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1.
Int J Hyperthermia ; 37(1): 55-65, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31918587

RESUMO

Introduction: An abscopal effect is a clinical observation whereby a local treatment is associated with regression of metastatic cancer at a site distant from the primary location of treatment. Here, we describe the clinical systemic effect induced by regional hyperthermia combined with low-dose chemotherapy and provide immunologic correlates.Case presentation: A 15-year-old patient had been diagnosed with alveolar rhabdomyosarcoma (ARMS). All previous treatment options failed in the patient including haploidentical stem cell transplantation and donor lymphocyte infusion. The patient presented with local and metastatic disease, and upon admission, underwent regional hyperthermia combined with low-dose chemotherapy. Immediately following therapy severe skin reactions were observed. Skin biopsies revealed an intraepithelial lymphocytic infiltration dominated by CD3+/CD8+ T cells with a regular network of dendritic cells. Clinical images compared before and during sequential treatment cycles showed complete metabolic response of the local tumor for more than 10 months of therapy. In addition, metastases completely regressed although they were not direct targets of regional hyperthermia. The systemic effect was associated with enhanced frequency of NK cells and T cells expressing the lectin-like natural-killer group 2 D activating receptor (NKG2D), an increase of the CD56bright subset of NK cells, as well as an increase of effector/memory and effector CD8+ and CD4+ T cells in the blood while the percentage of CD25+FOXP3+ regulatory T cells declined.Conclusions: Regional hyperthermia combined with low-dose chemotherapy had the potential to create a systemic effect which was associated with activation of NK cells and T cells.

2.
Radiat Oncol ; 15(1): 5, 2020 Jan 02.
Artigo em Inglês | MEDLINE | ID: mdl-31898519

RESUMO

BACKGROUND/AIM: mmune checkpoint inhibition (CPI) has an increasing impact in the multimodal treatment of locally advanced non-small cell lung cancer (LA-NSCLC). Increasing evidence suggests treatment outcome depending on tumor cell PD-L1 expression. The purpose of this retrospective study was to investigate the prognostic value of PD-L1 expression on tumor cells in combination with CD8+ tumor stroma-infiltrating lymphocyte (TIL) density in inoperable LA-NSCLC treated with concurrent chemoradiotherapy (CRT). PATIENTS AND METHOD: We retrospectively assessed clinical characteristics and initial tumor biopsy samples of 31 inoperable LA-NSCLC patients treated with concurrent CRT. Prognostic impact of tumor cell PD-L1 expression (0% versus ≥1%) and CD8+ TIL density (0-40% vs. 41-100%) for local control, progression-free (PFS) and overall survival (OS) as well as correlations with clinicopathological features were evaluated. RESULTS: Median OS was 14 months (range: 3-167 months). The OS rates at 1- and 2 years were 68 and 20%. Local control of the entire cohort at 1 and 2 years were 74 and 61%. Median PFS, 1-year and 2-year PFS were 13 ± 1.4 months, 58 and 19%. PD-L1 expression < 1% on tumor cells was associated with improved OS, PFS and local control in patients treated with concurrent CRT. Univariate analysis showed a trend towards improved OS and local control in patients with low CD8+ TIL density. Evaluation of Tumor Immunity in the MicroEnvironment (TIME) appears to be an independent prognostic factor for local control, PFS and OS. The longest and shortest OS were achieved in patients with type I (PD-L1neg/CD8low) and type IV (PD-L1pos/CD8low) tumors (median OS: 57 ± 37 vs. 10 ± 5 months, p = 0.05), respectively. CONCLUSION: Assessment of PD-L1 expression on tumor cells in combination with CD8+ TIL density can be a predictive biomarker in patients with inoperable LA-NSCLC treated with concurrent CRT.

3.
Vasa ; 49(1): 31-38, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31621550

RESUMO

Background: To assess the vascular and clinical course of acute symptomatic extracranial internal carotid artery (ICA) occlusion. Patients and methods: Patients with an acute ischemic event in the anterior circulation and corresponding extracranial ICA occlusion at CT angiography and/or color-coded duplex sonography underwent recurrent duplex follow-up for detection of spontaneous recanalization. Stroke recurrence and functional outcome 4.5 months after the ischemic index event assessed by modified Rankin scale served as secondary outcome parameters. Results: 133 patients (91 men, mean age 62.3 years, SD 10.8) demonstrated symptomatic occlusion of the extracranial ICA with open intracranial ICA and open middle cerebral artery and were followed-up for spontaneous recanalization. Twenty-eight recanalized spontaneously, 25 to high-grade focal stenosis within 12 days, revealing an early cumulative recanalization rate of 23 %. Detection of recanalization was independently associated with de novo dual anti-platelet therapy (adjusted odds ratio [OR], 3.24; 95 % confidence interval [CI], 1.34 to 7.80). Ischemic recurrence occurred in 16 patients, of which 10 deemed to be embolic and 5 hemodynamic. Spontaneous ICA recanalization and an exhausted cerebrovascular reserve in the hemisphere distal to the occluded ICA were both independently associated with the occurrence of a recurrent ischemic event at Cox regression. An increasing NIHSS score at admission, a decreasing middle cerebral artery flow velocity and an ischemic recurrence independently predicted poor outcome (modified Rankin scale 3 to 6) in multivariate analysis. Conclusions: Acute symptomatic extracranial ICA occlusion is an unstable condition with frequent spontaneous recanalization to severe stenosis and early embolic stroke recurrence, demanding appropriate prevention especially in those patients with only mild deficit.


Assuntos
Doenças das Artérias Carótidas , Estenose das Carótidas , Embolia , Acidente Vascular Cerebral , Idoso , Artéria Carótida Interna , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Resultado do Tratamento
4.
Clin Neurophysiol ; 131(2): 414-419, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31877491

RESUMO

OBJECTIVE: The pedunculopontine nucleus (PPN) has been proposed as a new deep brain stimulation (DBS) target for the treatment in idiopathic Parkinson's syndrome (IPS) and progressive supranuclear palsy (PSP). In IPS, levodopa has been shown to induce alpha activity in the PPN, indicating a possible physiological role for these oscillations in movement control. Despite shared clinical features, the PPN is more severely affected in PSP than IPS. Here we investigated neuronal oscillations in the PPN in PSP and the influence of levodopa and movement. METHODS: Local field potentials were recorded bilaterally from the PPN of 4 PSP patients at rest, with levodopa and during self-paced leg movements. RESULTS: During rest, levodopa administration was associated with significantly increased alpha and reduced gamma activity in the PPN. Without levodopa, continuous movements were associated with reduced alpha and beta power. These differences between oscillatory power during movement and resting state were not observed with levodopa administration. CONCLUSION: In PSP the changes in neuronal oscillations in the PPN region on levodopa administration are similar to those reported in IPS. The enhancement of lower frequency oscillations in the PPN is possibly influenced by a dopaminergic activation of the striatal pathway and a reduced pallidal inhibition. SIGNIFICANCE: Levodopa influences neuronal oscillations at low and high frequencies in the PPN region in Parkinsonian disorders.

5.
Cell Physiol Biochem ; 53(5): 820-831, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31701729

RESUMO

BACKGROUND/AIMS: MLK4 (KIAA1804) is the second most frequently mutated kinase in microsatellite stable (MSS) colorectal carcinomas (CRC). This molecule is known to regulate different physiological cellular processes, including cell cycle, senescence and apoptosis, and mechanistic evidence has been provided that MLK4 plays a role in carcinogenesis. However, whether this kinase exerts a tumor suppressive role or an oncogenic function is still an object of debate. This study aims to elucidate the role of MLK4 in the pathogenesis of CRC by investigating human tumor specimens. METHODS: This study assessed MLK4 expression levels by immunohistochemistry in surgical tumor samples from 204 early-stage CRC patients and their correlation with various clinical-pathological features and patients' outcomes. In addition, MLK4 mRNA transcription was analysed in an independent cohort of 786 colon cancer samples. RESULTS: Loss of MLK4 staining was associated with poor overall (OS) and progression free survival (PFS) in CRC patients during a univariate analysis (OS:101 vs 164 months, p=0.0002; PFS:85 vs 125 months, p=0.0001), as well as in multivariate analysis (OS:HR=1.70; p=0.001; PFS:HR=1,61; p=0.001). This was confirmed by analysis of MLK4 mRNA in the second independent cohort. A subgroup analysis according to KRAS mutation status showed that MLK4 staining was associated with better OS and PFS in KRAS mutated cases (HR=2.77; p=0.0001 and HR=2.31; p=0.0003, respectively) and microsatellite stable tumors (HR=1.87; p=0.002 and HR=1.06; p=0.006) but not in KRAS wildtype and microsatellite unstable tumors. CONCLUSION: By providing the first report from clinical specimens on the prognostic significance of MLK4, we define an oncogenic loss-of-function of this kinase and suggest a possible role in the interaction with KRAS signaling in determining an aggressive phenotype of CRC. These findings warrant the further investigation of MLK4 in wider cohorts and various clinical settings.


Assuntos
Neoplasias Colorretais/patologia , MAP Quinase Quinase Quinases/metabolismo , Instabilidade de Microssatélites , Proteínas Proto-Oncogênicas p21(ras)/metabolismo , Idoso , Neoplasias do Colo/metabolismo , Neoplasias do Colo/patologia , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/mortalidade , Feminino , Humanos , Estimativa de Kaplan-Meier , MAP Quinase Quinase Quinases/genética , Masculino , Mutação , Prognóstico , Intervalo Livre de Progressão , Modelos de Riscos Proporcionais , Proteínas Proto-Oncogênicas p21(ras)/genética
6.
BMC Neurol ; 19(1): 226, 2019 Sep 16.
Artigo em Inglês | MEDLINE | ID: mdl-31526396

RESUMO

BACKGROUND: Due to improvements in both the quality and availability of intracranial imaging as well as the evolution of surgical and endovascular techniques during the last decade, the number of treatments of unruptured intracranial aneurysms (UIA) has increased steadily. However, it is not generally known that vasospasm can arise after an uneventful clipping. CASE PRESENTATION: We present a case of a 69-year-old woman who suffered from vasospasm and delayed cerebral ischemia that occurred after an uneventful clipping of a UIA. The aneurysm of the right middle cerebral artery was found incidentally via magnetic resonance imaging ordered after the patient complained of a short period of slight gait disturbances. To avoid a subarachnoid hemorrhage and consecutive complications like vasospasms, the patient elected microsurgical treatment. Clipping was managed by keyhole approach. Temporal clipping of the M1 was not necessary. After clip placement, appropriate flow in all distal segments was confirmed by indocyanine green video-angiography and micro-Doppler. The patient was discharged seven days after surgery without neurological deficits. After 12 days, the patient developed at home a sudden drooping on the left side of the face. Upon admission to the emergency room, the patient was alert but slightly confused. Neurological examination revealed a left-sided hemiparesis and motor speech disorder. In contrast to the preoperative transfemoral catheter angiography, the subsequent right internal carotid angiogram showed clear signs of vasospasm along the M1 and M2 segments of the right middle cerebral artery. Antithrombotic treatment with acetylsalicylic acid was begun. In accordance with guidelines for the treatment of subarachnoid hemorrhage and vasospasm, nimodipine was added. After 11 days the patient was discharged with no symptoms. CONCLUSION: Cerebral vasospasm as a cause of ischemic stroke after uneventful surgery for a UIA seems to be a rare but possibly underestimated etiology that demands particular attention with respect to providing appropriate treatment. In future, it may be prudent to perform follow-up transcranial ultrasonography testing after the clipping of a UIA, especially considering the availability of potentially neuroprotective medications like nimodipine.


Assuntos
Isquemia Encefálica/etiologia , Aneurisma Intracraniano/cirurgia , Procedimentos Neurocirúrgicos/efeitos adversos , Vasoespasmo Intracraniano/etiologia , Idoso , Feminino , Humanos
7.
Clin Neurol Neurosurg ; 186: 105509, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31522081

RESUMO

OBJECTIVE: After a decompressive craniectomy (DC), a cranioplasty (CP) is often performed in order to improve neurosurgical outcome and cerebral blood circulation. But even though the performance of a CP subsequent to a DC has become routine medical practice, patients can in fact develop many complications from the surgery that could prolong hospitalization and lead to unfavorable prognoses. This study investigates one of the most frequent complications, bone flap infection, in order to identify prognostic factors of its development. PATIENTS AND METHODS: In this single-center study, we have retrospectively examined 329 CPs performed between 2002 and 2017. Multiple categorical and metric parameters (e.g., timing of CP, bone flap material, specific laboratory signs of infection and reason for DC) were analyzed applying unadjusted and multivariable testing. RESULTS: Bone flap infection occurred in 24 patients (7.3%). A CP performed more than six months after a DC is associated with a significantly increased risk of infection (OR = 0.308 [0.118; 0.803], p = 0.016). However, with CPs performed after twelve months, the incidence decreases, but without provable statistical impact. In addition, bone flap infection is strongly related to the neurological outcome and the material used for the skull implant, with the use of synthetic bone flaps leading to a marked increase in the rate of infection (p < 0.001). CONCLUSIONS: This study supports the hypothesis that the risk of infection is higher the longer the elapsed time between DC and CP, especially if more than six months. Based on our results, the best DC-CP time frame for keeping the infection rate low is performing the CP within the first six months after the DC. In the event that the CP cannot be performed within the first six months, a CP performed twelve months or more after the DC seems to have a favorable outcome as well.

8.
J Cancer Res Clin Oncol ; 145(11): 2689-2697, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31541339

RESUMO

PURPOSE: Gastric cancer is the third leading cause of cancer-related death. Recently, innovative diagnostic and prognostic molecular subtypes have been proposed. We revealed that extranodal extension (ENE) of lymph-node metastases independently influences survival. Therefore, the aim of the present study was to evaluate novel molecular subtyping with regard to the growth pattern of lymph-node metastases. METHODS: A total of 189 gastric carcinomas with lymph-node metastases were analyzed. The expression of p53, SOX2, SOX9, and the mismatch-repair gene products MLH1, PMS2, MSH2, and MSH6 were analyzed by immunohistochemistry. To determine the correlation with EBV infection, in situ hybridization for EBV-encoded small RNA (EBER) was applied. RESULTS: ENE was present in 36% of patients. EBV-positive carcinoma was evident in 5.8%, and p53 aberrant (chromosomal instable) tumors in 22.2%, a gastric cancer with deficient mismatch-repair status in 9%, and MSS/p53neg/EBVneg tumors were seen in 63% of patients. There was no significant correlation between the presence or absence of ENE and the molecular subtypes. However, a significant association between molecular subgroups and the Lauren classification, the oncogene SOX2, and tumor grading was detected. CONCLUSION: The present findings suggest that alterations in gastric cancer leading to ENE are not associated with alterations underpinning the molecular subgroups. Nonetheless, molecular subtyping on the basis of IHC and ISH is feasible and might become clinical routine. Thus, further studies are needed to clarify the mechanisms of extranodal extension in gastric cancer.


Assuntos
Adenocarcinoma/classificação , Adenocarcinoma/secundário , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Neoplasias Gástricas/classificação , Neoplasias Gástricas/patologia , Adenocarcinoma/genética , Adenocarcinoma/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Seguimentos , Humanos , Metástase Linfática , Masculino , Pessoa de Meia-Idade , Prognóstico , Neoplasias Gástricas/genética , Neoplasias Gástricas/metabolismo , Taxa de Sobrevida , Adulto Jovem
9.
Allergy ; 74(12): 2394-2405, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31269238

RESUMO

BACKGROUND: Signal transducer and activator of transcription 3 hyper-IgE syndrome (STAT3-HIES) is caused by heterozygous mutations in the STAT3 gene and is associated with eczema, elevated serum IgE, and recurrent infections resembling severe atopic dermatitis, while clinically relevant specific IgE is almost absent. METHODS: To investigate the impact of STAT3 signaling on B-cell responses, we assessed lymph node and bone marrow, blood B and plasma cell subsets, somatic hypermutations in Ig genes, and in vitro proliferation and antibody production in STAT3-HIES patients and healthy controls. RESULTS: Lymph nodes of STAT3-HIES patients showed normal germinal center architecture and CD138+ plasma cells residing in the paracortex, which expressed IgE, IgG, and IgM but not IgA. IgE+ plasma cells were abundantly present in STAT3-HIES bone marrow. Proliferation of naive B cells upon stimulation with CD40L and IL-4 was similar in patients and controls, while patient cells showed reduced responses to IL-21. IgE, IgG1, IgG3 and IgA1 transcripts showed reduced somatic hypermutations. Peripheral blood IgE+ memory B-cell frequencies were increased in STAT3-HIES, while other memory B-cell frequencies except for IgG4+ cells were decreased. CONCLUSIONS: Despite impaired STAT3 signaling, STAT3-HIES patients can mount in vivo T-cell-dependent B-cell responses, while circulating memory B cells, except for those expressing IgG4 and IgE, were reduced. Reduced molecular maturation demonstrated the critical need of STAT3 signaling for optimal affinity maturation and B-cell differentiation, supporting the need for immunoglobulin substitution therapy and explaining the high IgE serum level in the majority with absent allergic symptoms.

10.
Ann Clin Transl Neurol ; 6(6): 1134-1137, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31211179

RESUMO

The rarity of primary angiitis of the central nervous system (PACNS) demands diagnostic and prognostic biomarkers. We retrospectively measured Neurofilament light chain (NFL) concentrations in cerebrospinal fluid in a severely relapsing PACNS patient at multiple time points during the course of the disease. A marked increase in NFL levels preceding the onset of neuro-axonal damage and arterial-vessel abnormalities was observed with magnetic resonance imaging as well as with MR- and conventional angiography. Thus, marked elevation of NFL in PACNS seems to occur ahead of definitive radiological abnormalities and might serve as a diagnostic biomarker.

11.
Allergy ; 74(9): 1691-1702, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30793327

RESUMO

BACKGROUND: Pulmonary complications are responsible for high morbidity and mortality rates in patients with the rare immunodeficiency disorder STAT3 hyper-IgE syndrome (STAT3-HIES). The aim of this study was to expand knowledge about lung disease in STAT3-HIES. METHODS: The course of pulmonary disease, radiological and histopathological interrelations, therapeutic management, and the outcome of 14 STAT3-HIES patients were assessed. RESULTS: The patients' quality of life was compromised most by pulmonary disease. All 14 patients showed first signs of lung disease at a median onset of 1.5 years of age. Lung function revealed a mixed obstructive-restrictive impairment with reduced FEV1 and FVC in 75% of the patients. The severity of lung function impairment was associated with Aspergillus fumigatus infection and prior lung surgery. Severe lung tissue damage, with reduced numbers of ATP-binding cassette sub-family A member 3 (ABCA3) positive type II pneumocytes, was observed in the histological assessment of two deceased patients. Imaging studies of all patients above 6 years of age showed severe airway and parenchyma destruction. Lung surgeries frequently led to complications, including fistula formation. Long-term antifungal and antibacterial treatment proved to be beneficial, as were inhalation therapy, chest physiotherapy, and exercise. Regular immunoglobulin replacement therapy tended to stabilize lung function. CONCLUSIONS: Due to its severity, pulmonary disease in STAT3-HIES patients requires strict monitoring and intensive therapy.

13.
PLoS One ; 13(11): e0207726, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30475854

RESUMO

Glucocorticoid (GC) refractory relapses in patients with multiple sclerosis (MS) or clinically isolated syndrome (CIS), who are in potential need of treatment escalation, are a key challenge in routine clinical practice. The pro-inflammatory cytokine macrophage migration inhibitory factor (MIF) has been shown to be an endogenous counter-regulator of GC, and potentiates autoimmune-mediated neuroinflammation. In order to evaluate whether MIF levels are elevated in the cerebrospinal fluid (CSF) of MS patients (CSF-MIF), and whether they are higher still during a GC refractory relapse, we compared CSF-MIF concentrations of CIS/MS patients with acute optic neuritis as their first inflammatory episode (ON, n = 20), CIS/MS patients with a stable disease progression/without relapse (CIS/MS w/o, n = 18), and healthy controls (HC, n = 20) using ANOVA. Mean CSF-MIF concentrations in CIS/MS w/o patients were significantly higher than in ON patients and HCs, whereas ON patients and HCs did not differ. A subgroup analysis of the ON group revealed 10 patients to be responsive to GC-treatment (GC-ON) and 10 patients refractory under GC-treatment (rGC-ON). However, mean CSF-MIF concentrations did not differ between GC-ON and rGC-ON cases. We therefore conclude that MIF is not suitable for distinguishing GC responders from non-responders in a group of patients with acute optic neuritis, but it rather mirrors the ongoing inflammation in long-term MS disease progression.


Assuntos
Glucocorticoides/uso terapêutico , Fatores Inibidores da Migração de Macrófagos/líquido cefalorraquidiano , Esclerose Múltipla/complicações , Neurite Óptica/complicações , Neurite Óptica/tratamento farmacológico , Adolescente , Adulto , Idoso , Biomarcadores/líquido cefalorraquidiano , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Neurite Óptica/líquido cefalorraquidiano , Resultado do Tratamento , Adulto Jovem
14.
Med Oncol ; 36(1): 5, 2018 Nov 20.
Artigo em Inglês | MEDLINE | ID: mdl-30460421

RESUMO

We have recently identified a positive feedback loop in which c-MYC increases silent information regulator 1 (SIRT1) protein level and activity through transcriptional activation of nicotinamide phosphoribosyltransferase (NAMPT) and NAD+ increase. Here, we determined the relevance of the c-MYC-NAMPT-SIRT1 feedback loop, including the SIRT1 inhibitor deleted in breast cancer 1 (DBC1), for the development of conventional and serrated colorectal adenomas. Immunohistochemical analyses of 104 conventional adenomas with low- and high-grade dysplasia and of 157 serrated lesions revealed that elevated expression of c-MYC, NAMPT, and SIRT1 characterized all conventional and serrated adenomas, whereas DBC1 was not differentially regulated. Analyzing publicly available pharmacogenomic databases from 43 colorectal cancer cell lines demonstrated that responsiveness towards a NAMPT inhibitor was significantly associated with alterations in PTEN and TGFBR2, while features such as BRAF or RNF43 alterations, or microsatellite instability typical for serrated route colorectal cancer, showed increased sensitivities for inhibition of NAMPT and SIRT1. Our findings suggest an activation of the c-MYC-NAMPT-SIRT1 feedback loop that may crucially contribute to initiation and development of both routes to colorectal cancer. Targeting of NAMPT or SIRT1 may represent novel therapeutic strategies with putative higher sensitivity of the serrated route colorectal cancer subtype.


Assuntos
Adenoma/patologia , Neoplasias Colorretais/patologia , Citocinas/metabolismo , Nicotinamida Fosforribosiltransferase/metabolismo , Proteínas Proto-Oncogênicas c-myc/metabolismo , Sirtuína 1/metabolismo , Adenoma/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias Colorretais/metabolismo , Retroalimentação Fisiológica/fisiologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Transdução de Sinais/fisiologia
16.
Cancers (Basel) ; 10(10)2018 Oct 18.
Artigo em Inglês | MEDLINE | ID: mdl-30340430

RESUMO

Liver resection is a curative treatment for hepatocellular carcinoma (HCC). Tumor-infiltrating leukocytes (TILs) are important players in predicting HCC recurrence. However, the invasive margin could not be confirmed as relevant for HCC. The migration of immune cells into HCC may originate from intratumoral vessels. No previous study has examined perivascular (PV) infiltration. Tumors from 60 patients were examined. Immunohistochemistry was performed against CD3, CD8, CD20, and CD66b. TILs were counted in the PV regions using an algorithm for quantification of the tumor immune stroma (QTiS). The results were correlated with overall (OS) and disease-free survival (DFS), clinical parameters, and laboratory values. PV infiltration of TILs was predominant in resected HCC. Higher PV infiltration of CD3⁺ (p = 0.016) and CD8⁺ (p = 0.028) independently predicted better OS and DFS, respectively. CD20⁺ showed a trend towards better DFS (p = 0.076). Scoring of CD3⁺, CD8⁺, and CD20⁺ independently predicted OS and DFS (p < 0.01). The amount of perivascular-infiltrating CD3⁺ cells is an independent predictor of better OS, and CD8⁺ cells independently predict prolonged DFS. Our novel perivascular infiltration scoring (PVIS) can independently predict both DFS and OS in resected HCC patients.

17.
Carcinogenesis ; 39(9): 1176-1184, 2018 09 21.
Artigo em Inglês | MEDLINE | ID: mdl-29901779

RESUMO

Colorectal carcinogenesis is a progressive multistep process involving the sequential accumulation of genetic alterations in tumor suppressor genes and oncogenes. Downregulated by oncogenes 1 (Dro1/Ccdc80) has been shown to be a potent tumor suppressor of colorectal carcinogenesis in the genetic ApcMin/+ mouse model. In ApcMin/+ mice, loss of DRO1 strongly increases colonic tumor multiplicity and leads to the regular formation of adenocarcinoma in the colon. To investigate DRO1's role in chemically induced as well as inflammation-associated colorectal carcinogenesis, the effect of Dro1 inactivation was studied in mice subjected to the carcinogen azoxymethane (AOM) and upon combined treatment with AOM and the proinflammatory agent dextran sodium sulfate (DSS), respectively. Loss of DRO1 increases multiplicity of preneoplastic aberrant crypt foci and colonic tumors upon administration of AOM. Combined treatment with AOM and DSS leads to increased colonic tumor number and promotes formation of adenocarcinoma in the colon. Moreover, Dro1 inactivation aggravates histological signs of acute and chronic DSS-induced colitis, strongly enlarges the size of ulcerative lesions in the intestinal lining, and exacerbates clinical signs and morbidity by DSS. Our results demonstrate DRO1 to be a strong tumor suppressor in the chemically induced colon carcinogenic mouse model. Additionally, we demonstrate DRO1 to inhibit colitis-associated colon cancer formation and uncover a novel putative role for DRO1 in inflammatory bowel disease.


Assuntos
Adenocarcinoma/genética , Carcinogênese/genética , Colite/genética , Neoplasias Colorretais/genética , Glicoproteínas/genética , Peptídeos e Proteínas de Sinalização Intercelular/genética , Adenocarcinoma/patologia , Animais , Azoximetano/toxicidade , Carcinógenos/toxicidade , Neoplasias Colorretais/patologia , Sulfato de Dextrana/toxicidade , Transição Epitelial-Mesenquimal/genética , Proteínas da Matriz Extracelular , Genes Supressores de Tumor , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout
18.
BMC Cancer ; 18(1): 483, 2018 04 27.
Artigo em Inglês | MEDLINE | ID: mdl-29703178

RESUMO

BACKGROUND: Extra-capsular growth (ECG) describes the extension of neoplastic cells beyond the lymph node capsule. Aim of this study was to investigate the prognostic value of ECG and its association with a stem cell like phenotype indicated by expression of the transcription factor SOX9 in gastric cancer. METHODS: By histological evaluation, 199 patients with nodal positive gastric cancer or adeoncarcinoma of the esophageal-gastric junction (AEG) were divided into two groups according to the presence (ECG) or absence (ICG) of extracapsular growth in at least one nodal metastasis. Of these, 194 patients were stained for SOX9 and SOX2 using immunohistochemistry. Seventeen nodal negative patients (pT3/4, pN0, pM0) served as controls. RESULTS: Seventy-three patients (36.7%) showed ECG. ECG was associated with lower overall survival (p < 0.0001), advanced pT- (p = 0.03) and pN- category (p < 0.0001) and lymphovascular invasion (p = 0.014). In multivariate analysis, ECG was found to be an independent prognostic factor (HR = 2.1; 95% CI 1.7-3.4; p = 0.001). SOX9 expression correlated significantly with ECG (96% SOX9 high in ECG patients vs. 79% SOX9 high in patients with ICG; p = 0.002). Controls showed significantly reduced SOX9 expression compared to nodal positive carcinomas (59% vs. 85% high SOX9 expression; p = 0.006). No significant correlation of ECG and SOX2 (59% SOX2 negative in ECG patients vs. 64% in patients with ICG, p = 0.48) could be obtained. CONCLUSIONS: Patients with ECG exhibit poorer prognosis and ECG was found to be an independent prognostic factor. Thus, ECG turns out to be a morphological biomarker for a more aggressive phenotype in gastric cancer. This is supported by the fact that ECG correlates with the expression of SOX9, which has been described in the context of pro-oncogenic properties of tumours. However, the fact that SOX2 failed to show significant results indicate that ECG is not associated with a distinct cancer stem cell phenotype in gastric cancer.


Assuntos
Linfonodos/patologia , Fatores de Transcrição SOX9/metabolismo , Neoplasias Gástricas/metabolismo , Neoplasias Gástricas/patologia , Idoso , Idoso de 80 Anos ou mais , Feminino , Expressão Gênica , Humanos , Imuno-Histoquímica , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Estadiamento de Neoplasias , Prognóstico , Fatores de Transcrição SOX9/genética , Fatores de Transcrição SOXB1/metabolismo , Neoplasias Gástricas/mortalidade , Carga Tumoral
19.
Virchows Arch ; 473(2): 199-207, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-29675807

RESUMO

Loss of CDX2 expression has been proposed to be a prognostic biomarker in colorectal cancer (CRC) correlating with shorter overall (OS) and progression-free survival (PFS). Since metastatic disease, mismatch repair (MMR) deficiency, and the mutational status of BRAF are considered to be important prognostic determinants in CRC, the present study aimed to analyze CDX2 expression in correlation with these parameters. Immunohistochemistry for CDX2, hMLH1, and hMSH2 was applied to a study cohort of 503 CRC specimens (FIRE-3) and a matched case-control collection of 50 right-sided CRC specimens with synchronous distant metastases and 50 right-sided CRCs without distant metastases. Furthermore, the mutational status of BRAF gene was analyzed utilizing pyrosequencing. CDX2 expression significantly correlates with reduced OS (p = 0.008) within the study population. In both cohorts, a significant correlation of CDX2 expression and MMR deficiency as well as the presence of a BRAF mutation (each p > 0.001) was observed, whereas no correlation of CDX2 expression and synchronous metastasis could be obtained. In the case-control study, only patients with proficient MMR status showed a correlation of CDX2 loss and synchronous metastasis, whereas in patients with deficient MMR status and CDX2 loss, no distant metastases at the time of diagnosis were found (p = 0.003). We could demonstrate that the reduced OS of CDX2-negative CRC patients is not caused by higher rates of distant metastases. Furthermore, our data indicate that the prognostic impact of CDX2 depends on the MMR status and the BRAF mutational status of the tumors. Thus, it could be concluded that CDX2 is not an independent prognostic biomarker in CRC.


Assuntos
Adenocarcinoma/patologia , Biomarcadores Tumorais/análise , Fator de Transcrição CDX2/biossíntese , Neoplasias Colorretais/patologia , Adenocarcinoma/genética , Adenocarcinoma/metabolismo , Adulto , Idoso , Fator de Transcrição CDX2/análise , Estudos de Casos e Controles , Neoplasias Colorretais/genética , Neoplasias Colorretais/metabolismo , Reparo de Erro de Pareamento de DNA/genética , Análise Mutacional de DNA , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Prognóstico , Proteínas Proto-Oncogênicas B-raf/genética
20.
PLoS One ; 13(3): e0193970, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29543836

RESUMO

Inflammation plays an important role in the pathogenesis of ischemic stroke including an acute and prolonged inflammatory process. The role of neutrophil granulocytes as first driver of the immune reaction from the blood site is under debate due to controversial findings. In bone marrow chimeric mice we were able to study the dynamics of tdTomato-expressing neutrophils and GFP-expressing microglia after photothrombosis using intravital two-photon microscopy. We demonstrate the infiltration of neutrophils into the brain parenchyma and confirm a long-lasting contact between neutrophils and microglia as well as an uptake of neutrophils by microglia clearing the brain from peripheral immune cells.


Assuntos
Microglia/patologia , Neutrófilos/patologia , Acidente Vascular Cerebral/patologia , Animais , Encéfalo/patologia , Modelos Animais de Doenças , Feminino , Granulócitos/patologia , Inflamação/patologia , Camundongos , Camundongos Endogâmicos C57BL , Infiltração de Neutrófilos/fisiologia
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