A1, COL4A1, SLCO1A2) were over-represented in patients with sinusoidal dilatation. CONCLUSIONS: This molecular signature confirms the involvement of angiogenesis and coagulation in sinusoidal injuries induced by oxaliplatin and reinforces a potential protective role of bevacizumab and aspirin, as suggested in retrospective clinical studies.
Assuntos
Antineoplásicos/efeitos adversos , Perfilação da Expressão Gênica , Fígado/irrigação sanguínea , Compostos Organoplatínicos/efeitos adversos , Transdução de Sinais/fisiologia , Doenças Vasculares/induzido quimicamente , Doenças Vasculares/fisiopatologia , Antineoplásicos/uso terapêutico , Estudos de Casos e Controles , Adesão Celular/genética , Adesão Celular/fisiologia , Neoplasias Colorretais/patologia , Dilatação Patológica/fisiopatologia , Matriz Extracelular/genética , Matriz Extracelular/fisiologia , Feminino , Humanos , Neoplasias Hepáticas/irrigação sanguínea , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/secundário , Masculino , Pessoa de Meia-Idade , Neovascularização Patológica/genética , Neovascularização Patológica/fisiopatologia , Compostos Organoplatínicos/uso terapêutico , Oxaliplatina , Estudos Retrospectivos , Transdução de Sinais/genéticaRESUMO
Gene fusions provide access to new therapeutic opportunities for patients treated for a colorectal cancer (CRC). However, they do not excess 1% of patients. A better identification of patients in whom gene fusions are highly prevalent is a major issue in a therapeutic and medico-economics perspective. This study assesses the rates of gene fusions in CRC patients with MSI/RAS-BRAFWT in our routine practice detected with a commercially available NGS-based fusion panel. Among the 130 MSI CRC tumors, 43 (33%) were KRAS-NRAS-BRAFWT. A gene fusion was detected in 7 (25.9%) of the 27 MSI/RAS-BRAFWT samples, which had RNA suitable for analysis after quality control. These fusions involved mainly NTRK1/3 (n = 5), as well as ALK (n = 1) and BRAF (n = 1). In the present study, we confirm that patients with MSI/RAS-BRAFWT CRCs represent a subpopulation in which targetable gene fusions are overrepresented. Our results support the use of a two-step algorithm for molecular screening, in which metastatic CRC patients would have routine MSI and RAS/BRAF testing, and then only those with MSI/RAS-BRAFWT would be screened with dedicated NGS RNA panel for gene fusions.
Assuntos
Neoplasias Colorretais , Detecção Precoce de Câncer , Neoplasias Colorretais/patologia , Fusão Gênica , Humanos , Instabilidade de Microssatélites , Mutação , Proteínas Proto-Oncogênicas B-raf/genética , Proteínas Proto-Oncogênicas p21(ras)/genética , RNARESUMO
[This corrects the article DOI: 10.3389/fonc.2021.747692.].
RESUMO
Histopathological growth patterns (HGPs) are a reliable, reproducible, and strong prognostic biomarker that can be assessed on haematoxylin and eosin-stained sections of resected colorectal liver metastases (CRLM). Assessment estimates the relative fraction of the tumour-liver interface for each of the three growth patterns; the desmoplastic HGP reflects good prognosis. Whether preoperative chemotherapy affects the HGP is currently unclear. The present international multicentre study evaluates this in an original cohort of 877 consecutive patients treated in the Netherlands, an external validation cohort of 1,203 consecutive patients treated in the USA, and a post hoc analysis from the phase III randomised controlled European Organization for Research and Treatment of Cancer (EORTC) 40983 trial (n = 70). All patients underwent resection of CRLM with or without preoperative systemic chemotherapy. Trial patients were randomised between perioperative chemotherapy and resection or resection alone. HGPs were determined according to consensus guidelines and compared for preoperative treatment status. Data from three separate tumour regression grading systems were available for the trial cohort. These were correlated with HGP stratified for treatment arm. In the original cohort, the average presence of desmoplastic HGP was 43% for chemo-naïve versus 67% for preoperatively treated patients (p < 0.001). A significant association between chemotherapy and desmoplastic HGP was found on multivariable analysis (ß [95% confidence interval, CI]: 24.57 [18.28-30.87], p < 0.001). In the validation cohort, the average presence of desmoplastic HGP was 40% for chemo-naïve versus 63% for preoperatively treated patients (p < 0.001). This association remained on multivariable analysis (ß [95% CI]: 24.18 [18.70-29.66], p < 0.001). In the EORTC 40983 trial, the average desmoplastic HGP presence was 33% in the resection arm versus 61% in the chemotherapy arm (p = 0.005). Chemotherapy was independently associated with an increase in desmoplastic HGP (ß [95% CI]: 23.29 [1.78-44.79], p = 0.022). All three tumour regression gradings were significantly associated with the desmoplastic HGP in the chemotherapy arm (all p < 0.04). None were associated in the resection arm (all p > 0.11). Preoperative chemotherapy induces histopathological changes that alter the HGP of CRLM.