In vivo assessment of intratumoral aspirin injection to treat hepatic tumors

AIM: To study the antineoplastic efficacy of 10% aspirin intralesional injection on VX2 hepatic tumors in a rabbit model. METHODS: Thirty-two male rabbits (age: 6-9 wk; body weight: 1700-2500 g) were inoculated with VX2 hepatic tumor cells (104 cells/rabbit) via supraumbilical median laparotomy. On day 4 post-implantation, when the tumors were about 1 cm in diameter, the rabbits were randomly divided into the following groups (n = 8 each group) to assess early (24 h) and late (7 d) antineoplastic effects of intratumoral injection of 10% bicarbonate aspirin solution (experimental groups) in comparison to intratumoral injection of physiological saline solution (control groups): group 1, 24 h control; group 2, 24 h experimental; group 3, 7 d control; group 4, 7 d experimental. The serum biochemistry profile (measurements of glycemia, alkaline phosphatase, gamma-glutamyl transferase, aspartateaminotransferase, and alanine aminotransferase) and body weight measurements were obtained for all animals at the following time points: D0, before tumor implant; D4, day of treatment; D5, day of sacrifice for groups 1 and 2; D11, day of sacrifice for groups 3 and 4. Gross assessments of the abdominal and thoracic cavities were carried out upon sacrifice. The resected liver tissues, including hepatic tumors, were qualitatively (general morphology, signs of necrosis) and quantitatively (tumor area) assessed by histopathological analysis. RESULTS: Gross examination showed no alterations, besides the left hepatic lobe tumors, had occurred in the thoracic and abdominal cavities of any animal at any time point evaluated. However, the features of the tumor foci were distinctive between the groups. Compared to the control groups, which showed normal unabated tumor progression, the aspirin-treated groups showed imprecise but limited tumor boundaries and a general red-white coloration (indicating hemorrhaging) at 24 h post-treatment, and development of yellow-white areas of a cicatricial aspect at 7 d after treatment. At all time points evaluated, all except one biochemical parameters tested within the reference range (P > 0.05); a significant increase was detected in the alkaline phosphatase level of the control group 3 on D11 (P < 0.05). At 24 h post-treatment, the aspirintreated groups showed extensive coagulation necrosis accompanied by a remarkable absence of viable tumor foci; at 7 d after treatment, the tumors had completely disappeared in these animals and fibrous necrotic nod- ules had developed. In contrast, throughout the study course, the tumors of the control groups remained unchanged, showing tumor nodules without necrosis at the time point corresponding to 24 h post-treatment and increased amounts of tumor nodules at the time point corresponding to 7 d post-treatment. Quantitative analysis of the remaining tumor area revealed that the aspirin-treated groups had significantly smaller tumor foci at 24 h post-treatment (8.5% ± 0.7%) andat 7 d after treatment (11.0% ± 4.2%), compared to those in the control groups (24 h: 98.5% ± 1.5% and 7 d: 94.0% ± 2.7%; both,P < 0.005). CONCLUSION: Intralesional injection of a 10% aspirin solution causes destruction of VX2 hepatic tumors in rabbits without evidence of relapse at 7 d after treat- ment administration.

Evaluation of micelles incorporated into thermosensitive hydrogels for intratumoral delivery and controlled release of docetaxel:A dual approach for in situ treatment of tumors

The in situ gelling hybrid hydrogel system has been reported to effectively concentratechemotherapeutic drugs at the tumor site and sustain their release for a long period. DTX-micelles(docetaxel-loaded mixed micelles) are able to increase the solubility of DTX inwater, and then a high drug loading rate of hydrogels can be achieved by encapsulatingthe docetaxel-loaded mixed micelles into the hydrogels. The thermosensitive nature ofDTX-MM-hydrogels(thermosensitive hydrogels incorporated with docetaxel-loaded mixedmicelles) can accelerate the formation of a depot of this drug-loaded system at the siteof administration. Therefore, the hydrogels provide a much slower release compared withDTX-micelles and DTX-injection. An in vivo retention study has demonstrated that the DTX-MM-hydrogels can prolong the drug retention time and in viv o trials have shown that theDTX-MM-hydrogels have a higher antitumor efficacy and systemic safety. In conclusion, theDTX-MM-hydrogels prepared in this study have considerable potential as a drug deliverysystem, with higher tumor inhibition effects and are less toxic to normal tissues.

Magnetic Particle Imaging for Magnetic Hyperthermia Treatment: Visualization and Quantification of the Intratumoral Distribution and Temporal Change of Magnetic Nanoparticles in Vivo

Purpose: Magnetic hyperthermia treatment (MHT) is a strategy for cancer therapy using the tem-perature rise of magnetic nanoparticles (MNPs) under an alternating magnetic field (AMF). Re-cently, a new imaging method called magnetic particle imaging (MPI) has been introduced. MPI allows imaging of the spatial distribution of MNPs. The purpose of this study was to investigate the feasibility of visualizing and quantifying the intratumoral distribution and temporal change of MNPs and predicting the therapeutic effect of MHT using MPI. Materials and Methods: Colon-26 cells (1 × 106 cells) were implanted into the backs of eight-week-old male BALB/c mice. When the tumor volume reached approximately 100 mm3, mice were divided into untreated (n = 10) and treated groups (n = 27). The tumors in the treated group were directly injected with MNPs (Resovist?) with iron concentrations of 500 mM (A, n = 9), 400 mM (B, n = 8), and 250 mM (C, n = 10), respectively, and MHT was performed using an AMF with a frequency of 600 kHz and a peak amplitude of 3.5 kA/m. The mice in the treated group were scanned using our MPI scanner immediately before, immediately after, 7 days, and 14 days after MHT. We drew a region of interest (ROI) on the tumor in the MPI image and calculated the average, maximum, and total MPI values and the number of pixels by taking the threshold value for extracting the contour as 40% of the maximum MPI value (pixel value) within the ROI. These parameters in the untreated group were taken as zero. We also measured the relative tumor volume growth (RTVG) defined by (V-V0)/V0, where V0 and V are the tumor volumes immediately before and after MHT, respectively. Results: The average, maximum, and total MPI values decreased up to 7 days after MHT and remained almost constant thereafter in all groups, whereas the number of pixels tended to increase with time. The RTVG values in Groups A and B were significantly lower than those in the control group 3 days or more and 5 days or more after MHT, respectively. The above four parameters were significantly inversely correlated with the RTVG values 5, 7, and 14 days after MHT. Conclusion: MPI can visualize and quantify the intratumoral distribution and temporal change of MNPs before and after MHT. Our results suggest that MPI will be useful for predicting the therapeutic effect of MHT and for the treatment planning of MHT.

Observation of intratumoral injection of radiosensitizer

The present study made in 92 mice showed that hydrogen peroxide com-pound injected directly into the tumor could to some extent sensitize the hypoxiccells of S180 solid tumor to radiate,for example,both the tumor regression rateand the mouse survival rate 40d after radiation in the hydrogen peroxide com-pound group were significantly greater than those in the radiation alone group.The increasing rate of tumor diameter in 10d was 77.10%,47.09%,and 47.47%-10.4% in groups of control,radiation alone,radiosensitizer alone,radiationand hydrogen peroxide compound,respectively.Some of the problems aboutthe intratumoral injection of radiosensitizer were discussed.

Percutaneous Ethanol Intratumoral Injection for Treatment of Small Primary Liver Cancer：Summary of 240 Cases

Objective To evaluate the therapeutic effects of percutaneous ethanol intratumoral injection(PETT) for treatment of small primary liver cancer(SPLC). Methods 240 patients with surgically or pathologically proved SPLC(<3 cm in diameter)were treated by PETT(under the guidance of B-ultrasound).Of the 240 patients ,163 had recurrent liver cancer,55 had inoperable liver cancer because of cardiac ,pulmonary ,hepat-ic and renal dydfunctions or due to the close proximity of trmor to the major vessels,and 22 refused to receive surgical resection.In 40 pa-tients who received surgical resection after PETT treatment, the resected tumors were pathologically evaluated for necrotic status and the pa-tients were followed up postoperatively.Results Postoperative1-,2- and 3-year survival rate of the 240 patients was 94.9%,84.2% and 66.3% respectively.Conclusion PETTcan be used as a non-invasive treatment for SPLC,and preoperative PETT appears to be helpful in reducing recurrence of postoperative liver cancer.

Photodynamic eradication of intratumoral microbiota with bacteria-targeted micelles overcomes gemcitabine resistance of pancreatic cancer

Increasing evidence suggests that intratumoral microbiota plays a pivotal role in tumor progression,immunosurveillance,metastasis,and chemosensitivity.Particularly,in pancreatic ductal adenocarcinoma,tumor-resident Gammaproteobacteria could transform the chemotherapeutic drug gemcitabine(Gem)into its inactive form,thus rendering chemotherapy ineffective.Herein,a strategy for selectively eradicating intratumoral bacteria was described for overcoming Gem resistance in a pancreatic cancer animal model.An antimicrobial peptide was linked with photosensitizer through a poly(ethylene glycol)chain,which can self-assemble into micelles with a diameter of∼20 nm.The micelles could efficiently kill bacteria under light irradiation by inducing membrane depolarization,thereby inhibiting Gem metabolism.In a bacteria-resident pancreatic cancer animal model,the selective photodynamic eradication of intratumoral bacteria was demonstrated to efficiently reverse Gem resistance.This research highlights antibacterial photodynamic therapy as a promising adjuvant strategy for cancer therapy by modulating intratumoral microbiota.

Preoperatively predicting vessels encapsulating tumor clusters in hepatocellular carcinoma:Machine learning model based on contrast-enhanced computed tomography

BACKGROUND Recently,vessels encapsulating tumor clusters(VETC)was considered as a distinct pattern of tumor vascularization which can primarily facilitate the entry of the whole tumor cluster into the bloodstream in an invasion independent manner,and was regarded as an independent risk factor for poor prognosis in hepatocellular carcinoma(HCC).AIM To develop and validate a preoperative nomogram using contrast-enhanced computed tomography(CECT)to predict the presence of VETC+in HCC.METHODS We retrospectively evaluated 190 patients with pathologically confirmed HCC who underwent CECT scanning and immunochemical staining for cluster of differentiation 34 at two medical centers.Radiomics analysis was conducted on intratumoral and peritumoral regions in the portal vein phase.Radiomics features,essential for identifying VETC+HCC,were extracted and utilized to develop a radiomics model using machine learning algorithms in the training set.The model’s performance was validated on two separate test sets.Receiver operating characteristic(ROC)analysis was employed to compare the identified performance of three models in predicting the VETC status of HCC on both training and test sets.The most predictive model was then used to constructed a radiomics nomogram that integrated the independent clinical-radiological features.ROC and decision curve analysis were used to assess the performance characteristics of the clinical-radiological features,the radiomics features and the radiomics nomogram.RESULTS The study included 190 individuals from two independent centers,with the majority being male(81%)and a median age of 57 years(interquartile range:51-66).The area under the curve(AUC)for the combined radiomics features selected from the intratumoral and peritumoral areas were 0.825,0.788,and 0.680 in the training set and the two test sets.A total of 13 features were selected to construct the Rad-score.The nomogram,combining clinicalradiological and combined radiomics features could accurately predict VETC+in all three sets,with AUC values of 0.859,0.848 and 0.757.Decision curve analysis revealed that the radiomics nomogram was more clinically useful than both the clinical-radiological feature and the combined radiomics models.CONCLUSION This study demonstrates the potential utility of a CECT-based radiomics nomogram,incorporating clinicalradiological features and combined radiomics features,in the identification of VETC+HCC.

Light-triggered nitric oxide release and structure transformation of peptide for enhanced intratumoral retention and sensitized photodynamic therapy

Tumor-targeted delivery of nanomedicine is of great importance to improve therapeutic efficacy of cancer and minimize systemic side effects.Unfortunately,nowadays the targeting efficiency of nanomedicine toward tumor is still quite limited and far from clinical requirements.In this work,we develop an innovative peptide-based nanoparticle to realize light-triggered nitric oxide(NO)release and structural transformation for enhanced intratumoral retention and simultaneously sensitizing photodynamic therapy(PDT).The designed nanoparticle is self-assembled from a chimeric peptide monomer,TPP-RRRKLVFFK-Ce6,which contains a photosensitive moiety(chlorin e6,Ce6),aβ-sheet-forming peptide domain(Lys-Leu-Val-Phe-Phe,KLVFF),an oligoarginine domain(RRR)as NO donor and a triphenylphosphonium(TPP)moiety for targeting mitochondria.When irradiated by light,the constructed nanoparticles undergo rapid structural transformation from nanosphere to nanorod,enabling to achieve a significantly higher intratumoral accumulation by 3.26 times compared to that without light irradiation.More importantly,the conversion of generated NO and reactive oxygen species(ROS)in a light-responsive way to peroxynitrite anions(ONOO)with higher cytotoxicity enables NO to sensitize PDT in cancer treatment.Both in vitro and in vivo studies demonstrate that NO sensitized PDT based on the well-designed transformable nanoparticles enables to eradicate tumors efficiently.The light-triggered transformable nanoplatform developed in this work provides a new strategy for enhanced intratumoral retention and improved therapeutic outcome.

Chemo-photothermal immunotherapy for eradication of orthotopic tumors and inhibition of metastasis by intratumoral injection of polydopamine versatile hydrogels

Cancer remains one of the leading causes of death globally and metastasis always leads to treatment failure.Here,we develop a versatile hydrogel loading photothermal agents,chemotherapeutics,and immune-adjuvants to eradicate orthotopic tumors and inhibit metastasis by combinational therapy.Hydrogel networks were synthesized via the thiol-Michael addition of polydopamine(PDA)with thiolated hyaluronic acid.PDA acted as a cross-linking agent and endowed the hydrogel with excellent photothermal property.Meanwhile,a chemotherapeutic agent,doxorubicin(DOX),was loaded in the hydrogel viaπ-πstacking with PDA and an immune-adjuvant,CpG-ODN,was loaded via electrostatic interaction.The release of DOX from the hydrogel was initially slow but accelerated due to near infrared light irradiation.The hydrogels showed remarkably synergistic effect against 4T1 cancer cells and stimulated plenty of cytokines secreting from RAW264.7 cells.Moreover,the hydrogels eradicated orthotopic murine breast cancer xenografts and strongly inhibited metastasis after intratumoral injection and light irradiation.The high anticancer efficiency of this chemo-photothermal immunotherapy resulted from the strong synergistic effect of the versatile hydrogels,including the evoked host immune response.The combinational strategy of chemo-photothermal immunotherapy is promising for highly effective treatment of breast cancer.

iRGD-reinforced, photo-transformable nanoclusters toward cooperative enhancement of intratumoral penetration and antitumor efficacy

Insufficient intratumoral penetration greatly hurdles the anticancer performance of nanomedicine. To realize highly efficient tumor penetration in a precisely and spatiotemporally controlled manner, far-red light-responsive nanoclusters (NCs) capable of size shrinkage and charge conversion were developed and co-administered with iRGD to synergistically improve the intratumoral penetration and the anticancer efficacy. The NCs were constructed using the singlet oxygen-sensitive (SOS) polyethylene glycolpolyurethane-polyethylene glycol (PEG-(1O2)PU-PEG) triblock copolymer to encapsulate the doxorubicin (DOX)-loaded, chlorin e6 (Ce6)-conjugated polyamindoamine (PAMAM) dendrimer (DCD) via the double-emulsion method. Co-administration of iRGD notably increased the permeability of NCs within tumor vasculature and tumor tissues. In addition, upon far-red light irradiation (660 nm) of tumors at low optical density (10 mW/cm2), the generated 1O2 could disintegrate the NCs and release the DCD with positive surface charge and ultra-small size (~ 5 nm), which synergized with iRGD to enable deep intratumoral penetration. Consequently, the local 1O2 at lethal concentrations along with the released DOX efficiently and cooperatively eradicated tumor cells. This study provides a convenient approach to spatiotemporally promote the intratumoral penetration of nanomedicine and mediate programmed anticancer therapy.

New insights from the widening homogeneity perspective to target intratumor heterogeneity

Precision medicine has shed new light on the treatment of heterogeneous cancer patients.However,intratumor heterogeneity strongly constrains the clinical benefit of precision medicine.Thus,rethinking therapeutic strategies from a different facet within the precision medicine framework will not only diversify clinical interventions,but also provide an avenue for precision medicine.Here,we explore the current approaches for targeting intratumor hetero-geneity and their limitations.Furthermore,we propose a theoretical strategy with a“homogenization”feature based on iatrogenic evolutionary selection to target intratumor heterogeneity.

Metal-polyphenol-network coated CaCO_(3)as pH-responsive nanocarriers to enable effective intratumoral penetration and reversal of multidrug resistance for augmented cancer treatments

Construction of multifunctional stimuli-responsive nanotherapeutics enabling improved intratumoral penetration of therapeutics and reversal of multiple-drug resistance(MDR)is potent to achieve effective cancer treatment.Herein,we report a general method to synthesize pH-dissociable calcium carbonate(CaCO_(3))hollow nanoparticles with amorphous CaCO_(3)as the template,gallic acid(GA)as the organic ligand,and ferrous ions as the metallic center via a one-pot coordination reaction.The obtained GA–Fe@CaCO_(3)exhibits high loading efficiencies to both oxidized cisplatin prodrug and doxorubicin,yielding drug loaded GA-Fe@CaCO_(3)nanotherapeutics featured in pH-responsive size shrinkage,drug release,and Fenton catalytic activity.Compared to nonresponsive GA-Fe@silica nanoparticles prepared with silica nanoparticles as the template,such GA-Fe@CaCO_(3)confers significantly improved intratumoral penetration capacity.Moreover,both types of drug-loaded GA–Fe@CaCO_(3)nanotherapeutics exhibit synergistic therapeutic efficacies to corresponding MDR cancer cells because of the GA–Fe mediated intracellular oxidative stress amplification that could reduce the efflux of engulfed drugs by impairing the mitochondrial-mediated production of adenosine triphosphate(ATP).As a result,it is found that the doxorubicin loaded GA-Fe@CaCO_(3)exhibits superior therapeutic effect towards doxorubicin-resistant 4T1 breast tumors via combined chemodynamic and chemo-therapies.This work highlights the preparation of pH-dissociable CaCO_(3)-based nanotherapeutics to enable effective tumor penetration for enhanced treatment of drug-resistant tumors.

Pediatric gliomatosis cerebri presenting with intratumoral hemorrhage leading to poor outcome

Gliomatosis cerebri(GC)is an uncommon disease,defined as diffuse infiltration of neoplastic glial cells involving at least three cerebral lobes.GCs in young population are rare.We described a case of 14-year-old woman with GC who did not receive any recommended treatment,because the patient’s family refused.The patient had a rapid deterioration in 5 months after first symptoms due to intratumoral bleeding.This is the first case report of intratumoral bleeding after diagnosis of GC is made,resulting in poor outcome.GC may acquire possibility of intratumoral hemorrhage through its development.

SWI在不同病理类型肺癌脑转移瘤诊断中的应用

目的 分析磁敏感加权成像(SWI)与对比增强T_(1)WI(CE-T_(1)WI)对不同病理类型肺癌脑转移瘤检出率的差异,并探讨转移瘤内易感性信号(intratumoral susceptibility signals ITSS)与原发性肺癌病理类型的关联性,为临床提供参考价值。方法 77例经病理证实肺癌患者被纳入,其中鳞癌组18例、腺癌组38例、小细胞癌组21例。所有患者均行颅脑常规MRI平扫、SWI及CE-T_(1)WI,并行3个月后随访观察证实。结果 SWI与CE-T_(1)WI对肺鳞癌脑转移瘤检出率差异无统计学意义(P=0.622),而对腺癌组(P<0.01)与小细胞癌(P=0.018)脑转移瘤检出率有统计学差异。不同病理类型肺癌脑转移瘤内ITSS形态有差异,肺鳞癌转移瘤以点、线状居多,腺癌转移瘤以结节状居多,小细胞癌转移瘤以不规则形居多。结论 SWI、CE-T_(1)WI对肺鳞癌脑转移瘤检出率差异无统计学意义,对腺癌与小细胞癌脑转移瘤检出率有统计学差异,不同组织类型肺癌脑转移瘤内ITSS形态存在差异。

Impact of gut microbiome in the development and treatment of pancreatic cancer:Newer insights

The gut microbiome plays an important role in the variation of pharmacologic response.This aspect is especially important in the era of precision medicine,where understanding how and to what extent the gut microbiome interacts with drugs and their actions will be key to individualizing therapy.The impact of the composition of the gut microbiome on the efficacy of newer cancer therapies such as immune checkpoint inhibitors and chimeric antigen receptor T-cell treatment has become an active area of research.Pancreatic adenocarcinoma(PAC)has a poor prognosis even in those with potentially resectable disease,and treatment options are very limited.Newer studies have concluded that there is a synergistic effect for immunotherapy in combination with cytotoxic drugs,in the treatment of PAC.A variety of commensal microbiota can affect the efficacy of conventional chemotherapy and immunotherapy by modulating the tumor microenvironment in the treatment of PAC.This review will provide newer insights on the impact that alterations made in the gut microbial system have in the development and treatment of PAC.

Immuno-oncology-microbiome axis of gastrointestinal malignancy

Research on the relationship between the microbiome and cancer has been controversial for centuries.Recent works have discovered that the intratumor microbiome is an important component of the tumor microenvironment(TME).Intratumor bacteria,the most studied intratumor microbiome,are mainly localized in tumor cells and immune cells.As the largest bacterial reservoir in human body,the gut microbiome may be one of the sources of the intratumor microbiome in gastrointestinal malignancies.An increasing number of studies have shown that the gut and intratumor microbiome play an important role in regulating the immune tone of tumors.Moreover,it has been recently proposed that the gut and intratumor microbiome can influence tumor progression by modulating host metabolism and the immune and immune tone of the TME,which is defined as the immuno-oncology-microbiome(IOM)axis.The proposal of the IOM axis provides a new target for the tumor microbiome and tumor immunity.This review aims to reveal the mechanism and progress of the gut and intratumor microbiome in gastrointestinal malignancies such as esophageal cancer,gastric cancer,liver cancer,colorectal cancer and pancreatic cancer by exploring the IOM axis.Providing new insights into the research related to gastrointestinal malignancies.

卡瑞利珠单抗联合化疗对晚期胃癌患者治疗效果及瘤内微生物群的影响

目的探究卡瑞利珠单抗(SHR-1210)联合化疗对晚期胃癌患者治疗效果及瘤内微生物群的影响。方法选取2020年4月—2021年5月收治的92例晚期胃癌,根据治疗方法不同均分为研究组和对照组,研究组接受SHR-1210联合化疗,对照组接受化疗。比较2组治疗效果,治疗前后血清癌胚抗原(CEA)、癌抗原19-9(CA19-9)水平,治疗后瘤内微生物群检出率、自然杀伤细胞(NK细胞)、T淋巴细胞亚群水平,以及不良反应和随访2年无进展生存率、总生存率。结果治疗后,研究组总有效率为89.1%(41/46)高于对照组的56.5%(26/46)(P<0.01)。治疗后,研究组血清CEA、CA19-9水平、瘤内微生物群检出率、CD8+及NK细胞水平低于对照组(P<0.05,P<0.01)。治疗后,研究组CD4+、CD4+/CD8+水平高于对照组,随访2年无进展生存率、总生存率高于对照组(P<0.05,P<0.01)。研究组不良反应总发生率低于对照组(P<0.01)。结论SHR-1210联合化疗可降低晚期胃癌患者血清CEA、CA19-9水平,减少瘤内微生物群,大幅度提高治疗安全性,改善预后,效果显著。

瘤内免疫注射联合放疗用于肿瘤治疗的研究进展

近年来,随着肿瘤免疫治疗的迅速发展,肿瘤治疗性疫苗技术日益受到关注。相较于个体化新抗原疫苗,原位疫苗技术无需经历个体化抗原检测、抗原肽定制合成等繁琐的步骤,即可在肿瘤局部形成“抗原库”以启动较强的抗肿瘤免疫,且能提高部分患者对于免疫检查点抑制剂的反应率,在现阶段具有较高的临床转化潜力。本文主要介绍原位疫苗最主要的两种实现方式:放射治疗和瘤内免疫注射,同时阐述它们作为原位疫苗的作用机制和二者联合应用的临床前及临床研究现状,使该领域得到更多研究者和临床医生的关注。