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2.
Cancers (Basel) ; 13(18)2021 Sep 07.
Artigo em Inglês | MEDLINE | ID: mdl-34572733

RESUMO

BACKGROUND: Online information gathering can increase patients' engagement in decision-making. The quality of online resources available for monoclonal gammopathy of undetermined significance (MGUS) was evaluated. METHODS: 900 websites from Google, Bing, Yahoo, and 150 YouTube videos were assessed. RESULTS: The websites did not differ regarding their search rank or between the search engines. The median time since last update was 24 months. The 86 unique websites showed a medium to poor general quality (JAMA score 3/4, only 8.1% websites with a valid HON certificate). The patient- (user-) focused quality was poor (sum DISCERN score 27/80 points). The reading level was difficult (11th US school grade). The content level was very low (13/50 points). 12.8% of websites contained misleading/wrong facts. Websites provided by scientific/governmental organizations had a higher content level. For the 61 unique videos, the median time since upload was 34 months. The videos showed a medium general quality (HON Foundation score). The patient- (user-) focused quality was poor (sum DISCERN score 24 points). The content level was very low (6 points). CONCLUSION: MGUS-relevant online sources showed a low quality that was provided on a high reading level. Incorporation of quality indices and regular review of online content is warranted.

3.
Cancer Cell ; 39(10): 1388-1403.e10, 2021 Oct 11.
Artigo em Inglês | MEDLINE | ID: mdl-34506739

RESUMO

Localized radiotherapy (RT) induces an immunogenic antitumor response that is in part counterbalanced by activation of immune evasive and tissue remodeling processes, e.g., via upregulation of programmed cell death-ligand 1 (PD-L1) and transforming growth factor ß (TGF-ß). We report that a bifunctional fusion protein that simultaneously inhibits TGF-ß and PD-L1, bintrafusp alfa (BA), effectively synergizes with radiotherapy, leading to superior survival in multiple therapy-resistant murine tumor models with poor immune infiltration. The BA + RT (BART) combination increases tumor-infiltrating leukocytes, reprograms the tumor microenvironment, and attenuates RT-induced fibrosis, leading to reconstitution of tumor immunity and regression of spontaneous lung metastases. Consistently, the beneficial effects of BART are in part reversed by depletion of cytotoxic CD8+ T cells. Intriguingly, targeting of the TGF-ß trap to PD-L1+ endothelium and the M2/lipofibroblast-like cell compartment by BA attenuated late-stage RT-induced lung fibrosis. Together, the results suggest that the BART combination has the potential to eradicate therapy-resistant tumors while sparing normal tissue, further supporting its clinical translation.

4.
Cancers (Basel) ; 13(17)2021 Aug 26.
Artigo em Inglês | MEDLINE | ID: mdl-34503110

RESUMO

BACKGROUND: The development of non-small cell lung cancer (NSCLC) involves the progressive accumulation of genetic and epigenetic changes. These include somatic oncogenic KRAS and EGFR mutations and inactivating TP53 tumour suppressor mutations, leading to activation of canonical NF-κB. However, the mechanism(s) by which canonical NF-κB contributes to NSCLC is still under investigation. METHODS: Human NSCLC cells were used to knock-down RelA/p65 (RelA/p65KD) and investigate its impact on cell growth, and its mechanism of action by employing RNA-seq analysis, qPCR, immunoblotting, immunohistochemistry, immunofluorescence and functional assays. RESULTS: RelA/p65KD reduced the proliferation and tumour growth of human NSCLC cells grown in vivo as xenografts in immune-compromised mice. RNA-seq analysis identified canonical NF-κB targets mediating its tumour promoting function. RelA/p65KD resulted in the upregulation of the metastasis suppressor CD82/KAI1/TSPAN27 and downregulation of the proto-oncogene ROS1, and LGR6 involved in Wnt/ß-catenin signalling. Immunohistochemical and bioinformatics analysis of human NSCLC samples showed that CD82 loss correlated with malignancy. RelA/p65KD suppressed cell migration and epithelial-to-mesenchymal cell transition (EMT), mediated, in part, by CD82/KAI1, through integrin-mediated signalling involving the mitogenic ERK, Akt1 and Rac1 proteins. CONCLUSIONS: Canonical NF-κB signalling promotes NSCLC, in part, by downregulating the metastasis suppressor CD82/KAI1 which inhibits cell migration, EMT and tumour growth.

5.
Ther Adv Med Oncol ; 13: 1758835921996509, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34408792

RESUMO

Background: Epidermal growth factor receptor-mutated (EGFR+) non-small-cell lung cancer (NSCLC) patients failing tyrosine kinase inhibitors (TKI) can benefit from next-line targeted therapies, but implementation is challenging. Methods: EGFR+ NSCLC patients treated with first/second-generation (1G/2G) TKI at our institution with a last follow-up after osimertinib approval (February 2016), were analyzed retrospectively, and the results compared with published data under osimertinib. Results: A total of 207 patients received erlotinib (37%), gefitinib (16%) or afatinib (47%). The median age was 66 years, with a predominance of female (70%), never/light-smokers (69%). T790M testing was performed in 174/202 progressive cases (86%), positive in 93/174 (53%), and followed by osimertinib in 87/93 (94%). Among the 135 deceased patients, 94 (70%) received subsequent systemic treatment (43% chemotherapy, 39% osimertinib), while 30% died without, either before (4%) or after progression, due to rapid clinical deterioration (22%), patient refusal of further therapy (2%), or severe competing illness (2%). Lack of subsequent treatment was significantly (4.5x, p < 0.001) associated with lack of T790M testing, whose most frequent cause (in approximately 50% of cases) was also rapid clinical decline. Among the 127 consecutive patients with failure of 1G/2G TKI started after November 2015, 47 (37%) received osimertinib, with a median overall survival of 36 months versus 24 and 21 months for patients with alternative and no subsequent therapies (p = 0.003). Conclusion: Osimertinib after 1G/2G TKI failure prolongs survival, but approximately 15% and 30% of patients forego molecular retesting and subsequent treatment, respectively, mainly due to rapid clinical deterioration. This is an important remediable obstacle to sequential TKI treatment for EGFR+ NSCLC. It pertains also to other actionable resistance mechanisms emerging under 1G/2G inhibitors or osimertinib, whose rate for lack of next-line therapy is similar (approximately 35% in the FLAURA/AURA3 trials), and highlights the need for closer monitoring alongside broader profiling of TKI-treated EGFR+ NSCLC in the future.

6.
Respiration ; : 1-9, 2021 Aug 12.
Artigo em Inglês | MEDLINE | ID: mdl-34384085

RESUMO

BACKGROUND: Lung-sparing cytoreductive surgery by extended pleurectomy and decortication (EPD) in combination with hyperthermic intrathoracic chemoperfusion (HITOC) forms a promising treatment strategy for malignant pleural mesothelioma and recurrent pleural thymic malignancies. OBJECTIVES: The objective of this study was to scrutinize the surgical procedure and perioperative patient management with emphasis on perioperative morbidity and local tumor control. METHODS: In 2014, a standardized EPD and HITOC procedure was implemented at the Thoraxklinik Heidelberg. This retrospective analysis included clinical data of consecutive patients with pleural mesothelioma and pleural metastasized malignancies treated by EPD and HITOC. The surgical procedure, perioperative management, lung function data, and progression-free survival (PFS) were analyzed. RESULTS: In the time range between April 2, 2014 and July 2018, 76 patients with pleural malignancies have been treated with EPD and HITOC, and were analyzed retrospectively. It included 61 patients with pleural mesothelioma and 15 patients with pleural metastases of thymic malignancies (12), non-small cell lung cancer (1), colorectal carcinoma (1), and sarcoma (1). Perioperative morbidity following EPD and HITOC treatments represented 23.7% of overall malignancies, while 30- and 90-day mortality were 0 and 1.3%, respectively. Median PFS lasted 18.4 months for mesothelioma and 72.2 months for thymic malignancies. CONCLUSION: Combining EPD with HITOC can be performed in patients with either pleural mesothelioma or pleural metastases resulting in low perioperative morbidity and mortality as well as remarkable local tumor control.

7.
Transplant Cell Ther ; 27(10): 876.e1-876.e11, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34214737

RESUMO

In multiple myeloma, local radiation therapy (RT) of osseous lesions before peripheral blood stem cell (PBSC) mobilization is assumed to impair the PBSC mobilization and collection. However, the results of previously published studies are inconsistent and do not evaluate detailed metrics of RT and PBSC outcome parameters. In total, 352 patients undergoing PBSC mobilizations and RT in first-line treatment were evaluated. Patients were grouped into RT (n = 283) and no RT (n = 69) before PBSC mobilization. Except for the International Staging System score, both groups were homogeneous regarding the first diagnosis characteristics, first-line treatments, and response parameters. RT metrics (RT yes versus no, volume of irradiated hematopoietic bone marrow [BM], biologically equivalent doses in 2 Gy fractions [EQD2]) were analyzed for the following PBSC outcome parameters: achievement of the PBSC collection goal, CD34+ cell collection yield, duration of the mobilization phase, and number of leukapheresis (LP) sessions to reach the collection goal. No statistically significant differences in the percentage of collection failures to reach at least 3 sufficient PBSC transplants were identified comparing patients with (n = 32 [11%]) and without RT (n = 4 [6%]) before PBSC mobilization (P = .265). However, patients with RT before PBSC mobilization showed a significant prolongation of the PBSC mobilization (median 1 day, P =.026) and required a higher number of LP sessions to reach the collection goal (median 1 LP, P < .001) compared with patients who received RT after PBSC mobilization. Moreover, patients with RT before PBSC mobilization reached a significantly lower CD34+ cell collection result (mean 8.94 versus 9.81 × 106/kg body weight [bw], P = .002). No correlation was identified between the overall CD34+ cell yield and the volume of irradiated hematopoietic BM or EQD2, respectively. In the RT before PBSC mobilization group, patients who required more than 1 LP session to reach the PBSC collection goal after RT had a significantly higher percentage of radiated hematopoietic BM compared to those who required only 1 LP session (mean 9.7% versus 7.2%, P = .002). Overall, our study indicates a negative impact of RT on PBSC mobilization and collection. Apart from emergency settings, it might be beneficial to postpone RT to a post-PBSC collection time point. © 2021 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.


Assuntos
Mieloma Múltiplo , Células-Tronco de Sangue Periférico , Mobilização de Células-Tronco Hematopoéticas , Humanos , Leucaférese , Mieloma Múltiplo/radioterapia , Transplante Autólogo
8.
Front Oncol ; 11: 703893, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34268127

RESUMO

Introduction: PD-(L)1 inhibitors have improved prognosis of non-small-cell lung cancer (NSCLC), but can also cause immune-related adverse events (irAEs) that complicate management. Methods: We analyzed NSCLC patients receiving PD-(L)1 inhibitors from 2012 to 2020 in a German academic center. Results: IrAE showed comparable frequencies in stage IV (198/894 or 22%) vs. III (14/45 or 31%, p = 0.15), after anti-PD-(L)1 monotherapy vs. chemoimmunotherapy (139/483 vs. 58/213, p = 0.75), and across treatment lines. In stage IV, irAE occurred after 3.1 months in median, affected multiple organs (median 2) in 27/894 patients and were associated with PD-L1 positivity (25 vs. 14%, p = 0.003), lower neutrophil-to-lymphocyte ratios (29 vs. 17%, p < 0.001 for NLR dichotomized at 5), better ECOG status (26 vs. 18% for 0 vs. 1, p = 0.004), but not related to age, sex, smoking and palliative radiotherapy. Two hundred thirty two irAEs occurred mostly in endocrine glands (4.9%), lungs (4.4%), the musculoskeletal system (4.2%), colon (4.1%), liver (3.7%), and skin (2.6%), while pneumonitis was most frequent with durvalumab following definitive chemoradiation (16% or 7/45, p < 0.01). IrAE severity was grade 1 in 11%, 2 in 41%, 3 in 36%, and 4 in 11% events, while two were lethal (<1%, myocarditis and pneumonitis). Therapy was suspended in 72%, while steroids were initiated in 66% and complemented by other immunosuppressants in 6%, with longest treatment duration for rheumatic events (mean >3 months), and average cumulative prednisone doses >700 mg for all organs, except for skin. Patients developing irAE had longer progression-free (PFS) and overall survival (OS) in multivariable 12/14-week landmark analyses including ECOG status, treatment line, treatment type, PD-L1 TPS, and NLR (median PFS 17 vs. 10 months, HR = 0.68, p = 0.009; median OS 37 vs. 15 months, HR = 0.40, p < 0.001), regardless of grade. OS was longest with skin (95% at 2 years) and shortest with pneumonitis, hepatitis, neurologic, and cardiologic irAE (38, 37, 28, and 0% at 2 years, p < 0.001). Conclusions: Approximately one-fourth of immunotherapy-treated NSCLC patients develop irAEs, most of which necessitate treatment suspension and steroids. Despite more frequent occurrence with PD-L1 positive tumors, lower NLR, and better ECOG PS, irAEs are independently associated with longer survival, especially when affecting the skin. Lethality is below 1%.

9.
Cancers (Basel) ; 13(13)2021 Jun 26.
Artigo em Inglês | MEDLINE | ID: mdl-34206844

RESUMO

The discrimination of malignant melanoma from benign nevi may be difficult in some cases. For this reason, immunohistological and molecular techniques are included in the differential diagnostic toolbox for these lesions. These methods are time consuming when applied subsequently and, in some cases, no definitive diagnosis can be made. We studied both lesions by imaging mass spectrometry (IMS) in a large cohort (n = 203) to determine a different proteomic profile between cutaneous melanomas and melanocytic nevi. Sample preparation and instrument setting were tested to obtain optimal results in term of data quality and reproducibility. A proteomic signature was found by linear discriminant analysis to discern malignant melanoma from benign nevus (n = 113) with an overall accuracy of >98%. The prediction model was tested in an independent set (n = 90) reaching an overall accuracy of 93% in classifying melanoma from nevi. Statistical analysis of the IMS data revealed mass-to-charge ratio (m/z) peaks which varied significantly (Area under the receiver operating characteristic curve > 0.7) between the two tissue types. To our knowledge, this is the largest IMS study of cutaneous melanoma and nevi performed up to now. Our findings clearly show that discrimination of melanocytic nevi from melanoma is possible by IMS.

10.
Molecules ; 26(12)2021 Jun 10.
Artigo em Inglês | MEDLINE | ID: mdl-34200965

RESUMO

Glycosylation is the most prevalent and varied form of post-translational protein modifications. Protein glycosylation regulates multiple cellular functions, including protein folding, cell adhesion, molecular trafficking and clearance, receptor activation, signal transduction, and endocytosis. In particular, membrane proteins are frequently highly glycosylated, which is both linked to physiological processes and of high relevance in various disease mechanisms. The cellular glycome is increasingly considered to be a therapeutic target. Here we describe a new strategy to compare membrane glycoproteomes, thereby identifying proteins with altered glycan structures and the respective glycosites. The workflow started with an optimized procedure for the digestion of membrane proteins followed by the lectin-based isolation of glycopeptides. Since alterations in the glycan part of a glycopeptide cause mass alterations, analytical size exclusion chromatography was applied to detect these mass shifts. N-glycosidase treatment combined with nanoUPLC-coupled mass spectrometry identified the altered glycoproteins and respective glycosites. The methodology was established using the colon cancer cell line CX1, which was treated with 2-deoxy-glucose-a modulator of N-glycosylation. The described methodology is not restricted to cell culture, as it can also be adapted to tissue samples or body fluids. Altogether, it is a useful module in various experimental settings that target glycan functions.


Assuntos
Glicoproteínas/metabolismo , Proteínas de Membrana/metabolismo , Linhagem Celular Tumoral , Glucose/metabolismo , Glicopeptídeos/metabolismo , Glicosilação , Humanos , Polissacarídeos/metabolismo , Proteômica/métodos
11.
Front Oncol ; 11: 673901, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34307143

RESUMO

Background: Large-cell neuroendocrine lung carcinoma (LCNEC) is a rare pulmonary neoplasm with poor prognosis and limited therapeutic options. Methods: We retrospectively analyzed all patients with metastatic LCNEC in the records of a large German academic center since 2010. Results: 191 patients were identified with a predominance of male (68%) smokers (92%) and a median age of 65 years. The single most important factor associated with outcome was the type of systemic treatment, with a median overall survival (OS) of 26.4 months in case of immune checkpoint inhibitor administration (n=13), 9.0 months for other patients receiving first-line platinum doublets (n=129), and 4.0 months with non-platinum chemotherapies (n=17, p<0.01). Other patient characteristics independently associated with longer OS were a lower baseline serum LDH (hazard ratio [HR] 0.54, p=0.008) and fewer initial metastatic sites (HR 0.52, p=0.006), while the platinum drug type (cisplatin vs. carboplatin) and cytotoxic partner (etoposide vs. paclitaxel), patients' smoking status and baseline levels of tumor markers (NSE, CYFRA 21-1, CEA) did not matter. 12% (23/191) of patients forewent systemic treatment, mainly due to tumor-related clinical deterioration (n=13), while patient refusal of therapy (n=5) and severe concomitant illness (n=5) were less frequent. The attrition between successive treatment lines was approximately 50% and similar for platinum-based vs. other therapies, but higher in case of a worse initial ECOG status or higher serum LDH (p<0.05). 19% (36/191) of patients had secondary stage IV disease and showed fewer metastatic sites, better ECOG status and longer OS (median 12.6 vs. 8.7 months, p=0.030). Among the 111 deceased patients with palliative systemic treatment and complete follow-up, after exclusion of oligometastatic cases (n=8), administration of local therapies (n=63 or 57%) was associated with a longer OS (HR 0.58, p=0.008), but this association did not persist with multivariable testing. Conclusions: Highly active systemic therapies, especially immunotherapy and platinum doublets, are essential for improved outcome in LCNEC and influence OS stronger than clinical disease parameters, laboratory results and other patient characteristics. The attrition between chemotherapy lines is approximately 50%, similar to other NSCLC. Patients with secondary metastatic disease have a more favorable clinical phenotype and longer survival.

12.
Histochem Cell Biol ; 156(3): 253-272, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34152508

RESUMO

Wild-type lectins have distinct types of modular design. As a step to explain the physiological importance of their special status, hypothesis-driven protein engineering is used to generate variants. Concerning adhesion/growth-regulatory galectins, non-covalently associated homodimers are commonly encountered in vertebrates. The homodimeric galectin-7 (Gal-7) is a multifunctional context-dependent modulator. Since the possibility of conversion from the homodimer to hybrids with other galectin domains, i.e. from Gal-1 and Gal-3, has recently been discovered, we designed Gal-7-based constructs, i.e. stable (covalently linked) homo- and heterodimers. They were produced and purified by affinity chromatography, and the sugar-binding activity of each lectin unit proven by calorimetry. Inspection of profiles of binding of labeled galectins to an array-like platform with various cell types, i.e. sections of murine epididymis and jejunum, and impact on neuroblastoma cell proliferation revealed no major difference between natural and artificial (stable) homodimers. When analyzing heterodimers, acquisition of altered properties was seen. Remarkably, binding properties and activity as effector can depend on the order of arrangement of lectin domains (from N- to C-termini) and on the linker length. After dissociation of the homodimer, the Gal-7 domain can build new functionally active hybrids with other partners. This study provides a clear direction for research on defining the full range of Gal-7 functionality and offers the perspective of testing applications for engineered heterodimers.


Assuntos
Galectinas/metabolismo , Engenharia de Proteínas , Linhagem Celular Tumoral , Galectinas/análise , Galectinas/isolamento & purificação , Humanos , Espectrometria de Massas
13.
Transl Lung Cancer Res ; 10(5): 2118-2131, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-34164264

RESUMO

Background: Liquid rebiopsies can detect resistance mutations to guide therapy of anaplastic lymphoma kinase-rearranged (ALK+) non-small-cell lung cancer (NSCLC) failing tyrosine kinase inhibitors (TKI). Here, we analyze how their results relate to the anatomical pattern of disease progression and patient outcome. Methods: Clinical, molecular, and radiologic characteristics of consecutive TKI-treated ALK+ NSCLC patients were analyzed using prospectively collected plasma samples and the 17-gene targeted AVENIO kit, which covers oncogenic drivers and all TP53 exons. Results: In 56 patients, 139 instances of radiologic changes were analyzed, of which 133 corresponded to disease progression. Circulating tumor DNA (ctDNA) alterations were identified in most instances of extracranial progression (58/94 or 62%), especially if concomitant intracranial progression was also present (89%, P<0.001), but rarely in case of isolated central nervous system (CNS) progression (8/39 or 21%, P<0.001). ctDNA detectability correlated with presence of "short" echinoderm microtubule-associated protein-like 4 (EML4)-ALK fusion variants (mainly V3, E6:A20) and/or TP53 mutations (P<0.05), and presented therapeutic opportunities in <50% of cases. Patients with extracranial progression and positive liquid biopsies had shorter survival from the start of palliative treatment (mean 52 vs. 69 months, P=0.002), regardless of previous and subsequent therapy and initial ECOG performance status. Furthermore, for patients with extracranial progression, ctDNA detectability was associated with shorter next-line progression-free survival (PFS) (3 vs. 13 months, P=0.003) if they were switched to another systemic therapy (49/86 samples), and with shorter time-to-next-treatment (TNT) (3 vs. 8 months, P=0.004) if they were continued on the same treatment due to oligoprogression (37/86). In contrast, ctDNA detectability was not associated with the outcome of patients showing CNS-only progression. In 6/6 cases with suspicion of non-neoplastic radiologic lung changes (mainly infection or pneumonitis), ctDNA results remained negative. Conclusions: Positive blood-based liquid rebiopsies in ALK+ NSCLC characterize biologically more aggressive disease and are common with extracranial, but rare with CNS-only progression or benign radiologic changes. These results reconcile the increased detection of ALK resistance mutations with other features of the high-risk EML4-ALK V3-associated phenotype. Conversely, most oligoprogressive patients with negative liquid biopsies have a more indolent course without need for early change of systemic treatment.

14.
Artigo em Inglês | MEDLINE | ID: mdl-34125345

RESUMO

INTRODUCTION: The advent of immune checkpoint blockade (ICB) has led to significantly improved disease outcome in lung adenocarcinoma (ADC), but response of ALK/EGFR-positive tumors to immune therapy is limited. The underlying immune biology is incompletely understood. METHODS: We performed comparative mRNA expression profiling of 31 ALK-positive, 40 EGFR-positive and 43 ALK/EGFR-negative lung ADC focused on immune gene expression. The presence and levels of tumor infiltration lymphocytes (TILs) as well as fourteen specific immune cell populations were estimated from the gene expression profiles. RESULTS: While total TILs were not lower in ALK-positive and EGFR-positive tumors compared to ALK/EGFR-negative tumors, specific immunosuppressive characteristics were detected in both subgroups: In ALK-positive tumors, regulatory T cells were significantly higher compared to EGFR-positive (fold change: FC = 1.9, p = 0.0013) and ALK/EGFR-negative tumors (FC = 2.1, p = 0.00047). In EGFR-positive tumors, cytotoxic cells were significantly lower compared to ALK-positive (FC = - 1.7, p = 0.016) and to ALK/EGFR-negative tumors (FC = - 2.1, p = 2.0E-05). A total number of 289 genes, 40 part of cytokine-cytokine receptor signaling, were differentially expressed between the three subgroups. Among the latter, five genes were differently expressed in both ALK-positive and EGFR-positive tumors, while twelve genes showed differential expression solely in ALK-positive tumors and eleven genes solely in EGFR-positive tumors. CONCLUSION: Targeted gene expression profiling is a promising tool to read out tumor microenvironment characteristics from routine diagnostic lung cancer biopsies. Significant immune reactivity including specific immunosuppressive characteristics in ALK- and EGFR-positive lung ADC, but not a total absence of immune infiltration supports further clinical evaluation of immune-modulators as partners of ICB in such tumors.

15.
Cancers (Basel) ; 13(10)2021 May 17.
Artigo em Inglês | MEDLINE | ID: mdl-34067726

RESUMO

The diagnosis and the subtyping of non-Hodgkin lymphoma (NHL) are challenging and require expert knowledge, great experience, thorough morphological analysis, and often additional expensive immunohistological and molecular methods. As these requirements are not always available, supplemental methods supporting morphological-based decision making and potentially entity subtyping are required. Deep learning methods have been shown to classify histopathological images with high accuracy, but data on NHL subtyping are limited. After annotation of histopathological whole-slide images and image patch extraction, we trained and optimized an EfficientNet convolutional neuronal network algorithm on 84,139 image patches from 629 patients and evaluated its potential to classify tumor-free reference lymph nodes, nodal small lymphocytic lymphoma/chronic lymphocytic leukemia, and nodal diffuse large B-cell lymphoma. The optimized algorithm achieved an accuracy of 95.56% on an independent test set including 16,960 image patches from 125 patients after the application of quality controls. Automatic classification of NHL is possible with high accuracy using deep learning on histopathological images and routine diagnostic applications should be pursued.

16.
Int J Mol Sci ; 22(10)2021 May 20.
Artigo em Inglês | MEDLINE | ID: mdl-34065423

RESUMO

Identification of pancreatic ductal adenocarcinoma (PDAC) and precursor lesions in histological tissue slides can be challenging and elaborate, especially due to tumor heterogeneity. Thus, supportive tools for the identification of anatomical and pathological tissue structures are desired. Deep learning methods recently emerged, which classify histological structures into image categories with high accuracy. However, to date, only a limited number of classes and patients have been included in histopathological studies. In this study, scanned histopathological tissue slides from tissue microarrays of PDAC patients (n = 201, image patches n = 81.165) were extracted and assigned to a training, validation, and test set. With these patches, we implemented a convolutional neuronal network, established quality control measures and a method to interpret the model, and implemented a workflow for whole tissue slides. An optimized EfficientNet algorithm achieved high accuracies that allowed automatically localizing and quantifying tissue categories including pancreatic intraepithelial neoplasia and PDAC in whole tissue slides. SmoothGrad heatmaps allowed explaining image classification results. This is the first study that utilizes deep learning for automatic identification of different anatomical tissue structures and diseases on histopathological images of pancreatic tissue specimens. The proposed approach is a valuable tool to support routine diagnostic review and pancreatic cancer research.


Assuntos
Adenocarcinoma/patologia , Carcinoma Ductal Pancreático/patologia , Ductos Pancreáticos/patologia , Neoplasias Pancreáticas/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Aprendizado Profundo , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Redes Neurais de Computação
17.
Transfus Med Hemother ; 48(2): 91-98, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33976609

RESUMO

Introduction: Recently, we identified a huge discrepancy between the collection practice and the actual utilization of cryopreserved peripheral blood stem cells (PBSCs) for high-dose chemotherapy (HDCT) and autologous blood stem cell transplantation (ABSCT). Specifically, patients with Burkitt lymphoma, acute leukemia, and myeloproliferative neoplasms (MPN) were frequently not referred for ABSCT after successful PBSC collection. Objective: The aim of this study was to identify variables that are associated with the non-utilization of PBSC grafts. Methods: We retrospectively analyzed the collection, storage, and disposal of PBSC grafts in Burkitt lymphoma (n = 18), acute lymphoblastic leukemia (ALL, n = 22), MPN (n = 18), and acute myeloid leukemia (AML, n = 71) patients. Patients who underwent autologous PBSC collection at 2 collection and transplantation centers between 2001 and 2012 were included and followed up until 2016. Results: None of the Burkitt lymphoma patients were referred for ABSCT. Only in 1 (6%) patient, the graft was discarded after the patient's death. In all other patients (n = 17, 94%), the grafts were stored independently of the patient's status (death, n = 4, 22%; no follow-up, n = 6, 33%; no indication for ABSCT given, n = 7, 39%). In ALL patients, 4 (18%) patients underwent ABSCT after a median follow-up of 74 (1-182) months. In the remaining patients, PBSC grafts were either discarded (8 patients, 36%) or stored until the reference date (10 patients, 45%). Seven of 18 MPN patients (39%) underwent ABSCT. ABSCT was performed in 24 (34%) AML patients. In 20 (28%) patients who were not referred to ABSCT, an allogeneic transplantation (TPL) was performed. Fifteen (21%) patients received palliative care or deceased, and their grafts were discarded in all but 1 patient. Additional grafts were discarded in 21 (31%) patients and stored in 9 (13%) patients who underwent ABSCT or allogeneic TPL (n = 44). Conclusions: As the role and efficacy of autologous HDCT/ABSCT are not established in the analyzed entities, the indication for PBSC collection should be reanalyzed in regular intervals. Moreover, PBSC grafts from patients who have deceased, have insufficient grafts, or have already undergone an allogeneic TPL should be considered for disposal or (if applicable) for research use, to economize storage costs on a rational basis.

18.
Case Rep Oncol ; 14(1): 477-482, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33976623

RESUMO

Tyrosine kinase inhibitors (TKIs) represent the standard treatment for patients with non-small cell lung cancer (NSCLC) harboring epidermal growth factor receptor (EGFR) mutations. The duration of the response is, however, limited in time owing to the development of resistance mechanisms to both first- and second-generation agents such as MET oncogene amplification. This report describes the successful results obtained with the combination of the third-generation TKI osimertinib with the multitargeted TKI and MET inhibitor crizotinib in a patient with EGFR-mutant NSCLC with emerging MET amplification with a tolerable toxicity profile.

19.
BMC Cancer ; 21(1): 486, 2021 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-33933015

RESUMO

BACKGROUND: Synaptophysin, chromogranin and CD56 are recommended markers to identify pulmonary tumors with neuroendocrine differentiation. Whether the expression of these markers in pulmonary adenocarcinoma and pulmonary squamous cell carcinoma is a prognostic factor has been a matter of debate. Therefore, we investigated retrospectively a large cohort to expand the data on the role of synaptophysin, chromogranin and CD56 in non-small cell lung cancer lacking morphological features of neuroendocrine differentiation. METHODS: A cohort of 627 pulmonary adenocarcinomas (ADC) and 543 squamous cell carcinomas (SqCC) lacking morphological features of neuroendocrine differentiation was assembled and a tissue microarray was constructed. All cases were stained with synaptophysin, chromogranin and CD56. Positivity was defined as > 1% positive tumor cells. Data was correlated with clinico-pathological features including overall and disease free survival. RESULTS: 110 (18%) ADC and 80 (15%) SqCC were positive for either synaptophysin, chromogranin, CD56 or a combination. The most commonly positive single marker was synaptophysin. The least common positive marker was chromogranin. A combination of ≤2 neuroendocrine markers was positive in 2-3% of ADC and 0-1% of SqCC. There was no significant difference in overall survival in tumors with positivity for neuroendocrine markers neither in ADC (univariate: P = 0.4; hazard ratio [HR] = 0.867; multivariate: P = 0.5; HR = 0.876) nor in SqCC (univariate: P = 0.1; HR = 0.694; multivariate: P = 0.1, HR = 0.697). Likewise, there was no significant difference in disease free survival. CONCLUSIONS: We report on a cohort of 1170 cases that synaptophysin, chromogranin and CD56 are commonly expressed in ADC and SqCC and that their expression has no impact on survival, supporting the current best practice guidelines.


Assuntos
Adenocarcinoma/química , Antígeno CD56/análise , Carcinoma de Células Escamosas/química , Cromograninas/análise , Neoplasias Pulmonares/química , Sinaptofisina/análise , Adenocarcinoma/mortalidade , Adenocarcinoma/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Análise de Variância , Biomarcadores Tumorais/análise , Carcinoma de Células Escamosas/mortalidade , Carcinoma de Células Escamosas/patologia , Diferenciação Celular , Intervalo Livre de Doença , Feminino , Humanos , Neoplasias Pulmonares/mortalidade , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Análise Serial de Tecidos
20.
Front Oncol ; 11: 670483, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33959513

RESUMO

Background: Anaplastic lymphoma kinase-rearranged non-small-cell lung cancer (ALK+ NSCLC) is a model disease for use of targeted therapies (TKI), which are administered sequentially to maximize patient survival. Methods: We retrospectively analyzed the flow of 145 consecutive TKI-treated ALK+ NSCLC patients across therapy lines. Suitable patients that could not receive an available next-line therapy ("attrition") were determined separately for various treatments, based on the approval status of the respective targeted drugs when each treatment failure occurred in each patient. Results: At the time of analysis, 70/144 (49%) evaluable patients were still alive. Attrition rates related to targeted treatments were approximately 25-30% and similar for administration of a second-generation (2G) ALK inhibitor (22%, 17/79) or any subsequent systemic therapy (27%, 27/96) after crizotinib, and for the administration of lorlatinib (27%, 6/22) or any subsequent systemic therapy (25%, 15/61) after any 2G TKI. The rate of chemotherapy implementation was 67% (62/93). Both administration of additional TKI (median overall survival [mOS] 59 vs. 41 months for multiple vs. one TKI lines, logrank p=0.002), and chemotherapy (mOS 41 vs. 16 months, logrank p<0.001) were significantly associated with longer survival. Main reason for patients foregoing any subsequent systemic treatment was rapid clinical deterioration (n=40/43 or 93%) caused by tumor progression. In 2/3 of cases (29/43), death occurred under the first failing therapy, while in 11/43 the treatment was switched, but the patient did not respond, deteriorated further, and died within 8 weeks. Conclusions: Despite absence of regulatory obstacles and no requirement for specific acquired mutations, 25-30% of ALK+ NSCLC patients forego subsequent systemic therapy due to rapid clinical deterioration, in several cases (approximately 1/3) associated with an ineffective first next-line choice. These results underline the need for closer patient monitoring and broader profiling in order to support earlier and better directed use of available therapies.

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