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1.
Br J Cancer ; 128(7): 1369-1376, 2023 03.
Artigo em Inglês | MEDLINE | ID: mdl-36717673

RESUMO

BACKGROUND: Fast and accurate diagnostics are key for personalised medicine. Particularly in cancer, precise diagnosis is a prerequisite for targeted therapies, which can prolong lives. In this work, we focus on the automatic identification of gastroesophageal adenocarcinoma (GEA) patients that qualify for a personalised therapy targeting epidermal growth factor receptor 2 (HER2). We present a deep-learning method for scoring microscopy images of GEA for the presence of HER2 overexpression. METHODS: Our method is based on convolutional neural networks (CNNs) trained on a rich dataset of 1602 patient samples and tested on an independent set of 307 patient samples. We additionally verified the CNN's generalisation capabilities with an independent dataset with 653 samples from a separate clinical centre. We incorporated an attention mechanism in the network architecture to identify the tissue regions, which are important for the prediction outcome. Our solution allows for direct automated detection of HER2 in immunohistochemistry-stained tissue slides without the need for manual assessment and additional costly in situ hybridisation (ISH) tests. RESULTS: We show accuracy of 0.94, precision of 0.97, and recall of 0.95. Importantly, our approach offers accurate predictions in cases that pathologists cannot resolve and that require additional ISH testing. We confirmed our findings in an independent dataset collected in a different clinical centre. The attention-based CNN exploits morphological information in microscopy images and is superior to a predictive model based on the staining intensity only. CONCLUSIONS: We demonstrate that our approach not only automates an important diagnostic process for GEA patients but also paves the way for the discovery of new morphological features that were previously unknown for GEA pathology.


Assuntos
Adenocarcinoma , Neoplasias Esofágicas , Humanos , Redes Neurais de Computação , Neoplasias Esofágicas/genética , Neoplasias Esofágicas/patologia , Adenocarcinoma/genética , Adenocarcinoma/patologia , Hibridização In Situ , Receptores ErbB
2.
J Transl Med ; 21(1): 552, 2023 08 17.
Artigo em Inglês | MEDLINE | ID: mdl-37592303

RESUMO

BACKGROUND: The prognosis of esophageal adenocarcinoma (EAC) and gastric adenocarcinoma (GAC) remains poor, and new therapeutic approaches are urgently needed. Claudin 6 (CLDN6) is an oncofetal antigen that is largely absent in healthy tissues and upregulated in several cancers, making it a promising therapeutical target. In this study, the expression of CLDN6 was assessed in an large Caucasian EAC and GAC cohort. METHODS: RNA-Seq data from 89 EACs and 371 GACs were obtained from The Cancer Genome Atlas project and EAC/GAC cases were stratified by CLDN6 mRNA expression based on a survival-associated cutoff. For groups with CLDN6 expression above or below this cutoff, differential gene expression analyses were performed using DESeq, and dysregulated biological pathways were identified using the Enrichr tool. Additionally, CLDN6 protein expression was assessed in more than 800 EACs and almost 600 GACs using a CLDN6-specific immunohistochemical antibody (clone 58-4B-2) that is currently used in Phase I/II trials to identify patients with CLDN6-positive tumors (NCT05262530; NCT04503278). The expression of CLDN6 was also correlated with histopathological parameters and overall survival (OS). RESULTS: EACs and GACs with high CLDN6 mRNA levels displayed an overexpression of pathways regulating the cell cycle, DNA replication, and receptor / extracellular matrix interactions. CLDN6 protein expression was associated with shorter OS in EAC and GAC, both in treatment-naïve subgroups and cohorts receiving neoadjuvant therapy. In multivariate analysis, CLDN6 protein expression was an independent adverse prognostic factor in EAC associated with a shorter OS (HR: 1.75; p = 0.01) and GAC (HR: 2.74; p = 0.028). CONCLUSIONS: High expression of CLDN6 mRNA is associated with the dysregulation of distinct biological pathways regulating cell growth, proliferation, and cell-matrix interactions. Clinically, the expression of CLDN6 protein is a valuable adverse prognostic marker in EAC and GAC.


Assuntos
Adenocarcinoma , Neoplasias Gástricas , Humanos , Proteínas de Junções Íntimas , Claudinas/genética , Adenocarcinoma/genética , Neoplasias Gástricas/genética , Ácido Aminocaproico , Anticorpos
3.
Ann Surg Oncol ; 30(12): 7422-7433, 2023 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-37210683

RESUMO

BACKGROUND: The question of the ideal neoadjuvant therapy for locally advanced esophagogastric adenocarcinoma has not been answered to date. Multimodal treatment has become a standard treatment for these adenocarcinomas. Currently, perioperative chemotherapy (FLOT) or neoadjuvant chemoradiation (CROSS) is recommended. METHODS: A monocentric retrospective analysis compared long-term survival after CROSS versus FLOT. The study enrolled patients with adenocarcinoma of the esophagus (EAC) or the esophagogastric junction type I or II undergoing oncologic Ivor-Lewis esophagectomy between January 2012 and December 2019. The primary objective was to determine the long-term outcome in terms of overall survival. The secondary objectives were to determine differences regarding the histopathologic categories after neoadjuvant treatment and the histomorphologic regression. RESULTS: The findings showed no survival advantage for one or the other treatment in this highly standardized cohort. All the patients underwent open (CROSS: 9.4% vs. FLOT: 22%), hybrid (CROSS: 82% vs. FLOT: 72%), or minimally invasive (CROSS: 8.9% vs. FLOT: 5.6%) thoracoabdominal esophagectomy. The median post-surgical follow-up period was 57.6 months (95% confidence interval [CI] 23.2-109.7 months), and the median survival was longer for the CROSS patients (54 months) than for the FLOT patients (37.2 months) (p = 0.053). The overall 5-years survival was 47% for the entire cohort (48% for the CROSS and 43% for the FLOT patients). The CROSS patients showed a better pathologic response and fewer advanced tumor stages. CONCLUSION: The improved pathologic response after CROSS cannot be translated into longer overall survival. To date, the choice of which neoadjuvant treatment to use can be made only on the basis of clinical parameters and the patient's performance status.


Assuntos
Adenocarcinoma , Neoplasias Esofágicas , Neoplasias Gástricas , Humanos , Terapia Neoadjuvante , Esofagectomia , Resultado do Tratamento , Estudos Retrospectivos , Neoplasias Esofágicas/patologia , Junção Esofagogástrica/patologia , Adenocarcinoma/patologia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Gástricas/patologia
4.
Int J Colorectal Dis ; 38(1): 262, 2023 Nov 03.
Artigo em Inglês | MEDLINE | ID: mdl-37919535

RESUMO

PURPOSE: Pain and reduced quality of life (QoL) are major subjects of interest after surgery for hemorrhoids. The aim of this study was to find predictive parameters for postoperative pain and QoL after hemorrhoidectomy. METHODS: This is a follow-up analysis of data derived from a multicenter randomized controlled trial including 770 patients, which examines the usefulness of tamponade after hemorrhoidectomy. Different pre-, intra-, and postoperative parameters were correlated with pain level assessed by NRS and QoL by the EuroQuol. RESULTS: At univariate analysis, relevant (NRS > 5/10 pts.) early pain within 48 h after surgery was associated with young age (≤ 40 years, p = 0.0072), use of a tamponade (p < 0.0001), relevant preoperative pain (p = 0.0017), pudendal block (p < 0.0001), and duration of surgery (p = 0.0149). At multivariate analysis, not using a pudendal block (OR 2.64), younger age (OR 1.55), use of a tamponade (OR 1.70), and relevant preoperative pain (OR 1.56) were significantly associated with relevant early postoperative pain. Relevant pain on day 7 was significantly associated only with relevant early pain (OR 3.13, p < 0.001). QoL overall remained at the same level. However, n = 229 (33%) patients presented an improvement of QoL and n = 245 (36%) an aggravation. Improvement was associated with a reduction of pain levels after surgery (p < 0.0001) and analgesia with opioids (p < 0.0001). CONCLUSION: Early relevant pain affects younger patients but can be prevented by avoiding tamponades and using a pudendal block. Relevant pain after 1 week is associated only with early pain. Relief in preexisting pain and opioids improve QoL. TRIAL REGISTRATION: DRKS00011590 12 April 2017.


Assuntos
Hemorroidectomia , Hemorroidas , Humanos , Adulto , Hemorroidectomia/efeitos adversos , Hemorroidectomia/métodos , Qualidade de Vida , Seguimentos , Estudos Prospectivos , Dor Pós-Operatória/tratamento farmacológico , Dor Pós-Operatória/etiologia , Hemorroidas/cirurgia , Hemorroidas/complicações , Analgésicos Opioides , Resultado do Tratamento
5.
Ann Surg Oncol ; 2022 Apr 11.
Artigo em Inglês | MEDLINE | ID: mdl-35403919

RESUMO

BACKGROUND: This study analyzed the long-term survival after pathological complete response (pCR) with and without nodal metastases and associated recurrence following multimodal treatment of esophageal cancer. The recurrence pattern after pCR is of importance for different postoperative surveillance strategies. METHODS: A cohort of 890 patients with esophageal cancer received neoadjuvant therapy followed by transthoracic esophagectomy. Only patients with pCR of the primary tumor with and without nodal metastasis were analyzed. A clinicopathological database was set up and completed with long-term follow up information on recurrent disease. RESULTS: The specimen of 201 patients (23%) demonstrated pCR, 84% without (ypT0N0) and 16% with residual nodal disease (ypT0N+). For ypT0N0 patients, the 5-year overall survival was significantly higher than for patients with metastatic nodes (77% vs. 24%) (p < 0.0001). Sixty-eight percent of patients had no evidence of tumor recurrence, whereas 32% had proven relapse. For patients with and without tumor recurrence, 5-year survival rates were 14% and 93%, respectively (p < 0.0001). For patients with recurrent disease, median survival time was 27 for locoregional, 44 for distant, and 24 months for combined recurrence (p = 0.302). In the multivariable Cox-regression analysis, node-positive disease predicted both locoregional and metastatic recurrence. CONCLUSIONS: Pathological CR offers long-term survival in patients without nodal metastases but outcome significantly deteriorates with the presence of nodal metastases. Follow-up recommendations may therefore be adopted in patients with pCR. Furthermore, "watch-and-wait" surveillance strategies with suspected clinical complete response have to be considered with caution.

6.
Br J Surg ; 109(8): 746-753, 2022 07 15.
Artigo em Inglês | MEDLINE | ID: mdl-35574811

RESUMO

BACKGROUND: Recent findings support the hypothesis of sex-related differences in inflammatory and immunological responses to trauma. The aim of this study was to address sex-specific aspects in patients who underwent pancreatic surgery. METHODS: This retrospective study used data from the German StuDoQ registry. Patients who underwent pancreatic surgery between 2010 and 2020 were stratified according to procedure (pancreatic head resection, distal pancreatectomy (DP), total pancreatectomy (TP)). Each cohort underwent propensity score matching (PSM) with the co-variables BMI, ASA, age, coronary heart disease (CHD), diabetes, hypertension with medication, and histology to level the distribution of co-morbidities between men and women. The main outcomes were morbidity and mortality. RESULTS: The total cohort consisted of 10 224 patients (45.3 per cent women). Men had higher ASA grades, and more often had CHD, diabetes, and hypertension with medication. Women had fewer overall complications (57.3 versus 60.1 per cent; P = 0.005) and a lower mortality rate (3.4 versus 4.9 per cent; P < 0.001). Rates of pancreatic surgery-specific complications, such as clinically relevant postoperative pancreatic fistula (POPF) (grade B/C: 14 versus 17 per cent; P < 0.001), delayed gastric emptying (grade B/C: 7.8 versus 9.2 per cent; P = 0.014), and postpancreatectomy haemorrhage (grade B/C: 7.1 versus 9.0 per cent; P < 0.001), were also lower in women. After PSM, 8358 patients were analysed. In the pancreatic head resection cohort (5318 patients), women had fewer complications (58.6 versus 61.4 per cent; P = 0.044), a lower in-hospital mortality rate (3.6 versus 6.1 per cent; P < 0.001), and less often had clinically relevant POPF (11.6 versus 16.2 per cent; P < 0.001). After DP, the clinically relevant POPF rate was lower in women (22.5 versus 27.3 per cent; P = 0.012). In the TP cohort, men more often developed intra-abdominal abscess requiring drainage (5.0 versus 2.3 per cent; P = 0.050). CONCLUSION: Women had favourable outcomes after pancreatic surgery.


Assuntos
Hipertensão , Neoplasias Pancreáticas , Feminino , Humanos , Hipertensão/complicações , Masculino , Pancreatectomia/efeitos adversos , Pancreatectomia/métodos , Fístula Pancreática/epidemiologia , Fístula Pancreática/etiologia , Neoplasias Pancreáticas/complicações , Neoplasias Pancreáticas/cirurgia , Complicações Pós-Operatórias/epidemiologia , Complicações Pós-Operatórias/etiologia , Complicações Pós-Operatórias/cirurgia , Estudos Retrospectivos
7.
Dis Esophagus ; 35(4)2022 Apr 19.
Artigo em Inglês | MEDLINE | ID: mdl-34561712

RESUMO

Self-expandable metal stents (SEMS) and endoscopic vacuum therapy (EVT) are endoscopic options for treating leaks of the esophagus. VACStent® is a variant of SEMS that aims to combine the advantages of SEMS and EVT in one device. Due to this unique construction, VACStent® can build a barrier to the leak and facilitate wound healing with EVT, all while maintaining intestinal passage. We present the first prospective feasibility study of VACStent® for treating leaks of the upper gastrointestinal tract. Between September 2019 and November 2020, we performed a prospective, investigator-initiated, single-center study and included all patients who underwent endoscopic stenting with VACStent® for various kinds of esophageal leaks, such as spontaneous, iatrogenic or anastomotic leaks. We included 20 patients, who underwent a total of 24 endoscopic VACStent® implantations. Technical success of the application of the VACStent® was achieved in all interventions (n = 24, 100%). Overall, clinical success in closing the leaks with VACStent® treatment was achieved in 60% of patients (12/20). No severe VACStent® treatment-related adverse events occurred. Oral feeding with supplement high-energy drinks failed in all patients due to clogging of the suction tube. VACStent® is a safe and feasible endoscopic treatment option for leaks of the upper gastrointestinal tract. However, our data could not show the expected advantage of orally feeding the patients during the treatment with the VACStent® in its current form. Efficacy of VACStent® compared to EVT or SEMS needs to be investigated in a further study. ClinicalTrials.gov Identifier: NCT03962179.


Assuntos
Fístula Anastomótica , Esôfago , Tratamento de Ferimentos com Pressão Negativa , Stents , Fístula Anastomótica/diagnóstico por imagem , Fístula Anastomótica/cirurgia , Endoscopia , Esôfago/diagnóstico por imagem , Esôfago/cirurgia , Estudos de Viabilidade , Seguimentos , Humanos , Tratamento de Ferimentos com Pressão Negativa/efeitos adversos , Tratamento de Ferimentos com Pressão Negativa/métodos , Estudos Prospectivos , Stents/efeitos adversos , Resultado do Tratamento
8.
Semin Cancer Biol ; 60: 334-343, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31445220

RESUMO

More than 70% of gastrointestinal (GI) cancers are diagnosed with metastases, leading to poor prognosis. For some cancer patients with limited sites of metastatic tumors, the term oligometastatic disease (OMD) has been coined as opposed to systemic polymetastasis (PMD) disease. Stephan Paget first described an organ-specific pattern of metastasis in 1889, now known as the "seed and soil" theory where distinct cancer types are found to metastasize to different tumor-specific sites. Our understanding of the biology of tumor metastasis and specifically the molecular mechanisms driving their formation are still limited, in particular, as it relates to the genesis of oligometastasis. In the following review, we discuss recent advances in general understanding of this metastatic behavior including the role of specific signaling pathways, various molecular features and biomarkers, as well as the interaction of carcinoma cells with their tissue microenvironments (both primary and metastatic niches). The unique features that underlie OMD provide potential targets for localized therapy. As it relates to clinical practice, OMD is emerging as treatable with surgical resection and/or other local therapy options. Strategies currently being applied in the clinical management of OMD will be discussed including surgical, radiation-based therapy, ablation procedures, and the results of emerging clinical trials involving immunotherapy.


Assuntos
Neoplasias Gastrointestinais/etiologia , Neoplasias Gastrointestinais/metabolismo , Biomarcadores , Terapia Combinada , Gerenciamento Clínico , Progressão da Doença , Suscetibilidade a Doenças , Neoplasias Gastrointestinais/patologia , Neoplasias Gastrointestinais/terapia , Humanos , Cariótipo , Metástase Neoplásica , Fenótipo , Resultado do Tratamento
9.
BMC Cancer ; 21(1): 1239, 2021 Nov 18.
Artigo em Inglês | MEDLINE | ID: mdl-34794396

RESUMO

BACKGROUND: According to current guidelines, treatment of patients with hepatic oligometastasis in pancreatic cancer is not reflected and systemic chemotherapy is recommended in those patients. Retrospective data suggest beneficial outcomes in patients with hepatic oligometastasis, though prospective data from clinical trials addressing this particular patient group is not available. METHODS: In this single arm, phase-2 trial, survival data from patients receiving neoadjuvant chemotherapy followed by R0/R1 resection will be compared to historic data from patients with oligometastatic adenocarcinoma of the pancreas. The clinical trial will focus on a well-defined patient collective with metastatic load limited to the liver as target organ with a maximum of five metastases. The combination of liposomal irinotecan (nal-IRI), oxaliplatin (OX) and 5-fluouracil (5-FU)/folinic acid (FA) (nal-IRI + OX+ 5-FU/FA, NAPOX) was chosen as neoadjuvant chemotherapy; the choice was based on an ongoing clinical study in which NAPOX appeared manageable, with promising anti-tumor activity in first-line treatment of patients with metastatic pancreatic adenocarcinoma. In total 150 patients will be enrolled for this trial with an aim of 55 patients receiving a complete macroscopic synchronous tumor and metastatic resection. DISCUSSION: This is the first clinical study to prospectively evaluate the value of multimodality therapy concepts in oligometastatic pancreatic cancer. TRIAL REGISTRATION NUMBERS: EudraCT 2019-002734-37 ; NCT04617457 .


Assuntos
Adenocarcinoma/tratamento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Hepáticas/secundário , Terapia Neoadjuvante/métodos , Neoplasias Pancreáticas/tratamento farmacológico , Qualidade de Vida , Adenocarcinoma/mortalidade , Adenocarcinoma/secundário , Adenocarcinoma/cirurgia , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Quimioterapia Adjuvante/efeitos adversos , Quimioterapia Adjuvante/métodos , Feminino , Fluoruracila/administração & dosagem , Alemanha , Humanos , Irinotecano/administração & dosagem , Leucovorina/administração & dosagem , Lipossomos , Neoplasias Hepáticas/mortalidade , Neoplasias Hepáticas/cirurgia , Masculino , Terapia Neoadjuvante/efeitos adversos , Oxaliplatina/administração & dosagem , Neoplasias Pancreáticas/mortalidade , Neoplasias Pancreáticas/patologia , Neoplasias Pancreáticas/cirurgia , Intervalo Livre de Progressão
10.
Gastric Cancer ; 24(6): 1213-1226, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34009535

RESUMO

BACKGROUND: Tumor-associated neutrophils (TANs) have recently been identified as a relevant component of the tumor microenvironment (TME) in solid tumors. Within the TME TANs mediate either tumor-promoting or tumor-inhibiting activities. So far, their prognostic relevance remains to be determined. This study aims to evaluate the prognostic relevance of TANs in different molecular subtypes of gastric and esophageal adenocarcinoma. METHODS: We analyzed a total of 1118 Caucasian patients divided into gastric adenocarcinoma (n = 458) and esophageal adenocarcinoma cohort (n = 660) of primarily resected and neoadjuvant-treated individuals. The amount of CD66b + TANs in the tumor stroma was determined using quantitative image analysis and correlated to both molecular, as well as clinical data. RESULTS: An accumulation of TANs in the tumor stroma of gastric carcinomas was associated to a significant favorable prognosis (p = 0.026). A subgroup analysis showed that this effect was primarily related to the molecular chromosomal instable subtype (CIN) of gastric carcinomas (p = 0.010). This was only observed in female patients (p = 0.014) but not in male patients (p = 0.315). The same sex-specific effect could be confirmed in adenocarcinomas of the esophagus (p = 0.027), as well as in female individuals after receiving neoadjuvant therapy (p = 0.034). CONCLUSIONS: Together, we show a sex-specific prognostic effect of TANs in gastric cancer within a Caucasian cohort. For the first time, we showed that this sex-specific prognostic effect of TANs can also be seen in esophageal cancer.


Assuntos
Adenocarcinoma/mortalidade , Neoplasias Esofágicas/mortalidade , Neutrófilos/patologia , Neoplasias Gástricas/mortalidade , Adenocarcinoma/patologia , Antígenos CD , Moléculas de Adesão Celular , Estudos de Coortes , Terapia Combinada , Neoplasias Esofágicas/patologia , Feminino , Proteínas Ligadas por GPI , Identidade de Gênero , Alemanha , Humanos , Masculino , Pessoa de Meia-Idade , Terapia Neoadjuvante , Prognóstico , Neoplasias Gástricas/patologia , Análise de Sobrevida
11.
Cancer Immunol Immunother ; 69(4): 523-533, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31960110

RESUMO

The outcome in esophageal adenocarcinoma (EAC) is still poor with only 20% of patients in Western populations surviving for more than 5 years. Almost nothing is known about the precise composition of immune cells and their gene expression profiles in primary resected EACs and also nothing compared to neoadjuvant treated EACs. This study analyzes and compares immune profiles of primary resected and neoadjuvant treated esophageal adenocarcinoma and unravels possible targets for immunotherapy. We analyzed 47 EAC in total considering a set of 30 primary treatment-naive EACs and 17 neoadjuvant pretreated (12 × CROSS, 5 × FLOT) using the Nanostring's panel-based gene expression platform including 770 genes being important in malignant tumors and their immune micromileu. Most of the significantly altered genes are involved in the regulation of immune responses, T-and B cell functions as well as antigen processing. Chemokine-receptor axes like the CXCL9, -10,-11/CXCR3- are prominent in esophageal adenocarcinoma with a fold change of up to 9.5 promoting cancer cell proliferation and metastasis. ARG1, as a regulator of T-cell fate is sixfold down-regulated in untreated primary esophageal tumors. The influence of the currently used neoadjuvant treatment revealed a down-regulation of nearly all important checkpoint markers and inflammatory related genes in the local microenvironment. We found a higher expression of checkpoint markers like LAG3, TIM3, CTLA4 and CD276 in comparison to PD-L1/PD-1 supporting clinical trials analyzing the efficacy of a combination of different checkpoint inhibitors in EACs. We found an up-regulation of CD38 or LILRB1 as examples of additional immune escape mechanism.


Assuntos
Adenocarcinoma/terapia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Esofágicas/terapia , Perfilação da Expressão Gênica/métodos , Regulação Neoplásica da Expressão Gênica , Adenocarcinoma/genética , Adenocarcinoma/imunologia , Antígenos B7/genética , Antígenos B7/imunologia , Antígeno CTLA-4/genética , Antígeno CTLA-4/imunologia , Quimiorradioterapia/métodos , Neoplasias Esofágicas/genética , Neoplasias Esofágicas/imunologia , Esofagectomia/métodos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Monitorização Imunológica , Terapia Neoadjuvante , Linfócitos T/imunologia , Linfócitos T/metabolismo
12.
BMC Cancer ; 20(1): 12, 2020 Jan 06.
Artigo em Inglês | MEDLINE | ID: mdl-31906887

RESUMO

BACKGROUND: The SWI/SNF complex is an important chromatin remodeler, commonly dysregulated in cancer, with an estimated mutation frequency of 20%. ARID1A is the most frequently mutated subunit gene. Almost nothing is known about the other familiar members of the SWI/SNF complexes, SMARCA2 (BRM), SMARCA4 (BRG1) and SMARCB1 (INI1), in oesophageal adenocarcinoma (EAC). METHODS: We analysed a large cohort of 685 patients with EAC. We used four different antibodies to detect a loss-of-protein of ARID1A BRM, BRG1 and INI1 by immunohistochemistry and correlated these findings with molecular and clinical data. RESULTS: Loss of ARID1A, BRG1, BRM and INI1 was observed in 10.4, 3.4, 9.9 and 2% of EAC. We found a co-existing protein loss of ARID1A and BRM in 9.9% and of ARID1A and BRG1 in 2.2%. Patients with loss of ARID1A and TP53 wildtype EACs showed a shortened overall survival compared with AIRDA1A-positive tumours [median overall survival was 60.1 months (95%CI 1.2-139.9 months)] in patients with ARIDA-1A expression and 26.2 months (95%CI 3.7-19.1 months) in cases of ARIDA-1A loss (p = 0.044). Tumours with loss or expression of ARID1A and TP53 loss were not associated with a difference in survival. Only one tumour revealed high microsatellite instability (MSI-H) with concomitant ARID1A loss. All other ARID1A loss-EACs were microsatellite-stable (MSS). No predictive relevance was seen for SWI/SNF-complex alterations and simultaneous amplification of different genes (PIK3CA, KRAS, c-MYC, MET, GATA6, ERBB2). CONCLUSION: Our work describes, for the first time, loss of one of the SWI/SNF ATPase subunit proteins in a large number of adenocarcinomas of the oesophagus. Several papers discuss possible therapeutic interventions for tumours showing a loss of function of the SWI/SNF complex, such as PARP inhibitors or PI3K and AKT inhibitors. Future studies will be needed to show whether SWI/SNF complex-deficient EACs may benefit from personalized therapy.


Assuntos
Adenocarcinoma/metabolismo , Adenosina Trifosfatases/genética , DNA Helicases/metabolismo , Proteínas de Ligação a DNA/metabolismo , Neoplasias Esofágicas/metabolismo , Proteínas Nucleares/metabolismo , Proteína SMARCB1/metabolismo , Fatores de Transcrição/metabolismo , Adenocarcinoma/genética , Adenocarcinoma/mortalidade , Adenocarcinoma/patologia , Adenosina Trifosfatases/metabolismo , Idoso , Biomarcadores Tumorais/análise , Montagem e Desmontagem da Cromatina , Estudos de Coortes , DNA Helicases/genética , Proteínas de Ligação a DNA/genética , Neoplasias Esofágicas/genética , Neoplasias Esofágicas/mortalidade , Neoplasias Esofágicas/patologia , Feminino , Humanos , Imuno-Histoquímica , Estimativa de Kaplan-Meier , Mutação com Perda de Função , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Proteínas Nucleares/genética , Prognóstico , Proteína SMARCB1/genética , Fatores de Transcrição/genética , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismo
13.
Surg Endosc ; 34(6): 2722-2729, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-31659506

RESUMO

BACKGROUND: Minimally invasive single-port surgery is often associated with large incisions up to 2-3 cm, complicated handling due to the lack of triangulation, and instrument crossing. Aim of this prospective study was to perform true single-port surgery (cholecystectomy) without the use of assisting trocars using a new surgical platform that allows for triangulation incorporating robotic features, and to measure the perioperative outcome and cosmetic results. METHODS: As the first European site after FDA and CE-mark approval, the new device has been introduced to our academic center. In patients with cholecystitis and cholecystolithiasis, the operation was performed through only one 15-mm trocar. For patients safety, intraoperative cholangiography using intravenous ICG and a standard Stryker 1588 system was routinely performed. RESULTS: Symphonx was used in n = 12 patients for abdominal surgery (6 females, mean age 42.5 [30-77], mean BMI 26.2 [19.3-38.9]. A total of 8 patients underwent surgery using no additional ports besides the 15-mm trocar; in the remaining patients, one assisting instrument (3-5 mm) was used. Mean OR time was 107 [72-221] minutes. The postoperative course was uneventful in 11 patients; in one patient, a seroma at the surgical site required interventional drainage 1 month postoperatively. No intraoperative complications occurred. CONCLUSION: This is the first human case series using the commercially available symphonX platform for abdominal laparoscopic surgery and the first series using the system without assisting instruments. Laparoscopic cholecystectomy in patients with cholecystitis and cholecystolithiasis using the symphonX platform through only one 15-mm trocar is feasible, safe, and more cost-efficient compared to robotic platforms.


Assuntos
Colangiografia/métodos , Colecistectomia Laparoscópica/instrumentação , Colecistite/cirurgia , Colecistolitíase/cirurgia , Robótica/instrumentação , Instrumentos Cirúrgicos , Adulto , Idoso , Colecistectomia Laparoscópica/métodos , Desenho de Equipamento , Estudos de Viabilidade , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Robótica/métodos
14.
Br J Cancer ; 120(1): 69-78, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30377339

RESUMO

BACKGROUND: Immune infiltration is implicated in the development of acquired resistance to anti-angiogenic cancer therapy. We therefore investigated the correlation between neutrophil infiltration in metastasis of colorectal cancer (CRC) patients and survival after treatment with bevacizumab. Our study identifies CD177+ tumour neutrophil infiltration as an adverse prognostic factor for bevacizumab treatment. We further demonstrate that a novel anti-VEGF/anti-Ang2 compound (BI-880) can overcome resistance to VEGF inhibition in experimental tumour models. METHODS: A total of 85 metastatic CRC patients were stratified into cohorts that had either received chemotherapy alone (n = 39) or combined with bevacizumab (n = 46). Tumour CD177+ neutrophil infiltration was correlated to clinical outcome. The impact of neutrophil infiltration on anti-VEGF or anti-VEGF/anti-Ang2 therapy was studied in both xenograft and syngeneic tumour models by immunohistochemistry. RESULTS: The survival of bevacizumab-treated CRC patients in the presence of CD177+ infiltrates was significantly reduced compared to patients harbouring CD177- metastases. BI-880 treatment reduced the development of hypoxia associated with bevacizumab treatment and improved vascular normalisation in xenografts. Furthermore, neutrophil depletion or BI-880 treatment restored treatment sensitivity in a syngeneic tumour model of anti-VEGF resistance. CONCLUSIONS: Our findings implicate CD177 as a biomarker for bevacizumab and suggest VEGF/Ang2 inhibition as a strategy to overcome neutrophil associated resistance to anti-angiogenic treatment.


Assuntos
Neoplasias Colorretais/tratamento farmacológico , Isoantígenos/genética , Neovascularização Patológica/tratamento farmacológico , Receptores de Superfície Celular/genética , Fator A de Crescimento do Endotélio Vascular/genética , Proteínas de Transporte Vesicular/genética , Idoso , Inibidores da Angiogênese/administração & dosagem , Animais , Anticorpos Monoclonais Humanizados/administração & dosagem , Bevacizumab/administração & dosagem , Biomarcadores Tumorais/genética , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Resistencia a Medicamentos Antineoplásicos/genética , Feminino , Proteínas Ligadas por GPI/genética , Humanos , Masculino , Camundongos , Pessoa de Meia-Idade , Metástase Neoplásica , Células-Tronco Neoplásicas/efeitos dos fármacos , Neovascularização Patológica/genética , Neovascularização Patológica/patologia , Neutrófilos/efeitos dos fármacos , Fator A de Crescimento do Endotélio Vascular/antagonistas & inibidores , Ensaios Antitumorais Modelo de Xenoenxerto
15.
BMC Cancer ; 19(1): 1261, 2019 Dec 30.
Artigo em Inglês | MEDLINE | ID: mdl-31888547

RESUMO

BACKGROUND: To date, patients with metastasized pancreatic ductal adenocarcinoma (PDAC M1) are regarded as a uniform collective. We hypothesize the existence of oligometastatic disease (OMD): a state of PDAC M1 disease with better tumor biology, limited metastasis, and increased survival. METHODS: Data of 128 PDAC M1 patients treated at the University of Cologne between 2008 and 2018 was reviewed. Interdependence between clinical parameter was calculated using the Mann-Whitney U-Test. Survival curves were generated using the Kaplan-Meier method and analyzed using the log-rank test. RESULTS: Eighty-one (63%) patients had metastases confined to one organ (single organ metastasis, SOG) whereas the remaining 47 (37%) showed multiple metastatic sites (multi-organ metastasis, MOG). Survival analysis revealed a median overall survival (OS) of 12.2 months for SOG vs 4.5 months for MOG (95% CI 5.7-9.8; p < 0.001). We defined limited disease by the presence of ≤4 metastases in liver or lung. Limited disease together with CA 19-9 baseline < 1000 U/ml and response or stable disease after first-line chemotherapy defined OMD. We identified 8 patients with hepatic metastases and 2 with pulmonary metastases matching all OMD criteria. This group of 10 (7.8%) had a median overall survival of 19.4 vs 7.2 months compared to the remaining patients (95% CI 5.7-9.8; p = 0.009). CONCLUSION: We propose a definition of oligometastatic disease in PDAC including anatomical criteria and biological criteria reflecting better tumor biology. The 10 OMD patients (7.8%) survived significantly longer and might even benefit from surgical resection in the future.


Assuntos
Adenocarcinoma/tratamento farmacológico , Carcinoma Ductal/tratamento farmacológico , Neoplasias Pancreáticas/tratamento farmacológico , Adenocarcinoma/mortalidade , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais , Carcinoma Ductal/mortalidade , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Invasividade Neoplásica , Metástase Neoplásica , Neoplasias Pancreáticas/mortalidade , Fenótipo , Estudos Retrospectivos , Análise de Sobrevida
16.
BMC Cancer ; 19(1): 38, 2019 Jan 08.
Artigo em Inglês | MEDLINE | ID: mdl-30621632

RESUMO

BACKGROUND: HER2 (ERBB2 or HER2/neu) is a tyrosine-kinase increasing cell proliferation. Overexpression/amplification of HER2 is correlated with worse prognosis in solid malignancies. Consequently, HER2 targeting is established in breast and upper gastrointestinal tract cancer. There are conflicting data concerning the impact of HER2 overexpression on esophageal adenocarcinoma (EAC), as most studies do not differ between cancers of the esophagus/gastroesophageal junction and the stomach. The aim of this study was to analyze the expression/amplification of HER2 in EAC in correlation to clinicopathological data to verify its prognostic impact. METHODS: We analyzed 428 EAC patients that underwent transthoracic thoraco-abdominal esophagectomy between 1997 and 2014. We performed HER2 immunohistochemistry (IHC) according to the guidelines and fluorescence-in-situ-hybridization (FISH) for IHC score2+, using tissue micro arrays (TMA) with up to eight biopsies from the surface and infiltration area of a single tumor for evaluating HER2-heterogeneity and single-spot TMA. The HER2-status was correlated with clinicopathological data. RESULTS: HER2-positivity was found in up to 14.9% in our cohort (IHC score 3+ or IHC score 2+ with gene amplification) and demonstrated a significantly better overall survival (OS) in correlation to HER2-negative tumors (median OS 70.1 vs. 24.6 months, p = 0.006). HER2-overexpression was more frequently seen in lower tumor stages (pT1/pT2, p = 0.038), in the absence of lymphatic metastases (pN0/pN+, p = 0.020), and was significantly associated with better histological grading (G1/G2) (p = 0.041). CONCLUSION: We demonstrated a positive prognostic impact of HER2 overexpression in a large cohort of EAC, contrary to other solid malignancies including gastric cancer and breast cancer, but consistent to the results of a large study on EAC from 2012.


Assuntos
Adenocarcinoma/genética , Biomarcadores Tumorais/genética , Neoplasias Esofágicas/genética , Prognóstico , Receptor ErbB-2/genética , Adenocarcinoma/epidemiologia , Adenocarcinoma/patologia , Adenocarcinoma/cirurgia , Adulto , Idoso , Proliferação de Células/genética , Neoplasias Esofágicas/epidemiologia , Neoplasias Esofágicas/patologia , Neoplasias Esofágicas/cirurgia , Esofagectomia , Junção Esofagogástrica/patologia , Feminino , Amplificação de Genes/genética , Regulação Neoplásica da Expressão Gênica/genética , Humanos , Hibridização in Situ Fluorescente , Metástase Linfática , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Análise Serial de Tecidos
17.
BMC Cancer ; 19(1): 531, 2019 May 31.
Artigo em Inglês | MEDLINE | ID: mdl-31151416

RESUMO

BACKGROUND: Molecular markers predicting survival in esophageal adenocarcinoma (EAC) are rare. Specifically, in favorable oncologic situations, e.g. nodal negativity or major neoadjuvant therapy response, there is a lack of additional risk factors that serve to predict patients' outcome more precisely. This study evaluated X-linked inhibitor of apoptosis protein (XIAP) as a potential marker improving outcome prediction. METHODS: Tissue microarrays from 362 patients that were diagnosed with resectable EAC were included in the study. XIAP was stained by immunohistochemistry and correlated to clinical outcome, molecular markers and markers of the cellular tumor microenvironment. RESULTS: XIAP did not impact on overall survival (OS) in the whole study collective. Subgroup analyses stratifying for common genetic markers (TP53, ERBB2, ARID1A/SWI/SNF) did not disclose any impact of XIAP expression on survival. Detailed subgroup analyses of [1] nodal negative patients, [2] highly T-cell infiltrated tumors and [3] therapy responders to neoadjuvant treatment revealed a significant inverse role of high XIAP expression in these specific oncologic situations; elevated XIAP expression detrimentally affected patients' outcome in these subgroups. [1]: OS XIAP low: 202 months (m) vs. XIAP high: 38 m; [2]: OS 116 m vs. 28.2 m; [3]: OS 31 m vs. 4 m). CONCLUSIONS: Our data suggest XIAP expression in EAC as a worthy tool to improve outcome prediction in specific oncologic settings that might directly impact on clinical diagnosis and treatment of EAC in the future.


Assuntos
Adenocarcinoma/metabolismo , Adenocarcinoma/mortalidade , Neoplasias Esofágicas/metabolismo , Neoplasias Esofágicas/mortalidade , Linfócitos do Interstício Tumoral/metabolismo , Terapia Neoadjuvante , Subpopulações de Linfócitos T/metabolismo , Proteínas Inibidoras de Apoptose Ligadas ao Cromossomo X/metabolismo , Adenocarcinoma/patologia , Adenocarcinoma/terapia , Idoso , Biomarcadores Tumorais/metabolismo , Neoplasias Esofágicas/patologia , Neoplasias Esofágicas/terapia , Esofagectomia , Feminino , Humanos , Imuno-Histoquímica , Linfonodos/patologia , Masculino , Terapia Neoadjuvante/métodos , Prognóstico , Estudos Retrospectivos , Taxa de Sobrevida
18.
Exp Mol Pathol ; 107: 51-56, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30707896

RESUMO

Expression of the retinoic acid-induced protein 3 (RAI3) has been suggested to predict clinical outcome in a variety of malignancies. However, its role in esophageal cancers remains unclear. Immunohistochemical RAI3 staining was analyzed on tissue microarrays containing 359 esophageal adenocarcinomas (EAC) and 254 esophageal squamous cell carcinomas (ESCC). RAI3 immunostaining was typically absent or weakly detectable in the membranes in benign esophageal tissues. RAI3 staining was higher in malignant than in benign esophagus epithelium. High-levels of RAI3 staining were found in 79.2% of interpretable EACs and 55.9% of ESCCs. In EACs, strong RAI3 staining was associated with advanced pathological tumor stage (p < .0001), high UICC stage (p < .0001), high tumor grade (p = .0133), and positive lymph nodal status (p = .0002). Additionally, high RAI3 staining predicted shortened overall survival of EAC and ESCC patients (p = .0298 and p = .0227). RAI3 overexpression is associated with poor prognosis in esophageal cancers. We propose that RAI3 overexpression might play a biologically relevant role of RAI3 in esophageal cancers.


Assuntos
Adenocarcinoma/patologia , Biomarcadores Tumorais/análise , Neoplasias Esofágicas/patologia , Carcinoma de Células Escamosas do Esôfago/patologia , Receptores Acoplados a Proteínas G/biossíntese , Adenocarcinoma/mortalidade , Adulto , Idoso , Neoplasias Esofágicas/mortalidade , Carcinoma de Células Escamosas do Esôfago/mortalidade , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico
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