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1.
Int J Cancer ; 154(3): 504-515, 2024 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-37908048

RESUMO

The management of anal squamous cell carcinoma (ASCC) has yet to experience the transformative impact of precision medicine. Conducting genomic analyses may uncover novel prognostic biomarkers and offer potential directions for the development of targeted therapies. To that end, we assessed the prognostic and theragnostic implications of pathogenic variants identified in 571 cancer-related genes from surgical samples collected from a homogeneous, multicentric French cohort of 158 ASCC patients who underwent abdominoperineal resection treatment. Alterations in PI3K/AKT/mTOR, chromatin remodeling, and Notch pathways were frequent in HPV-positive tumors, while HPV-negative tumors often harbored variants in cell cycle regulation and genome integrity maintenance genes (e.g., frequent TP53 and TERT promoter mutations). In patients with HPV-positive tumors, KMT2C and PIK3CA exon 9/20 pathogenic variants were associated with worse overall survival in multivariate analysis (Hazard ratio (HR)KMT2C = 2.54, 95%CI = [1.25,5.17], P value = .010; HRPIK3CA = 2.43, 95%CI = [1.3,4.56], P value = .006). Alterations with theragnostic value in another cancer type was detected in 43% of patients. These results suggest that PIK3CA and KMT2C pathogenic variants are independent prognostic factors in patients with ASCC with HPV-positive tumors treated by abdominoperineal resection. And, importantly, the high prevalence of alterations bearing potential theragnostic value strongly supports the use of genomic profiling to allow patient enrollment in precision medicine clinical trials.


Assuntos
Neoplasias do Ânus , Carcinoma de Células Escamosas , Protectomia , Humanos , Neoplasias do Ânus/genética , Neoplasias do Ânus/patologia , Neoplasias do Ânus/cirurgia , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/cirurgia , Carcinoma de Células Escamosas/patologia , Classe I de Fosfatidilinositol 3-Quinases/genética , Mutação , Infecções por Papillomavirus/complicações , Infecções por Papillomavirus/genética , Fosfatidilinositol 3-Quinases/genética , Prognóstico
2.
Br J Cancer ; 129(5): 772-781, 2023 09.
Artigo em Inglês | MEDLINE | ID: mdl-37443346

RESUMO

BACKGROUND: The immune landscape of uveal melanoma liver metastases (UMLM) has not been sufficiently studied. METHODS: Immune cell infiltrates (ICIs), PD-1 and PD-L1 were characterised in 62 UMLM and 28 primary uveal melanomas (PUM). ICI, PD-1 and PD-L1 were scored as: (1) % tumoral area occupied by tumour-infiltrating lymphocytes or macrophages (TILs, TIMs) and (2) % perTumoral (perT) area. ICIs and other variables including histopathologic growth patterns (HGPs), replacement and desmoplastic, of UMLM were analysed for their prognostic value. RESULTS: ICIs recognised by haematoxylin-eosin-saffron (HES) and IHC (e.g., T cells (CD3), B cells (CD20). Macrophages (CD68), (CD163), were primarily localised to the perT region in PUM and UMLM and were more conspicuous in UMLM. HES, CD3, CD4, FoxP3, CD8, CD20, PD-1 TILs were scant (<5%). TIMs were more frequent, particularly in UMLM than in PUM. Both CD68+ TIMs and HGPs remained significant on multivariate analysis, influencing overall (OS) and metastasis-specific overall survival (MSOS). CD68 + , CD163+ and CD20+ perT infiltrates in UMLM predicted increased OS and MSOS on univariate analysis. CONCLUSIONS: TILs and PD-L1 have no predictive value in PUM or UMLM. CD68+ and CD163+TIMs, CD20+ perT lymphocytes, and HGPs are important prognostic factors in UMLMs.


Assuntos
Neoplasias Hepáticas , Melanoma , Humanos , Antígeno B7-H1 , Receptor de Morte Celular Programada 1 , Melanoma/patologia , Neoplasias Hepáticas/patologia , Linfócitos do Interstício Tumoral , Prognóstico , Biomarcadores Tumorais/análise
3.
Ann Surg ; 278(4): e827-e834, 2023 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-36847256

RESUMO

OBJECTIVE: We report here the results of a prospective study of circulating tumor DNA (ctDNA) detection in patients undergoing uveal melanoma (UM) liver metastases resection (NCT02849145). BACKGROUND: In UM patients, the liver is the most common and often only site of metastases. Local treatments of liver metastases, such as surgical resection, have a likely benefit in selected patients. METHODS: Upon enrollment, metastatic UM patients eligible for curative liver surgery had plasma samples collected before and after surgery. GNAQ / GNA11 mutations were identified in archived tumor tissue and used to quantify ctDNA by droplet digital polymerase chain reaction which was then associated with the patient's surgical outcomes. RESULTS: Forty-seven patients were included. Liver surgery was associated with a major increase of cell-free circulating DNA levels, with a peak 2 days after surgery (∼20-fold). Among 40 evaluable patients, 14 (35%) had detectable ctDNA before surgery, with a median allelic frequency of 1.1%. These patients experienced statistically shorter relapse-free survival (RFS) versus patients with no detectable ctDNA before surgery (median RFS: 5.5 vs 12.2 months; hazard ratio=2.23, 95% CI: 1.06-4.69, P =0.04), and had a numerically shorter overall survival (OS) (median OS: 27.0 vs 42.3 months). ctDNA positivity at postsurgery time points was also associated with RFS and OS. CONCLUSIONS: This study is the first to report ctDNA detection rate and prognostic impact in UM patients eligible for surgical resection of their liver metastases. If confirmed by further studies in this setting, this noninvasive biomarker could inform treatment decisions in UM patients with liver metastases.


Assuntos
DNA Tumoral Circulante , Neoplasias Hepáticas , Humanos , DNA Tumoral Circulante/genética , Prognóstico , Estudos Prospectivos , Recidiva Local de Neoplasia , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/cirurgia , Biomarcadores Tumorais/genética , Mutação
4.
Lab Invest ; 102(11): 1214-1224, 2022 11.
Artigo em Inglês | MEDLINE | ID: mdl-35672380

RESUMO

The replacement histopathologic growth pattern (rHGP) in melanoma liver metastases connotes an aggressive phenotype (vascular co-option; angiotropic extravascular migratory spread) and adverse prognosis. Herein, replacement and desmoplastic HGP (dHGP) were studied in uveal melanoma liver metastases (MUM). In particular, L1CAM and a "laminin vascular network" were detected at the advancing front of 14/20 cases (p = 0.014) and 16/20 cases (p = 6.4e-05) rHGPs, respectively, but both were absent in the dHGP (8/8 cases) (p = 0.014, and p = 6.3e-05, respectively). L1CAM highlighted progressive extension of angiotropic melanoma cells along sinusoidal vessels in a pericytic location (pericytic mimicry) into the hepatic parenchyma. An inverse relationship between L1CAM expression and melanin index (p = 0.012) suggested differentiation toward an amelanotic embryonic migratory phenotype in rHGP. Laminin labeled the basement membrane zone interposed between sinusoidal vascular channels and angiotropic melanoma cells at the advancing front. Other new findings: any percentage of rHGP and pure rHGP had a significant adverse effect on metastasis-specific overall survival (p = 0.038; p = 0.0064), as well as predominant rHGP (p = 0.0058). Pure rHGP also was associated with diminished metastasis-free survival relative to dHGP (p = 0.040), possibly having important implications for mechanisms of tumor spread. In conclusion, we report for the first time that L1CAM and a laminin vascular network are directly involved in this high-risk replacement phenotype. Further, this study provides more detailed information about the adverse prognostic effect of the rHGP in MUM.


Assuntos
Neoplasias Hepáticas , Melanoma , Molécula L1 de Adesão de Célula Nervosa , Neoplasias Uveais , Humanos , Laminina , Melaninas , Melanoma/metabolismo
5.
Br J Cancer ; 127(2): 258-267, 2022 07.
Artigo em Inglês | MEDLINE | ID: mdl-35347325

RESUMO

BACKGROUND: The RECIST-based response variably matches the clinical benefit of systemic therapies for liver metastatic uveal melanoma (LMUM). The aims were to determine whether the tumour growth rate (TGR) can help predict the survival in patients with LMUM and to provide information for the management of first-line systemic treatment. METHODS: This retrospective study included 147 (training: n = 110, validation: n = 37) patients with LMUM treated with first-line systemic treatment between 2010 and 2021. Two TGR-derived parameters were calculated, TGR0 and TGR3m. Multivariate Cox analyses identified independent predictors of progression-free survival (PFS) and overall survival (OS). RESULTS: TGR3m was a strong independent prognostic factor of PFS and OS (p < 0.001). The RECIST-based response was no longer significant in the OS analyses. Only immunotherapy regimens correlated with higher OS (HR = 0.2; 95% CI, 0.1-0.5; p < 0.001) in the low-TGR3m (≤50%/m) subgroup. These findings were confirmed in the validation cohort. TGR0, disease-free interval (DFI), and the sum of target lesions at baseline were predictive factors of low TGR3m. DISCUSSION: The use of TGR3m would improve tumour assessment by identifying patients who would benefit from first-line immunotherapy regimens despite PD. TGR0, DFI and the sum of target lesions were correlated with TGR3m, which can support first-line treatment decision-making for immunotherapy.


Assuntos
Melanoma , Segunda Neoplasia Primária , Humanos , Imunoterapia , Fígado/patologia , Melanoma/tratamento farmacológico , Melanoma/patologia , Estudos Retrospectivos , Neoplasias Uveais
6.
Ann Surg Oncol ; 29(13): 8480-8491, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-35980554

RESUMO

BACKGROUND: Surgical management of liver metastases of uveal melanoma (LMUM) is associated with the best survival rates, especially for patients with a low tumor burden in the liver. The aim was to determine whether the tumor growth rate (TGR0) before liver resection helps predict survival in patients with resectable LMUM. METHODS: This retrospective study included 99 patients with LMUM treated with liver resection between November 2007 and November 2020. TGR0 was expressed as the percentage change in tumor volume over 1 month according to two pretreatment imaging scans. Multivariate Cox analyses identified independent predictors of disease-free survival (DFS) and overall survival (OS). RESULTS: DFS and OS had a statistically significant positive linear relationship (Spearman correlation r = 0.68, p < 0.001). A disease-free interval (DFI) > 24 months and a TGR0 ≤ 50%/month were independent factors associated with better DFS and OS. The 2-component model including TGR0 and DFI had a mean time-dependent area under the curve (AUC) of 0.81 (95% CI, 0.75-0.86) and 0.77 (95% CI, 0.67-0.87), respectively, for predicting DFS and OS. DFI with TGR0 defined three kinetic risk groups that had distinct DFS and OS outcomes (p < 0.001). Cytogenetic alterations at baseline were partially predictive factors of the kinetic risk score based on TGR0 and DFI. DISCUSSION: The assessment of TGR0 improves prognostic stratification by identifying patients at high risk of recurrence and poor survival after liver resection. TGR0 and DFI, reflecting tumor aggressivity, have the potential to be important markers for systemic adjuvant decisions.


Assuntos
Neoplasias Hepáticas , Neoplasias Uveais , Humanos , Estudos Retrospectivos , Neoplasias Uveais/cirurgia , Neoplasias Hepáticas/secundário , Prognóstico , Intervalo Livre de Doença , Taxa de Sobrevida
7.
Ann Surg ; 274(5): 797-804, 2021 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-34334647

RESUMO

OBJECTIVE: To perform a retrospective root-cause analysis of postoperative death after CRS and HIPEC procedures. BACKGROUND: The combination of CRS and HIPEC is an effective therapeutic strategy to treat peritoneal surface malignancies, however it is associated with significant postoperative mortality. METHODS: All patients treated with a combination of CRS and HIPEC between January 2009 and December 2018 in 22 French centers and died in the hospital, were retrospectively analyzed. Perioperative data of the 101 patients were collected by a local senior surgeon with a sole junior surgeon. Three independent experts investigated the typical root cause of death and provided conclusions on whether postoperative death was preventable (PREV group) or not (NON-PREV group). A typical root cause of preventable postoperative death was classified on a cause-and-effect diagram. RESULTS: Of the 5562 CRS+HIPEC procedures performed, 101 in-hospital deaths (1.8%) were identified, of which a total of 18 patients of 70 years old and above and 20 patients with ASA score of 3. Etiology of peritoneal disease was mainly colorectal. A total of 54 patients (53%) were classified in the PREV group and 47 patients (47%) in the NON-PREV group. The results of the study show that in the PREV group, WHO performance status 1-2 was more frequent and the Median Peritoneal Cancer Index was higher compared with those of the NON-PREV group. The cause of death in the PREV group was classified as: (i) preoperatively for debatable indication (59%), (ii) intraoperatively (30%) and (iii) postoperatively in 17 patients (31%). A multifactorial cause of death was found in 11 patients (20%). CONCLUSION: More than half of the postoperative deaths after combined CRS and HIPEC may be preventable, mainly by following guidelines regarding preoperative selection of the patients and adequate intraoperative decisions.


Assuntos
Procedimentos Cirúrgicos de Citorredução/mortalidade , Quimioterapia Intraperitoneal Hipertérmica/mortalidade , Neoplasias Peritoneais/terapia , Análise de Causa Fundamental/métodos , Idoso , Feminino , França/epidemiologia , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias Peritoneais/mortalidade , Período Pós-Operatório , Prognóstico , Estudos Retrospectivos , Taxa de Sobrevida/tendências
8.
Lancet Oncol ; 21(9): 1147-1154, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32717180

RESUMO

BACKGROUND: Diagnosis and treatment of colorectal peritoneal metastases at an early stage, before the onset of signs, could improve patient survival. We aimed to compare the survival benefit of systematic second-look surgery plus hyperthermic intraperitoneal chemotherapy (HIPEC), with surveillance, in patients at high risk of developing colorectal peritoneal metastases. METHODS: We did an open-label, randomised, phase 3 study in 23 hospitals in France. Eligible patients were aged 18-70 years and had a primary colorectal cancer with synchronous and localised colorectal peritoneal metastases removed during tumour resection, resected ovarian metastases, or a perforated tumour. Patients were randomly assigned (1:1) to surveillance or second-look surgery plus oxaliplatin-HIPEC (oxaliplatin 460 mg/m2, or oxaliplatin 300 mg/m2 plus irinotecan 200 mg/m2, plus intravenous fluorouracil 400 mg/m2), or mitomycin-HIPEC (mitomycin 35 mg/m2) alone in case of neuropathy, after 6 months of adjuvant systemic chemotherapy with no signs of disease recurrence. Randomisation was done via a web-based system, with stratification by treatment centre, nodal status, and risk factors for colorectal peritoneal metastases. Second-look surgery consisted of a complete exploration of the abdominal cavity via xyphopubic incision, and resection of all peritoneal implants if resectable. Surveillance after resection of colorectal cancer was done according to the French Guidelines. The primary outcome was 3-year disease-free survival, defined as the time from randomisation to peritoneal or distant disease recurrence, or death from any cause, whichever occurred first, analysed by intention to treat. Surgical complications were assessed in the second-look surgery group only. This study was registered at ClinicalTrials.gov, NCT01226394. FINDINGS: Between June 11, 2010, and March 31, 2015, 150 patients were recruited and randomly assigned to a treatment group (75 per group). After a median follow-up of 50·8 months (IQR 47·0-54·8), 3-year disease-free survival was 53% (95% CI 41-64) in the surveillance group versus 44% (33-56) in the second-look surgery group (hazard ratio 0·97, 95% CI 0·61-1·56). No treatment-related deaths were reported. 29 (41%) of 71 patients in the second-look surgery group had grade 3-4 complications. The most common grade 3-4 complications were intra-abdominal adverse events (haemorrhage, digestive leakage) in 12 (23%) of 71 patients and haematological adverse events in 13 (18%) of 71 patients. INTERPRETATION: Systematic second-look surgery plus oxaliplatin-HIPEC did not improve disease-free survival compared with standard surveillance. Currently, essential surveillance of patients at high risk of developing colorectal peritoneal metastases appears to be adequate and effective in terms of survival outcomes. FUNDING: French National Cancer Institute.


Assuntos
Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/cirurgia , Neoplasias Peritoneais/tratamento farmacológico , Neoplasias Peritoneais/cirurgia , Adolescente , Adulto , Idoso , Neoplasias Colorretais/patologia , Intervalo Livre de Doença , Feminino , Fluoruracila/administração & dosagem , Humanos , Hipertermia Induzida/métodos , Leucovorina/administração & dosagem , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Recidiva Local de Neoplasia/tratamento farmacológico , Recidiva Local de Neoplasia/patologia , Recidiva Local de Neoplasia/cirurgia , Oxaliplatina/administração & dosagem , Neoplasias Peritoneais/patologia , Neoplasias Peritoneais/secundário , Fatores de Risco , Cirurgia de Second-Look/métodos , Adulto Jovem
9.
J Surg Oncol ; 122(8): 1639-1646, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-33184896

RESUMO

BACKGROUND AND OBJECTIVES: The best surgical approach to rectal gastrointestinal stromal tumors (GISTs) is still debated, and both nonanatomic rectal resection (NARR) and anatomic rectal resection (ARR) are applied. The aim of this study was to evaluate the feasibility and oncological outcomes of NARR and ARR for rectal GISTs (R-GISTs). METHODS: Through a large French multicentre retrospective study, 35 patients were treated for R-GIST between 2001 and 2013. Patients who underwent NARR and ARR were compared. RESULTS: There were 23 (65.7%) patients in group ARR and 12 (34.3%) in group NARR. Significantly more patients in the group with ARR had a neoadjuvant treatment (86%) with tyrosine kinase inhibitor (TKI) (imatinib) compared to those with NARR (25%) (p < .01). The median preoperative tumor size was significantly different between the groups without and with neoadjuvant TKI: 30 ± 23 mm versus 64 ± 44.4 mm, respectively (p < .001). Overall postoperative morbidity was 20% (n = 7) (26% for ARR vs. 8% for NARR; p = .4). After a median follow-up of 60.2 (3.2-164.3) months, the 5-year disease-free survival rates were 79.5% (confidence interval [CI] 95%: 54-100) for the NARR group and 68% (CI 95%: 46.4-89.7) for the ARR group (p = .697), respectively. CONCLUSION: The use of NARR for small R-GIST's does not seem to impair the oncological prognosis.


Assuntos
Procedimentos Cirúrgicos do Sistema Digestório/mortalidade , Neoplasias Gastrointestinais/cirurgia , Tumores do Estroma Gastrointestinal/cirurgia , Reto/cirurgia , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Viabilidade , Feminino , Seguimentos , Neoplasias Gastrointestinais/patologia , Tumores do Estroma Gastrointestinal/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Reto/patologia , Estudos Retrospectivos , Taxa de Sobrevida
10.
Int J Cancer ; 145(7): 1852-1859, 2019 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-30714617

RESUMO

Anal squamous cell carcinoma (ASCC) is a rare tumour, but its incidence is increasing. Standard chemoradiotherapy fails to cure 20% of patients and no targeted therapy is currently approved for recurrent ASCC. The PI3K/Akt/mTOR pathway is frequently altered in this poorly characterised carcinoma. IGF2 was identified here as a key factor in ASCC oncogenesis, as IGF2 was shown to play a crucial role in the PI3K pathway with frequent (~60%) and mutually exclusive genomic alterations in IGF2, IGF1R, PTEN and PIK3CA genes. We also demonstrated that IGF2 expression is mainly due to cancer-associated fibroblasts and that IGF2 secreted by cancer-associated fibroblasts from ASCC samples promotes proliferation of a human ASCC cell line via IGF2 paracrine signalling. Altogether, these results highlight the key role of the IGF2/PI3K axis, and the major role of cancer-associated fibroblasts in tumour growth via IGF2 secretion, suggesting a major role of IGF2/IGF1R inhibitors in ASCC therapies.


Assuntos
Neoplasias do Ânus/metabolismo , Fibroblastos Associados a Câncer/metabolismo , Carcinoma de Células Escamosas/metabolismo , Fator de Crescimento Insulin-Like II/genética , Fator de Crescimento Insulin-Like II/metabolismo , Animais , Neoplasias do Ânus/genética , Carcinoma de Células Escamosas/genética , Linhagem Celular Tumoral , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Masculino , Camundongos , Mutação , Transplante de Neoplasias , Comunicação Parácrina , Fosfatidilinositol 3-Quinases/metabolismo , Transdução de Sinais
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