RESUMO
Current cancer therapies focus on reducing immunosuppression and remodeling the tumor microenvironment to inhibit metastasis, cancer progression, and therapeutic resistance. Programmed death receptor 1 (PD-1) is expressed on immune T cells and is one of the so-called checkpoint proteins that can suppress or stop the immune response. To evade the immune system, cancer cells overexpress a PD-1 inhibitor protein (PD-L1), which binds to the surface of T cells to activate signaling pathways that induce immune suppression. This research aimed to synthesize PD-L1 inhibitory peptides (PD-L1-i) labeled with lutetium-177 (177Lu-DOTA-PD-L1-i) and actinium-225 (225Ac-HEHA-PD-L1-i) and to preclinically evaluate their potential as radiopharmaceuticals for targeted radiotherapy at the tumor microenvironment level. Using PD-L1-i peptide as starting material, conjugation with HEHA-benzene-SCN and DOTA-benzene-SCN was performed to yield DOTA-PD-L1-i and HEHA-PD-L1-I, which were characterized by FT-IR, UV-vis spectroscopy, and HPLC. After labeling the conjugates with 225Ac and 177Lu, cellular uptake in HCC827 cancer cells (PD-L1 positive), conjugate specificity evaluation by immunofluorescence, radiotracer effect on cell viability, biodistribution, biokinetics, and assessment of radiation absorbed dose in mice with in duced lung micrometastases were performed. 225Ac-HEHA-PD-L1-i and 177Lu-DOTA-PD-L1-i, obtained with radiochemical purities of 95 ± 3% and 98.5 ± 0.5%, respectively, showed in vitro and in vivo specific recognition for the PD-L1 protein in lung cancer cells and high uptake in HCC287 lung micrometastases (>30% ID). The biokinetic profiles of 177Lu-DOTA-PD-L1-i and 225Ac-DOTA-PD-L1-i showed rapid blood clearance with renal and hepatobiliary elimination and no accumulation in normal tissues. 225Ac-DOTA-PD-L1-i produced a radiation dose of 5.15 mGy/MBq to lung micrometastases. In the case of 177Lu-DOTA-PD-L1-i, the radiation dose delivered to the lung micrometastases was ten times (43 mGy/MBq) that delivered to the kidneys (4.20 mGy/MBq) and fifty times that delivered to the liver (0.85 mGy/MBq). Therefore, the radiotherapeutic PD-L1-i ligands of 225Ac and 177Lu developed in this research could be combined with immunotherapy to enhance the therapeutic effect in various types of cancer.
Assuntos
Antígeno B7-H1 , Compostos Radiofarmacêuticos , Camundongos , Animais , Compostos Radiofarmacêuticos/uso terapêutico , Distribuição Tecidual , Benzeno , Micrometástase de Neoplasia , Espectroscopia de Infravermelho com Transformada de Fourier , Microambiente Tumoral , Lutécio/uso terapêutico , Linhagem Celular TumoralRESUMO
INTRODUCCIÓN: Actualmente existe controversia respecto a los beneficios de realizar linfadenectomía en pacientes de melanoma con una biopsia selectiva de ganglio centinela (BSGC) positiva. La carga tumoral > 1 mm se ha propuesto como el parámetro mas relevante asociado a una linfadenectomía positiva y un deterioro de la supervivencia libre de enfermedad. MATERIAL Y MÉTODOS: Se analizaron los datos de 119 pacientes de melanoma con BSGC positiva atendidos en el periodo entre Junio de 1997 y Junio de 2017. Los pacientes se clasificaron según la carga tumoral en dos grupos: ≤ 1 mm and > 1 mm. RESULTADOS: La linfadenectomía resultó positiva en sólo 6 (10%) pacientes con una carga tumoral ≤ 1 mm, y en 23 (37.7%) pacientes con carga tumoral > 1 mm (p < 0.001). En análisis univariante, la carga tumoral fue el único factor predictivo de linfadenectomía positiva (OR 5.24 (1.94-14.13)). En análisis multivariante, la carga tumoral fue la única variable independiente de supervivencia específica de melanoma (SEM). CONCLUSION: Aunque la realización de linfadenectomía debe individualizarse en cada caso, la carga tumoral > 1 mm puede ser un factor predictivo de la presencia de ganglios no centinelas positivos en piezas de linfadenectomía, y un factor pronostico independiente importante para la SEM. BACKGROUND: The benefits of complete lymph node dissection (CLND) in melanoma patients with a positive sentinel lymph node biopsy (SLNB) have been recently questioned. Sentinel node (SN) tumor burden > 1 mm has been proposed as the most reliable parameter associated with positive CLND and poorer disease-free survival. MATERIAL AND METHODS: Between June 1997 and June 2017, data from 119 melanoma patients with positive SLNB were analyzed. Patients were classified by SN burden in two groups: ≤ 1 mm and > 1 mm. RESULTS: CLND was positive in 6 (10%) patients with SN tumor burden ≤ 1 mm and in 23 (37.7%) patients with > 1 mm (p < 0.001). In univariable analysis, SN tumor burden was the only predictive factor of positive CLND (OR 5.24 [1.94-14.13]). In multivariable analysis, SN tumor burden was the only independent factor of melanoma-specific survival (MSS). CONCLUSION: Although CLND should still be considered individually in patients with positive SLNB, SN tumor burden >1 mm might be a good predictive factor of additional positive non-sentinel nodes and a strong independent prognostic factor in melanoma-specific survival.
Assuntos
Melanoma , Micrometástase de Neoplasia , Humanos , Excisão de Linfonodo , Melanoma/cirurgia , Estadiamento de Neoplasias , Prognóstico , Estudos RetrospectivosRESUMO
OBJECTIVE: To analyze the predictive factors for non-sentinel lymph node (non-SLN) metastasis in early-stage cervical cancer. METHODS: We analyzed a series of 113 patients who underwent sentinel lymph node (SLN) mapping for cervical cancer. The SLNs were examined by immunohistochemistry (IHC) when the hematoxylin-eosin stain was negative. RESULTS: The overall bilateral detection rate was 81.5%, with a median of two SLNs resected. The study ultimately included 92 patients with SLNs that were mapped who had also undergone systematic pelvic lymph node dissection. Thirteen (14.1%) patients had positive SLNs, with a median of one positive SLN. Regarding the size of SLN metastasis, one (1.1%) had isolated tumor cells (ITC), seven (7.6%) had micrometastases, and five (5.4%) had macrometastases. Notably, 46.1% (6/13) had lymph node metastases detected only after IHC. Five (38.5%) cases had positive non-SLNs, with a median count of one positive lymph node. Parametrial invasion was the only risk factor for positive non-SLN (p = .045). Regarding the size of SLN metastasis, non-SLN involvement was present in the only case with ITC (1/1), 42.9% (3/7) of cases with micrometastases, and in 20% (1/5) with macrometastases. CONCLUSIONS: Our data suggest that parametrial invasion correlates with the risk of non-SLN metastasis in cervical cancer.
Assuntos
Linfonodos/patologia , Micrometástase de Neoplasia/patologia , Linfonodo Sentinela/patologia , Neoplasias do Colo do Útero/patologia , Adulto , Idoso , Feminino , Seguimentos , Humanos , Histerectomia/métodos , Excisão de Linfonodo/métodos , Linfonodos/cirurgia , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Estudos Retrospectivos , Linfonodo Sentinela/cirurgia , Biópsia de Linfonodo Sentinela/métodos , Neoplasias do Colo do Útero/cirurgia , Adulto JovemRESUMO
Introducción: Los criterios de calidad en la cirugía oncológica radical se basan en la extirpación completa del tumor, con márgenes libres, sin enfermedad macroscópica residual, con una linfadenectomía adecuada y mínima manipulación tumoral posible. A pesar de conseguir estos objetivos, puede quedar enfermedad residual no visible o micrometástasis, con potencial de crecimiento y diseminación dependiendo de la capacidad tumoral y de las defensas del huésped. Objetivos: Evaluar la influencia de los factores perioperatorios sobre la inmunidad del paciente oncológico intervenido quirúrgicamente y el efecto potencial de los fármacos anestésicos en la recurrencia, así como otros factores perioperatorios que pueden afectar la diseminación tumoral a largo plazo. Métodos: Se realizó una búsqueda bibliográfica electrónica de los artículos de los últimos 10 años que cumplieran con el objetivo trazado. Desarrollo: Durante el periodo perioperatorio la activación de la respuesta al estrés quirúrgico desencadena una serie de reacciones neuroendocrinas, humorales e inmunitarias complejas. La cirugía, con indudable potencial curativo, se relaciona con un estado de inmunosupresión por activación del eje HPA (hipotálamo- hipofisario- adrenal) y la inflamación. Por otro lado, la anestesia produce cambios biomoleculares que afectan la inmunidad celular y el número de NK (natural killer), que puede influir en la recurrencia del cáncer a largo plazo. Conclusiones: Disminuir el estrés quirúrgico y el psicológico, controlar el dolor quirúrgico, mantener normotermia, y una juiciosa transfusión sanguínea, además una técnica anestésica con disminución del consumo de opiáceos, puede resultar favorecedora para proteger la respuesta inmune antimetastásica del organismo y puede tener un efecto benéfico en la enfermedad oncológica(AU)
Introduction: The quality criteria in radical oncological surgery are based on complete tumor removal, with free margins, without residual macroscopic disease, with adequate lymphadenectomy and minimal possible tumor manipulation. Despite achieving these objectives, non-visible residual disease or micrometastasis may remain, likely to grow and spread depending on tumor capacity and the host's defenses. Objectives: To evaluate the influence of perioperative factors on the immunity of cancer patients operated on and the potential effect of anesthetic drugs on recurrence, as well as other perioperative factors that may affect long-term tumor spread. Methods: An electronic bibliographic search was carried out of the articles published in the last ten years and that fulfilled the established objective. Development: During the perioperative period, activation of the response to surgical stress triggers a series of complex neuroendocrine, humoral and immune reactions. Surgery, with unquestionable curative potential, is related to a state of immunosuppression due to activation of the hypothalamic-pituitary-adrenal axis and inflammation. On the other hand, anesthesia produces biomolecular changes that affect cellular immunity and the number of natural killers, which can influence cancer recurrence in the long term. Conclusions: To reduce surgical and psychological stress, to control surgical pain, to maintain normothermia, and a judicious blood transfusion, in addition to an anesthetic technique with reduced opiates usage, can be beneficial to protect the body's antimetastatic immune response and can have a beneficial effect on oncological disease(AU)
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Humanos , Doenças do Sistema Imunitário/complicações , Recidiva Local de Neoplasia/complicações , Estudos Retrospectivos , Período Perioperatório/métodos , Micrometástase de Neoplasia/prevenção & controle , Anestésicos/efeitos adversosRESUMO
Gastric carcinoma (GC) locoregional recurrence may occur even in cases where the tumor has been completely resected, possibly due to lymph node (LN) micrometastases. It is estimated that in 10% to 30% of cases, LN micrometastases are not detected by a conventional method for histological assessment of LN metastases with hematoxylin-eosin (HE). A cross-sectional study assessed 51 patients with GC by histological evaluation of the LN micrometastases through LN multi sectioning associated with immunohistochemistry analysis with monoclonal antibodies AE1 and AE3. Total gastrectomy was performed in 51% of patients. The total number of resected LN nodes was 1698, with a mean number of resected LN of 33.3 ± 13.2 per surgical specimen, of which 187 had metastasis. After the application of LN multisection and immunohistochemistry, LN micrometastases were found in 45.1% of the cases. LN staging changed in 29.4%, and tumor staging changed in 23.5% of the cases. In patients initially staged as pN0, LN staging and tumor staging changed, both in 19.2% of the cases. In patients initially staged as pN1 or more, LN staging changed in 40.0% of them, and tumor staging changed in 28.0% of the cases. The accuracy of HE for the histological staging of LN tumoral involvement was 76%, which was considered insufficient for CG patients staging. Investigation of LN micrometastasis through LN multisection and immunohistochemistry should be performed, particularly in cases where the presence of blood and lymphatic vessel invasion has been identified after conventional histological analysis, as well as in patients with advanced GC.
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Carcinoma/diagnóstico , Linfonodos/patologia , Recidiva Local de Neoplasia/diagnóstico , Neoplasias Gástricas/diagnóstico , Idoso , Carcinoma/patologia , Estudos Transversais , Feminino , Gastrectomia , Humanos , Imuno-Histoquímica , Metástase Linfática/patologia , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Micrometástase de Neoplasia/patologia , Recidiva Local de Neoplasia/patologia , Estadiamento de Neoplasias , Reprodutibilidade dos Testes , Neoplasias Gástricas/patologiaRESUMO
BACKGROUND AND AIM: Intrahepatic metastasis (IM) of hepatocellular carcinoma (HCC) occurs via vascular invasion; the tumor diameter that affects the risk of micro intra-hepatic metastasis (MIM) should be larger than that which affects the risk of micro vessel invasion (MVI). The aim of the present study was to determine the optimum tumor diameter cut-off value for predicting the presence of MIM in HCC patients without treatment history and HCC patients with a treatment history and to compare these diameters between cases of MVI and MIM. METHODS: This retrospective study included 621 patients without macroscopic vessel invasion or intrahepatic metastasis on preoperative imaging who underwent hepatectomy. The cut-off tumor diameter for predicting the presence of MIM was determined by a receiver operating characteristic curves analysis. RESULTS: The optimum cut-off value for predicting the presence of MIM in HCC patients without treatment history was 43 mm. In contrast, the optimum cut-off value for predicting the presence of MIM in HCC patients with a treatment history was 20 mm. Among 46 HCC patients with MIM without treatment history, there were 20 patients with MIM without MVI who were considered to have potential multi-centric (MC) tumors rather than IM. The cumulative overall survival rates in patients with MIM without MVI (potential MC) was significantly better than that in patients with both MIM and MVI (P = 0.022). CONCLUSIONS: The tumor diameter cut-off value for predicting MIM differed between HCC patients without treatment history and with a treatment history and slightly smaller than those for predicting MVI beyond our expectation.
Assuntos
Carcinoma Hepatocelular/patologia , Carcinoma Hepatocelular/cirurgia , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/cirurgia , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma Hepatocelular/irrigação sanguínea , Carcinoma Hepatocelular/mortalidade , Intervalo Livre de Doença , Feminino , Hepatectomia , Humanos , Neoplasias Hepáticas/irrigação sanguínea , Neoplasias Hepáticas/mortalidade , Masculino , Pessoa de Meia-Idade , Invasividade Neoplásica , Micrometástase de Neoplasia , Prognóstico , Estudos Retrospectivos , Taxa de Sobrevida , Carga TumoralRESUMO
PURPOSE: There is a gap in knowledge regarding the impact of micrometastases (MIC) and isolated tumor cells (ITCs) found in the sentinel lymph nodes of patients with endometrial cancer. Here, we present a meta-analysis of the published literature on the rate of MIC and ITCs after lymphatic mapping and determine trends in postoperative management. METHODS: Literature search of Medline and PubMed was done using the terms: micrometastases, isolated tumor cells, endometrial cancer, and sentinel lymph node. Inclusion criteria were: English-language manuscripts, retrospectives, or prospective studies published between January 1999 and June 2019. We removed manuscripts on sentinel node mapping that did not specify information on micrometastases or isolated tumor cells, non-English-language articles, no data about oncologic outcomes, and articles limited to ten cases or less. RESULTS: A total of 45 manuscripts were reviewed, and 8 studies met inclusion criteria. We found that the total number of patients with MIC/ITCs was 286 (187 and 99, respectively). The 72% of patients detected with MIC/ITCs in sentinel nodes received adjuvant therapies. The MIC/ITCs group has a higher relative risk of recurrence of 1.34 (1.07, 1.67) than the negative group, even if the adjuvant therapy was given. CONCLUSION: We noted that there is an increased relative risk of recurrence in patients with low-volume metastases, even after receiving adjuvant therapy. Whether adjuvant therapy is indicated remains a topic of debate because there are other uterine factors implicated in the prognosis. Multi-institutional tumor registries may help shed light on this important question.
Assuntos
Neoplasias do Endométrio/patologia , Micrometástase de Neoplasia/patologia , Recidiva Local de Neoplasia , Biópsia de Linfonodo Sentinela , Linfonodo Sentinela/patologia , Feminino , Humanos , Estudos Prospectivos , Estudos Retrospectivos , Biópsia de Linfonodo Sentinela/estatística & dados numéricosRESUMO
OBJECTIVES: Metastatic lymph node affectation is the main prognostic factor in localised lung cancer. However, the pathological study of lymph nodes reveals tumour relapse for 20% of patients after oncological curative surgery. Recently, EMT (epithelial-mesenchymal transition) has been established as one of the main factors related to lymphatic dissemination and metastasis. This study evaluated the prognostic value of EMT-related gene expression in micrometastatic sentinel lymph nodes (SLN) of non-small cell lung cancer (NSCLC) patients. METHODS: The presence of genes CDH1, CDH2, VIM, TWIST1, SNAI1, SNAI2, ZEB1, and ZEB2 in mRNA was analysed in tumours and in the SLN of NSCLC patients for whom surgery was planned for treatment. The significant association between the expression level of EMT-related markers and patients' clinicopathological characteristics and relapse was assessed. RESULTS: Of the 96 patients, 56 (58.33%) presented molecular micrometastasis in SLN, which showed higher CDH1, CDH2, and VIM expressions than non-micrometastatic ones. An association linking a low CDH1/CDH2 ratio in SLN with molecular micrometastasis, adenocarcinoma, and non-smoking patients was found. The multivariate Cox regression analysis proved the prognostic accuracy of the CDH1/CDH2 ratio in SLN. CONCLUSIONS: The molecular EMT status of SLN could be used as an independent prognosis predictor in early stage NSLCL patients, and as a new tool to better stratify and predict patient outcomes.
Assuntos
Carcinoma Pulmonar de Células não Pequenas/patologia , Transição Epitelial-Mesenquimal/genética , Neoplasias Pulmonares/patologia , Linfonodo Sentinela/patologia , Idoso , Antígenos CD/genética , Antígenos CD/metabolismo , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Caderinas/genética , Caderinas/metabolismo , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Feminino , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Metástase Linfática , Masculino , Micrometástase de Neoplasia , Prognóstico , Linfonodo Sentinela/metabolismo , Biópsia de Linfonodo SentinelaRESUMO
PURPOSE: To analyze the relationship between the size of metastatic sentinel lymph nodes (SLNs) and the risk of non-sentinel lymph node (non-SLN) metastasis in endometrial cancer. PATIENTS AND METHODS: From a total of 328 patients with endometrial cancer who underwent SLN mapping from January 2013 to April 2019, 142 patients also underwent systematic completion pelvic ± paraaortic node dissections, and they form the basis of this study. The SLNs were examined by immunohistochemistry (IHC) when the hematoxylin-eosin stain was negative. RESULTS: The median age was 60 years. The overall detection rate for SLNs was 87.5%, and bilateral SLNs were observed in 66.2%, with a median of 2 SLNs resected (range 1-8). Twenty-nine (20.4%) cases had positive SLNs, with a median of one positive SLN. Regarding the size of SLN metastasis, 5 (3.5%) cases had isolated tumor cells (ITCs), 13 (9.2%) had micrometastases, and 11 (7.7%) had macrometastases. Notably, 14/29 (48.3%) had node metastases that were detected after IHC. Eight (27.6%) patients had positive non-SLNs, with a median count of 7 positive nodes (range 2-23). Regarding the size of SLN metastasis, non-SLN involvement was not present in cases with ITC (0/5) but was present in 15.4% (2/13) of cases with micrometastases and 54.5% (6/11) of cases with macrometastases. The only risk factor for positive non-SLNs was the size of SLN metastasis. CONCLUSIONS: Our data suggest that size of SLN metastasis is associated with the risk of non-SLN metastasis. No patients with ITCs in SLNs had another metastatic lymph node in this study.