Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 70
Filtrar
1.
Updates Surg ; 2024 Feb 08.
Artigo em Inglês | MEDLINE | ID: mdl-38332391

RESUMO

Internal herniation (IH) is a common problem after laparoscopic Roux-en-Y gastric bypass surgery (RYGB). Routine closure of the mesenteric defects (MDs) reduces the risk of IH. Only very few articles report on risk factors for IH or describe detailed closing techniques. There is no consensus yet on the best closing method. The objective of this study is to determine the optimal stapling method for closure of MDs after RYGB. All performed RYGB procedures in our high-volume bariatric institute were included. Quality of the closure was scored in the categories poor, sub-optimal, and optimal, to see if the quality of the closure would predict the chance of reopening of the MDs and, therefore, the chance of IH. During any type of laparoscopy in the follow-up of the patient, the conditions of the MDs were stated, for example during diagnostic laparoscopy in symptomatic patients suspicious for IH or during laparoscopic cholecystectomy. Technically well-executed closure of Petersen's space (PS) with two rows of staples had a greater chance of still being closed upon re-inspection compared to closure with one row (odds ratio = 8.1; 95% confidence interval [1.2-53.2], p = 0.029). Optimal closure of the MD at the jejuno-jejunostomy (JJ-space, JJS) resulted in more closed JJSs upon re-inspection compared to sub-optimal closure (odds ratio = 3.6 [CI 95% 0.8-16.1], p = 0.099). Non-optimally closed MDs had higher reopening rates and, therefore, pose an additional risk for IH. Our classification provides a quality assessment of MD closure during RYGB and gives insight into how to optimize surgical technique.

2.
Data Brief ; 44: 108490, 2022 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-35959468

RESUMO

The data described was acquired as part of a clinical study with the aim to investigate the potential of tumor-reactive T-cell response as response to vaccination of pancreatic cancer patients with an allogenic tumor cell lysate vaccine (Lau et al., 2022). Proteomics analysis was carried out to identify tumor antigens that are shared between the allogeneic tumor cell lysate used for the vaccine and pancreatic ductal adenocarcinoma (PDAC) tissue samples. To this objective, cell lysates of the vaccine and of nine tissue samples were enzymatically digested and isotopically labeled with tandem mass tags (TMT) in a so-called six-plex manner (Thermo Fisher Scientific). Three pools were prepared by mixing the samples according to their TMT-labels. Subsequently, the three sample pools were fractionated into 24 fractions with high-pH reversed phase chromatography. These fractions were first analyzed on a nano-liquid chromatography (LC) system online coupled to a high-resolution Eclipse Orbitrap mass spectrometer (MS) equipped with a high-field asymmetric-waveform ion-mobility spectrometry (FAIMS) source using a data-dependent MS2 shotgun method. Overall, 126,618 unique peptide sequences, on basis of 768,638 peptide spectra matches and corresponding to 7,597 protein groups, were identified in the total sample set including 61 tumor antigens (Supplement Table S2 in Lau et al. 2022) that were prioritized by Cheever and co-workers as vaccine target antigens on basis of a series of objective criteria (Cheever et al., 2009). In the second phase of the experiment, this set of tumor antigens was targeted using a serial precursor selection (SPS) MS3 method. From this data, ion trap MS2 and Orbitrap MS3 fragment spectra were extracted for peptide identification (protein sequence database-dependent search) and relative quantification using the TMT labels, respectively. The dataset ultimately allowed the identification and quantification of 51 proteins and 163 related peptide precursors with the TMT labels (see Fig. 2B and Supplemental Fig. 8, Lau et al. 2022).

3.
Eur J Cancer ; 169: 20-31, 2022 07.
Artigo em Inglês | MEDLINE | ID: mdl-35490565

RESUMO

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is notorious for its poor prognosis even after curative resection. Responses to immunotherapy are rare and related to inadequate T-cell priming. We previously demonstrated the potency of allogeneic lysate-dendritic cell (DC) vaccination in a preclinical model. Here we translate this concept to patients. METHODS: In this phase I study, patients with resected PDAC were included when they demonstrated no radiologic signs of recurrence after standard-of-care treatment. Allogeneic tumour lysate-loaded autologous monocyte-derived DCs were injected at weeks 0, 2, 4 and at months 3 and 6. Objectives are feasibility, safety and immunogenicity of allogeneic tumour-DCs. The presence of tumour antigens shared between the vaccine and patient tumours was investigated. Immunological analyses were performed on peripheral blood, skin and tumour. RESULTS: Ten patients were included. DC production and administration were successful. All patients experienced a grade 1 injection-site and infusion-related reaction. Two patients experienced a grade 2 fever and 1 patient experienced a grade 3 dyspnoea. No vaccine-related serious adverse events were observed. Shared tumour antigens were found between the vaccine and patient tumours. All evaluated patients displayed a vaccine-induced response indicated by increased frequencies of Ki67+ and activated PD-1+ circulating T-cells. In addition, treatment-induced T-cell reactivity to autologous tumour of study patients was detected. Seven out of ten patients have not experienced disease recurrence or progression at a median follow-up of 25 months (15-32 months). CONCLUSION: Allogeneic tumour lysate-DC treatment is feasible, safe and induces immune reactivity to PDAC expressed antigens.


Assuntos
Vacinas Anticâncer , Transplante de Células-Tronco Hematopoéticas , Neoplasias Pancreáticas , Antígenos de Neoplasias , Vacinas Anticâncer/efeitos adversos , Células Dendríticas , Humanos , Imunoterapia/efeitos adversos , Recidiva Local de Neoplasia/tratamento farmacológico , Neoplasias Pancreáticas/tratamento farmacológico , Linfócitos T , Neoplasias Pancreáticas
4.
Cancer Immunol Immunother ; 70(6): 1569-1581, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33225419

RESUMO

Targeted cancer therapy with monoclonal antibodies has proven successful for different cancer types but is limited by the availability of suitable antibody targets. CD43s, a unique sialylated form of CD43 expressed by hematologic malignancies, is a recently identified target and antibodies interacting with CD43s may have therapeutic potential against acute myeloid leukemia (AML) and myelodysplastic syndrome. CD43s is recognized by the human antibody AT1413, that was derived from a high-risk AML patient who successfully cleared leukemia after allogeneic stem cell transplantation. Here we observed that AT1413 binds also to certain non-hematopoietic tumor cells, particularly melanoma and breast cancer. AT1413 immune precipitated CD43s from melanoma cells confirming that it recognizes the same target on melanoma as on AML. AT1413 induced antibody-dependent cellular cytotoxicity against short-term cultured patient-derived melanoma samples. However, AT1413 was unable to affect the growth of melanoma cells in vivo. To increase the efficacy of AT1413 as a therapeutic antibody, we generated two different formats of bispecific T-cell engaging antibodies (TCEs): one binding bivalently (bTCE) and the other monovalently (knob-in-hole; KiH) to both CD43s and CD3ε. In vitro, these TCEs redirected T-cell cytotoxicity against melanoma cells with differences in potencies. To investigate their effects in vivo, we grafted mice that harbor a human immune system with the melanoma cell line A375. Treatment with both AT1413 bTCE and AT1413 KiH significantly reduced tumor outgrowth in these mice. These data indicate a broad therapeutic potential of AT1413 that includes AML and CD43s-expressing solid tumors that originate from CD43-negative tissues.


Assuntos
Anticorpos Biespecíficos/farmacologia , Anticorpos Monoclonais/farmacologia , Antineoplásicos Imunológicos/farmacologia , Complexo CD3/imunologia , Leucossialina/imunologia , Melanoma/terapia , Ácido N-Acetilneuramínico/química , Linfócitos T/imunologia , Animais , Apoptose , Proliferação de Células , Citotoxicidade Imunológica , Feminino , Humanos , Técnicas In Vitro , Melanoma/imunologia , Melanoma/patologia , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto
5.
Breast Cancer Res Treat ; 175(3): 605-615, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30868392

RESUMO

PURPOSE: Tumor-infiltrating lymphocytes (TILs) are associated with pathological complete response (pCR) and survival after neoadjuvant chemotherapy (NAC) in patients with early breast cancer. We investigated the prognostic and predictive role of TILs, macrophages, and HLA class 1 expression after NAC with or without the potentially immune modulating compound zoledronic acid (ZA). METHODS: Baseline tumor biopsies from 196 patients in the NEOZOTAC trial were analyzed for CD8 (cytotoxic T-cells), FoxP3 (regulatory T-cells), CD68 (macrophages), and HLA class I (HCA2/HC10) expression by immunohistochemistry and subsequently related to pCR and disease-free survival (DFS). RESULTS: A strong intratumoral CD8+ infiltration or expression of HLA class 1 by cancer cells was associated with a higher pCR rate (p < 0.05). Clinical benefit of high CD8+ T-cell infiltration was found when cancer cells expressed HLA class 1 (pCR: 21.8% vs. 6.7%, p = 0.04) but not when HLA class 1 expression was lost or downregulated (pCR: 5.9% vs. 0%, p = 0.38). Interaction analyses revealed survival benefit between HLA class 1 expression and strong CD8+ T-cell infiltration, whereas in the absence or downregulation of HLA class 1 expression, high levels of CD8+ T-cells were associated with survival disadvantage (p for interaction 0.01; hazard ratio 0.41, 95% CI 0.15-1.10, p = 0.08 and hazard ratio 7.67, 95% CI 0.88-66.4, p = 0.07, respectively). Baseline immune markers were not related to ZA treatment. CONCLUSIONS: Strong baseline tumor infiltration with CD8+ T-cells in the presence of tumoral HLA class 1 expression in patients with HER2-negative breast cancer is related to a higher pCR rate and a better DFS after NAC.


Assuntos
Neoplasias da Mama/tratamento farmacológico , Linfócitos T CD8-Positivos/imunologia , Tratamento Farmacológico/métodos , Antígenos de Histocompatibilidade Classe I/metabolismo , Linfócitos do Interstício Tumoral/imunologia , Ácido Zoledrônico/uso terapêutico , Idoso , Neoplasias da Mama/imunologia , Ensaios Clínicos Fase III como Assunto , Intervalo Livre de Doença , Feminino , Humanos , Pessoa de Meia-Idade , Terapia Neoadjuvante , Prognóstico , Ensaios Clínicos Controlados Aleatórios como Assunto , Análise de Sobrevida , Resultado do Tratamento , Microambiente Tumoral
6.
J Immunother Cancer ; 7(1): 14, 2019 01 18.
Artigo em Inglês | MEDLINE | ID: mdl-30658697

RESUMO

Regulatory T cells (Tregs) may comprise different subsets allowing them to efficiently suppress different types of effector T cells. In this study, we show that high numbers of both conventional and Tbet co-expressing Foxp3hi Tregs accumulate in human papilloma virus (HPV)-driven oropharyngeal squamous cell carcinoma (OPSCC). The infiltration of Tbet+ Foxp3+ Tregs was strongly correlated with a concomitant tumor-specific and conventional type 1-oriented intratumoral T cell infiltrate. Both conventional CD4+CD25+CD127-Foxp3hi Tregs and their Tbethi counterparts exhibited an activated phenotype, co-expressed high levels of CTLA4 and Helios and exhibited a maximally demethylated Foxp3 gene locus TSDR, indicating their full capacity to impede a type 1 effector T cell response. Interestingly, while the prognostic value of conventional Tregs was neutral, a high intratumoral frequency of Tbet+ Tregs was associated with prolonged disease-specific survival, most likely because their presence reflected high numbers of effector T cells. The presence of these Tbet+ Tregs may in part explain why a dense type 1-oriented immune infiltrate in OPSCC is not enough to fully control tumor growth.


Assuntos
Linfócitos do Interstício Tumoral/imunologia , Neoplasias Orofaríngeas/imunologia , Infecções por Papillomavirus/imunologia , Proteínas com Domínio T/imunologia , Linfócitos T Reguladores/imunologia , Idoso , Idoso de 80 Anos ou mais , Feminino , Fatores de Transcrição Forkhead/imunologia , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias Orofaríngeas/etiologia , Infecções por Papillomavirus/complicações , Neoplasias do Colo do Útero/etiologia , Neoplasias do Colo do Útero/imunologia
7.
Oncoimmunology ; 7(8): e1465166, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30221063

RESUMO

Epithelial ovarian cancer (EOC) may cause abnormal blood levels of leukocytes. This paraneoplastic manifestation is associated with a worse response to therapy and shorter survival. To understand the complexity and nature of these leukocytes, we dissected the different populations of myeloid cells and analyzed their relation to clinical outcome. Therefore, baseline blood samples of 36 EOC patients treated either with carboplatin/doxorubucin or with gemcitabine were analyzed for different subsets of monocytes/macrophages, myeloid derived suppressor cells (MDSC) and dendritic cells (DC) using multiparameter flow cytometry as well as functional assays for myeloid cell mediated suppression of antigen-specific T cell reactivity. Healthy donor blood served as control. EOC patients displayed an increase in monocytes/macrophages, monocytic MDSC (mMDSC) and CD33-CD11b+CD14-CD15- double-negative MDSC (CD33- dnMDSC) and a decrease in the frequency of DC, across all EOC subtypes. A low frequency of DC and high frequencies of monocytes/macrophages and mMDSC, but not CD33- dnMDSC, were associated with poor overall survival. Patient's monocytes/macrophages and mMDSC, but not CD33- dnMDSC, were shown to suppress T cell reactivity in vitro. The mMDSC and DC frequencies were not altered upon treatment. Importantly, the mMDSC to DC ratio was the strongest independent, highly sensitive and specific, predictive factor for survival. This was irrespective of the type of chemotherapy or disease stage and outperformed classical parameters as WHO status or time from last chemotherapy. Thus, the baseline blood mMDSC to DC ratio is a robust, independent and easy to analyze predictive factor for EOC survival, and may assist patient selection for immunotherapy.

8.
Cancer Treat Rev ; 62: 18-28, 2018 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-29154022

RESUMO

At present, accumulating evidence suggests that inhibition of receptor activator of nuclear factor kappa-B ligand (RANKL) does not only induce an increase in bone mass and strength, but also has anti-tumor effects. Denosumab, an antibody targeting RANKL, is used to treat osteoporosis and to prevent skeletal related events (SREs) in patients with bone metastases originating from solid tumors. However, expression of RANKL and its receptor activator of nuclear factor kappa-B (RANK) is not solely restricted to cells involved in homeostasis of the bone and RANKL-RANK signalling appears to play a substantial role in many other processes in the body like mammary physiology, mammary tumorigenesis and the immune system. In pre-clinical models, RANKL inhibition has been shown to reduce skeletal tumor burden and distant metastases as well as to decrease mammary carcinogenesis. Clinically, RANKL inhibition improves bone-metastasis free survival in patients with prostate cancer and disease-free survival in patients with breast cancer. In addition, RANKL treatment may form a preventative strategy in patients at high risk for malignancies of the breast. Current clinical studies are evaluating the effect of denosumab on survival, the immune system and other biomarkers into a greater extent. To that purpose, a systematic review of the literature was performed and a narrative review synthesized, describing the present pre-clinical and clinical evidence of an anti-tumor effect of RANKL inhibition and the potential role of the immune system as one of the underlying mechanisms.


Assuntos
Conservadores da Densidade Óssea/uso terapêutico , Neoplasias Ósseas/prevenção & controle , Neoplasias da Mama/tratamento farmacológico , Denosumab/uso terapêutico , Ligante RANK/antagonistas & inibidores , Neoplasias Ósseas/secundário , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Feminino , Humanos , Ligante RANK/metabolismo , Receptor Ativador de Fator Nuclear kappa-B/metabolismo
9.
Oncoimmunology ; 6(2): e1267095, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28344877

RESUMO

New treatments based on combinations of standard therapeutic modalities and immunotherapy are of potential use, but require a profound understanding of immune modulatory properties of standard therapies. Here, the impact of standard (chemo)radiotherapy on the immune system of cervical cancer patients was evaluated. Thirty patients with cervical cancer were treated with external beam radiation therapy (EBRT), using conventional three-dimensional or intensity modulated radiation therapy without constraints for bone marrow sparing. Serial blood sampling for immunomonitoring was performed before, midway and at 3, 6 and 9 weeks after EBRT to analyze the composition of lymphocyte and myeloid-cell populations, the expression of co-stimulatory molecules, T-cell reactivity and antigen presenting cell (APC) function. Therapy significantly decreased the absolute numbers of circulating leukocytes and lymphocytes. Furthermore, the capacity of the remaining T cells to respond to antigenic or mitogenic stimulation was impaired. During treatment the frequency of both CD4+ and CD8+ T cells dropped and CD4+ T cells displayed an increased expression of programmed cell death-1 (PD-1). In vitro blocking of PD-1 successfully increased T-cell reactivity in all five samples isolated before radiotherapy but was less successful in restoring reactivity in samples isolated at later time points. Moreover, (chemo)radiotherapy was associated with an increase in both circulating monocytes and myeloid-derived suppressor cells (MDSCs) and an impaired capacity of APCs to stimulate allogeneic T cells. T-cell reactivity was slowly restored at 6-9 weeks after cessation of therapy. We conclude that conventional (chemo)radiotherapy profoundly suppresses the immune system in cervical cancer patients, and may restrict its combination with immunotherapy.

10.
Eur J Clin Microbiol Infect Dis ; 36(8): 1491-1503, 2017 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-28324192

RESUMO

The purpose of this study was to evaluate if an early exposure to human papillomavirus (HPV) during the prenatal period or infancy could result in HPV16-specific T helper (Th) responses resembling those of adults with HPV-induced lesions. We tested HPV16-specific cell-mediated immunity (CMI) in children born with HPV-positive umbilical cord blood and/or placenta or having persistent oral HPV infection and in constantly oral HPV-negative controls. Peripheral blood mononuclear cells from 33 children from the Finnish HPV Family Study cohort (mean age 14.7 years) were stimulated with peptide pools covering the amino acid sequence of the HPV16 E2, E6, and E7 proteins. Lymphocyte proliferation, secretion of cytokines (IFN-γ, TNF-α, IL-2, IL-4, IL-5, IL-10, IL-17A), and the frequency of Foxp3+ regulatory T-cells were determined in relation to the HPV DNA status during a 14-year follow-up. 73.6% of cases and 85.7% of controls responded against HPV16 E2, while reactivity against E6 was found in 10.5 and 35.7%, respectively. The proliferative response against E6 and E7 was more frequent in controls than in cases (p = 0.047). No HPV16-specific CMI response or antibodies were detected in two children with persistent oral HPV16. The profiles of induced cytokines indicated higher levels of IL-5, IL-10, and IL-17A in children with HPV DNA in placenta and/or cord blood than in other children. HPV16-specific CMI is common in HPV DNA-negative children. The cytokine profile in children infected with HPV16 during early life suggests that the viral dose and/or specific environment created by the placenta may have significant impact on the type of HPV-specific immunity.


Assuntos
Sangue Fetal/virologia , Papillomavirus Humano 16/imunologia , Papillomavirus Humano 16/isolamento & purificação , Troca Materno-Fetal , Placenta/virologia , Células Th2/imunologia , Adolescente , Antígenos Virais/imunologia , Proliferação de Células , Criança , Pré-Escolar , Citocinas/metabolismo , Feminino , Finlândia , Seguimentos , Humanos , Lactente , Recém-Nascido , Estudos Longitudinais , Masculino , Boca/virologia , Gravidez
11.
Eur J Gynaecol Oncol ; 38(1): 25-32, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-29767860

RESUMO

OBJECTIVE: To investigate prognostic factors in patients with recurrent cervical cancer after treatment of early-stage disease in order to identify high-risk patients who might benefit from alternative treatment strategies. STUDY DESIGN: The authors retrospectively analyzed clinical and pathology data from 130 recurrent cervical cancer patients after surgical treatment for early-stage disease. Patients were compared with a recurrence-free control group matched for age, FIGO Stage, and adjuvant treatment. Univariate and multivariate Cox regression analyses were performed to determine prognostic factors for recurrence and survival. RESULTS: Of 889 patients, 130 (14.6%) developed recurrent disease after primary treatment for early-stage cervical cancer. Local or loco-regional metastasis was observed in 45%, distant metastasis in 31%, and combined pelvic and distant metastasis in 24%. Median survival after recurrence was 12 months (range 1-107 months). Median five-year survival was 96% in the control group and 29% in the recurrence group. Tumor size ≥ 40 mm and lymph node metastasis were independent unfavorable prognostic factors for overall survival (OS) and disease-free survival (DFS). The number of positive lymph nodes (≥ one) and bilateral occurrence of pelvic lymph node metastasis were associated with adverse clinical outcome. CONCLUSIONS: Tumor size ≥ 40 mm and lymph node metastasis were independent unfavorable prognostic factors in surgically treated, early-stage cervical cancer patients. The combination of these factors was particularly associated with recurrence. Future trials should focus on the role of alternative adjuvant treatment strategies in patients at high risk of recurrent disease (e.g., by chemotherapy, immunotherapy or combinations thereof).


Assuntos
Carcinoma/patologia , Carcinoma/terapia , Recidiva Local de Neoplasia/epidemiologia , Recidiva Local de Neoplasia/patologia , Neoplasias do Colo do Útero/patologia , Neoplasias do Colo do Útero/terapia , Adulto , Idoso , Carcinoma/mortalidade , Terapia Combinada , Intervalo Livre de Doença , Feminino , Humanos , Histerectomia , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Estudos Retrospectivos , Taxa de Sobrevida , Neoplasias do Colo do Útero/mortalidade
12.
J Genet Couns ; 25(6): 1207-1214, 2016 12.
Artigo em Inglês | MEDLINE | ID: mdl-27098417

RESUMO

The use of whole exome sequencing (WES) for diagnostics of children with rare genetic diseases raises questions about best practices in genetic counselling. While a lot of attention is now given to pre-test counselling procedures for WES, little is known about how parents experience the (positive, negative, or inconclusive) WES results in daily life. To fill this knowledge gap, data were gathered through in-depth interviews with parents of 15 children who underwent WES analysis. WES test results, like results from other genetic tests, evoked relief as well as worries, irrespective of the type of result. Advantages of obtaining a conclusive diagnosis included becoming more accepting towards the situation, being enabled to attune care to the needs of the child, and better coping with feelings of guilt. Disadvantages experienced included a loss of hope for recovery, and a loss by parents of their social network of peers and the effort necessary to re-establish that social network. While parents with conclusive diagnoses were able to re-establish a peer community with the help of social media, parents receiving a possible diagnosis experienced hurdles in seeking peer support, as peers still needed to be identified. These types of psychosocial effects of WES test results for parents are important to take into account for the development of successful genetic counselling strategies.


Assuntos
Adaptação Psicológica , Aconselhamento Genético/psicologia , Testes Genéticos , Pais/psicologia , Doenças Raras/genética , Adulto , Criança , Exoma , Humanos , Doenças Raras/diagnóstico , Análise de Sequência de DNA
13.
Clin Genet ; 89(2): 244-50, 2016 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-25916247

RESUMO

As whole exome sequencing (WES) is just starting to be used as a diagnostic tool in paediatric neurology for children with a neurological disorder, and patient experiences and preferences with regard to counselling are relatively underexplored. This article explores experiences and preferences of parents with pre-test and post-test counselling in a trial that uses WES for diagnostics. Second, it maps information and communication needs which exceed the counselling protocol, in order to acquire insight into how it can be improved. Data were gathered through in-depth interviews with parents of 15 children who were included in the trial. Information and communication needs of parents differed from the protocol with respect to (i) the type and amount of information provided about WES research, (ii) incidental findings, (iii) communication about progress of the study, and (iv) the communication of the results. Furthermore, parents preferred to have more of a communicative exchange with health care providers about their daily struggles and concerns related to their life with a diseased child and wanted to know how a diagnosis could offer help. There are different ways to meet parental needs, but we suggest that assigning a case manager might be a helpful option that deserves further exploration.


Assuntos
Comunicação , Aconselhamento , Exoma/genética , Neurologia/métodos , Pais , Pediatria , Análise de Sequência de DNA/métodos , Criança , Humanos , Achados Incidentais , Consentimento Livre e Esclarecido , Encaminhamento e Consulta
14.
Ann Oncol ; 26(10): 2141-9, 2015 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-26216383

RESUMO

BACKGROUND: The immune system is important in epithelial ovarian cancer (EOC). Interleukin-6 is associated with chemoresistance and an immune-suppressive tumor microenvironment. We investigated whether a combination of chemotherapeutics, blockade of interleukin 6 (IL-6) receptor (IL-6R; tocilizumab), and immune enhancer interferon-α (Peg-Intron) is feasible, safe, and able to enhance immunity in patients with recurrent EOC. PATIENTS AND METHODS: In this dose-escalation study, patients received tocilizumab 1, 2, 4, or 8 mg/kg i.v., q4 weeks during the first three cycles of carboplatin (AUC5) plus doxorubicin [pegylated liposomal doxorubicin (PLD) 30 mg/m(2) or doxorubicin 50 mg/m(2) i.v., day 1, q4 weeks, for six cycles]. At the highest tocilizumab dose (8 mg/kg), Peg-Intron (1 µg/kg s.c.) was added. Peripheral blood mononuclear cells were collected for immunomonitoring at baseline, after three and six cycles. Dose-limiting toxicity (DLT), CA-125, and radiologic response were evaluated. RESULTS: In the 23 patients enrolled, no DLT was established. The most frequent grade 3/4 adverse events (CTCAE v4.03) were neutropenia (23%), febrile neutropenia (19%), and ileus (19%). No treatment-related deaths occurred. Using CT evaluation, 11 of 21 assessable patients responded, 6 had stable disease and 3 progressive disease. Patients receiving highest dose tocilizumab showed a functional blockade of IL-6R with increased levels of serum IL-6 (P = 0.02) and soluble IL-6R (P = 0.008). Consequently, immune cells displayed decreased levels of pSTAT3, myeloid cells produced more IL-12 and IL-1ß while T cells were more activated and secreted higher amounts of effector cytokines interferon-γ and tumor necrosis factor-α. An increase in sIL-6R was potentially associated with a survival benefit (P = 0.03). CONCLUSIONS: Functional IL-6R blocking is feasible and safe in EOC patients treated with carboplatin/(pegylated liposomal)doxorubicin, using 8 mg/kg tocilizumab. This combination is recommended for phase II evaluation based on immune parameters. CLINICAL TRIAL REGISTER: NCT01637532.


Assuntos
Adenocarcinoma de Células Claras/tratamento farmacológico , Adenocarcinoma Mucinoso/tratamento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Cistadenocarcinoma Seroso/tratamento farmacológico , Neoplasias do Endométrio/tratamento farmacológico , Recidiva Local de Neoplasia/tratamento farmacológico , Neoplasias Ovarianas/tratamento farmacológico , Adenocarcinoma de Células Claras/sangue , Adenocarcinoma de Células Claras/patologia , Adenocarcinoma Mucinoso/sangue , Adenocarcinoma Mucinoso/patologia , Adulto , Idoso , Anticorpos Monoclonais Humanizados/administração & dosagem , Biomarcadores Tumorais/sangue , Antígeno Ca-125/sangue , Carboplatina/administração & dosagem , Cistadenocarcinoma Seroso/sangue , Cistadenocarcinoma Seroso/patologia , Relação Dose-Resposta a Droga , Doxorrubicina/administração & dosagem , Doxorrubicina/análogos & derivados , Neoplasias do Endométrio/sangue , Neoplasias do Endométrio/patologia , Ensaio de Imunoadsorção Enzimática , Feminino , Seguimentos , Humanos , Interferon alfa-2 , Interferon-alfa/administração & dosagem , Interferon gama/sangue , Interleucina-6/sangue , Pessoa de Meia-Idade , Invasividade Neoplásica , Recidiva Local de Neoplasia/sangue , Recidiva Local de Neoplasia/patologia , Estadiamento de Neoplasias , Neoplasias Ovarianas/sangue , Neoplasias Ovarianas/patologia , Polietilenoglicóis/administração & dosagem , Prognóstico , Receptores de Interleucina-6/antagonistas & inibidores , Proteínas Recombinantes/administração & dosagem
15.
Eur J Paediatr Neurol ; 19(2): 233-9, 2015 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-25604808

RESUMO

BACKGROUND: The diagnostic trajectory of complex paediatric neurology may be long, burdensome, and expensive while its diagnostic yield is frequently modest. Improvement in this trajectory is desirable and might be achieved by innovations such as whole exome sequencing. In order to explore the consequences of implementing them, it is important to map the current pathway. To that end, this study assessed the healthcare resource use and associated costs in this diagnostic trajectory in the Netherlands. METHODS: Fifty patients presenting with complex paediatric neurological disorders of a suspected genetic origin were included between September 2011 and March 2012. Data on their healthcare resource utilization were collected from the hospital medical charts. Unit prices were obtained from the Dutch Healthcare Authority, the Dutch Healthcare Insurance Board, and the financial administration of the hospital. Bootstrap simulations were performed to determine mean quantities and costs. RESULTS: The mean duration of the diagnostic trajectory was 40 months. A diagnosis was established in 6% of the patients. On average, patients made 16 physician visits, underwent four imaging and two neurophysiologic tests, and had eight genetic and 16 other tests. Mean bootstrapped costs per patient amounted to €12,475, of which 43% was for genetic tests (€5,321) and 25% for hospital visits (€3,112). CONCLUSION: Currently, the diagnostic trajectories of paediatric patients who have complex neurological disease with a strong suspected genetic component are lengthy, resource-intensive, and low-yield. The data from this study provide a backdrop against which the introduction of novel techniques such as whole exome sequencing should be evaluated.


Assuntos
Doenças do Sistema Nervoso/diagnóstico , Doenças do Sistema Nervoso/economia , Exame Neurológico/economia , Neurologia/economia , Pediatria/economia , Adolescente , Fatores Etários , Criança , Pré-Escolar , Custos e Análise de Custo , Exoma/genética , Feminino , Testes Genéticos/economia , Recursos em Saúde/economia , Recursos em Saúde/estatística & dados numéricos , Hospitalização/economia , Humanos , Lactente , Recém-Nascido , Masculino , Programas Nacionais de Saúde/economia , Doenças do Sistema Nervoso/genética , Países Baixos , Análise de Sequência de DNA , Resultado do Tratamento
16.
Int J Cancer ; 135(4): 830-42, 2014 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-24415578

RESUMO

Immunotherapy of usual vulvar intraepithelial neoplasia (uVIN) is promising; however, many patients still fail to show clinical responses, which could be explained by an immune escape through alterations in human leukocyte antigen (HLA) expression. Therefore, we analyzed a cohort of patients with a primary (n = 43) and subsequent recurrent uVIN lesion (n = 20), vaccine-treated uVIN patients (n = 12), patients with human papillomavirus (HPV)-induced vulvar carcinoma (n = 21) and healthy controls (n = 26) for the expression of classical HLA-class I/II and nonclassical HLA-E/-G and MHC class I chain-related molecule A (MICA). HLA-class I was downregulated in 70% of uVIN patients, including patients with a clinical response to immunotherapy. Downregulation of HLA-class I is probably reversible, as only 15% of the uVIN cases displayed loss of heterozygosity (LOH) and HLA-class I could be upregulated in uVIN keratinocyte cultures by interferon γ. HLA-class I downregulation is more frequently associated with LOH in vulvar carcinomas (25-55.5%). HLA-class II was found to be focally expressed in 65% of uVIN patients. Of the nonclassical molecules, MICA was downregulated in 80% of uVIN whereas HLA-E and -G were expressed in a minority of cases. Their expression was more prominent in vulvar carcinoma. No differences were found between the alterations observed in paired primary and recurrent uVIN. Importantly, downregulation of HLA-B/C in primary uVIN lesions was associated with the development of recurrences and progression to cancer. We conclude that downregulation of HLA is frequently observed in premalignant HPV-induced lesions, including clinical responders to immunotherapy, and is associated with worse clinical outcome. However, in the majority of cases downregulation may still be reversible.


Assuntos
Carcinoma/imunologia , Antígenos HLA/metabolismo , Imunoterapia/métodos , Infecções por Papillomavirus/imunologia , Neoplasias Vulvares/imunologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma/terapia , Carcinoma/virologia , Estudos de Casos e Controles , Estudos de Coortes , Regulação para Baixo , Feminino , Regulação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Genótipo , Humanos , Interferon gama/metabolismo , Queratinócitos/citologia , Queratinócitos/efeitos dos fármacos , Queratinócitos/virologia , Perda de Heterozigosidade , Pessoa de Meia-Idade , Infecções por Papillomavirus/terapia , Recidiva , Neoplasias Vulvares/terapia , Neoplasias Vulvares/virologia
17.
Oncoimmunology ; 3(12): e962397, 2014 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-25964862

RESUMO

An increased level of interleukin-6 (IL-6) in epithelial ovarian cancer (EOC) is correlated with a worse prognosis. IL-6 stimulates tumor-growth and inflammation. We investigated the intricate interaction between the IL-6 signaling pathway and tumor-infiltrating myeloid cells (TIMs) to determine their prognostic impact in EOC. 160 EOC samples were analyzed for the expression of IL-6, its receptor (IL-6R) and downstream signaling via pSTAT3 by immunohistochemistry. Triple color immunofluorescence confocal microscopy was used to identify myeloid cell populations by CD14, CD33, and CD163. The relationship between these markers, tumor-infiltrating immune cells, clinical-pathological characteristics and survival was investigated. EOC displayed a dense infiltration with myeloid cells, in particular of the CD163+ type. The distribution pattern of all myeloid subtypes was comparable among the different histological subtypes. Analysis of the tumor cells revealed a high expression of IL-6R in 15% and of IL-6 in 23% of patients. Interestingly, tumors expressing IL-6 or IL-6R formed two different groups. Tumors with a high expression of IL-6R displayed low mature myeloid cell infiltration and a longer disease-specific survival (DSS), especially in late stage tumors. High expression of IL-6R was an independent prognostic factor for survival by multivariate analyses (hazard ratio = 0.474, p = 0.011). In contrast, tumors with high epithelial IL-6 expression displayed a dense infiltration of mature myeloid cells and were correlated with a shorter DSS. Furthermore, in densely CD8+ T-cell infiltrated tumors, the ratio between these lymphoid cells and CD163+ myeloid cells was predictive for survival. Thus, IL-6 and IL-6R are opposite markers for myeloid cell infiltration and survival.

18.
Int J Cancer ; 133(12): 2884-94, 2013 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-23740735

RESUMO

One of the hallmarks of cancer is the influx of myeloid cells. In our study, we investigated the constitution of tumor-infiltrating myeloid cells and their relationship to other tumor-infiltrating immune cells, tumor characteristics and the disease-specific survival of patients with cervical cancer (CxCa). Triple-color immunofluorescence confocal microscopy was used to locate, identify and quantify macrophages (CD14), their maturation status (CD33) and their polarization (CD163) in a cohort of 86 patients with cervical carcinoma. Quantification of the numbers of myeloid cells revealed that a strong intraepithelial infiltration of CD14+ cells, and more specifically the population of CD14+CD33-CD163- matured M1 macrophages, is associated with a large influx of intraepithelial T lymphocytes (p = 0.008), improved disease-specific survival (p = 0.007) and forms an independent prognostic factor for survival (p = 0.033). The intraepithelial CD8+ T-cell and regulatory T-cell (Treg) ratio also forms an independent prognostic factor (p = 0.010) and combination of these two factors reveals a further increased benefit in survival for patients whose tumor displays a dense infiltration with intraepithelial matured M1 macrophages and a high CD8 T-cell/Treg ratio, indicating that both populations of immune cells simultaneously improve survival. Subsequently, we made a heatmap including all known immune parameters for these patients, whereby we were able to identify different immune signatures in CxCa. These results indicate that reinforcement and activation of the intratumoral M1 macrophages may form an attractive immunotherapeutic option in CxCa.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Receptores de Lipopolissacarídeos/análise , Linfócitos do Interstício Tumoral/imunologia , Células Mieloides/imunologia , Neoplasias do Colo do Útero/imunologia , Feminino , Humanos , Macrófagos/imunologia , Pessoa de Meia-Idade , Prognóstico , Microambiente Tumoral , Neoplasias do Colo do Útero/mortalidade
19.
Sci Eng Ethics ; 19(3): 963-81, 2013 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-23229374

RESUMO

In their 2007 paper, Swierstra and Rip identify characteristic tropes and patterns of moral argumentation in the debate about the ethics of new and emerging science and technologies (or "NEST-ethics"). Taking their NEST-ethics structure as a starting point, we considered the debate about tissue engineering (TE), and argue what aspects we think ought to be a part of a rich and high-quality debate of TE. The debate surrounding TE seems to be predominantly a debate among experts. When considering the NEST-ethics arguments that deal directly with technology, we can generally conclude that consequentialist arguments are by far the most prominently featured in discussions of TE. In addition, many papers discuss principles, rights and duties relevant to aspects of TE, both in a positive and in a critical sense. Justice arguments are only sporadically made, some "good life" arguments are used, others less so (such as the explicit articulation of perceived limits, or the technology as a technological fix for a social problem). Missing topics in the discussion, at least from the perspective of NEST-ethics, are second "level" arguments-those referring to techno-moral change connected to tissue engineering. Currently, the discussion about tissue engineering mostly focuses on its so-called "hard impacts"-quantifiable risks and benefits of the technology. Its "soft impacts"-effects that cannot easily be quantified, such as changes to experience, habits and perceptions, should receive more attention.


Assuntos
Teoria Ética , Ciência/ética , Justiça Social , Responsabilidade Social , Tecnologia/ética , Engenharia Tecidual/ética , Direitos Humanos , Humanos , Obrigações Morais , Qualidade de Vida
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...