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1.
Mod Pathol ; 34(1): 4-12, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33041332

RESUMO

Histopathologically scoring the response of pancreatic ductal adenocarcinoma (PDAC) to neoadjuvant treatment can guide the selection of adjuvant therapy and improve prognostic stratification. However, several tumor response scoring (TRS) systems exist, and consensus is lacking as to which system represents best practice. An international consensus meeting on TRS took place in November 2019 in Amsterdam, The Netherlands. Here, we provide an overview of the outcomes and consensus statements that originated from this meeting. Consensus (≥80% agreement) was reached on a total of seven statements: (1) TRS is important because it provides information about the effect of neoadjuvant treatment that is not provided by other histopathology-based descriptors. (2) TRS for resected PDAC following neoadjuvant therapy should assess residual (viable) tumor burden instead of tumor regression. (3) The CAP scoring system is considered the most adequate scoring system to date because it is based on the presence and amount of residual cancer cells instead of tumor regression. (4) The defining criteria of the categories in the CAP scoring system should be improved by replacing subjective terms including "minimal" or "extensive" with objective criteria to evaluate the extent of viable tumor. (5) The improved, consensus-based system should be validated retrospectively and prospectively. (6) Prospective studies should determine the extent of tissue sampling that is required to ensure adequate assessment of the residual cancer burden, taking into account the heterogeneity of tumor response. (7) In future scientific publications, the extent of tissue sampling should be described in detail in the "Materials and methods" section.


Assuntos
Carcinoma Ductal Pancreático/terapia , Terapia Neoadjuvante , Neoplasias Pancreáticas/terapia , Resultado do Tratamento , Antineoplásicos , Quimioterapia Adjuvante , Humanos , Países Baixos , Pancreatectomia
2.
World J Surg ; 45(8): 2482-2491, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-33895862

RESUMO

BACKGROUND: Small bowel neuroendocrine neoplasms (SB-NEN) are rare cancers, population-based studies are needed to study this rare indolent disease. The aim of this study was to explore trends in epidemiology, treatment and survival outcomes of patients with SB-NEN based on Dutch nationwide data. PATIENTS AND METHODS: Patients with grade 1 or 2 SB-NEN diagnosed between 2005 and 2015 were retrieved from the Netherlands Cancer Registry and linked to The Nationwide Network and Registry of Histo- and Cytopathology in the Netherlands. Age-adjusted incidence rates were calculated based using the direct standardization method. Survival analyses were performed with the Kaplan-Meier method. RESULTS: A total of 1132 patients were included for epidemiological analyses. The age-adjusted incidence rate of SB-NEN increased from 0.52 to 0.81 per 100.000 person-years between 2005 and 2015. Incidence was higher for males than females (0.93 vs. 0.69 in 2015). Most patients had grade 1 tumours (83%). Surgery was performed in 86% of patients, with resection of the primary tumour in 99%. During the study period, administration of somatostatin analogues (SSAs) increased from 5 to 22% for stage III and from 27 to 63% for stage IV disease. Mean follow-up was 61 (standard deviation 38) months. Survival data were complete for 975/1132 patients and five-year overall survival was 75% for stage I-II, 75% for stage III and 57% for stage IV. CONCLUSIONS: This study shows an increase in the incidence of SB-NEN in the Netherlands. A predominant role of surgery was found in all disease stages. Use of SSAs has increased over time.


Assuntos
Tumores Neuroendócrinos , Feminino , Humanos , Incidência , Lactente , Masculino , Países Baixos/epidemiologia , Tumores Neuroendócrinos/epidemiologia , Tumores Neuroendócrinos/terapia , Prevalência , Sistema de Registros , Estudos Retrospectivos , Taxa de Sobrevida
3.
Clin Transplant ; 32(2)2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-29193362

RESUMO

Donor-specific alloantibodies (DSA) have been associated with rejection and shorter graft survival after orthotopic liver transplantation (OLT). We examined the role of DSA in nonanastomotic biliary strictures (NAS) after OLT. Patients receiving first OLT who developed NAS (n = 68) and a control group without NAS (n = 83), with pre-OLT and 12 months post-OLT serum samples, were included. DSA were specified using the Luminex single antigen test. Risk factors for NAS and graft survival were analyzed. The presence of preformed DSA was not significantly different between patients with NAS and controls (P = .89). After 12 months, 26.5% of NAS patients and 16.9% of controls had generated de novo DSA (P = .15). Neither de novo class I DSA nor de novo class II DSA were associated with NAS. De novo DSA generally developed after the diagnosis of NAS. Time-dependent regression analysis identified both NAS (aHR 8.05, CI 3.28 - 19.77, P < .01) and de novo class II DSA (aHR 2.84, CI 1.38 - 5.82, P < .01) as independent risk factors for graft loss. Preformed or de novo DSA were not associated with the development of NAS. However, NAS as well as de novo class II DSA were independent risk factors for graft loss after OLT.


Assuntos
Doenças dos Ductos Biliares/sangue , Constrição Patológica/sangue , Rejeição de Enxerto/sangue , Antígenos HLA/imunologia , Isoanticorpos/sangue , Transplante de Fígado/efeitos adversos , Adulto , Doenças dos Ductos Biliares/diagnóstico , Doenças dos Ductos Biliares/etiologia , Constrição Patológica/diagnóstico , Constrição Patológica/etiologia , Feminino , Seguimentos , Rejeição de Enxerto/diagnóstico , Rejeição de Enxerto/etiologia , Sobrevivência de Enxerto , Humanos , Masculino , Pessoa de Meia-Idade , Complicações Pós-Operatórias , Prognóstico , Fatores de Risco
4.
Br J Cancer ; 117(6): 1215-1223, 2017 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-28742792

RESUMO

BACKGROUND: A substantial fraction of familial colorectal cancer (CRC) and polyposis heritability remains unexplained. This study aimed to identify predisposing loci in patients with these disorders. METHODS: Homozygosity mapping was performed using 222 563 SNPs in 302 index patients with various colorectal neoplasms and 3367 controls. Linkage analysis, exome and whole-genome sequencing were performed in a family affected by microsatellite stable CRCs. Candidate variants were genotyped in 10 554 cases and 21 480 controls. Gene expression was assessed at the mRNA and protein level. RESULTS: Homozygosity mapping revealed a disease-associated region at 1q32.3 which was part of the linkage region 1q32.2-42.2 identified in the CRC family. This includes a region previously associated with risk of CRC. Sequencing identified the p.Asp1432Glu variant in the MIA3 gene (known as TANGO1 or TANGO) and 472 additional rare, shared variants within the linkage region. In both cases and controls the population frequency was 0.02% for this MIA3 variant. The MIA3 mutant allele showed predominant mRNA expression in normal, cancer and precancerous tissues. Furthermore, immunohistochemistry revealed increased expression of MIA3 in adenomatous tissues. CONCLUSIONS: Taken together, our two independent strategies associate genetic variations in chromosome 1q loci and predisposition to familial CRC and polyps, which warrants further investigation.


Assuntos
Polipose Adenomatosa do Colo/genética , Translocador Nuclear Receptor Aril Hidrocarboneto/genética , Cromossomos Humanos Par 1/genética , Neoplasias Colorretais/genética , Predisposição Genética para Doença , Proteínas de Neoplasias/genética , Translocador Nuclear Receptor Aril Hidrocarboneto/metabolismo , Mapeamento Cromossômico , Proteínas Ativadoras de GTPase/genética , Proteínas Ativadoras de GTPase/metabolismo , Ligação Genética , Genótipo , Homozigoto , Humanos , Repetições de Microssatélites , Proteínas de Neoplasias/metabolismo , Polimorfismo de Nucleotídeo Único , Lesões Pré-Cancerosas/genética , Lesões Pré-Cancerosas/metabolismo , RNA Mensageiro/metabolismo
5.
JHEP Rep ; 6(7): 101088, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38974367

RESUMO

Background & Aims: Autoimmune hepatitis (AIH) and primary biliary cholangitis (PBC) can co-exist in AIH-PBC, requiring combined treatment with immunosuppression and ursodeoxycholic acid (UDCA). The Paris criteria are commonly used to identify these patients; however, the optimal diagnostic criteria are unknown. We aimed to evaluate the use and clinical relevance of both Paris and Zhang criteria. Methods: Eighty-three patients with a clinical suspicion of AIH-PBC who were treated with combination therapy were included. Histology was re-evaluated. Characteristics and long-term outcomes were retrospectively compared to patients with AIH and PBC. Results: Seventeen (24%) patients treated with combination therapy fulfilled the Paris criteria. Fifty-two patients (70%) fulfilled the Zhang criteria. Patients who met Paris and Zhang criteria more often had inflammation and fibrosis on histology compared to patients only meeting the Zhang criteria. Ten-year liver transplant (LT)-free survival was 87.3% (95% CI 78.9-95.7%) in patients with AIH-PBC. This did not differ in patients in or outside the Paris or Zhang criteria (p = 0.46 and p = 0.40, respectively) or from AIH (p = 0.086). LT-free survival was significantly lower in patients with PBC and severe hepatic inflammation - not receiving immunosuppression - compared to those with AIH-PBC (65%; 95% CI 52.2-77.8% vs. 87%; 95% CI 83.2-90.8%; hazard ratio 0.52; p = 0.043). Conclusions: In this study, patients with AIH-PBC outside Paris or Zhang criteria were frequently labeled as having AIH-PBC and were successfully treated with combination therapy with similar outcomes. LT-free survival was worse in patients with PBC and hepatic inflammation than in those treated as having AIH-PBC. More patients may benefit from combination therapy. Impact and implications: This study demonstrated that patients with AIH-PBC variant syndrome treated with combined therapy consisting of immunosuppressants and ursodeoxycholic acid often do not fulfill the Paris criteria. They do however have comparable response to therapy and long-term outcomes as patients who do fulfill the diagnostic criteria. Additionally, patients with PBC and additional signs of hepatic inflammation have poorer long-term outcomes compared to patients treated as having AIH-PBC. These results implicate that a larger group of patients with features of both AIH and PBC may benefit from combined treatment. With our results, we call for improved consensus among experts in the field on the diagnosis and management of AIH-PBC variant syndrome.

7.
BMC Cancer ; 13: 277, 2013 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-23739040

RESUMO

BACKGROUND: p53 (encoded by TP53) is involved in DNA damage repair, cell cycle regulation, apoptosis, aging and cellular senescence. TP53 is mutated in around 50% of human cancers. Nevertheless, the consequences of p53 inactivation in colon cancer outcome remain unclear. Recently, a new role of p53 together with CSNK1A1 in colon cancer invasiveness has been described in mice. METHODS: By combining data on different levels of p53 inactivation, we aimed to predict p53 functionality and to determine its effects on colon cancer outcome. Moreover, survival effects of CSNK1A1 together with p53 were also studied.Eighty-three formalin fixed paraffin embedded colon tumors were enriched for tumor cells using flow sorting, the extracted DNA was used in a custom SNP array to determine chr17p13-11 allelic state; p53 immunostaining, TP53 exons 5, 6, 7 and 8 mutations were determined in combination with mRNA expression analysis on frozen tissue. RESULTS: Patients with a predicted functional p53 had a better prognosis than patients with non functional p53 (Log Rank p=0.009). Expression of CSNK1A1 modified p53 survival effects. Patients with low CSNK1A1 expression and non-functional p53 had a very poor survival both in the univariate (Log Rank p<0.001) and in the multivariate survival analysis (HR=4.74 95% CI 1.45 - 15.3 p=0.009). CONCLUSION: The combination of mutational, genomic, protein and downstream transcriptional activity data predicted p53 functionality which is shown to have a prognostic effect on colon cancer patients. This effect was specifically modified by CSKN1A1 expression.


Assuntos
Adenocarcinoma/genética , Biomarcadores Tumorais/genética , Neoplasias do Colo/genética , Proteína Supressora de Tumor p53/genética , Adenocarcinoma/metabolismo , Adenocarcinoma/mortalidade , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/análise , Neoplasias do Colo/metabolismo , Neoplasias do Colo/mortalidade , Feminino , Citometria de Fluxo , Humanos , Imuno-Histoquímica , Hibridização in Situ Fluorescente , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Prognóstico , Análise Serial de Tecidos , Proteína Supressora de Tumor p53/análise , Proteína Supressora de Tumor p53/metabolismo
8.
J Nucl Med ; 64(1): 82-89, 2023 01.
Artigo em Inglês | MEDLINE | ID: mdl-35680414

RESUMO

Tumor visualization with near-infrared fluorescence (NIRF) imaging might aid exploration and resection of pancreatic cancer by visualizing the tumor in real time. Conjugation of the near-infrared fluorophore IRDye800CW to the monoclonal antibody bevacizumab enables targeting of vascular endothelial growth factor A. The aim of this study was to determine whether intraoperative tumor-specific imaging of pancreatic cancer with the fluorescent tracer bevacizumab-800CW is feasible and safe. Methods: In this multicenter dose-escalation phase I trial, patients in whom pancreatic ductal adenocarcinoma (PDAC) was suspected were administered bevacizumab-800CW (4.5, 10, or 25 mg) 3 d before surgery. Safety monitoring encompassed allergic or anaphylactic reactions and serious adverse events attributed to bevacizumab-800CW. Intraoperative NIRF imaging was performed immediately after laparotomy, just before and after resection of the specimen. Postoperatively, fluorescence signals on the axial slices and formalin-fixed paraffin-embedded tissue blocks from the resected specimens were correlated with histology. Subsequently, tumor-to-background ratios (TBR) were calculated. Results: Ten patients with clinically suspected PDAC were enrolled in the study. Four of the resected specimens were confirmed PDACs; other malignancies were distal cholangiocarcinoma, ampullary carcinoma, and neuroendocrine tumors. No serious adverse events were related to bevacizumab-800CW. In vivo tumor visualization with NIRF imaging differed per tumor type and was nonconclusive. Ex vivo TBRs were 1.3, 1.5, and 2.5 for the 4.5-, 10-, and 25-mg groups, respectively. Conclusion: NIRF-guided surgery in patients with suspected PDAC using bevacizumab-IRDye800CW is feasible and safe. However, suboptimal TBRs were obtained because no clear distinction between pancreatic cancer from normal or inflamed pancreatic tissue was achieved. Therefore, a more tumor-specific tracer than bevacizumab-IRDye800CW for PDAC is preferred.


Assuntos
Carcinoma Ductal Pancreático , Neoplasias Pancreáticas , Humanos , Bevacizumab , Fator A de Crescimento do Endotélio Vascular , Estudos de Viabilidade , Neoplasias Pancreáticas/diagnóstico por imagem , Neoplasias Pancreáticas/cirurgia , Neoplasias Pancreáticas/patologia , Carcinoma Ductal Pancreático/diagnóstico por imagem , Carcinoma Ductal Pancreático/cirurgia , Imagem Óptica/métodos , Corantes Fluorescentes , Neoplasias Pancreáticas
9.
Cell Rep ; 42(6): 112581, 2023 06 27.
Artigo em Inglês | MEDLINE | ID: mdl-37269289

RESUMO

Pancreatic ductal adenocarcinoma (PDAC) is a devastating disease with a limited set of known driver mutations but considerable cancer cell heterogeneity. Phosphoproteomics provides a readout of aberrant signaling and has the potential to identify new targets and guide treatment decisions. Using two-step sequential phosphopeptide enrichment, we generate a comprehensive phosphoproteome and proteome of nine PDAC cell lines, encompassing more than 20,000 phosphosites on 5,763 phospho-proteins, including 316 protein kinases. By using integrative inferred kinase activity (INKA) scoring, we identify multiple (parallel) activated kinases that are subsequently matched to kinase inhibitors. Compared with high-dose single-drug treatments, INKA-tailored low-dose 3-drug combinations against multiple targets demonstrate superior efficacy against PDAC cell lines, organoid cultures, and patient-derived xenografts. Overall, this approach is particularly more effective against the aggressive mesenchymal PDAC model compared with the epithelial model in both preclinical settings and may contribute to improved treatment outcomes in PDAC patients.


Assuntos
Carcinoma Ductal Pancreático , Neoplasias Pancreáticas , Humanos , Linhagem Celular Tumoral , Carcinoma Ductal Pancreático/genética , Neoplasias Pancreáticas/genética , Combinação de Medicamentos , Neoplasias Pancreáticas
10.
PLoS One ; 18(1): e0280939, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36696439

RESUMO

BACKGROUND: The diagnostic process of patients with suspect pancreatic lesions is often lengthy and prone to repeated diagnostic procedures due to inconclusive results. Targeted Next-Generation Sequencing (NGS) performed on cytological material obtained with fine needle aspiration (FNA) or biliary duct brushing can speed up this process. Here, we study the incremental value of NGS for establishing the correct diagnosis, and subsequent treatment plan in patients with inconclusive diagnosis after regular diagnostic work-up for suspect pancreatic lesions. METHODS: In this prospective cross-sectional cohort study, patients were screened for inclusion in four hospitals. NGS was performed with AmpliSeq Cancer Hotspot Panel v2 and v4b in patients with inconclusive cytology results or with an uncertain diagnosis. Diagnostic results were evaluated by the oncology pancreatic multidisciplinary team. The added value of NGS was determined by comparing diagnosis (malignancy, cystic lesion or benign condition) and proposed treatment plan (exploration/resection, neoadjuvant chemotherapy, follow-up, palliation or repeated FNA) before and after integration of NGS results. Final histopathological analysis or a 6-month follow-up period were used as the reference standard in case of surgical intervention or non-invasive treatment, respectively. RESULTS: In 50 of the 53 included patients, cytology material was sufficient for NGS analysis. Diagnosis before and after integration of NGS results differed in 24% of the patients. The treatment plan was changed in 32% and the diagnosis was substantiated by the NGS data in 44%. Repetition of FNA/brushing was prevented in 14% of patients. All changes in treatment plan were correctly made after integration of NGS. Integration of NGS increased overall diagnostic accuracy from 68% to 94%. INTERPRETATION: This study demonstrates the incremental diagnostic value of NGS in patients with an initial inconclusive diagnosis. Integration of NGS results can prevent repeated EUS/FNA, and can also rigorously change the final diagnosis and treatment plan.


Assuntos
Neoplasias Pancreáticas , Humanos , Estudos Transversais , Neoplasias Pancreáticas/diagnóstico , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/patologia , Estudos Prospectivos , Pâncreas/patologia , Sequenciamento de Nucleotídeos em Larga Escala , Aspiração por Agulha Fina Guiada por Ultrassom Endoscópico
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