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1.
Neuroendocrinology ; 109(4): 346-361, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31280274

RESUMO

Metastatic neuroendocrine cancer still constitutes a palliative situation, lacking promising treatment options. Oncolytic virotherapy, a novel type of virus-based immunotherapy, lyses tumor cells using genetically engineered viruses thereby activating the immune system to induce an optimized antitumor response which could bring down tumor masses to a stage of minimal residual tumor disease. The oncolytic vector talimogene laherparepvec (T-VEC, herpes simplex virus [HSV] type 1) has already shown excellent safety profiles in clinical studies and has become the first ever FDA/EMA-approved oncolytic virus (OV). This work presents a first preclinical assessment of this state-of-the-art OV, using a panel of human neuroendocrine tumor/neuroendocrine carcinoma (NET/NEC) cell lines. Cytotoxicity, transgene expression, and viral replication patterns were studied. Furthermore, the antiproliferative activity was compared to the one of mTOR inhibitor Everolimus and also interactions between the OV and Everolimus were evaluated. Moreover, virostatic effects of ganciclovir (GCV) on replication of T-VEC were assessed and electron microscopic pictures were taken to comprehend viral envelopment and details of the replication cycle of T-VEC in human neuroendocrine cancer. It could be shown that T-VEC infects, replicates in, and lyses human NET/NEC cells exhibiting high oncolytic efficiencies already at quite low virus concentrations. Interestingly, Everolimus was not found to have any relevant impact on rates of viral replication, but no additive effects could be proved using a combinatorial therapy regimen. On the other hand, GCV was shown to be able to limit replication of T-VEC, thus establishing an important safety feature for future treatments of NET/NEC patients. Taken together, T-VEC opens up a promising novel treatment option for NET/NEC patients, warranting its further preclinical and clinical development.

2.
Swiss Med Wkly ; 149: w20107, 2019 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-31340054

RESUMO

PURPOSE: Extra-abdominal desmoid tumours are benign and rare, and lead to a persistent treatment dilemma because of their high recurrence rate and their heterogeneous behaviour. The goal of this retrospective study was to evaluate the results of different treatment modalities for extra-abdominal desmoid tumours at four sarcoma treatment centres. METHODS: The mean follow-up time for the 96 patients included in the study (63.5% female; mean age 38.9 years) was 8.4 years (2.0–40.5 years). The initial treatments were surgery (n = 44), surgery with radiation (n = 16), watchful waiting (n = 15), radiation only (n = 9), or systemic treatment (n = 12). Patient demographics, tumour sites, and the follow-up status of all patients were reviewed and evaluated for each of the treatment modalities. RESULTS: The local recurrence rate was 45.5% in patients with primary surgical treatment and 37.5% following surgery combined with irradiation. Patients who were treated with radiation alone showed regressive (33.3%) or stable disease (66.6%). Systemic treatment alone resulted in disease progression in 41.7% of our patients. In the watchful waiting group, 73.3% showed stable disease, 20.0% showed spontaneous regression, and 6.7% showed progression after a mean follow-up of 4.1 years (2.0–11.5 years). CONCLUSIONS: Our results suggest that a watchful waiting approach should be the first line treatment in asymptomatic desmoid tumours. However, radiation can help improve local control rates in patients who have undergone surgery. Progression and local recurrence rates following systemic treatment were comparable to those observed in surgery combined with radiation.

3.
Mol Oncol ; 13(7): 1548-1558, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31116510

RESUMO

The GILUPI CellCollector (CC) is a novel in vivo circulating tumor cell (CTC) detection device reported to overcome the limitations of small blood sample volumes. The aim of this prospective, blinded study was to evaluate the clinical application of the CC and to compare its performance to the CellSearch (CS) system in M0 and M1 colorectal cancer (CRC) patients. A total of 80 patients (31 M0, 49 M1) with CRC were enrolled. CTCs were simultaneously measured in the peripheral blood using CS and the CC, and the results of both assays were correlated to clinicopathological variables and overall survival. The total number of detected CTCs and CTC-positive patients did not significantly differ between both assays. In the M0 patients, the CC detected CTCs more frequently than CS. There was no significant difference in total CTC numbers detected with the CC between M0 and M1 patients. In addition, no significant correlation with clinicopathological parameters or overall survival was observed with CC CTCs. In contrast, detection of CTCs with CS was significantly correlated with Union for International Cancer Control stage and reduced overall survival. There was no correlation between CTCs detected by the CC and the CS system. Using in silico analysis, we estimate that CC screens a volume of 0.33-18 mL during in vivo application, in contrast to much higher volumes reported elsewhere. In conclusion, while being safe and easy to use, the CC did not outperform CS in terms of CTC yield or sensitivity. While CTC detection in M0 CRC patients was significantly increased with the CC, the clinical relevance of these CTCs appears inferior to the cells identified by the CS system.

4.
Anticancer Res ; 39(4): 2015-2023, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30952745

RESUMO

BACKGROUND/AIM: Reconstruction of diaphyseal tibial sarcomas with extracorporeal irradiated autograft is a rarely applied technique and is analyzed in this study. PATIENTS AND METHODS: Eight patients with malignant sarcomas received local treatment by means of a wide resection and reimplantation of an extracorporeally-irradiated autograft. The graft was combined with an ipsilateral vascularized fibula when a full-thickness segment of the tibia had to be resected and no cortex could be preserved (n=5). Oncological and functional results were recorded. RESULTS: All patients had clear margins after resection, and with no local recurrence 72 months after treatment. Full weight-bearing was allowed at the time of radiological consolidation of the irradiated grafts (after a median of five months). The functional results were good and excellent in 7 of 8 patients, respectively. CONCLUSION: Extracorporeal irradiation grafting is a suitable method for the treatment of localised and resectable tibial sarcomas.


Assuntos
Neoplasias Ósseas , Reimplante , Sarcoma , Neoplasias de Tecidos Moles , Tíbia/cirurgia , Adolescente , Adulto , Neoplasias Ósseas/radioterapia , Neoplasias Ósseas/cirurgia , Criança , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Sarcoma/radioterapia , Sarcoma/cirurgia , Neoplasias de Tecidos Moles/radioterapia , Neoplasias de Tecidos Moles/cirurgia , Adulto Jovem
5.
Swiss Med Wkly ; 149: w20032, 2019 Mar 25.
Artigo em Inglês | MEDLINE | ID: mdl-30950502

RESUMO

The effects of oncological treatment, congenital anomalies, traumatic injuries and post-infection damage critically require sufficient amounts of tissue for structural and functional surgical reconstructions. The patient’s own body is typically the gold standard source of transplant material, but in children autologous tissue is available only in small quantities and with severe morbidity at donor sites. Engineering of tissue grafts starting from a small amount of autologous material, combined with suitable surgical manipulation of the recipient site, is expected to enhance child and adolescent health, and to offer functional restoration for long-term wellbeing. Moreover, engineered tissues based on patient-derived cells represent invaluable models to investigate mechanisms of disease and to develop/test novel therapeutic approaches. In view of these great opportunities, here we introduce the currently limited successful implementation of tissue engineering in paediatric settings and discuss the open challenges in the field. A particular focus is on the specific needs and envisioned strategies in the areas of bone and osteochondral regeneration in children.

6.
Orthop Surg ; 11(2): 277-284, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30883009

RESUMO

OBJECTIVE: To report on a CT scan virtual periacetabular osteotomy (PAO) process to evaluate the potential risk of different PAO cutting planes. METHODS: A total of 123 patients (64 men and 59 women) underwent virtual PAO. We defined two retroacetabular cutting (RC) planes: the RC plane and the RC+ plane (10 mm posteriorly as compared to the RC plane). Subsequently, we measured the anatomical minimum distance between the acetabulum and the sciatic notch, the minimum distance between the acetabulum and the retroacetabular cutting plane (osteotomy of the posterior column), and the osteotomy length in the cranio-caudal direction. RESULTS: The mean (standard deviation [SD]) minimum distance between the acetabulum and the sciatic notch was 25.82 ± 3.52 mm (95% confidence intervals [CI], 25.36-26.25 mm). In men, the mean (SD) minimum distance between the acetabulum and sciatic notch (27.18 ± 3.47 mm; 95% CI, 26.56-27.78 mm) was significantly (3 mm) larger than in women (24.34 ± 2.92 mm; 95% CI, 23.82-24.89 mm; P < 0.001). The mean (SD) minimum distance between the acetabulum and the retroacetabular plane was significantly larger for the RC+ plane (6.97 ± 0.91 mm) than for the RC plane (P < 0.001). In men, this distance (10.23 ± 3.84 mm) was significantly (2.3 mm) larger than in women (7.94 ± 3.45 mm; P < 0.001). The mean (SD) osteotomy length was significantly larger for the RC+ plane (61.78 ± 6.75 mm) than for the RC plane (68.48 ± 6.65) mm; P < 0.001). All three evaluated parameters had significantly shorter lengths in women than in men. CONCLUSION: The safety space for PAO in women was narrower than in men. By shifting the RC plane 10 mm into the posterior direction, the RC+ plane provides a safer cutting distance and shorter osteotomy line in the PAO than the RC plan, which is important to avoid intraarticular penetration.

7.
Gait Posture ; 68: 506-513, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30623844

RESUMO

BACKGROUND: Structural leg length discrepancy (LLD) is a common phenomenon. However, its effect on spinal gait kinematics remains unclear. RESEARCH QUESTION: How does LLD affect spinal gait kinematics in patients with structural LLD and what is the immediate effect of a shoe lift?. METHODS: 10 adolescents with structural LLD (20-60 mm) and 14 healthy controls were included. All of whom were fitted with a trunk marker set and requested to walk barefoot as well as with an orthotic shoe lift (only patients). Data were collected using a 12-camera motion capture system. Group comparisons were conducted using one-dimensional Statistical Parametric Mapping (SPM). RESULTS: Patients with LLD showed statistically significant increased frontal plane lumbar bending angles to the longer side (p = 0.007), increased pelvic drop on the shorter side (p < 0.001) and increased hip adduction angles on the longer leg (p < 0.001) compared to the healthy controls. In the sagittal plane, patients demonstrated changed knee (shorter leg) and ankle joint (longer leg) motion. All gait deviations observed in patients with LLD could immediately be altered by correcting the LLD using a shoe lift. SIGNIFICANCE: Due to the LLD, patients showed a lateral pelvic drop on the shorter side, which appeared to be compensated for by a contralateral bending in the lumbar spine and a lateral shift of the pelvis towards the longer side. In addition, the use of an orthotic correction seems to be a suitable option to instantly normalize gait kinematics in patients with mild to moderate LLD.


Assuntos
Marcha/fisiologia , Articulação do Joelho/fisiopatologia , Desigualdade de Membros Inferiores/fisiopatologia , Vértebras Lombares/fisiopatologia , Caminhada/fisiologia , Adolescente , Fenômenos Biomecânicos , Criança , Feminino , Humanos , Desigualdade de Membros Inferiores/reabilitação , Masculino , Sapatos
8.
Surg Laparosc Endosc Percutan Tech ; 29(4): 267-270, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30676540

RESUMO

BACKGROUND: Previous lower abdominal surgery is generally considered as a relative contraindication for laparoscopic totally extraperitoneal (TEP) inguinal hernia repair. Our objective was to investigate the feasibility and safety of TEP repair in patients with a history of lower abdominal surgery. MATERIALS AND METHODS: A retrospective analysis of 301 patients with inguinal hernia who underwent elective laparoscopic TEP repair between August 2010 and August 2014 was conducted. One-hundred five patients (34.9%) had previously undergone lower abdominal surgery. The main outcome measures included intraoperative and postoperative morbidity and mortality. Secondary outcomes were immediate postoperative pain, presence of chronic pain at follow-up, and hernia recurrence. RESULTS: Patient demographics and clinical variables were balanced between the 2 groups, with the exception of age. Intraoperative morbidity was similar between cases without previous lower abdominal surgery (nPS) and cases with history of lower abdominal surgery (PS) [nPS vs. PS: 0.5% (n=1) vs. 2.8% (n=3), P=0.09]. Overall 30-day morbidity was found to be significantly higher in the PS patient group [nPS vs. PS: 1.5% (n=3) vs. 6.6% (n=7), P=0.018]. Mortality was nil. There were no differences noted between the 2 groups with respect to early postoperative pain and chronic inguinal pain. Complete follow-up information was available for 149 of 301 patients (follow-up rate of 49.5%, range: 3 to 48 mo) with a mean follow-up time of 20.38 months (SD=7.7). There was no statistically significant difference noted in the recurrence rate between the 2 patient groups at follow-up [nPS vs. PS: 3.2% (n=3) vs. 1.8% (n=1), P=0.6]. CONCLUSIONS: The present work demonstrates higher incidence of postoperative scrotal hematoma after TEP repair in patients with history of previous lower abdominal surgery. All remaining outcomes of interest were found to be similar between the 2 patient groups. Further trials will be needed to verify our findings.

9.
J Pathol ; 248(1): 116-122, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30549028

RESUMO

Non-ossifying fibroma (NOF), which occasionally results in pathologic fracture, is considered the most common benign and self-limiting lesion of the growing skeleton. By DNA sequencing we have identified hotspot KRAS, FGFR1 and NF1 mutations in 48 of 59 patients (81.4%) with NOF, at allele frequencies ranging from 0.04 to 0.61. Our findings define NOF as a genetically driven neoplasm caused in most cases by activated MAP-kinase signalling. Interestingly, this driving force either diminishes over time or at least is not sufficient to prevent autonomous regression and resolution. Beyond its contribution to a better understanding of the molecular pathogenesis of NOF, this study adds another benign lesion to the spectrum of KRAS- and MAP-kinase signalling-driven tumours. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

10.
Int J Cancer ; 2018 Aug 24.
Artigo em Inglês | MEDLINE | ID: mdl-30144031

RESUMO

To determine the role of BRAFV600E mutation and MAPK signaling as well as the effects of BRAF and MEK directed therapy in gastroenteropancreatic neuroendocrine neoplasia (GEP-NEN), with a focus on highly aggressive gastroenteropancreatic neuroendocrine carcinoma (GEP-NEC). Using Sanger sequencing of BRAF exon 15 we determined the frequency of BRAFV600E mutations in 71 primary GEP-NENs. MEK phosphorylation was examined by immunohistochemistry in corresponding tissue samples. To evaluate the biological relevance of BRAFV600E mutation and MAPK signaling in GEP-NECs, effects of a pharmacological BRAF and MEK inhibition were analyzed in NEC cell lines both in vitro and in vivo. BRAFV600E mutation was detected in 9.9% of all GEP-NENs. Interestingly, only NECs of the colon harbored BRAFV600E mutations, leading to a mutation frequency of 46.7% in this subgroup of patients. In addition, a BRAFV600E mutation was significantly associated with high levels of MEK phosphorylation (pMEK) and advanced tumor stages. Pharmacological inhibition of BRAF and MEK abrogated NEC cell growth, inducing G1 cell cycle arrest and apoptosis only in BRAFV600E mutated cells. BRAF inhibitor dabrafenib and MEK inhibitor trametinib prevented growth of BRAFV600E positive NEC xenografts. High frequencies of BRAFV600E mutation and elevated expression levels of pMEK were detected in biologically aggressive and highly proliferative colorectal NECs. We provide evidence that targeting BRAF oncogene may represent a therapeutic strategy for patients with BRAF mutant colorectal NECs.

11.
Langenbecks Arch Surg ; 403(5): 547-554, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30066108

RESUMO

INTRODUCTION: The definitive treatment of pilonidal sinus disease (PSD) is surgical. There is still no consensus as to the most appropriate off-midline primary closure technique. The aim of this meta-analysis has been to compare Karydakis flap reconstruction (KF) to Limberg flap transposition (LF) with regard to short- and long-term postoperative outcomes. METHODS: A systematic literature search for randomized controlled trials (RCTs) comparing KF to LF was performed. Data regarding postoperative outcomes were extracted and compared by meta-analysis. The odds ratio and standardized mean differences with 95% confidence intervals (CIs) were calculated. RESULTS: Eight RCTs were identified comparing KF (n = 554) to LF (n = 567). There was no significant difference noted between KF and LF with regard to the primary outcome variable, recurrence rate (OR = 1.07; 95% CI [0.59-1.92]; p = 0.83; 7 studies; I2 = 40%). LF was associated with a lower rate of post-operative seroma (OR = 2.03; 95% CI [1.15, 3.59]; p = 0.01; 7 studies; I2 = 0%). No further significant differences were noted in the secondary endpoints between the two study groups. CONCLUSIONS: Recurrence rates of PSD were found to be similar in both study groups. Post-operative seroma rate was significantly higher in the KF group. The meta-analysis did not indicate any further statistically significant differences between the two surgical procedures.

12.
Neuroendocrinology ; 107(3): 246-256, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30025411

RESUMO

BACKGROUND: Gastroenteropancreatic neuroendocrine carcinomas (GEP-NECs) are biologically aggressive tumors, associated with a very poor survival. Due to their rarity, our knowledge on GEP-NEC biology is very limited. The aim of this study was to establish a GEP-NEC cell line model that might contribute to a better understanding of this rare malignant disease to further develop novel therapeutic approaches in preclinical studies. METHODS: Small cell neuroendocrine cancer cell line NEC-DUE3 was derived from a lymph node metastasis of a neuroendocrine carcinoma (NEC) located at the anal canal. Morphological characteristics and the expression of neuroendocrine markers were comprehensively investigated. For genetic profiling, NEC-DUE3 cells were analyzed by DNA fingerprinting. Chromosomal aberrations were mapped by array comparative genomic hybridization. NEC-DUE3 cell tumorigenicity was evaluated in vivo and the sensitivity to chemotherapeutic agents was assessed in vitro. RESULTS: NEC-DUE3 cells were characterized by the expression of molecular markers that are commonly observed in GEP-NECs, were sensitive to treatment with cisplatin, and able to form tumors in immunodeficient mice. CONCLUSION: We established and characterized the first small cell GEP-NEC cell line that may serve as a valuable tool to create a better understanding of the biology of these rare tumors and to develop novel treatment strategies.

13.
Blood ; 132(3): 307-320, 2018 Jul 19.
Artigo em Inglês | MEDLINE | ID: mdl-29724897

RESUMO

Heat shock protein 90 (HSP90) stabilizes many client proteins, including the BCR-ABL1 oncoprotein. BCR-ABL1 is the hallmark of chronic myeloid leukemia (CML) in which treatment-free remission (TFR) is limited, with clinical and economic consequences. Thus, there is an urgent need for novel therapeutics that synergize with current treatment approaches. Several inhibitors targeting the N-terminal domain of HSP90 are under investigation, but side effects such as induction of the heat shock response (HSR) and toxicity have so far precluded their US Food and Drug Administration approval. We have developed a novel inhibitor (aminoxyrone [AX]) of HSP90 function by targeting HSP90 dimerization via the C-terminal domain. This was achieved by structure-based molecular design, chemical synthesis, and functional preclinical in vitro and in vivo validation using CML cell lines and patient-derived CML cells. AX is a promising potential candidate that induces apoptosis in the leukemic stem cell fraction (CD34+CD38-) as well as the leukemic bulk (CD34+CD38+) of primary CML and in tyrosine kinase inhibitor (TKI)-resistant cells. Furthermore, BCR-ABL1 oncoprotein and related pro-oncogenic cellular responses are downregulated, and targeting the HSP90 C terminus by AX does not induce the HSR in vitro and in vivo. We also probed the potential of AX in other therapy-refractory leukemias. Therefore, AX is the first peptidomimetic C-terminal HSP90 inhibitor with the potential to increase TFR in TKI-sensitive and refractory CML patients and also offers a novel therapeutic option for patients with other types of therapy-refractory leukemia because of its low toxicity profile and lack of HSR.

14.
Eur J Pediatr ; 177(7): 1071-1080, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-29728840

RESUMO

Diagnostic tools for the management of acute osteomyelitis (OM) and septic arthritis (SA) have improved over the last decade. To investigate the influence and availability of magnetic resonance imaging (MRI) and nucleic acid testing (NAT), a retrospective cohort study was done. Patients admitted with acute OM or SA between 2005 and 2014 were identified using ICD-10 discharge codes. Ninety-six children were identified: OM, n = 45; SA, n = 42; and OM + SA, n = 9. Diagnostic imaging was performed in 100% of OM or OM + SA and 95% of SA patients. MRI was performed in 85% of OM patients, 26% of SA patients and 100% OM + SA patients. In patients with OM or SA, concomitant joint/bone involvement was detected in 24 and 36% of patients, respectively. In 58% of patients, a pathogen was detected (Staphylococcus aureus, Streptococcus pyogenes and Streptococcus pneumoniae being most common). Blood and tissue culture were positive in 41 and 86% for OM patients and in 14 and 41%, respectively, for SA patients. In 42% of patients, no pathogen was identified, of which 40% had no material for blood or tissue culture/NAT taken. CONCLUSION: Optimal use of imaging modalities including MRI and systematic pathogen detection including NAT should be advocated to limit use of broad spectrum antibiotics and treatment duration. What is Known: • Magnetic resonance imaging and sonography have the best sensitivity for detection of acute osteomyelitis and septic arthritis in children. • Systematic use of blood cultures, tissue cultures and nucleic acid testing improves pathogen detection in children with acute osteomyelitis and septic arthritis. What is New: • The added value of imaging modalities other than magnetic resonance and sonography for detection of osteomyelitis and septic arthritis is limited, and their routine use should be questioned. • Despite availability of optimal pathogen detection methods, missed opportunities to improve pathogen detection are frequent.


Assuntos
Artrite Infecciosa/diagnóstico , Diagnóstico por Imagem/estatística & dados numéricos , Técnicas Microbiológicas/estatística & dados numéricos , Osteomielite/diagnóstico , Doença Aguda , Antibacterianos/administração & dosagem , Artrite Infecciosa/microbiologia , Artrite Infecciosa/terapia , Biomarcadores , Criança , Pré-Escolar , Estudos de Coortes , Feminino , Humanos , Masculino , Osteomielite/microbiologia , Osteomielite/terapia , Estudos Retrospectivos
15.
J Cancer ; 9(6): 929-940, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29581772

RESUMO

Background: Follicular thyroid carcinoma's (FTC) often benign course is partially due to adjuvant radioactive iodine (RAI) treatment. However, once the tumour has spread and fails to retain RAI, the therapeutic options are limited and the outcome is poor. In this subset of patients, the identification of novel druggable biomarkers appears invaluable. Here, we investigated the stage dependent expression and functional role of the C-X-C chemokine receptors type 4 and 7 (CXCR4/7) in FTC. Methods: CXCR4/7 expression was examined in 44 FTC and corresponding non-neoplastic thyroid specimens as well as 10 FTC distant metastases and 18 follicular adenomas using tissue microarray technology. Expression levels were correlated with clinicopathological variables as well as overall and recurrence free survival. Changes regarding cell cycle activation, tumour cell invasiveness and mRNA expression of genes related to epithelial-mesenchymal transition (EMT) were investigated after treatment with recombinant human SDF1α/CXCL12 (rh-SDF1α) and CXCR4 antagonists AMD3100 and WZ811. Results: CXCR4/7 expression was associated with large tumour size, advanced UICC stage as well as shorter overall and recurrence free survival. CXCR4 was significantly higher expressed in distant metastases than in primary tumour cores. In addition, rh-SDF1α induced invasive growth, cell cycle activation and EMT, while CXCR4 antagonists significantly reduced FTC invasiveness in vitro. Conclusion: Here we provide first evidence of the biological importance of the CXCR4/CXCR7/CXCL12 axis in FTC. Our findings underscore the therapeutic potential of this chemokine receptor family in advanced FTC and offer new valuable insight into the oncogenesis of metastatic FTC.

16.
Oncol Lett ; 15(3): 3779-3789, 2018 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-29467895

RESUMO

Based on their overexpression and important roles in progression and therapy-resistance in malignant diseases, the inhibitor of apoptosis protein family (IAP) members, survivin and X-linked inhibitor of apoptosis protein (XIAP), represent attractive candidates for targeted therapy. The present study investigated the prognostic and biological relevance of survivin and XIAP in esophageal squamous-cell carcinoma (ESCC) and esophageal adenocarcinoma (EAC). Survivin and XIAP expression was analyzed by immunohistochemistry using tissue microarrays containing 120 ESCC and 90 EAC samples as well as the corresponding non-neoplastic esophageal mucosa samples. IAP expression levels were then correlated to clinicopathological parameters and overall survival to identify any associations. In addition, esophageal cancer cell lines were treated with the survivin inhibitor YM155, and the XIAP inhibitors Birinapant and GDC-0152 in vitro. Survivin and XIAP expression were significantly increased in EAC and ESCC when compared with tumor-adjacent mucosa. In patients with ESCC XIAP expression was associated with female gender and advanced tumor stages, and nuclear survivin expression was associated with poor grading. High XIAP expression was identified as an independent negative prognostic marker in ESCC. By contrast, XIAP inhibitors did not affect cancer cell viability in vitro, and the small molecule survivin inhibitor YM155 significantly reduced cell viability and proliferation in esophageal cancer cell lines. Western blot analysis revealed a dose dependent decrease of survivin accompanied by an increased poly (adenosine diphosphate-ribose) polymerase cleavage following YM155 treatment. These findings underline the potential role of survivin and XIAP in the oncogenesis of esophageal cancer and provide a rationale for future clinical studies investigating the therapeutic efficacy of IAP directed therapies in patients with esophageal cancer.

17.
Endocr Relat Cancer ; 25(3): 295-308, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-29317481

RESUMO

Follicular thyroid cancer's (FTC) excellent long-term prognosis is mainly dependent on postoperative radioactive iodine (RAI) treatment. However, once the tumour becomes refractory, the 10-year disease-specific survival rate drops below 10%. The aim of our study was to evaluate the prognostic and biological role of the TRAIL system in FTC and to elucidate the influence of small-molecule-mediated antagonisation of inhibitor of apoptosis proteins (IAPs) on TRAIL sensitivity in vitro Tissue microarrays were constructed from forty-four patients with histologically confirmed FTC. Expression levels of TRAIL and its receptors were correlated with clinicopathological data and overall as well as recurrence-free survival. Non-iodine-retaining FTC cell lines TT2609-bib2 and FTC133 were treated with recombinant human TRAIL alone and in combination with Smac mimetics GDC-0152 or Birinapant. TRAIL-R2/DR5 as well as TRAIL-R3/DcR1 and TRAIL-R4/DcR2 were significantly higher expressed in advanced tumour stages. Both decoy receptors were negatively associated with recurrence-free and overall survival. TRAIL-R4/DcR2 additionally proved to be an independent negative prognostic marker in FTC (HR = 1.446, 95% CI: 1.144-1.826; P < 0.001). In vitro, the co-incubation of Birinapant or GDC-0152 with rh-TRAIL-sensitised FTC cell lines for TRAIL-induced apoptosis, through degradation of cIAP1/2. The TRAIL system plays an important role in FTC tumour biology. Its decoy receptors are associated with poor prognosis as well as earlier recurrence. The specific degradation of cIAP1/2 sensitises FTC cells to TRAIL-induced apoptosis and might highlight a new point of attack in patients with RAI refractory disease.

18.
Horm Metab Res ; 50(1): 23-28, 2018 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-29169190

RESUMO

Calcitonin (CT), a tumor marker for medullary thyroid cancer (MTC), can be stimulated with pentagastrin or calcium. Because of the unavailability of pentagastrin, basal CT measurement is frequently used for the preoperative diagnosis of MTC. The aim of the study was to define basal serum calcitonin (bCT) cut-off thresholds for diagnosing MTC. Within a retrospective analysis, 114 patients (51 males) were included fulfilling the criteria of an increased preoperative bCT level (>10 pg/ml) and the criteria of an available postoperative histology analysis. Based on a ROC plot analysis, the cut-off values for the diagnosis of MTC vs. non-malignancy (C cell hyperplasia and goiter) were identified. The most precise bCT thresholds for the identification of MTC were ≥46 pg/ml for males (sensitivity: 93.6%, specificity: 95.0%, PPV: 97%, NPV: 90%) and ≥35 pg/ml for females (sensitivity: 87.3%, specificity: 87.5%, PPV: 98%, NPV: 50%). Using these cut-offs, only 6% of male patients were not identified of having MTC, whereas 5% were false positive (having instead C cell hyperplasia). In females, the discrepancy was higher since 13% of female MTC patients were false negative by using the cut-off of ≥35 pg/ml, and 13% had false positive results (suffering from C cell hyperplasia). Gender-specific bCT cut-offs for the identification of MTC vs. C cell hyperplasia and non-malignancy were defined, which can be used in clinical routine. In female patients, however, the accuracy is much lower compared to males.


Assuntos
Calcitonina/sangue , Carcinoma Neuroendócrino/sangue , Carcinoma Neuroendócrino/diagnóstico , Neoplasias da Glândula Tireoide/sangue , Neoplasias da Glândula Tireoide/diagnóstico , Feminino , Humanos , Hiperplasia , Masculino , Pessoa de Meia-Idade , Curva ROC , Valores de Referência , Sensibilidade e Especificidade
19.
J Pediatr Orthop B ; 27(5): 399-403, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-28704303

RESUMO

This study aimed to determine the alteration in maximum isokinetic torque in patients after intramedullary femoral leg lengthening. Thirty patients with a median leg-length discrepancy of 3.0 cm underwent femoral limb lengthening with an intramedullary motorized device. Maximum isokinetic, concentric torque of the extensors, and flexors of the knee was measured before (n=30) and 2 years after surgery (n=21). Postoperatively, a significant difference remained for the maximum isokinetic torque of the extensors (22%) between the lengthened and the normal leg, which might have been caused by muscle response to the distraction procedure itself in the form of higher stiffness, less immediate displacement, and inconsistent force relaxation properties. However, we provide evidence that physiotherapy after limb lengthening should focus on extensors to prevent loss of strength.

20.
Br J Cancer ; 117(12): 1837-1845, 2017 Dec 05.
Artigo em Inglês | MEDLINE | ID: mdl-29112684

RESUMO

BACKGROUND: Medullary thyroid carcinoma (MTC) is a rare and challenging endocrine malignancy. Once spread, the therapeutic options are limited and the outcome poor. For these patients, the identification of new druggable biological markers is of great importance. Here, we investigated the prognostic and biological role of the C-X-C chemokine receptors type 4 and 7 (CXCR4/7) in MTC. METHODS: Eighty-six MTC and corresponding non-neoplastic thyroid specimens were immunohistochemically stained for CXCR4/7 using tissue microarray technology and expression levels correlated with clinicopathological variables. Medullary thyroid carcinoma cell line TT was treated with recombinant human SDF1α/CXCL12 (rh-SDF1α) and CXCR4 antagonists AMD3100 and WZ811. Changes in cell cycle activation, tumour cell invasiveness as well as changes in mRNA expression levels of genes associated with epithelial-mesenchymal transition (EMT) were investigated. RESULTS: High CXCR4 expression was associated with large tumour size and metastatic disease. CXCR4 antagonists significantly reduced tumour cell invasiveness, while the treatment with rh-SDF1α stimulated invasive growth, caused cell cycle activation and induced EMT. CONCLUSIONS: The CXCR4/CXCR7/CXCL12 axis plays an important role in MTC. We provide first evidence that the chemokine receptors might serve as potential therapeutic targets in patients with advanced MTC and offer new valuable insight into the underlying molecular machinery of metastatic MTC.


Assuntos
Carcinoma Neuroendócrino/metabolismo , Carcinoma Neuroendócrino/patologia , Receptores CXCR4/metabolismo , Receptores CXCR/metabolismo , Neoplasias da Glândula Tireoide/metabolismo , Neoplasias da Glândula Tireoide/patologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Aminopiridinas/farmacologia , Antígenos CD/genética , Benzilaminas/farmacologia , Caderinas/genética , Carcinoma Neuroendócrino/genética , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Quimiocina CXCL12/farmacologia , Criança , Transição Epitelial-Mesenquimal/genética , Feminino , Fator 9 de Crescimento de Fibroblastos/genética , Proteínas Ligadas por GPI/genética , Expressão Gênica/efeitos dos fármacos , Compostos Heterocíclicos/farmacologia , Humanos , Imuno-Histoquímica , Masculino , Pessoa de Meia-Idade , Invasividade Neoplásica/genética , Metástase Neoplásica , Fenótipo , Prognóstico , Receptores CXCR4/antagonistas & inibidores , Proteínas Recombinantes/farmacologia , Estudos Retrospectivos , Fatores de Transcrição da Família Snail/genética , Taxa de Sobrevida , Neoplasias da Glândula Tireoide/genética , Análise Serial de Tecidos , Carga Tumoral , Vimentina/genética , Adulto Jovem
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