RESUMO
Near-infrared photoimmunotherapy (NIR-PIT) is a new type of cancer therapy that employs antibody-IRDye700DX conjugates (AbPCs) and near-infrared (NIR) light at a wavelength of 689 nm, the excitation wavelength of IR700. Administered intravenously, injected AbPCs bind specifically to cells expressing the target antigen, whereupon NIR light exposure causes rapid, selective killing. This process induces an anticancer T cell response, leading to sustained anticancer host immune response. Programmed cell death ligand-1 (PD-L1) is a major inhibitory immune checkpoint molecule expressed in various cancers. In this study, we first assessed the efficacy of PD-L1-targeted NIR-PIT (αPD-L1-PIT) in immune-competent tumor mouse models. αPD-L1-PIT showed a significant therapeutic effect on the tumor models with high PD-L1 expression. Furthermore, αPD-L1-PIT induced an abscopal effect on distant tumors and long-term immunological memory. In contrast, αPD-L1-PIT was not as effective for tumor models with low PD-L1 expression. To improve the efficacy of PD-L1-targeted NIR-PIT, PEGylated interferon-gamma (IFNγ) was administered with αPD-L1-PIT. The combination therapy improved the treatment efficacy by increasing PD-L1 expression leading to more efficient cell killing by αPD-L1-PIT. Furthermore, the PEGylated IFNγ led to a CD8+ T cell-dominant tumor microenvironment (TME) with an enhanced anticancer T cell response after αPD-L1-PIT. As a result, even so-called cold tumors exhibited complete responses after αPD-L1-PIT. Thus, combination therapy of PEGylated IFNγ and PD-L1-targeted NIR-PIT has the potential to be an important future strategy for cancer immunotherapy.
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Antígeno B7-H1 , Imunoterapia , Raios Infravermelhos , Fototerapia , Microambiente Tumoral , Animais , Microambiente Tumoral/imunologia , Microambiente Tumoral/efeitos dos fármacos , Antígeno B7-H1/antagonistas & inibidores , Antígeno B7-H1/imunologia , Antígeno B7-H1/metabolismo , Camundongos , Imunoterapia/métodos , Linhagem Celular Tumoral , Fototerapia/métodos , Humanos , Feminino , Indóis/farmacologia , Indóis/uso terapêutico , Imunoconjugados/farmacologia , Imunoconjugados/uso terapêutico , Camundongos Endogâmicos C57BLRESUMO
Considering the cost and invasiveness of monitoring postoperative minimal residual disease (MRD) of colorectal cancer (CRC) after adjuvant chemoradiotherapy (ACT), we developed a favorable approach based on methylated circulating tumor DNA to detect MRD after radical resection. Analyzing the public database, we identified the methylated promoter regions of the genes FGD5, GPC6, and MSC. Using digital polymerase chain reaction (dPCR), we termed the "amplicon of methylated sites using a specific enzyme" assay as "AMUSE." We examined 180 and 114 pre- and postoperative serial plasma samples from 28 recurrent and 19 recurrence-free pathological stage III CRC patients, respectively. The results showed 22 AMUSE-positive of 28 recurrent patients (sensitivity, 78.6%) and 17 AMUSE-negative of 19 recurrence-free patients (specificity, 89.5%). AMUSE predicted recurrence 208 days before conventional diagnosis using radiological imaging. Regarding ACT evaluation by the reactive response, 19 AMUSE-positive patients during their second or third blood samples showed a significantly poorer prognosis than the other patients (p = 9E-04). The AMUSE assay stratified four groups by the altered patterns of tumor burden postoperatively. Interestingly, only 34.8% of cases tested AMUSE-negative during ACT treatment, indicating eligibility for ACT. The AMUSE assay addresses the clinical need for accurate MRD monitoring with universal applicability, minimal invasiveness, and cost-effectiveness, thereby enabling the timely detection of recurrences. This assay can effectively evaluate the efficacy of ACT in patients with stage III CRC following curative resection. Our study strongly recommends reevaluating the clinical application of ACT using the AMUSE assay.
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Neoplasias Colorretais , Recidiva Local de Neoplasia , Neoplasia Residual , Humanos , Neoplasias Colorretais/terapia , Neoplasias Colorretais/patologia , Neoplasias Colorretais/genética , Masculino , Feminino , Pessoa de Meia-Idade , Idoso , Metilação de DNA , DNA Tumoral Circulante/sangue , DNA Tumoral Circulante/genética , Prognóstico , Quimiorradioterapia Adjuvante/métodos , Regiões Promotoras Genéticas , Biomarcadores Tumorais/sangue , Biomarcadores Tumorais/genética , Adulto , Estadiamento de Neoplasias , Idoso de 80 Anos ou mais , Reação em Cadeia da Polimerase/métodosRESUMO
Epidermal growth factor receptor (EGFR) has emerged as an important therapeutic target in many cancers, and overexpression of EGFR is frequently observed in hepatocellular carcinomas (HCCs). Near-infrared photoimmunotherapy (NIR-PIT) is a new anticancer treatment that selectively damages the cell membrane of cancer cells after NIR light-induced photochemical reaction of IR700, which is bound to a targeting antibody on the cell membrane. NIR-PIT using cetuximab-IR700 has already been approved in Japan, is under review by the US Food and Drug Administration (FDA) for advanced head and neck cancers, and its safety has been established. However, EGFR has not been investigated as a target in NIR-PIT in HCCs. Here, we investigate the application of NIR-PIT using cetuximab-IR700 to HCCs using xenograft mouse models of EGFR-expressing HCC cell lines, Hep3B, HuH-7, and SNU-449. In vitro NIR-PIT using EGFR-targeted cetuximab-IR700 killed cells in a NIR light dose-dependent manner. In vivo NIR-PIT resulted in a delayed growth compared with untreated controls. In addition, in vivo NIR-PIT in both models showed histological signs of cancer cell damage, such as cytoplasmic vacuolation and nuclear dysmorphism. A significant decrease in Ki-67 positivity was also observed after NIR-PIT, indicating decreased cancer cell proliferation. This study suggests that NIR-PIT using cetuximab-IR700 has potential for the treatment of EGFR-expressing HCCs.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , Humanos , Animais , Camundongos , Cetuximab/farmacologia , Cetuximab/uso terapêutico , Carcinoma Hepatocelular/tratamento farmacológico , Fármacos Fotossensibilizantes , Linhagem Celular Tumoral , Neoplasias Hepáticas/tratamento farmacológico , Imunoterapia/métodos , Receptores ErbB , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
BACKGROUND: Driver alterations may represent novel candidates for driver gene-guided therapy; however, intrahepatic cholangiocarcinoma (ICC) with multiple genomic aberrations makes them intractable. Therefore, the pathogenesis and metabolic changes of ICC need to be understood to develop new treatment strategies. We aimed to unravel the evolution of ICC and identify ICC-specific metabolic characteristics to investigate the metabolic pathway associated with ICC development using multiregional sampling to encompass the intra- and inter-tumoral heterogeneity. METHODS: We performed the genomic, transcriptomic, proteomic and metabolomic analysis of 39-77 ICC tumour samples and eleven normal samples. Further, we analysed their cell proliferation and viability. RESULTS: We demonstrated that intra-tumoral heterogeneity of ICCs with distinct driver genes per case exhibited neutral evolution, regardless of their tumour stage. Upregulation of BCAT1 and BCAT2 indicated the involvement of 'Val Leu Ile degradation pathway'. ICCs exhibit the accumulation of ubiquitous metabolites, such as branched-chain amino acids including valine, leucine, and isoleucine, to negatively affect cancer prognosis. We revealed that this metabolic pathway was almost ubiquitously altered in all cases with genomic diversity and might play important roles in tumour progression and overall survival. CONCLUSIONS: We propose a novel ICC onco-metabolic pathway that could enable the development of new therapeutic interventions.
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Neoplasias dos Ductos Biliares , Colangiocarcinoma , Humanos , Proteômica , Aminoácidos de Cadeia Ramificada , Colangiocarcinoma/genética , Colangiocarcinoma/patologia , Ductos Biliares Intra-Hepáticos/patologia , Neoplasias dos Ductos Biliares/genética , TransaminasesRESUMO
AIM: The purpose of this study was to investigate the visualization of fine biliary ducts with knowledge-based iterative model reconstruction (IMR) in low-dose drip infusion computed tomography (CT) cholangiography (DIC-CT) as compared with filtered back projection (FBP) and hybrid iterative reconstruction (iDose4 ). METHODS: A total of 38 patients underwent DIC-CT for living donor liver transplantation. CT was performed approximately 20 min after the end of the infusion of meglumine iotroxate (100 mL). Images were reconstructed using FBP, iDose4 , and IMR, and 1-mm slice images at fixed window level and width were prepared for assessment. Two reviewers independently evaluated the quality of visualization of the fine biliary ducts of the caudate lobe (B1) using a 5-point scale. The visualization scores of three reconstructed images were compared using the Kruskal-Wallis test and Mann-Whitney U-test. RESULTS: For reviewer 1, the visualization score of IMR was significantly higher than that of FBP (P = 0.012), and tended to be higher than that of iDose4 (P = 0.078). For reviewer 2, the visualization score of IMR was significantly higher than those of both FBP and iDose4 (P < 0.01). CONCLUSIONS: IMR showed better visualization of B1 on DIC-CT than FBP or iDose4 . DIC-CT reconstructed with IMR may be useful to the anatomical grasp of biliary tracts in cases of hepatectomy.
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PURPOSE: This retrospective study evaluates the impact of preoperative lipiodol marking on the outcomes of computed tomography (CT)-guided cryoablation for histologically diagnosed sporadic renal cell carcinoma (RCC). METHODS: This study analyzed the data of 173 patients who underwent CT-guided cryoablation for histologically proven sporadic RCC at a single institution between April 2014 and December 2020. The local control rate (LCR), recurrence-free survival rate (RFSR), overall survival rate (OSR), changes in renal function, and complications in patients with (n = 85) and without (n = 88) preoperative lipiodol marking were compared. RESULTS: The 5-year LCR and 5-year RFSR were significantly higher in patients with lipiodol marking (97.51% and 93.84%, respectively) than in those without (72.38% and 68.10%, respectively) (P value <0.01, log-rank test). There were no significant differences between the two groups regarding the 5-year OSR (97.50% vs. 86.82%) or the deterioration in chronic kidney disease stage (12.70% vs. 16.43%). Grade ≥3 complications occurred in patients with lipiodol marking (n = 2, retroperitoneal hematoma and cerebral infarction in 1 patient each) and without (n = 5; urinary fistula in 2, colonic perforation in 2, urinary infection in 1). CONCLUSION: Lipiodol marking before CT-guided cryoablation for sporadic RCC is a feasible approach to improving local control and RFS while mitigating the decline in renal function. Additionally, it may help reduce complications.
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Carcinoma de Células Renais , Criocirurgia , Neoplasias Renais , Humanos , Carcinoma de Células Renais/diagnóstico por imagem , Carcinoma de Células Renais/cirurgia , Óleo Etiodado , Neoplasias Renais/diagnóstico por imagem , Neoplasias Renais/cirurgia , Criocirurgia/métodos , Estudos Retrospectivos , Tomografia Computadorizada por Raios X/métodos , Resultado do TratamentoRESUMO
BACKGROUND: Noninvasive in vivo cell tracking is valuable in understanding the mechanisms that enhance anti-cancer immunity. We have recently developed a new method called phototruncation-assisted cell tracking (PACT), that uses photoconvertible cell tracking technology to detect in vivo cell migration. This method has the advantages of not requiring genetic engineering of cells and employing tissue-penetrant near-infrared light. METHODS: We applied PACT to monitor the migration of immune cells between a tumour and its tumour-draining lymph node (TDLN) after near-infrared photoimmunotherapy (NIR-PIT). FINDINGS: PACT showed a significant increase in the migration of dendritic cells (DCs) and macrophages from the tumour to the TDLN immediately after NIR-PIT. This migration by NIR-PIT was abrogated by inhibiting the sphingosine-1-phosphate pathway or Gαi signaling. These results were corroborated by intranodal immune cell profiles at two days post-treatment; NIR-PIT significantly induced DC maturation and increased and activated the CD8+ T cell population in the TDLN. Furthermore, PACT revealed that NIR-PIT significantly enhanced the migration of CD8+ T cells from the TDLN to the tumour four days post-treatment, which was consistent with the immunohistochemical assessment of tumour-infiltrating lymphocytes and tumour regression. INTERPRETATION: Immune cells dramatically migrated between the tumour and TDLN following NIR-PIT, indicating its potential as an immune-stimulating therapy. Also, PACT is potentially applicable to a wide range of immunological research. FUNDING: This work was supported by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Centre for Cancer Research (grant number: ZIA BC011513 and ZIA BC011506).
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Linfócitos T CD8-Positivos , Carbocianinas , Rastreamento de Células , Humanos , Linhagem Celular Tumoral , Fototerapia/métodos , Imunoterapia/métodos , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Enfortumab vedotin (EV), an antibody-drug conjugate (ADC) that targets Nectin-4, has shown promising results in the treatment of bladder cancer. However, multiple resistance mechanisms that are unique to ADCs limit the therapeutic potential of EV in clinical practice. Here, we developed and tested a Nectin-4-targeted near-infrared photoimmunotherapy (NIR-PIT) that utilizes the same target as EV but utilizes a distinct cytotoxic and immunotherapeutic pathway in preclinical models of bladder cancer. NIR-PIT was effective in vitro against luminal subtype human bladder cancer cell lines (RT4, RT112, MGH-U3, SW780, and HT1376-luc), but not against other subtype cell lines (UMUC3 and T24). In vivo, the tumor site was clearly visible by Nectin-4-IR700 fluorescence 24 h after its administration, suggesting the potential as an intraoperative imaging modality. NIR-PIT significantly suppressed tumor growth and prolonged survival in SW780 and RT112 xenograft models. Weekly treatment with NIR-PIT further improved tumor control in RT112 xenograft models. The effectiveness of NIR-PIT was also confirmed in HT1376-luc orthotopic xenograft models. Histological analysis verified that NIR-PIT induced a significant pathologic response. Taken together, Nectin-4-targeted NIR-PIT shows promise as a treatment for luminal subtype bladder cancers.
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Fármacos Fotossensibilizantes , Neoplasias da Bexiga Urinária , Humanos , Nectinas/genética , Fármacos Fotossensibilizantes/farmacologia , Fármacos Fotossensibilizantes/uso terapêutico , Linhagem Celular Tumoral , Fototerapia/métodos , Imunoterapia/métodos , Neoplasias da Bexiga Urinária/tratamento farmacológico , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
PURPOSE: To elucidate how precisely microvascular invasion (MVI) in hepatocellular carcinoma (HCC) can be predicted using multiparametric assessment of gadoxetic acid-enhanced MRI. METHODS: In this retrospective single-center study, patients who underwent liver resection or transplantation of HCC were evaluated. Data obtained in patients who underwent liver resection were used as the training set. Nine kinds of MR findings for predicting MVI were compared between HCCs with and without MVI by univariate analysis, followed by multiple logistic regression analysis. Using significant findings, a predictive formula for diagnosing MVI was obtained. The diagnostic performance of the formula was investigated in patients who underwent liver resection (validation set 1) and in patients who underwent liver transplantation (validation set 2) using a receiver operating characteristic curve analysis. The area under the curves (AUCs) of these three groups were compared. RESULTS: A total of 345 patients with 356 HCCs were selected for analysis. Tumor diameter (D) (P = 0.021), tumor washout (TW) (P < 0.01), and peritumoral hypointensity in the hepatobiliary phase (PHH) (P < 0.01) were significantly associated with MVI after multivariate analysis. The AUCs for predicting MVI of the predictive formula were as follows: training set, 0.88 (95% confidence interval (CI) 0.82,0.93); validation set 1, 0.81 (95% CI 0.73,0.87); validation set 2, 0.67 (95% CI 0.51,0.80). The AUCs were not significantly different among three groups (training set vs validation set 1; P = 0.15, training set vs validation set 2; P = 0.09, validation set 1 vs validation set 2; P = 0.29, respectively). CONCLUSION: Our multiparametric assessment of gadoxetic acid-enhanced MRI performed quite precisely and with good reproducibility for predicting MVI.
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Carcinoma Hepatocelular , Meios de Contraste , Gadolínio DTPA , Neoplasias Hepáticas , Invasividade Neoplásica , Humanos , Carcinoma Hepatocelular/diagnóstico por imagem , Carcinoma Hepatocelular/patologia , Neoplasias Hepáticas/diagnóstico por imagem , Neoplasias Hepáticas/patologia , Feminino , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Idoso , Imageamento por Ressonância Magnética/métodos , Adulto , Microvasos/diagnóstico por imagem , Microvasos/patologia , Aumento da Imagem/métodosRESUMO
Regulatory T cells (Tregs) play a crucial role in mediating immunosuppression in the tumor microenvironment. Furthermore, Tregs contribute to the lack of efficacy and hyperprogressive disease upon Programmed cell death protein 1 (PD-1) blockade immunotherapy. Thus, Tregs are considered a promising therapeutic target, especially when combined with PD-1 blockade. However, systemic depletion of Tregs causes severe autoimmune adverse events, which poses a serious challenge to Treg-directed therapy. Here, we developed a novel treatment to locally and predominantly damage Tregs by near-infrared duocarmycin photorelease (NIR-DPR). In this technology, we prepared anti-CD25 F(ab')2 conjugates, which site-specifically uncage duocarmycin in CD25-expressing cells upon exposure to NIR light. In vitro, CD25-targeted NIR-DPR significantly increased apoptosis of CD25-expressing HT2-A5E cells. When tumors were irradiated with NIR light in vivo, intratumoral CD25+ Treg populations decreased and Ki-67 and Interleukin-10 expression was suppressed, indicating impaired functioning of intratumoral CD25+ Tregs. CD25-targeted NIR-DPR suppressed tumor growth and improved survival in syngeneic murine tumor models. Of note, CD25-targeted NIR-DPR synergistically enhanced the efficacy of PD-1 blockade, especially in tumors with higher CD8+/Treg PD-1 ratios. Furthermore, the combination therapy induced significant anti-cancer immunity including maturation of dendritic cells, extensive intratumoral infiltration of cytotoxic CD8+ T cells, and increased differentiation into CD8+ memory T cells. Altogether, CD25-targeted NIR-DPR locally and predominantly targets Tregs in the tumor microenvironment and synergistically improves the efficacy of PD-1 blockade, suggesting that this combination therapy can be a rational anti-cancer combination immunotherapy.
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Duocarmicinas , Receptor de Morte Celular Programada 1 , Linfócitos T Reguladores , Microambiente Tumoral , Animais , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/efeitos dos fármacos , Camundongos , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Receptor de Morte Celular Programada 1/imunologia , Microambiente Tumoral/efeitos dos fármacos , Microambiente Tumoral/imunologia , Duocarmicinas/farmacologia , Imunoconjugados/farmacologia , Imunoconjugados/uso terapêutico , Humanos , Linhagem Celular Tumoral , Feminino , Subunidade alfa de Receptor de Interleucina-2/metabolismo , Subunidade alfa de Receptor de Interleucina-2/imunologia , Inibidores de Checkpoint Imunológico/farmacologia , Inibidores de Checkpoint Imunológico/uso terapêutico , Modelos Animais de Doenças , Camundongos Endogâmicos C57BL , Apoptose/efeitos dos fármacos , Raios InfravermelhosRESUMO
The bones are a common site for metastasis arising from solid tumors such as breast and prostate cancer. Chemotherapy, including immunotherapy, is rarely curative. Radiotherapy with pain palliation can temporize bone metastases but is generally considered a short-term solution and retreatment is difficult. Surgery is often necessary, yet recovery times might exceed life expectancy. Therefore, there is a need to develop new approaches to bone metastases that are effective but minimally invasive. Near-infrared photoimmunotherapy (NIR-PIT) uses antibodies labeled with IRDye700DX (IR700) which is activated by NIR light, resulting in rapid cell membrane damage and immunogenic cell death. NIR-PIT using an anti-epidermal growth factor receptor (EGFR) antibody-IR700 conjugate in patients with recurrent head and neck cancer received qualified approval in Japan in 2020 and is now widely used there. However, no bone metastases have yet been treated. In this study, the efficacy of NIR-PIT for bone metastases was investigated using a bone metastases mouse model successfully established by caudal artery injection of a human triple-negative breast cancer cell line, MDAMB468-GFP/luc. The bone metastatic lesions were treated with NIR-PIT using the anti-EGFR antibody, panitumumab-IR700 conjugate. Bioluminescence imaging and histological evaluation showed that EGFR-targeted NIR-PIT has a therapeutic effect on bone metastatic lesions in mice. In addition, micro-CT showed that repeated NIR-PIT led to repair of metastasis-induced bone destruction and restored bone cortex continuity consistent with healing. These data suggest that NIR-PIT has the potential for clinical application in the treatment of bone metastases.
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Neoplasias Ósseas , Fármacos Fotossensibilizantes , Humanos , Animais , Camundongos , Linhagem Celular Tumoral , Fototerapia/métodos , Imunoterapia/métodos , Panitumumabe , Neoplasias Ósseas/tratamento farmacológico , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Aim: Evaluation of lymphatic drainage can be challenging to differentiate between separate drainage basins because only one 'color' is typically employed in sentinel node studies. This study aimed to test the feasibility of multicolor in vivo lymphangiography using newly developed organic polymer dots. Materials & methods: Biocompatible, purely organic, hydroporphyrin-doped near-infrared-emitting polymer dots were developed and evaluated for in vivo multicolor imaging in mouse lymph nodes. Results & conclusion: The authors demonstrated successful multicolor in vivo fluorescence lymphangiography using polymer dots, each tuned to a different emission spectrum. This allows minimally invasive visualization of at least four separate lymphatic drainage basins using fluorescent nanoparticles, which have the potential for clinical translation.
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Pontos Quânticos , Biópsia de Linfonodo Sentinela , Animais , Camundongos , Biópsia de Linfonodo Sentinela/métodos , Polímeros , Linfonodos , Diagnóstico por Imagem/métodosRESUMO
IL15 is a potent inducer of differentiation and proliferation of CD8+ T and natural killer (NK) cells, making it a promising candidate for cancer immunotherapy. However, limited efficacy of systemic monotherapy utilizing intravenous IL15 suggests the needs for alternative routes of administration or combination treatment with other therapies. Near-infrared photoimmunotherapy (NIR-PIT) is a highly selective anticancer treatment that elicits a massive release of tumor antigens and immunogenic signals. Here, we investigated whether intratumoral IL15 can enhance the effectiveness of cancer cell-targeted NIR-PIT using syngeneic murine tumor models. Intratumoral injection of IL15 was more effective than intraperitoneal IL15 in vivo in suppressing tumor growth and inducing intratumoral immune responses. When the efficacy of CD44-targeted NIR-PIT was compared in vivo between IL15-secreting MC38 (hIL15-MC38) and parental MC38 tumors, the hIL15-MC38/NIR-PIT group showed the best tumor growth inhibition and survival. In addition, the hIL15-MC38/NIR-PIT group showed significant dendritic cell maturation and significant increases in the number and Granzyme B expression of tumor-infiltrating CD8+ T, NK, and natural killer T cells compared with the treated parental line. Furthermore, intratumoral IL15 injection combined with CD44-targeted NIR-PIT showed significant tumor control in MC38 and Pan02-luc tumor models. In bilateral tumor models, CD44-targeted NIR-PIT in hIL15-MC38 tumors significantly suppressed the growth of untreated MC38 tumors, suggesting abscopal effects. Mice that achieved complete response after the combination therapy completely rejected later tumor rechallenge. In conclusion, local IL15 administration synergistically improves the efficacy of cancer cell-targeted NIR-PIT probably by inducing stronger anticancer immunity, indicating its potential as an anticancer treatment strategy.
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Interleucina-15 , Neoplasias , Animais , Camundongos , Fototerapia , Imunoterapia , Neoplasias/terapia , Antígenos de Neoplasias , Linhagem Celular Tumoral , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
PURPOSE: To clarify the relationship between extracellular volume (ECV) measured by dual-energy CT (DECT) and efficacy of preoperative neoadjuvant chemotherapy (NAC) in patients with pancreatic ductal adenocarcinoma (PDAC), as compared with single-energy CT (SECT). METHODS: We enrolled 67 patients with PDAC who underwent dynamic contrast-enhanced CT with a dual-energy CT system prior to NAC. Attenuation values were measured on unenhanced and the equilibrium-phase 120-kVp equivalent CT images for PDAC and the aorta. ΔHU-tumor, ΔHU-tumor/ΔHU-aorta, and SECT-ECV were calculated. Iodine densities of the tumor and aorta were measured in the equilibrium phase, and DECT-ECV of the tumor was calculated. Response to NAC was evaluated and the correlation between imaging parameters and response to NAC was statistically assessed. RESULTS: Tumor DECT-ECVs were significantly lower in the response group (n = 7) than in the non-response group (n = 60), with most significant difference (p = 0.0104). DECT-ECV showed highest diagnostic value with an Az value of 0.798. When using the optimal cut off value of DECT-ECV (<26.0 %), sensitivity, specificity, accuracy, positive predictive value, and negative value for predicting response group were 71.4 %, 85.0 %, 83.6 %, 35.7 % and 96.2 %, respectively. CONCLUSION: PDAC with lower DECT-ECV can potentially show better response to NAC. DECT-ECV might be a useful biomarker for predicting response to NAC in patients with PDAC.
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Carcinoma Ductal Pancreático , Neoplasias Pancreáticas , Humanos , Terapia Neoadjuvante , Neoplasias Pancreáticas/diagnóstico por imagem , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/cirurgia , Carcinoma Ductal Pancreático/diagnóstico por imagem , Carcinoma Ductal Pancreático/tratamento farmacológico , Carcinoma Ductal Pancreático/cirurgia , Tomografia Computadorizada por Raios X/métodos , Estudos Retrospectivos , Meios de Contraste/uso terapêutico , Neoplasias PancreáticasRESUMO
The immune system is recognized as an important factor in regulating the development, progression, and metastasis of cancer. Myeloid-derived suppressor cells (MDSCs) are a major immune-suppressive cell type by interfering with T cell activation, promoting effector T cell apoptosis, and inducing regulatory T cell expansion. Consequently, reducing or eliminating MDSCs has become a goal of some systemic immunotherapies. However, by systemically reducing MDSCs, unwanted side effects can occur. Near-infrared photoimmunotherapy (NIR-PIT) is a newly developed treatment that selectively kills targeted cells without damaging adjacent normal cells. The aim of this study is to evaluate the antitumor efficacy of MDSC-directed NIR-PIT utilizing anti-Ly6G antibodies to specifically destroy polymorphonuclear (PMN)-MDSCs in the tumor microenvironment (TME) in syngeneic mouse models. PMN-MDSCs were selectively eliminated within tumors by Ly6G-targeted NIR-PIT. There was significant tumor growth suppression and prolonged survival in three treated tumor models. In the early phase after NIR-PIT, dendritic cell maturation/activation and CD8+ T cell activation were enhanced in both intratumoral tissues and tumor-draining lymph nodes, and NK cells demonstrated increased expression of cytotoxic molecules. Host immunity remained activated in the TME for at least one week after NIR-PIT. Abscopal effects in bilateral tumor models were observed. Furthermore, the combination of NIR-PIT targeting cancer cells and PMN-MDSCs yielded synergistic effects and demonstrated highly activated host tumor immunity. In conclusion, we demonstrated that selective local PMN-MDSCs depletion by NIR-PIT could be a promising new cancer immunotherapy.
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Células Supressoras Mieloides , Animais , Camundongos , Imunoterapia , Fototerapia , Microambiente Tumoral , Ativação LinfocitáriaRESUMO
PURPOSE: To investigate whether the iodine density of liver parenchyma in the equilibrium phase and extracellular volume fraction (ECV) measured by deep learning-based spectral computed tomography (CT) can enable noninvasive liver fibrosis staging. METHOD: We retrospectively analyzed 63 patients who underwent dynamic CT using deep learning-based spectral CT before a hepatectomy or liver transplantation. The iodine densities of the liver parenchyma (I-liver) and abdominal aorta (I-aorta) were independently measured by two radiologists using iodine density images at the equilibrium phase. The iodine-density ratio (I-ratio: I-liver/I-aorta) and CT-ECV were calculated. Spearman's rank correlation analysis was used to evaluate the relationship between the I-ratio or CT-ECV and liver fibrosis stage, and receiver operating characteristic (ROC) analysis was used to evaluate the diagnostic performances of the I-ratio and CT-ECV. RESULTS: The I-ratio and CT-ECV showed significant positive correlations with liver fibrosis stage (ρ = 0.648, p < 0.0001 and ρ = 0.723, p < 0.0001, respectively). The areas under the ROC curve for the CT-ECV were 0.882 (F0 vs ≥ F1), 0.873 (≤F1 vs ≥ F2), 0.848 (≤F2 vs ≥ F3), and 0.891 (≤F3 vs F4). CONCLUSIONS: Deep learning-based spectral CT may be useful for noninvasive assessments of liver fibrosis.
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Aprendizado Profundo , Iodo , Humanos , Fígado/diagnóstico por imagem , Fígado/patologia , Cirrose Hepática/diagnóstico por imagem , Cirrose Hepática/patologia , Estudos Retrospectivos , Tomografia Computadorizada por Raios X/métodosRESUMO
BACKGROUND/AIM: We investigated whether the malignant switch of intraductal papillary mucinous neoplasm (IPMN) of the pancreas can be predicted by using the T1ϱ, T2, and apparent diffusion coefficient (ADC) values of cyst fluid. PATIENTS AND METHODS: We retrospectively analyzed the magnetic resonance (MR) images of 60 patients (26 males, 34 females, mean age 61 years) with branch-duct type and mixed-type IPMNs. The IPMNs were diagnosed clinically in 39 patients and histologically in 21 patients. The malignant potential was classified by MR imaging based on the international consensus guidelines for the management of IPMN established in 2017. Morphologically, 42 patients had "worrisome features" and three had "high-risk stigmata." Histologically, 14 lesions were diagnosed as low-grade dysplasia and seven as intermediate-grade dysplasia. The T1ϱ, T2, and ADC values of cyst fluid in each patient's largest cyst were measured on the same slice, avoiding solid components. Spearman's rank correlation test was used to determine the correlation between the morphological malignancy and the T1ϱ, T2, and ADC values. These values were also compared between the low-grade and intermediate-grade groups by Mann-Whitney U-test. RESULTS: There was a significant rank-correlation between the morphological classification and T2 value (p=0.04). The T2 value of the intermediate-grade group was significantly higher than that of the low-grade group (p=0.03). No significant correlations were morphologically or histologically obtained regarding T1ϱ and ADC. CONCLUSION: The T2 value of cyst fluid together with other MR-signs may be useful for predicting the malignant switch in IPMN of the pancreas.
Assuntos
Adenocarcinoma Mucinoso , Carcinoma Ductal Pancreático , Cistos , Neoplasias Intraductais Pancreáticas , Neoplasias Pancreáticas , Adenocarcinoma Mucinoso/diagnóstico por imagem , Adenocarcinoma Mucinoso/patologia , Carcinoma Ductal Pancreático/diagnóstico por imagem , Carcinoma Ductal Pancreático/patologia , Líquido Cístico , Feminino , Humanos , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Pâncreas/diagnóstico por imagem , Pâncreas/patologia , Neoplasias Pancreáticas/diagnóstico por imagem , Neoplasias Pancreáticas/patologia , Estudos RetrospectivosRESUMO
BACKGROUND/AIM: Alternative splicing plays a vital role in cancer development and progression. The splicing C complex is involved in alternative splicing. However, the role of PRKR-interacting protein 1 (PRKRIP1), a component of the splicing C complex, in colorectal cancer (CRC) remains unclear. This study aimed to determine the clinicopathological, biological and prognostic significance of PRKRIP1 expression in CRC. MATERIALS AND METHODS: We used a bioinformatics approach to screen for oncogenes using The Cancer Genome Atlas (TCGA) and Cancer Cell Line Encyclopedia (CCLE) datasets and identified PRKRIP1 as a driver gene on chromosome 7q. The mRNA expression of PRKRIP1 was measured using reverse transcription-quantitative PCR in 165 surgically resected CRC samples in our hospital, and its localization was determined using immunohistochemical staining. Gene Set Enrichment Analysis (GSEA) was performed using TCGA dataset. RESULTS: High PRKRIP1 expression was significantly associated with poor prognosis in both the samples and TCGA dataset. A positive correlation was observed between copy number variation and PRKRIP1 expression in TCGA and CCLE datasets, and the frequency of PRKRIP1 mutations was less than 5%. Immunohistochemistry revealed that PRKRIP1 was located in the cytoplasm of tumor cells. GSEA revealed that PRKRIP1 expression was correlated with apoptosis-related gene sets. CONCLUSION: PRKRIP1 overexpression may be a poor prognostic biomarker for CRC. Although it is known that PRKRIP1, a spliceosome factor, is essential for splicing, we now revealed the way by which its expression accelerates CRC progression.
Assuntos
Neoplasias Colorretais , Proteínas de Ligação a RNA , Biomarcadores , Neoplasias Colorretais/patologia , Variações do Número de Cópias de DNA , Regulação Neoplásica da Expressão Gênica , Humanos , Prognóstico , Fatores de Processamento de RNA/genética , RNA Mensageiro , Proteínas de Ligação a RNA/genéticaRESUMO
PURPOSE: Most small renal cell carcinomas (small RCCs) will remain indolent after detection, but some stage I RCCs still metastasize. There are no risk-stratification imaging factors that could be used to identify poor-prognosis patients based on genomic profiling. Here, we evaluated the relationships between imaging parameters and RNA expressions in small RCC and attempted to identify imaging factors that could be used as effective biomarkers. METHODS: We acquired biopsy specimens of 18 clear cell carcinomas that had undergone perfusion CT (pCT) and MRI between April 2018 and March 2019. We performed RNA sequencing, assessed RNA expressions, and calculated each tumor's cell-cycle progression (CCP) score, which has prognostic value in predicting metastatic progression. We classified the tumors into two groups: clear cell type A (ccA) and type B (ccB). CcA has better survival compared to ccB. We evaluated the following characteristics of each tumor: tumor size, presence of pseudocapsule, and fat. We used the pCT and MRI to measure each tumor's volume transfer constant (Ktrans), rate constant (Kep), extracellular extravascular volume fraction (VE), fractional plasma volume (VP), and apparent diffusion coefficient (ADC). The correlations between these small RCC imaging parameters and the tumor size and RNA expressions were determined. RESULTS: The tumor size was significantly correlated with Kep and inversely correlated with VE, VP, ADC, and hallmark angiogenesis. The CCP score was significantly inversely correlated with Ktrans and Kep. The ccA tumors tended to show a pseudocapsule on MRI. CONCLUSION: Tumor size was correlated with low perfusion, but not with prognostic factors based on genomic profiling. Imaging parameters (e.g., Ktrans and Kep) and tumor characteristics (e.g., pseudocapsule) may enable gene-based risk stratification in small RCC.
Assuntos
Carcinoma de Células Renais/diagnóstico , Imagem de Difusão por Ressonância Magnética/métodos , Neovascularização Patológica/diagnóstico , Prognóstico , Idoso , Idoso de 80 Anos ou mais , Biópsia , Carcinoma de Células Renais/diagnóstico por imagem , Carcinoma de Células Renais/patologia , Meios de Contraste/administração & dosagem , Feminino , Humanos , Aumento da Imagem , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Neovascularização Patológica/diagnóstico por imagem , Neovascularização Patológica/patologia , Medição de RiscoRESUMO
A 73-year-old woman with portal vein stenosis caused by tumor recurrence after pancreatoduodenectomy was treated with stent placement without embolization of the jejunal varix. Anticoagulation therapy using heparin followed by rivaroxaban was administered after the procedure. She continued to receive systemic chemotherapy as an outpatient. Neither restenosis nor stent thrombosis was observed after 7 months. Based on the presented case and literature review, portal vein stenting is an effective treatment option for jejunal variceal bleeding caused by malignant portal venous stricture after pancreaticoduodenectomy. Antithrombotic therapy following portal venous stenting is required to prevent stent thrombosis in the majority of cases, although it has a risk of inducing recurrent variceal bleeding. Adjunctive jejunal variceal embolization can possibly be omitted in selected cases to obtain sufficient portal-SMV flow reconstruction.