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1.
Cancer Epidemiol ; 93: 102659, 2024 Sep 06.
Artigo em Inglês | MEDLINE | ID: mdl-39243580

RESUMO

BACKGROUND: Due to the rarity of pancreatic neuroendocrine neoplasms, only few population-representative studies on incidence and survival have been conducted. The aim was to provide up-to-date nationwide incidence and relative survival estimates of neuroendocrine (NE) neoplasms overall, NE tumors (NETs), NE carcinomas (NECs), and mixed NE neoplasms (MiNEN). METHODS: We distinguished between pancreatic NETs (functioning versus non-functioning), NECs and mixed NE neoplasms and analyzed data from 2009 through 2021 from all German cancer registries covering a population of more than 80 million. We calculated crude and age-standardized incidence rates and 5-year relative survival estimates (RS). RESULTS: Overall 6474, 4217, and 243 patients with pancreatic NETs, NECs, and mixed NE neoplasms, respectively were registered. While the age-standardized incidence of NETs has increased (+16.4 % per year, 95 %CI 12.2;20.7), the incidence of NEC has fallen (about -6.4 % per year, 95 %CI -8.0; -4.8). The crude RS was 77.7 % (standard error [SE] 0.9) for non-functioning NETs, 90.3 % for functioning NETs (SE 3.9), and 18.5 % (SE 3.9) for MiNEN. Large and small cell NECs had a low RS (9.1 % and 6.9 %, respectively). RS for G1 NETs was 88.2 %, while it was only 36.6 % for G3 NETs. Localized NETs had a RS of 92.8 %, while distant metastatic NETs had a RS of 45.0 %. CONCLUSIONS: The incidence of pancreatic NETs has increased markedly in Germany in the period 2009-2021. Subgroups of NETs (G1 grading or localized stage) have an excellent prognosis. RS of MiNEN is more similar to NECs than NETs.

2.
Theranostics ; 14(14): 5400-5412, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-39310095

RESUMO

Rationale: Positron Emission Tomography (PET) using the somatostatin receptor 2 (SSTR2)-antagonist satoreotide trizoxetan (68Ga-SSO120) is a novel, promising imaging modality for small-cell lung cancer (SCLC), which holds potential for theranostic applications. This study aims to correlate uptake in PET imaging with SSTR2 expression in immunohistochemistry (IHC) and to assess the prognostic value of 68Ga-SSO120 PET at initial staging of patients with SCLC. Methods: We analyzed patients who underwent 68Ga-SSO120 PET/CT during initial diagnostic workup of SCLC as part of institutional standard-of-care. SSTR2 expression in IHC was evaluated on a 4-level scale and correlated with normalized standardized uptake values and tumor-to-liver ratios (SUVmax and TLRpeak) in 68Ga-SSO120 PET on a lesion level. Highest lesion SUVmax/TLRpeak per patient, SSTR2 score in IHC, M status according to TNM classification, and other parameters were analyzed for association with overall survival (OS) and time to treatment failure (TTF) by univariate, multivariate (cut-off values were identified on data for best separation), and stratified Cox regression. Results: We included 54 patients (24 men/30 women, median age 65 years, 21 M0/33 M1 according to TNM classification). In 43 patients with available surplus tumor tissue samples, hottest lesion SUVmax/TLRpeak showed a significant correlation with the level of SSTR2-expression by tumor cells in IHC (Spearman's rho 0.86/0.81, both p < 0.001; ANOVA p < 0.001). High SSTR2 expression in IHC, 68Ga-SSO120 SUVmax and TLRpeak of the hottest lesion per patient, whole-body TLRmean, MTV, TLG, M status, and serum LDH showed a significant association with inferior TTF/OS in univariate analysis. In separate multivariate Cox regression (including sex, age, M stage, and LDH) higher hottest-lesion TLRpeak showed a significant association with shorter OS (HR = 0.26, 95%CI: 0.08-0.84, p = 0.02) and SSTR2 expression in IHC with significantly shorter TTF (HR = 0.24, 95%CI: 0.08-0.71, p = 0.001) and OS (HR = 0.22, 95%CI: 0.06-0.84, p = 0.03). In total, 12 patients (22.2%) showed low (< 1), 21 (38.9%) intermediate (≥ 1 but < 2), 14 (25.9%) high (≥ 2 but < 5), and 7 (13.0%) very high (≥ 5) whole-body mean TLRmean. Conclusion: In patients with SCLC, SSTR2 expression assessed by 68Ga-SSO120 PET and by IHC were closely correlated and associated with shorter survival. More than 75% of patients showed higher whole-body 68Ga-SSO120 tumor uptake than liver uptake and almost 40% high or very high uptake, possibly paving the way towards theranostic applications.


Assuntos
Imuno-Histoquímica , Neoplasias Pulmonares , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Receptores de Somatostatina , Carcinoma de Pequenas Células do Pulmão , Humanos , Feminino , Masculino , Receptores de Somatostatina/metabolismo , Idoso , Pessoa de Meia-Idade , Carcinoma de Pequenas Células do Pulmão/diagnóstico por imagem , Carcinoma de Pequenas Células do Pulmão/tratamento farmacológico , Carcinoma de Pequenas Células do Pulmão/metabolismo , Carcinoma de Pequenas Células do Pulmão/patologia , Carcinoma de Pequenas Células do Pulmão/mortalidade , Imuno-Histoquímica/métodos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/diagnóstico por imagem , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/mortalidade , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada/métodos , Radioisótopos de Gálio , Prognóstico , Idoso de 80 Anos ou mais , Adulto , Estudos Retrospectivos , Análise de Sobrevida , Compostos Radiofarmacêuticos , Somatostatina/metabolismo , Nanomedicina Teranóstica/métodos , Tomografia por Emissão de Pósitrons/métodos
3.
Artigo em Inglês | MEDLINE | ID: mdl-39315695

RESUMO

INTRODUCTION: In uveal melanoma (UM) patients with hepatic metastases, hepatic artery infusion chemotherapy (HAIC) is a viable, palliative treatment option. To evaluate the impact of two histomorphological patterns (spindle cell vs. epithelioid) of liver metastases on median overall survival (mOS) in UM patients undergoing HAIC. METHODS: A retrospective analysis with 60 UM patients (29 females, mean age: 61.6 ± 12.1 years) with hepatic metastases was performed. Histomorphological patterns in metastases were analysed and classified as either predominant spindle cell or epithelioid pattern. mOS between both patient groups was analysed using Kaplan-Meier curves and the log-rank test. RESULTS: In 73.3% (44/60) of the metastases, a predominant epithelioid pattern, in 21.7% (13/60) a predominant spindle cell pattern, and in 5% (3/60) other patterns were found. No significant differences between patients with an epithelioid (mOS: 14.2 months, 95% CI: 8.8-19.6) and a spindle cell pattern (mOS: 14.4 months, 95% CI: 4.3-24.5) were detected by the log-rank test, χ2(2) = 0.22, P = 0.881. CONCLUSION: Histomorphological patterns of UM metastases do not seem to be a predictor for mOS in UM patients undergoing HAIC.

4.
Nat Cardiovasc Res ; 3(5): 525-540, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-39195931

RESUMO

Post-injury dysfunction of humoral immunity accounts for infections and poor outcomes in cardiovascular diseases. Among immunoglobulins (Ig), IgA, the most abundant mucosal antibody, is produced by plasma B cells in intestinal Peyer's patches (PP) and lamina propria. Here we show that patients with stroke and myocardial ischemia (MI) had strongly reduced IgA blood levels. This was phenocopied in experimental mouse models where decreased plasma and fecal IgA were accompanied by rapid loss of IgA-producing plasma cells in PP and lamina propria. Reduced plasma IgG was detectable in patients and experimental mice 3-10 d after injury. Stroke/MI triggered the release of neutrophil extracellular traps (NETs). Depletion of neutrophils, NET degradation or blockade of NET release inhibited the loss of IgA+ cells and circulating IgA in experimental stroke and MI and in patients with stroke. Our results unveil how tissue-injury-triggered systemic NET release disrupts physiological Ig secretion and how this can be inhibited in patients.


Assuntos
Armadilhas Extracelulares , Infarto do Miocárdio , Neutrófilos , Armadilhas Extracelulares/metabolismo , Armadilhas Extracelulares/imunologia , Humanos , Animais , Infarto do Miocárdio/imunologia , Infarto do Miocárdio/patologia , Infarto do Miocárdio/metabolismo , Masculino , Neutrófilos/imunologia , Neutrófilos/metabolismo , Feminino , Modelos Animais de Doenças , Camundongos Endogâmicos C57BL , Acidente Vascular Cerebral/imunologia , Acidente Vascular Cerebral/patologia , Acidente Vascular Cerebral/metabolismo , Nódulos Linfáticos Agregados/imunologia , Nódulos Linfáticos Agregados/patologia , Nódulos Linfáticos Agregados/metabolismo , Imunoglobulina A/metabolismo , Imunoglobulina A/imunologia , Imunoglobulina A/sangue , Idoso , Pessoa de Meia-Idade , Imunoglobulina G/imunologia , Imunoglobulina G/metabolismo , Imunidade Humoral , Estudos de Casos e Controles , Camundongos , Plasmócitos/imunologia , Plasmócitos/metabolismo
5.
J Nucl Med ; 65(8): 1188-1193, 2024 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-38960716

RESUMO

The fibroblast activation protein (FAP) is highly expressed in tumor and stromal cells of mesothelioma and thus is an interesting imaging and therapeutic target. Previous data on PET imaging with radiolabeled FAP inhibitors (FAPIs) suggest high potential for superior tumor detection. Here, we report the data of a large malignant pleural mesothelioma cohort within a 68Ga-FAPI46 PET observational trial (NCT04571086). Methods: Of 43 eligible patients with suspected or proven malignant mesothelioma, 41 could be included in the data analysis of the 68Ga-FAPI46 PET observational trial. All patients underwent 68Ga-FAPI46 PET/CT, contrast-enhanced CT, and 18F-FDG PET/CT. The primary study endpoint was the association of 68Ga-FAPI46 PET uptake intensity and histopathologic FAP expression. Furthermore, secondary endpoints were detection rate and sensitivity, specificity, and positive and negative predictive values as compared with 18F-FDG PET/CT. Datasets were interpreted by 2 masked readers. Results: The primary endpoint was met, and the association between 68Ga-FAPI46 SUVmax or SUVpeak and histopathologic FAP expression was significant (SUVmax: r = 0.49, P = 0.037; SUVpeak: r = 0.51, P = 0.030).68Ga-FAPI46 and 18F-FDG showed similar sensitivity by histopathologic validation on a per-patient (100.0% vs. 97.3%) and per region (98.0% vs. 95.9%) basis. Per-region analysis revealed higher 68Ga-FAPI46 than 18F-FDG specificity (81.1% vs. 36.8%) and positive predictive value (87.5% vs. 66.2%). Conclusion: We confirm an association of 68Ga-FAPI46 uptake and histopathologic FAP expression in mesothelioma patients. Additionally, we report high sensitivity and superior specificity and positive predictive value for 68Ga-FAPI46 versus 18F-FDG.


Assuntos
Endopeptidases , Fluordesoxiglucose F18 , Gelatinases , Mesotelioma Maligno , Mesotelioma , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Humanos , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada/métodos , Masculino , Feminino , Idoso , Estudos Prospectivos , Pessoa de Meia-Idade , Mesotelioma/diagnóstico por imagem , Mesotelioma/metabolismo , Mesotelioma Maligno/diagnóstico por imagem , Mesotelioma Maligno/metabolismo , Gelatinases/metabolismo , Proteínas de Membrana/metabolismo , Serina Endopeptidases/metabolismo , Neoplasias Pulmonares/diagnóstico por imagem , Neoplasias Pulmonares/metabolismo , Idoso de 80 Anos ou mais
6.
EJNMMI Res ; 14(1): 66, 2024 Jul 18.
Artigo em Inglês | MEDLINE | ID: mdl-39023777

RESUMO

PURPOSE: Radiolabelled fibroblast activation protein inhibitors (FAPIs) are becoming increasingly important for imaging various tumour diseases. However, it is essential to be aware of potential pitfalls. Here, we investigate FAP expression in the thyroid gland in autoimmune thyroiditis (AIT). METHODS: AIT patients with pathological thyroid uptake on [68Ga]Ga-FAPI PET were compared with glucose metabolism on 2-[18F]FDG PET in terms of SUVmax/SUVpeak/SUVmean/tissue-to-background ratio (TBR), and with a healthy control group. RESULTS: Between September 2019 and July 2021, 6 patients presented with a visually increased thyroid uptake and TBR on [68Ga]Ga-FAPI PET. In the retrospective clinical work-up, all patients had known or newly diagnosed AIT. Compared to a matched healthy control group, FAP expression and glucose metabolism were significantly increased ([68Ga]Ga-FAPI (SUVpeak): 7.0 vs. 1.7; p = 0.004/(TBRbloodpool): 6.8 vs. 1.7; p = 0.002; 2-[18F]FDG (SUVpeak): 3.9 vs. 1.4; p = 0.004/(TBRbloodpool): 4.0 vs. 1.2; p = 0.041). However, there was no significant difference in median uptake between [68Ga]Ga-FAPI and 2-[18F]FDG PET (SUVpeak: 7.3 vs. 5.6; p = 0.104). CONCLUSION: Patients with AIT show higher thyroid uptake on [68Ga]Ga-FAPI and 2-[18F]FDG PET. Incidental thyroid uptake is another pitfall in the interpretation of [68Ga]Ga-FAPI PET and should prompt a clinical work-up.

7.
Support Care Cancer ; 32(7): 437, 2024 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-38879700

RESUMO

PURPOSE: Patients with advanced pancreatic and biliary tract cancer (aPBC) frequently suffer from high symptom burden. Exercise can reduce treatment side effects and improve patient-related outcomes (PROMs). However, evidence from prospective studies regarding feasibility and efficacy in advanced settings are sparse. The primary aim of this prospective, randomized-controlled study was to evaluate the feasibility and effects of exercise (ET) in patients with aPBC. METHODS: Patients with aPBC beyond first-line therapy were randomized according to the minimization procedure with stratification by gender, age, and loss of body weight in the past six months. The intervention group (IG) completed 3 training units/week for 8 weeks (1x supervised strength sessions, 2x individualized home-based sessions). Control group (CG) received recommendations on physical activity during cancer. RESULTS: 41 patients (stage IV pancreatic or biliary tract cancer) were included no adverse events related to exercise occurred during the trial. Physical function increased significantly in IG in 5 out of 7 physical domains. Comparison of IG and CG at 8 weeks (t2) showed significant differences in favour of IG in leg press (p=0.001), bench press (p=0.011), sit-to-stand (p=0.001) and crunch (0.006). Constipation revealed a significant difference in favour of IG at t2 (p=0.033). Quality of life stabilized/increased in IG during the study period compared to a decrease in CG. Throughout/Over the 8 weeks, fatigue notably reduced in the IG (p=0.028). CONCLUSION: Exercise is safe and feasible in patients with aPBC undergoing further line therapy. Significant improvements in physical functioning and increased quality of life were achieved. German Clinical Trials Register ID: DRKS00021179; Registration date 15.05.2020.


Assuntos
Neoplasias do Sistema Biliar , Terapia por Exercício , Neoplasias Pancreáticas , Qualidade de Vida , Humanos , Neoplasias do Sistema Biliar/tratamento farmacológico , Neoplasias do Sistema Biliar/terapia , Masculino , Feminino , Neoplasias Pancreáticas/tratamento farmacológico , Idoso , Pessoa de Meia-Idade , Estudos Prospectivos , Terapia por Exercício/métodos , Estudos de Viabilidade
8.
J Nucl Med ; 65(7): 1027-1034, 2024 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-38782454

RESUMO

Tumoral fibroblast activation protein expression is associated with proliferation and angiogenesis and can be visualized by PET/CT. We examined the prognostic value of [68Ga]Ga-fibroblast activation protein inhibitor (FAPI) (68Ga-FAPI)-46 PET/CT for different tumor entities in patients enrolled in 2 prospective imaging studies (NCT05160051, n = 30; NCT04571086, n = 115). Methods: Within 4 wk, 145 patients underwent 68Ga-FAPI-46 and [18F]FDG (18F-FDG) PET/CT. The association between overall survival (OS) and sex, age, tumor entity, total lesion number, highest SUVmax, and the presence of each nodal, visceral, and bone metastasis was tested using univariate Cox regression analysis. Multivariate analyses were performed for prognostic factors with P values of less than 0.05. Results: In the univariate analysis, shorter OS was associated with total lesion number and the presence of nodal, visceral, and bone metastases on 68Ga-FAPI-46 PET/CT (hazard ratio [HR], 1.06, 2.18, 1.69, and 2.05; P < 0.01, < 0.01, = 0.04, and = 0.02, respectively) and 18F-FDG PET/CT (HR, 1.05, 2.31, 1.76, and 2.30; P < 0.01, < 0.01, = 0.03, and < 0.01, respectively) and with SUVmax on 68Ga-FAPI-46 PET/CT (HR, 1.03; P = 0.03). In the multivariate analysis, total lesion number on 68Ga-FAPI-46 PET/CT was an independent risk factor for shorter OS (HR, 1.05; P = 0.02). In patients with pancreatic cancer, shorter OS was associated with total lesion number on 68Ga-FAPI-46 PET/CT (HR, 1.09; P < 0.01) and bone metastases on 18F-FDG PET/CT (HR, 31.39; P < 0.01) in the univariate analysis and with total lesion number on 68Ga-FAPI-46 PET/CT (HR, 1.07; P = 0.04) in the multivariate analyses. In breast cancer, total lesion number on 68Ga-FAPI-46 PET/CT (HR, 1.07; P = 0.02), as well as bone metastases on 18F-FDG PET/CT (HR, 9.64; P = 0.04), was associated with shorter OS in the univariate analysis. The multivariate analysis did not reveal significant prognostic factors. In thoracic cancer (lung cancer and pleural mesothelioma), the univariate and multivariate analyses did not reveal significant prognostic factors. Conclusion: Disease extent on 68Ga-FAPI-46 PET/CT is a predictor of short OS and may aid in future risk stratification by playing a supplemental role alongside 18F-FDG PET/CT.


Assuntos
Neoplasias , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Humanos , Masculino , Feminino , Pessoa de Meia-Idade , Idoso , Prognóstico , Neoplasias/diagnóstico por imagem , Neoplasias/patologia , Adulto , Análise de Sobrevida , Idoso de 80 Anos ou mais , Fluordesoxiglucose F18 , Quinolinas
9.
J Nucl Med ; 65(6): 880-887, 2024 Jun 03.
Artigo em Inglês | MEDLINE | ID: mdl-38724279

RESUMO

Fibroblast activation protein-α (FAP) is often highly expressed by sarcoma cells and by sarcoma-associated fibroblasts in the tumor microenvironment. This makes it a promising target for imaging and therapy. The level of FAP expression and the diagnostic value of 68Ga-FAP inhibitor (FAPI) PET for sarcoma subtypes are unknown. We assessed the diagnostic performance and accuracy of 68Ga-FAPI PET in various bone and soft-tissue sarcomas. Potential eligibility for FAP-targeted radiopharmaceutical therapy (FAP-RPT) was evaluated. Methods: This prospective observational trial enrolled 200 patients with bone and soft-tissue sarcoma who underwent 68Ga-FAPI PET/CT and 18F-FDG PET/CT (186/200, or 93%) for staging or restaging. The number of lesions detected and the uptake (SUVmax) of the primary tumor, lymph nodes, and visceral and bone metastases were analyzed. The Wilcoxon test was used for semiquantitative assessment. The association of 68Ga-FAPI uptake intensity, histopathologic grade, and FAP expression in sarcoma biopsy samples was analyzed using Spearman r correlation. The impact of 68Ga-FAPI PET on clinical management was investigated using questionnaires before and after PET/CT. Eligibility for FAP-RPT was defined by an SUVmax greater than 10 for all tumor regions. Results: 68Ga-FAPI uptake was heterogeneous among sarcoma subtypes. The 3 sarcoma entities with the highest uptake (mean SUVmax ± SD) were solitary fibrous tumor (24.7 ± 11.9), undifferentiated pleomorphic sarcoma (18.8 ± 13.1), and leiomyosarcoma (15.2 ± 10.2). Uptake of 68Ga-FAPI versus 18F-FDG was significantly higher in low-grade sarcomas (10.4 ± 8.5 vs. 7.0 ± 4.5, P = 0.01) and in potentially malignant intermediate or unpredictable sarcomas without a World Health Organization grade (not applicable [NA]; 22.3 ± 12.5 vs. 8.5 ± 10.0, P = 0.0004), including solitary fibrous tumor. The accuracy, as well as the detection rates, of 68Ga-FAPI was higher than that of 18F-FDG in low-grade sarcomas (accuracy, 92.2 vs. 80.0) and NA sarcomas (accuracy, 96.9 vs. 81.9). 68Ga-FAPI uptake and the histopathologic FAP expression score (n = 89) were moderately correlated (Spearman r = 0.43, P < 0.0002). Of 138 patients, 62 (45%) with metastatic sarcoma were eligible for FAP-RPT. Conclusion: In patients with low-grade and NA sarcomas, 68Ga-FAPI PET demonstrates uptake, detection rates, and accuracy superior to those of 18F-FDG PET. 68Ga-FAPI PET criteria identified eligibility for FAP-RPT in about half of sarcoma patients.


Assuntos
Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Compostos Radiofarmacêuticos , Sarcoma , Humanos , Masculino , Feminino , Sarcoma/diagnóstico por imagem , Sarcoma/metabolismo , Sarcoma/terapia , Pessoa de Meia-Idade , Adulto , Idoso , Adulto Jovem , Gradação de Tumores , Radioisótopos de Gálio , Endopeptidases , Idoso de 80 Anos ou mais , Estudos Prospectivos , Adolescente , Gelatinases/metabolismo , Gelatinases/antagonistas & inibidores , Serina Endopeptidases/metabolismo , Proteínas de Membrana/metabolismo , Quinolinas
11.
J Nucl Med ; 65(7): 1151-1159, 2024 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-38782455

RESUMO

Radiomics features can reveal hidden patterns in a tumor but usually lack an underlying biologic rationale. In this work, we aimed to investigate whether there is a correlation between radiomics features extracted from [18F]FDG PET images and histologic expression patterns of a glycolytic marker, monocarboxylate transporter-4 (MCT4), in pancreatic cancer. Methods: A cohort of pancreatic ductal adenocarcinoma patients (n = 29) for whom both tumor cross sections and [18F]FDG PET/CT scans were available was used to develop an [18F]FDG PET radiomics signature. By using immunohistochemistry for MCT4, we computed density maps of MCT4 expression and extracted pathomics features. Cluster analysis identified 2 subgroups with distinct MCT4 expression patterns. From corresponding [18F]FDG PET scans, radiomics features that associate with the predefined MCT4 subgroups were identified. Results: Complex heat map visualization showed that the MCT4-high/heterogeneous subgroup was correlating with a higher MCT4 expression level and local variation. This pattern linked to a specific [18F]FDG PET signature, characterized by a higher SUVmean and SUVmax and second-order radiomics features, correlating with local variation. This MCT4-based [18F]FDG PET signature of 7 radiomics features demonstrated prognostic value in an independent cohort of pancreatic cancer patients (n = 71) and identified patients with worse survival. Conclusion: Our cross-modal pipeline allows the development of PET scan signatures based on immunohistochemical analysis of markers of a particular biologic feature, here demonstrated on pancreatic cancer using intratumoral MCT4 expression levels to select [18F]FDG PET radiomics features. This study demonstrated the potential of radiomics scores to noninvasively capture intratumoral marker heterogeneity and identify a subset of pancreatic ductal adenocarcinoma patients with a poor prognosis.


Assuntos
Fluordesoxiglucose F18 , Neoplasias Pancreáticas , Humanos , Neoplasias Pancreáticas/diagnóstico por imagem , Neoplasias Pancreáticas/patologia , Neoplasias Pancreáticas/metabolismo , Feminino , Masculino , Pessoa de Meia-Idade , Idoso , Transportadores de Ácidos Monocarboxílicos/metabolismo , Carcinoma Ductal Pancreático/diagnóstico por imagem , Carcinoma Ductal Pancreático/patologia , Carcinoma Ductal Pancreático/metabolismo , Processamento de Imagem Assistida por Computador , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Proteínas Musculares/metabolismo , Compostos Radiofarmacêuticos , Tomografia por Emissão de Pósitrons , Radiômica
12.
Nat Commun ; 15(1): 4120, 2024 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-38750052

RESUMO

5q-associated spinal muscular atrophy (SMA) is a motoneuron disease caused by mutations in the survival motor neuron 1 (SMN1) gene. Adaptive immunity may contribute to SMA as described in other motoneuron diseases, yet mechanisms remain elusive. Nusinersen, an antisense treatment, enhances SMN2 expression, benefiting SMA patients. Here we have longitudinally investigated SMA and nusinersen effects on local immune responses in the cerebrospinal fluid (CSF) - a surrogate of central nervous system parenchyma. Single-cell transcriptomics (SMA: N = 9 versus Control: N = 9) reveal NK cell and CD8+ T cell expansions in untreated SMA CSF, exhibiting activation and degranulation markers. Spatial transcriptomics coupled with multiplex immunohistochemistry elucidate cytotoxicity near chromatolytic motoneurons (N = 4). Post-nusinersen treatment, CSF shows unaltered protein/transcriptional profiles. These findings underscore cytotoxicity's role in SMA pathogenesis and propose it as a therapeutic target. Our study illuminates cell-mediated cytotoxicity as shared features across motoneuron diseases, suggesting broader implications.


Assuntos
Encéfalo , Células Matadoras Naturais , Neurônios Motores , Atrofia Muscular Espinal , Oligonucleotídeos , Humanos , Atrofia Muscular Espinal/tratamento farmacológico , Atrofia Muscular Espinal/patologia , Atrofia Muscular Espinal/genética , Neurônios Motores/efeitos dos fármacos , Neurônios Motores/patologia , Neurônios Motores/metabolismo , Células Matadoras Naturais/imunologia , Células Matadoras Naturais/efeitos dos fármacos , Encéfalo/patologia , Encéfalo/efeitos dos fármacos , Feminino , Masculino , Proteína 2 de Sobrevivência do Neurônio Motor/genética , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/efeitos dos fármacos , Proteína 1 de Sobrevivência do Neurônio Motor/genética , Proteína 1 de Sobrevivência do Neurônio Motor/metabolismo , Análise de Célula Única , Citotoxicidade Imunológica/efeitos dos fármacos , Lactente , Pré-Escolar , Criança , Transcriptoma
13.
Med Image Anal ; 94: 103143, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38507894

RESUMO

Nuclei detection and segmentation in hematoxylin and eosin-stained (H&E) tissue images are important clinical tasks and crucial for a wide range of applications. However, it is a challenging task due to nuclei variances in staining and size, overlapping boundaries, and nuclei clustering. While convolutional neural networks have been extensively used for this task, we explore the potential of Transformer-based networks in combination with large scale pre-training in this domain. Therefore, we introduce a new method for automated instance segmentation of cell nuclei in digitized tissue samples using a deep learning architecture based on Vision Transformer called CellViT. CellViT is trained and evaluated on the PanNuke dataset, which is one of the most challenging nuclei instance segmentation datasets, consisting of nearly 200,000 annotated nuclei into 5 clinically important classes in 19 tissue types. We demonstrate the superiority of large-scale in-domain and out-of-domain pre-trained Vision Transformers by leveraging the recently published Segment Anything Model and a ViT-encoder pre-trained on 104 million histological image patches - achieving state-of-the-art nuclei detection and instance segmentation performance on the PanNuke dataset with a mean panoptic quality of 0.50 and an F1-detection score of 0.83. The code is publicly available at https://github.com/TIO-IKIM/CellViT.


Assuntos
Núcleo Celular , Redes Neurais de Computação , Humanos , Amarelo de Eosina-(YS) , Hematoxilina , Coloração e Rotulagem , Processamento de Imagem Assistida por Computador
14.
J Nucl Med ; 65(3): 372-378, 2024 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-38331453

RESUMO

To assess the diagnostic accuracy of 68Ga-labeled fibroblast activation protein inhibitor (FAPI) and 18F-labeled FDG PET for the detection of various tumors, we performed a head-to-head comparison of both imaging modalities across a range of tumor entities as part of our ongoing 68Ga-FAPI PET observational trial. Methods: The study included 115 patients with 8 tumor entities who received imaging with 68Ga-FAPI for tumor staging or restaging between October 2018 and March 2022. Of those, 103 patients received concomitant imaging with 68Ga-FAPI and 18F-FDG PET and had adequate lesion validation for accuracy analysis. Each scan was evaluated for the detection of primary tumor, lymph nodes, and visceral and bone metastases. True or false positivity and negativity to detected lesions was assigned on the basis of histopathology from biopsies or surgical excision, as well as imaging validation. Results: 68Ga-FAPI PET revealed higher accuracy than 18F-FDG PET in the detection of colorectal cancer (n = 14; per-patient, 85.7% vs. 78.6%; per-region, 95.6% vs. 91.1%) and prostate cancer (n = 22; per-patient, 100% vs. 90.9%; per-region, 96.4% vs. 92.7%). 68Ga-FAPI PET and 18F-FDG PET had comparable per-patient accuracy in detecting breast cancer (n = 16, 100% for both) and head and neck cancers (n = 10, 90% for both modalities). 68Ga-FAPI PET had lower per-patient accuracy than 18F-FDG PET in cancers of the bladder (n = 12, 75% vs. 100%) and kidney (n = 10, 80% vs. 90%), as well as lymphoma (n = 9, 88.9% vs. 100%) and myeloma (n = 10, 80% vs. 90%). Conclusion: 68Ga-FAPI PET demonstrated higher diagnostic accuracy than 18F-FDG PET in the diagnosis of colorectal cancer and prostate cancer, as well as comparable diagnostic performance for cancers of the breast and head and neck. Accuracy and impact on management will be further assessed in an ongoing prospective interventional trial (NCT05160051).


Assuntos
Fluordesoxiglucose F18 , Neoplasias , Tomografia por Emissão de Pósitrons , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias/diagnóstico por imagem , Quinolinas
15.
J Nucl Med ; 65(2): 252-257, 2024 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-38176718

RESUMO

Fibroblast activation protein α (FAPα) is expressed at high levels in several types of tumors. Here, we report the expression pattern of FAPα in solitary fibrous tumor (SFT) and its potential use as a radiotheranostic target. Methods: We analyzed FAPα messenger RNA and protein expression in biopsy samples from SFT patients using immunohistochemistry and multiplexed immunofluorescence. Tracer uptake and detection efficacy were assessed in patients undergoing clinical 68Ga-FAPα inhibitor (FAPI)-46 PET,18F-FDG PET, and contrast-enhanced CT. 90Y-FAPI-46 radioligand therapy was offered to eligible patients with progressive SFT. Results: Among 813 patients and 126 tumor entities analyzed from the prospective observational MASTER program of the German Cancer Consortium, SFT (n = 34) had the highest median FAPα messenger RNA expression. Protein expression was confirmed in tumor biopsies from 29 of 38 SFT patients (76%) in an independent cohort. Most cases showed intermediate to high FAPα expression by immunohistochemistry (24/38 samples, 63%), which was located primarily on the tumor cell surface. Nineteen patients who underwent 68Ga-FAPI-46 PET imaging demonstrated significantly increased tumor uptake, with an SUVmax of 13.2 (interquartile range [IQR], 10.2), and an improved mean detection efficacy of 94.5% (SEM, 4.2%), as compared with 18F-FDG PET (SUVmax, 3.2 [IQR, 3.1]; detection efficacy, 77.3% [SEM, 5.5%]). Eleven patients received a total of 34 cycles (median, 3 cycles [IQR, 2 cycles]) of 90Y-FAPI-46 radioligand therapy, which resulted in disease control in 9 patients (82%). Median progression-free survival was 227 d (IQR, 220 d). Conclusion: FAPα is highly expressed by SFT and may serve as a target for imaging and therapy. Further studies are warranted to define the role of FAPα-directed theranostics in the care of SFT patients.


Assuntos
Endopeptidases , Proteínas de Membrana , Quinolinas , Tumores Fibrosos Solitários , Humanos , Fluordesoxiglucose F18 , Radioisótopos de Gálio , Tomografia por Emissão de Pósitrons , RNA Mensageiro , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada
16.
Clin Epigenetics ; 16(1): 13, 2024 01 16.
Artigo em Inglês | MEDLINE | ID: mdl-38229153

RESUMO

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is an aggressive cancer with poor prognosis. It is marked by extraordinary resistance to conventional therapies including chemotherapy and radiation, as well as to essentially all targeted therapies evaluated so far. More than 90% of PDAC cases harbor an activating KRAS mutation. As the most common KRAS variants in PDAC remain undruggable so far, it seemed promising to inhibit a downstream target in the MAPK pathway such as MEK1/2, but up to now preclinical and clinical evaluation of MEK inhibitors (MEKi) failed due to inherent and acquired resistance mechanisms. To gain insights into molecular changes during the formation of resistance to oncogenic MAPK pathway inhibition, we utilized short-term passaged primary tumor cells from ten PDACs of genetically engineered mice. We followed gain and loss of resistance upon MEKi exposure and withdrawal by longitudinal integrative analysis of whole genome sequencing, whole genome bisulfite sequencing, RNA-sequencing and mass spectrometry data. RESULTS: We found that resistant cell populations under increasing MEKi treatment evolved by the expansion of a single clone but were not a direct consequence of known resistance-conferring mutations. Rather, resistant cells showed adaptive DNA hypermethylation of 209 and hypomethylation of 8 genomic sites, most of which overlap with regulatory elements known to be active in murine PDAC cells. Both DNA methylation changes and MEKi resistance were transient and reversible upon drug withdrawal. Furthermore, MEKi resistance could be reversed by DNA methyltransferase inhibition with remarkable sensitivity exclusively in the resistant cells. CONCLUSION: Overall, the concept of acquired therapy resistance as a result of the expansion of a single cell clone with epigenetic plasticity sheds light on genetic, epigenetic and phenotypic patterns during evolvement of treatment resistance in a tumor with high adaptive capabilities and provides potential for reversion through epigenetic targeting.


Assuntos
Carcinoma Ductal Pancreático , Neoplasias Pancreáticas , Animais , Camundongos , Metilação de DNA , Proteínas Proto-Oncogênicas p21(ras)/genética , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/genética , Carcinoma Ductal Pancreático/tratamento farmacológico , Carcinoma Ductal Pancreático/genética , DNA/metabolismo , Quinases de Proteína Quinase Ativadas por Mitógeno/genética , Quinases de Proteína Quinase Ativadas por Mitógeno/metabolismo , Quinases de Proteína Quinase Ativadas por Mitógeno/uso terapêutico , Linhagem Celular Tumoral , Mutação
17.
ACS Chem Biol ; 19(2): 266-279, 2024 02 16.
Artigo em Inglês | MEDLINE | ID: mdl-38291964

RESUMO

Bromodomain and extra-terminal domain (BET) proteins and histone deacetylases (HDACs) are prime targets in cancer therapy. Recent research has particularly focused on the development of dual BET/HDAC inhibitors for hard-to-treat tumors, such as pancreatic cancer. Here, we developed a new series of potent dual BET/HDAC inhibitors by choosing starting scaffolds that enabled us to optimally merge the two functionalities into a single compound. Systematic structure-guided modification of both warheads then led to optimized binders that were superior in potency to both parent compounds, with the best molecules of this series binding to both BRD4 bromodomains as well as HDAC1/2 with EC50 values in the 100 nM range in cellular NanoBRET target engagement assays. For one of our lead molecules, we could also show the selective inhibition of HDAC1/2 over all other zinc-dependent HDACs. Importantly, this on-target activity translated into promising efficacy in pancreatic cancer and NUT midline carcinoma cells. Our lead molecules effectively blocked histone H3 deacetylation in pancreatic cancer cells and upregulated the tumor suppressor HEXIM1 and proapoptotic p57, both markers of BET inhibition. In addition, they have the potential to downregulate the oncogenic drivers of NUT midline carcinoma, as demonstrated for MYC and TP63 mRNA levels. Overall, this study expands the portfolio of available dual BET/class I HDAC inhibitors for future translational studies in different cancer models.


Assuntos
Antineoplásicos , Carcinoma , Neoplasias Pancreáticas , Humanos , Inibidores de Histona Desacetilases/farmacologia , Inibidores de Histona Desacetilases/química , Proteínas Nucleares/metabolismo , Fatores de Transcrição/metabolismo , Farmacóforo , Neoplasias Pancreáticas/tratamento farmacológico , Linhagem Celular Tumoral , Antineoplásicos/farmacologia , Antineoplásicos/química , Proteínas de Ligação a RNA , Proteínas que Contêm Bromodomínio , Proteínas de Ciclo Celular/metabolismo
18.
Clin Transl Oncol ; 26(5): 1268-1272, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-37794220

RESUMO

PURPOSE: To analyze the 3-month life expectancy rate in pancreatic cancer (PC) patients treated within prospective trials from the German AIO study group. PATIENTS AND METHODS: A pooled analysis was conducted for patients with advanced PC that were treated within five phase II/III studies conducted between 1997 and 2017 (Gem/Cis, Ro96, RC57, ACCEPT, RASH). The primary goal for the current report was to identify the actual 3-month survival rate, a standard inclusion criterion in oncology trials. RESULTS: Overall, 912 patients were included, 83% had metastatic and 17% locally advanced PC; the estimated median overall survival (OS) was 7.1 months. Twenty-one percent of the participants survived < 3 months, with a range from 26% in RC57 to 15% in RASH. Significant predictors for not reaching 3-month OS were > 1 previous treatment line (p < 0.001) and performance status (p < 0.001). CONCLUSIONS: Despite the definition of a life expectancy of > 3 months as a standard inclusion criterion in clinical trials for advanced PC, a significant proportion of study patients does not survive > 3 months. TRIAL REGISTRATION NUMBERS: NCT00440167 (AIO-PK0104), NCT01729481 (RASH), NCT01728818 (ACCEPT).

19.
J Nucl Med ; 64(12): 1910-1917, 2023 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-37973185

RESUMO

The fibroblast activation protein (FAP) is highly expressed on carcinoma-associated fibroblasts in the stroma of pancreatic cancer and thus is a promising target for imaging and therapy. Preliminary data on PET imaging with radiolabeled FAP inhibitors (FAPIs) demonstrate superior tumor detection. Here we assess the accuracy of FAP-directed PET in patients with pancreatic cancer. Methods: Of 64 patients with suspected or proven pancreatic cancer, 62 (97%) were included in the data analysis of the 68Ga-FAPI PET observational trial (NCT04571086). All of these patients underwent contrast-enhanced CT, and 38 patients additionally underwent 18F-FDG PET. The primary study endpoint was the association of 68Ga-FAPI PET uptake intensity and histopathologic FAP expression. Secondary endpoints were detection rate, diagnostic performance, interreader reproducibility, and change in management. Datasets were interpreted by 2 masked readers. Results: The primary endpoint was met: The association between 68Ga-FAPI SUVmax and histopathologic FAP expression was significant (Spearman r, 0.48; P = 0.04). For histopathology-validated lesions, 68Ga-FAPI PET showed high sensitivity and positive predictive values (PPVs) on per-patient (sensitivity, 100%; PPV, 96.3%) and per-region (sensitivity, 100%; PPV, 97.0%) bases. In a head-to-head comparison versus 18F-FDG or contrast-enhanced CT, 68Ga-FAPI detected more tumor on a per-lesion (84.7% vs. 46.5% vs. 52.9%), per-patient (97.4% vs. 73.7% vs. 92.1%), or per-region (32.6% vs. 18.8% vs. 23.7%) basis, respectively. 68Ga-FAPI PET readers showed substantial overall agreement on the basis of the Fleiss κ: primary κ, 0.77 (range, 0.66-0.88). Minor and major changes in clinical management occurred in 5 patients (8.4%) after 68Ga-FAPI PET. Conclusion: We confirmed an association of 68Ga-FAPI PET SUVmax and histopathologic FAP expression in pancreatic cancer patients. Additionally, we found high detection rate and diagnostic accuracy, superior to those of 18F-FDG PET/CT. 68Ga-FAPI might become a powerful diagnostic tool for pancreatic cancer work-up.


Assuntos
Adenocarcinoma , Fibroblastos Associados a Câncer , Neoplasias Pancreáticas , Quinolinas , Humanos , Adenocarcinoma/diagnóstico por imagem , Neoplasias Pancreáticas/diagnóstico por imagem , Radioisótopos de Gálio , Fluordesoxiglucose F18 , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Reprodutibilidade dos Testes
20.
Clin Transl Sci ; 16(12): 2483-2493, 2023 12.
Artigo em Inglês | MEDLINE | ID: mdl-37920921

RESUMO

Expression of CYP3A5 protein is a basal and acquired resistance mechanism of pancreatic ductal adenocarcinoma cells conferring protection against the CYP3A and CYP2C8 substrate paclitaxel through metabolic degradation. Inhibition of CYP3A isozymes restores the cells sensitivity to paclitaxel. The combination of gemcitabine and nab-paclitaxel is an established regimen for the treatment of metastasized or locally advanced inoperable pancreatic cancer. Cobicistat is a CYP3A inhibitor developed for the pharmacoenhancement of protease inhibitors. The addition of cobicistat to gemcitabine and nab-paclitaxel may increase the antitumor effect. We will conduct a phase I dose escalation trial with a classical 3 + 3 design to investigate the safety, tolerability, and pharmacokinetics (PKs) of gemcitabine, nab-paclitaxel, and cobicistat. Although the doses of gemcitabine (1000 mg/m2 ) and cobicistat (150 mg) are fixed, three dose levels of nab-paclitaxel (75, 100, and 125 mg/m2 ) will be explored to account for a potential PK drug interaction. After the dose escalation phase, we will set the recommended dose for expansion (RDE) and treat up to nine patients in an expansion part of the trial. The trial is registered under the following identifiers EudraCT-Nr. 2019-001439-29, drks.de: DRKS00029409, and ct.gov: NCT05494866. Overcoming resistance to paclitaxel by CYP3A5 inhibition may lead to an increased efficacy of the gemcitabine and nab-paclitaxel regimen. Safety, efficacy, PK, and RDE data need to be acquired before investigating this combination in a large-scale clinical study.


Assuntos
Carcinoma Ductal Pancreático , Citostáticos , Neoplasias Pancreáticas , Humanos , Gencitabina , Citocromo P-450 CYP3A , Inibidores do Citocromo P-450 CYP3A , Citostáticos/uso terapêutico , Desoxicitidina/efeitos adversos , Cobicistat , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Paclitaxel/efeitos adversos , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/patologia , Carcinoma Ductal Pancreático/tratamento farmacológico , Carcinoma Ductal Pancreático/patologia , Ensaios Clínicos Fase I como Assunto
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