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1.
Artigo em Inglês | MEDLINE | ID: mdl-34780010

RESUMO

A 9-year-old boy collapsed shortly after complaining of shortness of breath. Despite immediate resuscitation measures, the boy died. A few weeks earlier, he had received antibiotic treatment for respiratory infection. However, the post-mortem examination revealed an advanced tumor mass of the mediastinum with infiltration of vital structures, which was identified as a small blue round neoplasm with aspects of an extramedullary Ewing-like sarcoma by supplementary histological and immunohistochemical examinations.This dramatic clinical course of events shows that the possible presence of serious diseases should always be considered behind harmless symptoms, even in children.

2.
Technol Cancer Res Treat ; 20: 15330338211042139, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34595977

RESUMO

Background: Pancreatic cancer carries a devastating prognosis and is the fourth leading cause for cancer-related death in the United States and most European countries. Although one-third of patients receive a palliative third line therapy, the benefit of systemic therapy beyond second-line remains unclear. A plethora of clinical trials investigating novel drugs have failed over the past years. Due to the lack of established treatment regimens beyond second line, we offered nonpegylated liposomal doxorubicin, well known in other tumor entities, to pretreated pancreatic cancer patients requesting systemic therapy. Material and Methods: In this retrospective analysis, 28 patients with pancreatic carcinoma treated with nonpegylated liposomal doxorubicin (Myocet®) between 2012 and 2018 at our department were included. Results: For the majority of patients (n = 18, 64%), nonpeglyted liposomal doxorubicin was offered as a third-line therapy. Five patients received it as second line, four patients as fourth line, and one patient as fifth line of therapy. Half of the patients received at least a therapy cycle. The objective response rate to treatment was 7.1%. One patient had a period of radiologically confirmed stable disease with stable tumor markers. Another patient experienced partial remission. Conclusion: According to our findings the benefit of nonpegylated liposomal doxorubicin in pancreatic cancer beyond second line is limited.

3.
Pancreatology ; 2021 Sep 08.
Artigo em Inglês | MEDLINE | ID: mdl-34511398

RESUMO

BACKGROUND: Pancreatic carcinoma carries a devastating prognosis and is the 4th leading cause for cancer related death in the US and most European countries. Apart from imaging and CA 19-9, pancreatic carcinoma is still lacking reliable markers to assess tumor dynamics and to monitor treatment response over time. The aim of this study was to evaluate the feasibility of cell free tumor-DNA (cft-DNA), respectively KRAS mutation in peripheral blood, detection as a prognostic and predictive value for chemotherapy monitoring. METHODS: Serial plasma samples from 42 patients with KRAS mutated pancreatic cancer were prospectively collected and the ctKRAS Mutation Assay (Idylla™, Biocartis, Mechelen, Belgium) of cft-DNA was performed on 29 patients that did not receive curative surgery and went on to palliative chemotherapy. To monitor cft-DNA KRAS mutation levels during treatment quantitative assessment of cft-DNA was performed at baseline and during follow up at predetermined times. RESULTS: All 29 patients included in our analyses had a detected KRAS mutation in the tumor biopsy. In almost half (48.2%) of patients a KRAS mutation could also be detected in peripheral plasma. Patients with detectable KRAS mutations before treatment start in plasma had a significantly worse survival (16.8 months vs not reached, p < 0.031 and HR 3.303). Looking for a dynamic assessment of tumor response, we found a statistically significant association between the KRAS mutant ratio from first staging CT scan to basal levels with tumor response or progress (p = 0.014). CONCLUSION: Performing KRAS testing from peripheral blood for patients, who have no elevated tumor markers, might be a novel option for treatment monitoring complementing routine imaging techniques.

4.
Int J Mol Sci ; 22(17)2021 Aug 30.
Artigo em Inglês | MEDLINE | ID: mdl-34502317

RESUMO

Chronic lymphocytic leukemia (CLL) is considered a clonal B cell malignancy. Sporadically, CLL cases with multiple productive heavy and light-chain rearrangements were detected, thus leading to a bi- or oligoclonal CLL disease with leukemic cells originating either from different B cells or otherwise descending from secondary immunoglobulin rearrangement events. This suggests a potential role of clonal hematopoiesis or germline predisposition in these cases. During the screening of 75 CLL cases for kappa and lambda light-chain rearrangements, we could detect a single case with CLL cells expressing two distinct kappa and lambda light chains paired with two separate immunoglobulin heavy-chain variable regions. Furthermore, this patient also developed a prostate carcinoma. Targeted genome sequencing of highly purified light-chain specific CLL clones from this patient and from the prostate carcinoma revealed the presence of a rare germline polymorphism in the POLE gene. Hence, our data suggest that the detected SNP may predispose for cancer, particularly for CLL.


Assuntos
Processamento Alternativo , DNA Polimerase II/genética , Leucemia Linfocítica Crônica de Células B/patologia , Proteínas de Ligação a Poli-ADP-Ribose/genética , Polimorfismo de Nucleotídeo Único , Neoplasias da Próstata/patologia , Humanos , Leucemia Linfocítica Crônica de Células B/complicações , Leucemia Linfocítica Crônica de Células B/genética , Masculino , Pessoa de Meia-Idade , Prognóstico , Neoplasias da Próstata/complicações , Neoplasias da Próstata/genética
6.
Cancers (Basel) ; 13(15)2021 Jul 31.
Artigo em Inglês | MEDLINE | ID: mdl-34359763

RESUMO

Inhibition of histone deacetylases (HDACs) is a promising anti-cancer approach. For biliary tract cancer (BTC), only limited therapeutic options are currently available. Therefore, we performed a comprehensive investigation of HDAC expression and pharmacological HDAC inhibition into a panel of eight established BTC cell lines. The screening results indicate a heterogeneous expression of HDACs across the studied cell lines. We next tested the effect of six established HDAC inhibitors (HDACi) covering pan- and class-specific HDACis on cell viability of BTC cells and found that the effect (i) is dose- and cell-line-dependent, (ii) does not correlate with HDAC isoform expression, and (iii) is most pronounced for romidepsin (a class I HDACi), showing the highest reduction in cell viability with IC50 values in the low-nM range. Further analyses demonstrated that romidepsin induces apoptosis in BTC cells, reduces HDAC activity, and increases acetylation of histone 3 lysine 9 (H3K9Ac). Similar to BTC cell lines, HDAC 1/2 proteins were heterogeneously expressed in a cohort of resected BTC specimens (n = 78), and their expression increased with tumor grading. The survival of BTC patients with high HDAC-2-expressing tumors was significantly shorter. In conclusion, HDAC class I inhibition in BTC cells by romidepsin is highly effective in vitro and encourages further in vivo evaluation in BTC. In situ assessment of HDAC 2 expression in BTC specimens indicates its importance for oncogenesis and/or progression of BTC as well as for the prognosis of BTC patients.

7.
J Clin Med ; 10(13)2021 Jun 25.
Artigo em Inglês | MEDLINE | ID: mdl-34202001

RESUMO

BACKGROUND: Meticulous endoscopic characterization of gastrointestinal neoplasias (GN) is crucial to the clinical outcome. Hereby the indication and type of resection (endoscopically, en-bloc or piece-meal, or surgical resection) are determined. By means of established image-enhanced (IEE) and magnification endoscopy (ME) GN can be characterized in terms of malignancy and invasion depth. In this context, the statistical evidence and accuracy of these diagnostic procedures should be elucidated. Here, we present a systematic review of the literature. RESULTS: 21 Studies could be found which met the inclusion criteria. In clinical prospective trials and meta-analyses, the diagnostic accuracy of >90% for characterization of malignant neoplasms could be documented, if ME with IEE was used in squamous cell esophageal cancer, stomach, or colonic GN. CONCLUSIONS: Currently, by means of optical diagnosis, today's gastrointestinal endoscopy is capable of determining the histological subtype, exact lateral spread, and depth of invasion of a lesion. The prerequisites for this are an exact knowledge of the anatomical structures, the endoscopic classifications based on them, and a systematic learning process, which can be supported by training courses. More prospective clinical studies are required, especially in the field of Barrett's esophagus and duodenal neoplasia.

8.
Int J Mol Sci ; 22(11)2021 May 21.
Artigo em Inglês | MEDLINE | ID: mdl-34064196

RESUMO

BACKGROUND: Chimeric antigen receptor (CAR) T-cells are changing the therapeutic landscape of hematologic malignancies. Severe side effects include cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS), but prolonged cytopenia has also been reported. The underlying mechanism for prolonged cytopenia is poorly understood so far. CASES: Severe pancytopenia with grade 2-3 anemia was marked 2-3 months after treatment. Laboratory evaluation revealed undetectable levels of haptoglobin with increased reticulocyte counts. Coomb's tests were negative, no schistocytes were detected on blood smear, and infectious causes were ruled out. Increased erythropoiesis without lymphoma infiltration was noted on bone marrow biopsy. A spontaneous increase in haptoglobin and hemoglobin levels was observed after several weeks. For one patient, peripheral CAR-T levels were monitored over time. We observed a decline at the same time as hemoglobin levels began to rise, implying a potential causality. CONCLUSION: To our knowledge, we describe the first two cases of Coombs-negative hemolytic anemia after CAR-T treatment for B-cell lymphoma. We encourage routine monitoring for hemolytic anemia after CAR-T treatment and also encourage further investigations on the underlying mechanism.


Assuntos
Anemia Hemolítica/etiologia , Terapia Baseada em Transplante de Células e Tecidos/efeitos adversos , Pancitopenia/etiologia , Receptores de Antígenos Quiméricos/imunologia , Feminino , Neoplasias Hematológicas/imunologia , Neoplasias Hematológicas/terapia , Humanos , Linfoma/genética , Masculino , Pessoa de Meia-Idade
10.
Cancers (Basel) ; 13(7)2021 Mar 29.
Artigo em Inglês | MEDLINE | ID: mdl-33805268

RESUMO

BACKGROUND: Hepatocellular carcinoma (HCC) still represents a human tumor entity with very limited therapeutic options, especially for advanced stages. Here, immune checkpoint modulating drugs alone or in combination with local ablative techniques could open a new and attractive therapeutic "door" to improve outcome and response rate for patients with HCC. METHODS: Published data on HCC experimental to pre-(clinical) treatment strategies from standard of care to novel immunomodulatory concepts were summarized and discussed in detail. RESULTS: Overall, our knowledge of the role of immune checkpoints in HCC is dramatically increased in the last years. Experimental and pre-clinical findings could be translated to phase 1 and 2 clinical trials and became standard of care. Local ablative techniques of HCC could improve the effectivity of immune checkpoint inhibitors in situ. CONCLUSIONS: This review demonstrates the importance of immunomodulatory treatment strategies of HCC, whereby the "best treatment code" of immune checkpoint drugs, combination with ablative techniques and of timing must be evaluated in coming clinical trials.

11.
Cancers (Basel) ; 13(4)2021 Feb 06.
Artigo em Inglês | MEDLINE | ID: mdl-33561953

RESUMO

Diffuse large B-cell lymphoma (DLBCL) usually needs to be treated immediately after diagnosis from a single lymph node biopsy. However, several reports in other malignancies have shown substantial spatial heterogeneity within large tumours. Therefore, we collected multiple synchronous biopsies of twelve patients that had diagnostic or therapeutic resections of large lymphoma masses and performed next-generation sequencing of 213 genes known to be important for lymphoma biology. Due to the high tumour cell content in the biopsies, we were able to detect several mutations which were present with a stable allelic frequency across all the biopsies of each patient. However, ten out of twelve patients had spatially discordant mutations and similar results were found by the analysis of copy number variants. The median Jaccard similarity coefficient, a measure of the similarity of a sample set was 0.77 (range 0.47-1), and some of the involved genes such as CARD11, CD79B, TP53, and PTEN have a known prognostic or therapeutic relevance in DLBCL. This shows that single biopsies underestimate the complexity of the disease and might overlook possible mechanisms of resistance and therapeutic targets. In the future, the broader application of liquid biopsies will have to overcome these obstacles.

12.
Sci Rep ; 11(1): 564, 2021 01 12.
Artigo em Inglês | MEDLINE | ID: mdl-33436730

RESUMO

The regulatory (neuro)peptide galanin and its three receptors (GAL1-3R) are involved in immunity and inflammation. Galanin alleviated inflammatory bowel disease (IBD) in rats. However, studies on the galanin receptors involved are lacking. We aimed to determine galanin receptor expression in IBD patients and to evaluate if GAL2R and GAL3R contribute to murine colitis. Immunohistochemical analysis revealed that granulocytes in colon specimens of IBD patients (Crohn's disease and ulcerative colitis) expressed GAL2R and GAL3R but not GAL1R. After colitis induction with 2% dextran sulfate sodium (DSS) for 7 days, mice lacking GAL3R (GAL3R-KO) lost more body weight, exhibited more severe colonic inflammation and aggravated histologic damage, with increased infiltration of neutrophils compared to wild-type animals. Loss of GAL3R resulted in higher local and systemic inflammatory cytokine/chemokine levels. Remarkably, colitis-associated changes to the intestinal microbiota, as assessed by quantitative culture-independent techniques, were most pronounced in GAL3R-KO mice, characterized by elevated numbers of enterobacteria and bifidobacteria. In contrast, GAL2R deletion did not influence the course of colitis. In conclusion, granulocyte GAL2R and GAL3R expression is related to IBD activity in humans, and DSS-induced colitis in mice is strongly affected by GAL3R loss. Consequently, GAL3R poses a novel therapeutic target for IBD.


Assuntos
Colite Ulcerativa/genética , Colite Ulcerativa/microbiologia , Doença de Crohn/genética , Doença de Crohn/microbiologia , Microbioma Gastrointestinal , Expressão Gênica , Receptor Tipo 3 de Galanina/fisiologia , Animais , Colite Ulcerativa/terapia , Doença de Crohn/terapia , Humanos , Inflamação , Camundongos Endogâmicos C57BL , Camundongos Knockout , Terapia de Alvo Molecular , Ratos , Receptor Tipo 3 de Galanina/genética , Receptor Tipo 3 de Galanina/metabolismo
13.
Neuroendocrinology ; 111(10): 965-985, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33108790

RESUMO

INTRODUCTION: Autophagic cell death in cancer cells can be mediated by inhibition of deacetylases. Although extensive studies have focused on the autophagic process in cancer, little is known about the role of autophagy in degrading cytosolic and nuclear components of pancreatic neuroendocrine neoplastic (pNEN) cells leading to cell death, thus improving the therapy of patients affected by pNEN. METHODS: 2D and 3D human pNEN and pancreatic stellate cells were treated with panobinostat and bafilomycin. Autophagy markers were detected by RT-qPCR, immunofluorescence, and Western blot. Autophagosomes were detected by electron microscopy and their maturation by real-time fluorescence of LC3B stable transfected cells. ChIP was performed at the cAMP responsive element. Immunofluorescence was performed in murine pancreatic tissue. RESULTS: We observed that pan-deacetylase inhibitor panobinostat treatment causes autophagic cell death in pNEN cells. We also found that although AMPK-α phosphorylation is counterbalanced by phosphorylated AKT, it is not capable to inhibiting autophagic cell death. However, the binding activity of the cAMP responsive element is prompted by panobinostat. Although autophagy inhibition prevented autophagosome synthesis, maturation, and cell death, panobinostat treatment induced the accumulation of mature autophagosomes in the cytosol and the nucleus, leading to disruption of the organelles, cellular digestion, and decay. Observation of autophagosome membrane proteins Beclin1 and LC3B aggregation in murine pancreatic islets indicates that autophagy restoration may also lead to autophagosome aggregation in murine insulinoma cells. A basal low expression of autophagy markers was detectable in patients affected by pNEN, and, interestingly, the expression of these markers was significantly lower in metastatic pNEN. DISCUSSION/CONCLUSION: Our study highlights that the autophagy functional restoration and prolongation of this catabolic process, mediated by inhibition of deacetylase, is responsible for the reduction of pNEN cells. Prompting of autophagy cell death could be a promising strategy for the therapy of pNEN.

15.
Eur J Immunol ; 51(1): 191-196, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-32648940

RESUMO

Interleukin-31 (IL-31) is a Th2 cell-derived cytokine that has been closely linked to pruritic skin inflammation. More recently, enhanced IL-31 serum levels have also been observed in patients with allergic rhinitis and allergic asthma. Therefore, the main aim of this study was to unravel the contribution of IL-31 to allergen-induced lung inflammation. We analyzed lung inflammation in response to the timothy grass (Phleum pratense) pollen allergen Phl p 5 in C57BL/6 wild-type (wt) mice, IL-31 transgenic (IL-31tg) mice, and IL-31 receptor alpha-deficient animals (IL-31RA-/- ). IL-31 and IL-31RA levels were monitored by qRT-PCR. Cellular infiltrate in bronchoalveolar lavage fluid (BALF) and lung tissue inflammation, mucus production as well as epithelial thickness were measured by flow cytometry and histomorphology. While allergen challenge induced IL-31RA expression in lung tissue of wt and IL-31tg mice, high IL-31 expression was exclusively observed in lung tissue of IL-31tg mice. Upon Phl p 5 challenge, IL-31tg mice showed reduced numbers of leukocytes and eosinophils in BALF and lung tissue as well as diminished mucin expression and less pronounced epithelial thickening compared to IL-31RA-/- or wt animals. These findings suggest that the IL-31/IL-31RA axis may regulate local, allergen-induced inflammation in the lungs.


Assuntos
Alérgenos/efeitos adversos , Alérgenos/imunologia , Interleucinas/imunologia , Proteínas de Plantas/efeitos adversos , Proteínas de Plantas/imunologia , Pneumonia/imunologia , Animais , Asma/etiologia , Asma/imunologia , Asma/prevenção & controle , Líquido da Lavagem Broncoalveolar/imunologia , Modelos Animais de Doenças , Eosinófilos/imunologia , Feminino , Interleucinas/genética , Leucócitos/imunologia , Pulmão/imunologia , Pulmão/patologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Phleum/efeitos adversos , Phleum/imunologia , Pneumonia/etiologia , Pneumonia/prevenção & controle , Pólen/efeitos adversos , Pólen/imunologia , Receptores de Interleucina/deficiência , Receptores de Interleucina/genética , Receptores de Interleucina/imunologia
16.
Haematologica ; 106(8): 2102-2113, 2021 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-32616529

RESUMO

Adhesive properties of leukemia cells shape the degree of organ infiltration and the extent of leukocytosis. CD44 and the integrin VLA-4, a CD49d/CD29 heterodimer, are important factors of progenitor cell adhesion in bone marrow (BM). Here, we report their cooperation in acute myeloid leukemia (AML) by a novel non-classical CD44-mediated way of inside-out VLA-4 activation. In primary AML BM samples from patients and the OCI-AML3 cell line, CD44 engagement by hyaluronan induced inside-out activation of VLA-4 resulting in enhanced leukemia cell adhesion on VCAM-1. This was independent from VLA-4 affinity regulation but based on ligand-induced integrin clustering on the cell surface. CD44-induced VLA-4 activation could be inhibited by the Src family kinase inhibitor PP2 and the multikinase inhibitor midostaurin. In further consequence, the increased adhesion on VCAM-1 allowed AML cells to strongly bind stromal cells. Thereby VLA-4/VCAM-1 interaction promoted activation of Akt, MAPK, NF-kB and mTOR signaling and decreased AML cell apoptosis. Collectively, our investigations provide a mechanistic description of an unusual CD44 function in regulating VLA-4 avidity in AML, supporting AML cell retention in the supportive BM microenvironment.


Assuntos
Integrina alfa4beta1 , Leucemia Mieloide Aguda , Medula Óssea , Adesão Celular , Humanos , Receptores de Hialuronatos/genética , Microambiente Tumoral , Molécula 1 de Adesão de Célula Vascular/genética
17.
Adv Med Educ Pract ; 11: 695-705, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33117039

RESUMO

Purpose: New technologies like gamification are continuously integrated into medical education during the last years. However, the benefit and implementation of such gaming platforms are not clearly studied. This analysis assesses the feasibility of Kahoot! regarding simplicity and low-cost performance as a learning/teaching tool for medical education in (histo-)pathology. Materials and Methods: In this feasibility pilot study, we developed 36 modules for different benign and malignant tumors, covering four major topics: gastrointestinal tract, dermatology, urogenital tract, and hematology. Each module included histomorphological text-based questions for education of 2nd-year medical students. The online gaming-platform Kahoot! was anonymously implemented before and after "classical" medical education which included discussions of histological slides for each tumor entity using Microsoft PowerPoint-based presentations in combination with microscopical demonstrations. Participating students were invited to a seven-questions evaluation about the online educational approach. Results: Overall, 23 of 51 students of the study class completed the pre- and the post-evaluation of Kahoot! in one or more organ systems. The percentage of correct answers increased from the initial mean/median of 47.2/45% to 77.2/76.3%. Simultaneously, the time for answering questions decreased by roughly 50% (from mean/median time of 9.1/8.3 seconds to 5.1/4.3 seconds) from pre- to post-assessment. The results were independent of gender; however, there were scoring differences between the different organ systems. Students positively evaluated the routine implementation of the gaming-platform Kahoot! within medical education. Conclusion: Kahoot! is as a simple, direct, and low-cost application in medical teaching improving learning outcomes of pathomorphological topics with high acceptance by students. Kahoot!-based evaluations should be also performed in more advanced topics in the field of histopathology.

18.
Pleura Peritoneum ; 5(1): 20190031, 2020 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-32885035

RESUMO

Background: The body surface area (BSA) is taken as a measure for the effective contact area for dosing in hyperthermic intraperitoneal chemotherapy (HIPEC). Currently, the pharmacokinetic effect of the reduced peritoneal surface area (PSA) after cytoreductive surgery (CRS) during HIPEC remains unclear. Here a proprietary software solution (PEritoneal SUrface CAlculator (PESUCA)) to quantify the resected PSA in patients with peritoneal surface malignancies (PSM) undergoing CRS and HIPEC is presented. Methods: The PESUCA tool was programmed as a desktop and online software solution. The applicability was evaluated in 36 patients. The programming-algorithm is briefly summarized as follows: (1) calculation of BSA, (2) correlation to PSA, (3) calculation of the relative proportion of 40 different anatomical regions to total PSA before CRS, (4) instantaneous input of each resected proportion in the 40 anatomical regions during CRS, and (5) determination of the resected and remaining PSA after CRS. Results: The proof of concept revealed a mean PSA of all patients before CRS of 18,741 ± 321 cm2 compared to 13,611 ± 485 cm2 after CRS (p<0.0001). Patients' supramesocolic and inframesocolic visceral and parietal peritoneal area before and after CRS procedure were quantitatively determined. Conclusions: Here the first tool that enables detailed PSA quantification in patients with PSM undergoing CRS is presented. This makes the software a valuable contribution to ensue more accurate assessment and improved comparability of peritoneal disease extent. Furthermore, after external validation, PESUCA could be the basis for dose adjustment of intraperitoneal chemotherapy regimens based on the remaining PSA after CRS.

19.
J Clin Med ; 9(9)2020 Aug 27.
Artigo em Inglês | MEDLINE | ID: mdl-32867256

RESUMO

Reports on the prognostic role of programmed death-ligand 1 (PD-L1) expression in rectal cancer are controversial. We investigated expression patterns and changes of PD-L1 in rectal cancer patients undergoing neoadjuvant chemoradiotherapy (CRT). Seventy-two patients diagnosed with rectal cancer and/or treated with fluorouracil-based neoadjuvant CRT at the Department of Internal Medicine III of the Paracelsus Medical University Salzburg (Austria) between January 2003 and October 2012 were included. PD-L1 scoring was performed according to the tumor proportion score (TPS), combined positive score (CPS), and immune cell score (IC). PD-L1 TPS prior to neoadjuvant CRT had a statistically significant impact on survival (median: ≤1%: 95.4 months (95% CI: 51.8-not reached) vs. >1%: not reached, p = 0.03, log-rank). Patients with a PD-L1 TPS ≤1% prior to and after CRT showed an inferior survival compared to all other patients (median: 56.7 months (95% CI: 51.4-not reached) vs. not reached, p = 0.005, log-rank). In multivariate analysis, PD-L1 TPS prior to neoadjuvant CRT (>1% vs. ≤1%, hazard ratio: 0.29 (95% CI: 0.11-0.76), p = 0.01) remained independently associated with survival. In conclusion, low PD-L1 TPS was associated with inferior survival in rectal cancer patients undergoing neoadjuvant CRT. A prospective validation of the prognostic value of PD-L1 expression in rectal cancer patients within a clinical trial is necessitated.

20.
Mol Oncol ; 14(9): 1930-1946, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32615027

RESUMO

Genetic activation of hedgehog/glioma-associated oncogene homolog (HH/GLI) signaling causes basal cell carcinoma (BCC), a very frequent nonmelanoma skin cancer. Small molecule targeting of the essential HH effector Smoothened (SMO) has proven an effective therapy of BCC, though the frequent development of drug resistance poses major challenges to anti-HH treatments. In light of recent breakthroughs in cancer immunotherapy, we analyzed the possible immunosuppressive mechanisms in HH/GLI-induced BCC in detail. Using a genetic mouse model of BCC, we identified profound differences in the infiltration of BCC lesions with cells of the adaptive and innate immune system. Epidermal activation of Hh/Gli signaling led to an accumulation of immunosuppressive regulatory T cells, and to an increased expression of immune checkpoint molecules including programmed death (PD)-1/PD-ligand 1. Anti-PD-1 monotherapy, however, did not reduce tumor growth, presumably due to the lack of immunogenic mutations in common BCC mouse models, as shown by whole-exome sequencing. BCC lesions also displayed a marked infiltration with neutrophils, the depletion of which unexpectedly promoted BCC growth. The study provides a comprehensive survey of and novel insights into the immune status of murine BCC and serves as a basis for the design of efficacious rational combination treatments. This study also underlines the need for predictive immunogenic mouse models of BCC to evaluate the efficacy of immunotherapeutic strategies in vivo.


Assuntos
Carcinoma Basocelular/imunologia , Epiderme/patologia , Proteínas Hedgehog/metabolismo , Imunidade , Imunossupressão , Transdução de Sinais , Neoplasias Cutâneas/imunologia , Microambiente Tumoral/imunologia , Animais , Carcinoma Basocelular/patologia , Proliferação de Células , Quimiocinas/metabolismo , Proteínas de Checkpoint Imunológico/metabolismo , Camundongos , Neutrófilos/metabolismo , Oncogenes , Neoplasias Cutâneas/patologia , Linfócitos T/imunologia , Proteína GLI1 em Dedos de Zinco/metabolismo
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