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1.
Int J Cancer ; 146(8): 2296-2304, 2020 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-31901133

RESUMO

The tumor-stroma ratio (TSR) was evaluated as a promising parameter for breast cancer prognostication in clinically relevant subgroups of patients. The TSR was assessed on hematoxylin and eosin-stained tissue slides of 1,794 breast cancer patients from the Nottingham City Hospital. An independent second cohort of 737 patients from the Netherlands Cancer Institute to Antoni van Leeuwenhoek was used for evaluation. In the Nottingham Breast Cancer series, the TSR was an independent prognostic parameter for recurrence-free survival (RFS; HR 1.35, 95% CI 1.10-1.66, p = 0.004). The interaction term was statistically significant for grade and triple-negative status. Multivariate Cox regression analysis showed a more pronounced effect of the TSR for RFS in grade III tumors (HR 1.89, 95% CI 1.43-2.51, p < 0.001) and triple-negative tumors (HR 1.86, 95% CI 1.10-3.14, p = 0.020). Comparable hazard ratios and confidence intervals were observed for grade and triple-negative status in the ONCOPOOL study. The prognostic value of TSR was not modified by age, tumor size, histology, estrogen receptor status, progesterone receptor status, human epidermal growth factor receptor 2 status or lymph node status. In conclusion, patients with a stroma-high tumor had a worse prognosis compared to patients with a stroma-low tumor. The prognostic value of the TSR is most discriminative in grade III tumors and triple-negative tumors. The TSR was not modified by other clinically relevant parameters making it a potential factor to be included for improved risk stratification.

2.
Breast Cancer Res Treat ; 179(1): 37-45, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31535319

RESUMO

PURPOSE: The tumour microenvironment in older patients is subject to changes. The tumour-stroma ratio (TSR) was evaluated in order to estimate the amount of intra-tumoural stroma and to evaluate the prognostic value of the TSR in older patients with breast cancer (≥ 70 years). METHODS: Two retrospective cohorts, the FOCUS study (N = 619) and the Nottingham Breast Cancer series (N = 1793), were used for assessment of the TSR on haematoxylin and eosin stained tissue slides. RESULTS: The intra-tumoural stroma increases with age in the FOCUS study and the Nottingham Breast Cancer series (B 0.031, 95% CI 0.006-0.057, p = 0.016 and B 0.034, 95% CI 0.015-0.054, p < 0.001, respectively). Fifty-one per cent of the patients from the Nottingham Breast Cancer series < 40 years had a stroma-high tumour compared to 73% of the patients of ≥ 90 years from the FOCUS study. The TSR did not validate as an independent prognostic parameter in patients ≥ 70 years. CONCLUSIONS: The intra-tumoural stroma increases with age. This might be the result of an activated tumour microenvironment. The TSR did not validate as an independent prognostic parameter in patients ≥ 70 years in contrast to young women with breast cancer as published previously.

3.
Breast Cancer Res ; 21(1): 144, 2019 12 17.
Artigo em Inglês | MEDLINE | ID: mdl-31847907

RESUMO

BACKGROUND: Breast cancer survivors are at risk for contralateral breast cancer (CBC), with the consequent burden of further treatment and potentially less favorable prognosis. We aimed to develop and validate a CBC risk prediction model and evaluate its applicability for clinical decision-making. METHODS: We included data of 132,756 invasive non-metastatic breast cancer patients from 20 studies with 4682 CBC events and a median follow-up of 8.8 years. We developed a multivariable Fine and Gray prediction model (PredictCBC-1A) including patient, primary tumor, and treatment characteristics and BRCA1/2 germline mutation status, accounting for the competing risks of death and distant metastasis. We also developed a model without BRCA1/2 mutation status (PredictCBC-1B) since this information was available for only 6% of patients and is routinely unavailable in the general breast cancer population. Prediction performance was evaluated using calibration and discrimination, calculated by a time-dependent area under the curve (AUC) at 5 and 10 years after diagnosis of primary breast cancer, and an internal-external cross-validation procedure. Decision curve analysis was performed to evaluate the net benefit of the model to quantify clinical utility. RESULTS: In the multivariable model, BRCA1/2 germline mutation status, family history, and systemic adjuvant treatment showed the strongest associations with CBC risk. The AUC of PredictCBC-1A was 0.63 (95% prediction interval (PI) at 5 years, 0.52-0.74; at 10 years, 0.53-0.72). Calibration-in-the-large was -0.13 (95% PI: -1.62-1.37), and the calibration slope was 0.90 (95% PI: 0.73-1.08). The AUC of Predict-1B at 10 years was 0.59 (95% PI: 0.52-0.66); calibration was slightly lower. Decision curve analysis for preventive contralateral mastectomy showed potential clinical utility of PredictCBC-1A between thresholds of 4-10% 10-year CBC risk for BRCA1/2 mutation carriers and non-carriers. CONCLUSIONS: We developed a reasonably calibrated model to predict the risk of CBC in women of European-descent; however, prediction accuracy was moderate. Our model shows potential for improved risk counseling, but decision-making regarding contralateral preventive mastectomy, especially in the general breast cancer population where limited information of the mutation status in BRCA1/2 is available, remains challenging.

4.
Int J Cancer ; 2019 Nov 12.
Artigo em Inglês | MEDLINE | ID: mdl-31721193

RESUMO

Delayed time to chemotherapy (TTC) is associated with decreased outcomes of breast cancer patients. Recently, studies suggested that the association might be subtype-dependent and that TTC within 30 days should be warranted in patients with triple-negative breast cancer (TNBC). The aim of the current study is to determine if TTC beyond 30 days is associated with reduced 10-year overall survival in TNBC patients. We identified all TNBC patients diagnosed between 2006 and 2014 who received adjuvant chemotherapy in the Netherlands. We distinguished between breast-conserving surgery (BCS) vs. mastectomy given the difference in preoperative characteristics and outcomes. The association was estimated with hazard ratios (HRs) using propensity-score matched Cox proportional hazard analyses. In total, 3,016 patients were included. In matched patients who underwent BCS (n = 904), 10-year overall survival was favorable for patients with TTC within 30 days (84.4% vs. 76.9%, p = 0.001). Patients with TTC beyond 30 days were more likely than those with TTC within 30 days to die within 10 years after surgery (HR 1.69 (95% CI 1.22-2.34), p = 0.002). In matched patients who underwent mastectomy (n = 1,568), there was no difference in 10 years overall survival between those with TTC within or beyond 30 days (74.5% vs. 74.7%, p = 0.716), nor an increased risk of death for those with TTC beyond 30 days (HR 1.04 (95% CI 0.84-1.28), p = 0.716). Initiation of adjuvant chemotherapy beyond 30 days is associated with decreased 10 years overall survival in TNBC patients who underwent BCS. Therefore, timelier initiation of chemotherapy in TNBC patients undergoing BCS seems warranted.

5.
Talanta ; 205: 120104, 2019 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-31450448

RESUMO

Body fluid N-glycome analysis as well as glyco-proteoform profiling of existing protein biomarkers potentially provides a stratification layer additional to quantitative, diagnostic protein levels. For clinical omics applications, the collection of a dried blood spot (DBS) is increasingly pursued as an alternative to sampling milliliters of peripheral blood. Here we evaluate DBS cards as a blood collection strategy for protein N-glycosylation analysis aiming for high-throughput clinical applications. A protocol for facile N-glycosylation profiling from DBS is developed that includes sialic acid linkage differentiation. This protocol is based on a previously established total plasma N-glycome mass spectrometry (MS) method, with adjustments for the analysis of DBS specimens. After DBS-punching and protein solubilization N-glycans are released, followed by chemical derivatization of sialic acids and MS-measurement of N-glycan profiles. With this method, more than 80 different glycan structures are identified from a DBS, with RSDs below 10% for the ten most abundant glycans. N-glycan profiles of finger-tip blood and venous blood are compared and short-term stability of DBS is demonstrated. This method for fast N-glycosylation profiling of DBS provides a minimally invasive alternative to conventional serum and plasma protein N-glycosylation workflows. With simplified blood sampling this DBS approach has vast potential for clinical glycomics applications.


Assuntos
Teste em Amostras de Sangue Seco/métodos , Glicômica/métodos , Polissacarídeos/sangue , Humanos , Polissacarídeos/química , Ácidos Siálicos/química , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por Matriz/métodos
6.
Lancet Oncol ; 20(8): 1136-1147, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31221620

RESUMO

BACKGROUND: Approximately 15% of all breast cancers occur in women with a family history of breast cancer, but for whom no causative hereditary gene mutation has been found. Screening guidelines for women with familial risk of breast cancer differ between countries. We did a randomised controlled trial (FaMRIsc) to compare MRI screening with mammography in women with familial risk. METHODS: In this multicentre, randomised, controlled trial done in 12 hospitals in the Netherlands, women were eligible to participate if they were aged 30-55 years and had a cumulative lifetime breast cancer risk of at least 20% because of a familial predisposition, but were BRCA1, BRCA2, and TP53 wild-type. Participants who were breast-feeding, pregnant, had a previous breast cancer screen, or had a previous a diagnosis of ductal carcinoma in situ were eligible, but those with a previously diagnosed invasive carcinoma were excluded. Participants were randomly allocated (1:1) to receive either annual MRI and clinical breast examination plus biennial mammography (MRI group) or annual mammography and clinical breast examination (mammography group). Randomisation was done via a web-based system and stratified by centre. Women who did not provide consent for randomisation could give consent for registration if they followed either the mammography group protocol or the MRI group protocol in a joint decision with their physician. Results from the registration group were only used in the analyses stratified by breast density. Primary outcomes were number, size, and nodal status of detected breast cancers. Analyses were done by intention to treat. This trial is registered with the Netherlands Trial Register, number NL2661. FINDINGS: Between Jan 1, 2011, and Dec 31, 2017, 1355 women provided consent for randomisation and 231 for registration. 675 of 1355 women were randomly allocated to the MRI group and 680 to the mammography group. 218 of 231 women opting to be in a registration group were in the mammography registration group and 13 were in the MRI registration group. The mean number of screening rounds per woman was 4·3 (SD 1·76). More breast cancers were detected in the MRI group than in the mammography group (40 vs 15; p=0·0017). Invasive cancers (24 in the MRI group and eight in the mammography group) were smaller in the MRI group than in the mammography group (median size 9 mm [5-14] vs 17 mm [13-22]; p=0·010) and less frequently node positive (four [17%] of 24 vs five [63%] of eight; p=0·023). Tumour stages of the cancers detected at incident rounds were significantly earlier in the MRI group (12 [48%] of 25 in the MRI group vs one [7%] of 15 in the mammography group were stage T1a and T1b cancers; one (4%) of 25 in the MRI group and two (13%) of 15 in the mammography group were stage T2 or higher; p=0·035) and node-positive tumours were less frequent (two [11%] of 18 in the MRI group vs five [63%] of eight in the mammography group; p=0·014). All seven tumours stage T2 or higher were in the two highest breast density categories (breast imaging reporting and data system categories C and D; p=0·0077) One patient died from breast cancer during follow-up (mammography registration group). INTERPRETATION: MRI screening detected cancers at an earlier stage than mammography. The lower number of late-stage cancers identified in incident rounds might reduce the use of adjuvant chemotherapy and decrease breast cancer-related mortality. However, the advantages of the MRI screening approach might be at the cost of more false-positive results, especially at high breast density. FUNDING: Dutch Government ZonMw, Dutch Cancer Society, A Sister's Hope, Pink Ribbon, Stichting Coolsingel, J&T Rijke Stichting.

8.
Cell Oncol (Dordr) ; 42(3): 397-403, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30847807

RESUMO

PURPOSE: Lack of expression of the intestinal transcription factor CDX2 in colorectal cancer (CRC) identifies patients with a poor prognosis. This biomarker has previously been suggested to be prognostic in CRCs with a high stromal content based on mRNA expression data. We investigated the prognostic value of CDX2 expression in microsatellite stable CRC stratified by stromal content using microscopy-based techniques. METHODS AND RESULTS: The study included a cohort of 236 patients with stage I-IV CRC. We assessed by microscopy the tumour-stroma ratio (TSR) and the immunohistochemical CDX2 intensity. We found that patients of the stroma-high group had a worse prognosis compared to those of the stroma-low group [disease-free survival in a multivariate analysis (DFSmultivariate) HR 1.52 (95% CI 1.05-2.21)]. In our cohort, low CDX2 expression (14.6%) showed prognostic value for DFSmultivariate [HR 1.93 (95% CI 1.16-3.23)]. Interestingly, when stratifying the cohort by TSR, no prognostic difference was observed related to CDX2 expression in stroma-low tumours. However, CDX2 expression was found to be prognostic within the stroma-high group [DFSmultivariate HR 3.02 (95% CI 1.49-6.13)]. The p value for interaction between TSR and CDX2 status was borderline significant in DFS (p = 0.071). CONCLUSIONS: The present study confirms a poor outcome of patients with stroma-high tumours. Low CDX2 expression in tumours with a high stromal content identified patients with a particularly poor prognosis. The present study did not reveal a clear difference in TSR associated with CDX2 status and survival. This method, solely based on microscopy, identifies patients who have a high risk of relapse and a poor outcome, and who may benefit from targeted therapy.


Assuntos
Biomarcadores Tumorais/biossíntese , Fator de Transcrição CDX2/biossíntese , Neoplasias Colorretais/metabolismo , Células Estromais/metabolismo , Idoso , Neoplasias Colorretais/patologia , Neoplasias Colorretais/terapia , Feminino , Humanos , Imuno-Histoquímica , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Prognóstico , Estudos Retrospectivos , Células Estromais/patologia
9.
BMC Cancer ; 19(1): 284, 2019 Mar 29.
Artigo em Inglês | MEDLINE | ID: mdl-30922247

RESUMO

BACKGROUND: The tumor microenvironment has a critical role in regulating cancer cell behavior. Tumors with high stromal content are associated with poor patient outcome. The tumor-stroma ratio (TSR) identifies colorectal cancers (CRC) with poor patient prognosis based on hematoxylin & eosin stained sections. The desmoplastic reaction consists to a great extent of cancer-associated fibroblasts (CAFs) of which different subtypes are known. The aim of this study is to investigate and quantify CAFs present in the tumor stroma of CRC stratified by the TSR to possibly add prognostic significance to the TSR. METHODS: The expression of established CAF markers was compared between stroma-low and stroma-high tumors using transcriptomic data of 71 stage I - III CRC. Based on literature, fibroblast and stromal markers were selected to perform multiplex immunofluorescent staining on formalin fixed, paraffin-embedded tumor sections of patients diagnosed with stage III colon cancer. Antibodies against the following markers were used: αSMA, PDGFR -ß, FAP, FSP1 and the stromal markers CD45 and CD31 as reference. The markers were subsequently quantified in the stroma using the Vectra imaging microscope. RESULTS: The transcriptomic data showed that all CAF markers except one were higher expressed in stroma-high compared to stroma-low tumors. Histologically, stroma-high tumors showed a decreased number of FSP1+/CD45+ cells and a trend of an increased expression of FAP compared to stroma-low tumors. FAP was higher expressed at the invasive part compared to the tumor center in both stroma-high and stroma-low tumors. CONCLUSIONS: The increased expression of FAP at the invasive part and in stroma-high tumors might contribute to the invasive behavior of cancer cells. Future functional experiments should investigate the contribution of FAP to cancer cell invasion. Combining the quantity of the stroma as defined by the TSR with the activity level of CAFs using the expression of FAP may result in an expanded stroma-based tool for patient stratification.


Assuntos
Fibroblastos Associados a Câncer/química , Neoplasias Colorretais/genética , Gelatinases/genética , Perfilação da Expressão Gênica/métodos , Proteínas de Membrana/genética , Serina Endopeptidases/genética , Regulação para Cima , Biomarcadores Tumorais/genética , Linhagem Celular Tumoral , Neoplasias Colorretais/patologia , Regulação Neoplásica da Expressão Gênica , Humanos , Invasividade Neoplásica , Estadiamento de Neoplasias , Análise de Sequência com Séries de Oligonucleotídeos , Prognóstico , Microambiente Tumoral
11.
Ann Thorac Surg ; 107(4): 1024-1031, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30557538

RESUMO

BACKGROUND: Accurate staging of the mediastinal lymph nodes is of great importance to determine optimal treatment options in non-small cell lung cancer (NSCLC). In case of suspected mediastinal metastases, endoscopic/endobronchial ultrasound combined with mediastinoscopy is the gold standard. The diagnostic value of these procedures stands or falls by how they are technically performed. This study used data from the Dutch Lung Cancer Audit for Surgery to evaluate surgical performance of mediastinoscopies in The Netherlands. METHODS: The study included all patients with a mediastinoscopy for staging of NSCLC and subsequent resection from 2012 to 2016. Complete case analysis was performed, excluding patients with missing data on biopsies or tumor side. Location and number of biopsied stations and adherence to guidelines for performing mediastinoscopy were analyzed. The proportion of unforeseen mediastinal lymph node metastases (unforeseen N2) was compared between mediastinoscopies that did or did not comply with the Dutch guideline. RESULTS: The analysis included 1,729 patients. Mediastinoscopies were performed according to the Dutch guideline (requirements: biopsies of 2 ipsilateral stations, 1 contralateral station, and N7) in 51.4% (n = 888) and according to the European Society of Thoracic Surgeons guideline (N4 left, N4 right, and N7) in 75.4% (n = 1,303). Overall, unforeseen N2 was present in 10.2% (n = 140). In mediastinoscopies performed according to the Dutch guideline, unforeseen N2 occurred less often (8.6%) than in the nonadherence group (11.9%; p = 0.043). CONCLUSIONS: There is improvement potential in surgical performance of mediastinoscopy in The Netherlands, which is reflected by the percentage of guideline adherence and the occurrence of unforeseen N2.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/patologia , Carcinoma Pulmonar de Células não Pequenas/cirurgia , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/cirurgia , Linfonodos/patologia , Mediastinoscopia/métodos , Idoso , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Estudos de Coortes , Intervalo Livre de Doença , Feminino , Humanos , Neoplasias Pulmonares/mortalidade , Linfonodos/cirurgia , Masculino , Neoplasias do Mediastino/mortalidade , Neoplasias do Mediastino/secundário , Neoplasias do Mediastino/cirurgia , Pessoa de Meia-Idade , Invasividade Neoplásica/patologia , Estadiamento de Neoplasias , Países Baixos , Guias de Prática Clínica como Assunto/normas , Prognóstico , Sistema de Registros , Estudos Retrospectivos , Medição de Risco , Análise de Sobrevida , Resultado do Tratamento
12.
Ann Surg ; 270(2): 364-372, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-29727326

RESUMO

OBJECTIVE: To investigate the effects of different types of surgery on breast cancer prognosis in germline BRCA1/BRCA2 mutation carriers compared with noncarriers. SUMMARY OF BACKGROUND DATA: Although breast-conserving therapy (breast-conserving surgery followed by radiotherapy) has been associated with more local recurrences than mastectomy, no differences in overall survival have been found in randomized trials performed in the general breast cancer population. Whether breast-conservation can be safely offered to BRCA1/2 mutation carriers is debatable. METHODS: The study comprised a cohort of women with invasive breast cancer diagnosed <50 years and treated between 1970 and 2003 in 10 Dutch centers. Germline DNA for BRCA1/2 testing of most-prevalent mutations (covering ∼61%) was mainly derived from paraffin-blocks. Survival analyses were performed taking into account competing risks. RESULTS: In noncarriers (N = 5820), as well as in BRCA1 (N = 191) and BRCA2 (N = 70) mutation carriers, approximately half of the patients received breast-conserving therapy. Patients receiving mastectomy followed by radiotherapy had prognostically worse tumor characteristics and more often received systemic therapy. After adjustment for these potential confounders, patients who received breast-conserving therapy had a similar overall survival compared with patients who received mastectomy, both in noncarriers (hazard ratio [HR] = 0.95, confidence interval [CI] = 0.85-1.07, P = 0.41) and BRCA1 mutation carriers (HR = 0.80, CI = 0.42-1.51, P = 0.50). Numbers for BRCA2 were insufficient to draw conclusions. The rate of local recurrences after breast-conserving therapy did not differ between BRCA1 carriers (10-year risk = 7.3%) and noncarriers (10-year risk = 7.9%). CONCLUSION: Our results, together with the available literature, provide reassurance that breast-conserving therapy is a safe local treatment option to offer to BRCA1 mutation carriers with invasive breast cancer.


Assuntos
Proteína BRCA1/genética , Proteína BRCA2/genética , Neoplasias da Mama/cirurgia , DNA de Neoplasias/genética , Mastectomia Radical/métodos , Mastectomia Segmentar/métodos , Mutação , Adulto , Proteína BRCA1/metabolismo , Proteína BRCA2/metabolismo , Neoplasias da Mama/genética , Neoplasias da Mama/mortalidade , Análise Mutacional de DNA , Feminino , Heterozigoto , Humanos , Pessoa de Meia-Idade , Países Baixos/epidemiologia , Prognóstico , Taxa de Sobrevida/tendências
13.
Anal Chem ; 90(20): 11955-11961, 2018 10 16.
Artigo em Inglês | MEDLINE | ID: mdl-30230816

RESUMO

High-throughput mass spectrometry (MS) glycomics is an emerging field driven by technological advancements including sample preparation and data processing. Previously, we reported an automated protocol for the analysis of N-glycans released from plasma proteins that included sialic acid derivatization with linkage-specificity, namely, ethylation of α2,6-linked sialic acid residues and lactone formation of α2,3-linked sialic acids. In the current study, each step in this protocol was further optimized. Method improvements included minimizing the extent of side-reaction during derivatization, an adjusted glycan purification strategy and mass analysis of the released N-glycans by ultrahigh resolution matrix-assisted laser desorption/ionization Fourier transform ion cyclotron resonance MS. The latter resolved peak overlap and simplified spectral alignment due to high mass measurement precision. Moreover, this resulted in more confident glycan assignments and improved signal-to-noise for low-abundant species. The performance of the protocol renders high-throughput applications feasible in the exciting field of clinical glycomics.


Assuntos
Automação , Proteínas Sanguíneas/química , Ácido N-Acetilneuramínico/química , Polissacarídeos/sangue , Glicômica , Glicosilação , Humanos , Espectrometria de Massas , Polissacarídeos/química
14.
Oncotarget ; 9(59): 31502-31515, 2018 07 31.
Artigo em Inglês | MEDLINE | ID: mdl-30140386

RESUMO

The tumor microenvironment is a dominant determinant of cancer cell behavior. Reactive tumor stroma is associated with poor outcome perspective. The tumor-stroma ratio (TSR) is a strong independent prognostic factor in colorectal cancer and is easily assessed using conventional hematoxylin and eosin (H&E) stained paraffin sections at the invasive margin of the tumor. We aim to understand the biology of the tumor stroma in colorectal cancer by investigating the transcriptomic profiles of tumors classified by the TSR method. The TSR was assessed in a cohort of 71 colorectal cancer patients undergoing surgery without (neo)adjuvant therapy. In the cohort, stroma-high tumors were distinguished from stroma-low tumors at gene expression level in the upregulation of biological pathways related to extracellular matrix (ECM) remodeling and myogenesis. The activated microenvironment in stroma-high tumors overexpressed different types of collagen genes, THBS2 and 4 as well as INHBA, COX71A and LGALS1/galectin-1. The upregulation of THBS2, COX7A1 and LGALS1/galectin-1 in stroma-high tumors was validated in The Cancer Genome Atlas [corrected]. In conclusion, the gene expression data reflects the high stromal content of tumors assessed based on the histological method, the TSR. The composition of the microenvironment suggests an altered proteolysis resulting in ECM remodeling and invasive capacity of tumor cells.

15.
Oncotarget ; 9(55): 30610-30623, 2018 Jul 17.
Artigo em Inglês | MEDLINE | ID: mdl-30093973

RESUMO

Proteins are routinely measured in clinical laboratories for diagnosis, prognosis and therapy monitoring. Nevertheless, both test improvements (performance) and innovations (biomarkers) are needed, and protein N-glycosylation offers a rich source of potential markers. Here, we have analyzed the total serum N-glycome in a matched case-control study (124 cases versus 124 controls) of colorectal cancer patients. The results were validated in an independent sample cohort (both 61 cases versus 61 controls) and further tested in post-operative samples of cured patients. Our results revealed significant differences between patients and controls, with increased size (antennae) and sialylation of the N-glycans in the colorectal cancer patient sera as compared to mainly di-antennary N-glycans in sera from controls. Furthermore, glycan alterations showed strong associations with cancer stage and survival: The five-year survival rate largely varied between patients with an altered serum N-glycome (46%) and an N-glycome similar to controls (87%). Importantly, the total serum N-glycome showed prognostic value beyond age and stage. This clinical glycomics study provides novel serum biomarker candidates and shows the potential of total serum N-glycans as a prognostic panel. Moreover, serum N-glycome changes reverted to a control-like profile after successful treatment as was demonstrated from pre- and post-operative samples.

16.
J Natl Compr Canc Netw ; 16(7): 822-828, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-30006424

RESUMO

Background: According to Dutch guidelines, locally excised, low-risk, pT1 or ypT0-1 rectal cancer should not necessarily be followed by completion total mesorectal excision (cTME) in contrast to rectal cancers with higher T stages or unfavorable features. This study evaluated cTME after local excision at a national level with possible determinants for decision-making. Methods: All patients in the Dutch Colorectal Audit (DCRA) who underwent local excision of rectal cancer between 2012 and 2015 were included. Guideline adherence for performing cTME was determined with univariate and multivariate analyses to identify factors related to noncompliance. Results: According to the guidelines, of 530 included patients, cTME was indicated in 283 (53%), and among those, was performed in 82 (29%). Guideline adherence for performing cTME improved significantly (P<.001), from 10% in 2012 to 44% in 2015. Lower Charlson comorbidity index in patients with high-risk pT1 rectal cancer and younger patients (aged 61-70 years vs ≥80 years) with pT≥2 rectal cancer were associated with increased performance of cTME (odds ratio [OR], 13.50; 95% CI, 1.39-131.32, and OR, 6.25; 95% CI, 1.83-21.31, respectively). Conclusions: In this population-based study from the Netherlands, only a minority of patients underwent cTME after local excision of rectal cancer with pathologic features indicating the need for further treatment according to the guidelines. Although the percentage of patients undergoing cTME increased over time, the study indicated a tendency toward rectal-preserving treatment with potential oncologic risks.


Assuntos
Procedimentos Cirúrgicos do Sistema Digestório/normas , Fidelidade a Diretrizes/estatística & dados numéricos , Recidiva Local de Neoplasia/prevenção & controle , Tratamentos com Preservação do Órgão/normas , Neoplasias Retais/terapia , Reto/cirurgia , Idoso , Idoso de 80 Anos ou mais , Quimiorradioterapia Adjuvante , Auditoria Clínica/estatística & dados numéricos , Procedimentos Cirúrgicos do Sistema Digestório/métodos , Procedimentos Cirúrgicos do Sistema Digestório/estatística & dados numéricos , Intervalo Livre de Doença , Feminino , Humanos , Masculino , Margens de Excisão , Pessoa de Meia-Idade , Terapia Neoadjuvante/normas , Terapia Neoadjuvante/estatística & dados numéricos , Estadiamento de Neoplasias , Países Baixos/epidemiologia , Tratamentos com Preservação do Órgão/métodos , Tratamentos com Preservação do Órgão/estatística & dados numéricos , Guias de Prática Clínica como Assunto , Estudos Prospectivos , Neoplasias Retais/mortalidade , Neoplasias Retais/patologia , Reto/patologia , Resultado do Tratamento
17.
Int J Cancer ; 143(12): 3194-3200, 2018 12 15.
Artigo em Inglês | MEDLINE | ID: mdl-29978463

RESUMO

The tumor-stroma ratio (TSR) has previously been found to be a strong prognostic parameter in primary breast cancer tumors. Since the presence of tumor cells in lymph nodes is important for clinical decision making, the influence of TSR in the primary breast tumor combined with the TSR in tumor-positive lymph nodes on prognosis was evaluated. Women with invasive breast cancer without distant metastasis who underwent an axillary lymph node dissection between 1985 and 1994 at the Leiden University Medical Center were retrospectively analyzed. TSR assessment was performed on hematoxylin and eosin stained tissue slides. In total, 87 (45.5%) primary tumors were scored as stroma-low and 104 (54.5%) as stroma-high. Patients with a high stromal percentage in the primary tumors had a statistically significant worse relapse free period (RFP) compared to stroma-low tumors (HR 1.97, 95% CI 1.37-2.82, p < 0.001). A total number of 915 lymph nodes were assessed for TSR. In 101 (52.9%) patients, heterogeneity was observed between stroma percentage category in primary tumor and lymph nodes. The combination of TSR of the primary tumor combined with TSR of tumor-positive lymph nodes strengthened each other as independent prognostic parameter for RFP (p = 0.019). Patients with primary tumor stroma-low/lymph nodes stroma-low tumors showed strongly improved RFP rates compared to patients with primary tumor stroma-high/lymph node stroma-high tumors with 10-year percentages of 58 versus 8%, respectively. Assessing the TSR on tumor-positive lymph nodes can provide additional prognostic information. Stromal activation strongly differs between primary tumors and lymph node metastasis.


Assuntos
Neoplasias da Mama/patologia , Metástase Linfática/patologia , Células Estromais/patologia , Adulto , Axila/patologia , Intervalo Livre de Doença , Feminino , Humanos , Pessoa de Meia-Idade , Prognóstico , Estudos Retrospectivos
18.
Eur J Surg Oncol ; 44(9): 1361-1370, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-29937415

RESUMO

INTRODUCTION: The efficacy of auditing is still a subject of debate and concerns exist whether auditing promotes risk averse behaviour of physicians. This study evaluates the achievements made in colorectal cancer surgery since the start of a national clinical audit and assesses potential signs of risk averse behaviour. METHODS: Data were extracted from the Dutch ColoRectal Audit (2009-2016). Trends in outcomes were evaluated by uni and multivariable analyses. Patients were stratified according to operative risks and changes in outcomes were expressed as absolute (ARR) and relative risk reduction (RRR). To assess signs of risk averse behaviour, trends in stoma construction in rectal cancer were analysed. RESULTS: Postoperative mortality decreased from 3.4% to 1.8% in colon cancer and from 2.3% to 1% in rectal cancer. Surgical and non-surgical complications increased, but with less reintervention. For colon cancer, the high-risk elderly patients had the largest ARR for complicated postoperative course (6.4%) and mortality (5.9%). The proportion of patients receiving a diverting stoma or end colostomy after a (L)AR decreased 11% and 7%, respectively. In low rectal cancer, patients increasingly received a non-diverted primary anastomosis (5.4% in 2011 and 14.4% in 2016). CONCLUSIONS: No signs of risk averse behaviour was found since the start of the audit. Especially the high-risk elderly patients seem to have benefitted from improvements made in colon cancer treatment in the past 8 years. For rectal cancer, trends towards the construction of more primary anastomoses are seen. Future quality improvement measures should focus on reducing surgical and non-surgical complications.


Assuntos
Auditoria Clínica/tendências , Neoplasias Colorretais/cirurgia , Cirurgia Colorretal/normas , Procedimentos Cirúrgicos do Sistema Digestório/normas , Complicações Pós-Operatórias/epidemiologia , Idoso , Idoso de 80 Anos ou mais , Neoplasias Colorretais/mortalidade , Feminino , Mortalidade Hospitalar/tendências , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Países Baixos/epidemiologia , Estudos Retrospectivos , Taxa de Sobrevida/tendências
19.
Eur J Surg Oncol ; 44(12): 1849-1857, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-29937416

RESUMO

BACKGROUND: Obesity is an increasing problem worldwide that can influence perioperative and postoperative outcomes. However, the relationship between obesity and treatment-related perioperative and short-term postoperative morbidity after colorectal resections is still subject to debate. STUDY: Patients were selected from the DCRA, a population-based audit including 83 hospitals performing colorectal cancer (CRC) surgery. Data regarding primary resections between 2009 and 2016 were eligible for analyses. Patients were subdivided into six categories: underweight, normal weight, overweight and obesity class I, II and III. RESULTS: Of 71,084 patients, 17.7% with colon and 16.4% with rectal cancer were categorized as obese. Significant differences were found for the 30-day overall postoperative complication rate (p < 0.001), prolonged hospitalization (p < 0.001) and readmission rate (colon cancer p < 0.005; rectal cancer p < 0.002) in obese CRC patients. Multivariate analysis identified BMI ≥30 kg/m2 as independent predictor of a complicated postoperative course in CRC patients. Furthermore, obesity-related comorbidities were associated with higher postoperative morbidity, prolonged hospitalization and a higher readmission rate. No significant differences in performance were observed in postoperative outcomes of morbidly obese CRC patients between hospitals performing bariatric surgery and hospitals that did not. CONCLUSION: The real-life data analysed in this study reflect daily practice in the Netherlands and identify obesity as a significant risk factor in CRC patients. Obesity-related comorbidities were associated with higher postoperative morbidity, prolonged hospitalization and a higher readmission rate in obese CRC patients. No differences were observed between hospitals performing bariatric surgery and hospitals that did not.


Assuntos
Neoplasias Colorretais/cirurgia , Complicações Intraoperatórias/epidemiologia , Obesidade/complicações , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Tempo de Internação/estatística & dados numéricos , Masculino , Pessoa de Meia-Idade , Países Baixos/epidemiologia , Readmissão do Paciente/estatística & dados numéricos , Complicações Pós-Operatórias/epidemiologia , Fatores de Risco , Resultado do Tratamento
20.
Psychooncology ; 27(7): 1772-1779, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-29624807

RESUMO

BACKGROUND: Meaning-centered group psychotherapy for cancer survivors (MCGP-CS) improves meaning, psychological well-being, and mental adjustment to cancer and reduces psychological distress. This randomized controlled trial was conducted to investigate the cost-utility of MCGP-CS compared with supportive group psychotherapy (SGP) and care-as-usual (CAU). METHODS: In total, 170 patients were randomized to MCGP-CS, SGP, or CAU. Intervention costs, direct medical and nonmedical costs, productivity losses, and health-related quality of life were measured until 6 months follow-up, using the TIC-P, PRODISQ, data from the hospital information system, and the EQ-5D. The cost-utility was calculated by comparing mean cumulative costs and quality-adjusted life years (QALYs). RESULTS: Mean total costs ranged from €4492 (MCGP-CS) to €5304 (CAU). Mean QALYs ranged .507 (CAU) to .540 (MCGP-CS). MCGP-CS had a probability of 74% to be both less costly and more effective than CAU, and 49% compared with SGP. Sensitivity analyses showed these findings are robust. If society is willing to pay €0 for one gained QALY, MCGP-CS has a 78% probability of being cost-effective compared with CAU. This increases to 85% and 92% at willingness-to-pay thresholds of €10 000 and €30 000, which are commonly accepted thresholds. CONCLUSIONS: MCGP-CS is highly likely a cost-effective intervention, meaning that there is a positive balance between the costs and gains of MCGP-CS, in comparison with SGP and CAU.


Assuntos
Sobreviventes de Câncer/psicologia , Neoplasias/economia , Neoplasias/terapia , Psicoterapia de Grupo/métodos , Qualidade de Vida/psicologia , Adulto , Idoso , Análise Custo-Benefício , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias/psicologia , Psicoterapia/economia , Psicoterapia de Grupo/economia , Anos de Vida Ajustados por Qualidade de Vida , Autoimagem , Grupos de Autoajuda/economia , Conduta Expectante
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