Ultrasound monitoring of temperature and coagulation change during tumor treatment with microwave ablation

Microwave ablation therapy has become an important method for tumor treatment in recent years. The temperature and the coagulation region need real-time noninvasive monitoring to ensure the safety and effective-ness during the treatment. The authors reviewed the ultrasonic monitoring methods for tumor microwave ablation therapy both at home and abroad. In addition, the authors also prospected this technique in the future.     

脊索瘤的临床治疗进展

脊索瘤是一种罕见的低度恶性肿瘤,临床治愈率低,复发率较高。手术切除是治疗脊索瘤的首选方法,目前公认的脊索瘤治疗方法是完整(或大块)切除。术后辅助放射治疗越来越多的应用于临床,而新药物的研发、术前动脉栓塞的应用,以及射频消融等都被用于脊索瘤的临床治疗。本文综述了目前临床上应用的诊疗进展,包括手术治疗、放射治疗、药物治疗及射频消融治疗等方法。     

脊索瘤的临床治疗进展

脊索瘤是一种罕见的低度恶性肿瘤,临床治愈率低,复发率较高。手术切除是治疗脊索瘤的首选方法,目前公认的脊索瘤治疗方法是完整（或大块）切除。术后辅助放射治疗越来越多的应用于临床,而新药物的研发、术前动脉栓塞的应用,以及射频消融等都被用于脊索瘤的临床治疗。本文综述了目前临床上应用的诊疗进展,包括手术治疗、放射治疗、药物治疗及射频消融治疗等方法。     

The Value of Proton Magnetic Resonance Spectroscopy in High-Intensity Focused Ultrasound Treatment of Experimental Liver Cancer

High-intensity focused ultrasound (HIFU) is a rapidly developing, non-invasive technique for local treatment of solid tumors that produce coagulative tumor necrosis. This study is aimed to investigate the feasibility of proton magnetic resonance spectroscopy (MRS) on early assessing treatment of HIFU ablation in rabbit with VX2 liver tumor. HIFU ablation was performed on normal liver and VX2 tumor in rabbit, and MRS was performed on normal liver and VX2 tumor before and 2 days after 100% HIFU ablation or 80% ablation in tumor volume. Choline (Cho) and choline/lipid (Cho/Lip) ratios between complete and partial HIFU ablation of tumor were compared. Tissues were harvested and sequentially sliced to confirm the necrosis. In normal liver, the Cho value liver was not obviously changed after HIFU (P > .05), but the Cho/Lip ratio was decreased (P < .05). Cho in liver VX2 tumor was much higher than that in normal liver (P < .001). Cho and Cho/Lip ratio were significantly decreased in tumor after complete HIFU ablation and partial HIFU ablation, and the Cho value in complete HIFU tumor ablation did not show any difference from that in normal liver after HIFU (P > .05); however, the Cho value in partial ablation was still higher than that in normal liver before or in tumor after complete HIFU treatment due to the residual part of tumors, and Cho/Lip ratio is lower than that in complete HIFU treatment (P < .001). The changes in MRS parameters were consistent with histopathologic changes of the tumor tissues after treatment. MRS could differentiate the complete tumor necrosis from residual tumor tissue, when combined with magnetic resonance imaging. We conclude that MRS may be applied as an important, non-invasive biomarker for monitoring the thoroughness of HIFU ablation.     

Activation of local and systemic anti-tumor immune responses by ablation of solid tumors with intratumoral electrochemical or alpha radiation treatments

Cancer, the most devastating chronic disease affecting humankind, is treated primarily by surgery, chemotherapy, and radiation therapy. Surgery and radiotherapy are mainly used for debulking the primary tumor, while chemotherapy is the most efficient anti-metastatic treatment. To control better metastatic cancer, the host immune system should be stimulated. Yet, successful specific stimulation of the immune system against tumors was seldom achieved even in antigenic tumors. Our working hypothesis is that aggressive in situ tumor ablation can release tumor antigens and danger signals, which will enhance anti-tumor T cell responses resulting in the destruction of residual malignant cells in primary tumors and distant metastases. We developed two efficient in situ ablation treatments for solid cancer, which can be used to destroy the primary tumors and stimulate anti-tumor immune responses. The first treatment, electrochemical ablation, is applied through intratumoral electrodes, which deliver unipolar-pulsed electric currents. The second treatment, diffusing alpha-emitters radiation therapy (DaRT), is based on intratumoral ²²⁴Ra-loaded wire(s) that release by recoil its daughter atoms. These short-lived alpha-emitting atoms spread in the tumor and spray it with lethal alpha particles. It was confirmed that these treatments effectively destroy various malignant animal and human primary solid tumors. As a consequence of such tumor ablation, tumor-derived antigenic material was released and provoked systemic T cell-dependent anti-tumor immunological reactions. These reactions conferred protection against a secondary tumor challenge and destroyed remaining malignant cells in the primary tumor as well as in distant metastases. Such anti-tumor immune responses could be further amplified by the immune adjuvant, CpG. Electrochemical ablation or DaRT together with chemotherapy and immunostimulatory agents can serve as treatment protocols for solid metastatic tumors and can be applied instead of or in combination with surgery.     

Identifying MRI Markers Associated with Early Response following Laser Ablation for Neurological Disorders: Preliminary Findings

There is a renewed interest in MR-guided laser interstitial thermal therapy (LITT) as a minimally invasive alternative to craniotomy for local treatment of various brain tumors and epilepsy. LITT allows for focused delivery of laser energy monitored in real time by MRI, for precise ablation of the lesion. Although highly promising, the long-term effects of laser ablation as a viable treatment option for neurological disorders have yet to be rigorously studied and quantified. In this work, we present a quantitative framework for monitoring per-voxel thermal-induced changes post-LITT over time on multi parametric MRI. We demonstrate that voxel-by-voxel quantification of MRI markers over time can enable a careful and accurate (a) characterization of early LITT-related changes (if and when they are exaggerated and when they subside), and (b) identification and monitoring of MRI markers that potentially allow for better quantification of response to LITT therapy. The framework was evaluated on two distinct cohorts of patients (GBM, epilepsy), who were monitored post-LITT at regular time-intervals via multi-parametric MRI. On a cohort of six GBM studies we found that (a) it may be important for the initial treatment-related changes to subside to more reliably capture MRI markers relating to tumor recurrence, and (b) T1w MRI and T2-GRE may better differentiate changes that may correspond to tumor recurrence from patients with no recurrence, as compared to T2w-MRI, and FLAIR. Similarly, our preliminary analysis of four epilepsy studies suggests that (a) early LITT changes (attributed to swelling, edema) appear to subside within 4-weeks post-LITT, and (b) ADC may be more reflective of early treatment changes (up to 1 month), while T1w may be more reflective of early delayed treatment changes (1 month, 3 months), while T2-w and T2-FLAIR appeared to be more sensitive to late treatment related changes (6-months post-LITT) compared to the other MRI protocols under evaluation.     

Synergy in cancer treatment between liposomal chemotherapeutics and thermal ablation

Minimally invasive image-guided tumor ablation using short duration heating via needle-like applicators using energies such as radiofrequency or microwave has seen increasing clinical use to treat focal liver, renal, breast, bone, and lung tumors. Potential benefits of this thermal therapy include reduced morbidity and mortality compared to standard surgical resection and ability to treat non-surgical patients. However, improvements to this technique are required as achieving complete ablation in many cases can be challenging particularly at margins of tumors>3 cm in diameter and adjacent to blood vessels. Thus, one very promising strategy has been to combine thermal tumor ablation with adjuvant nanoparticle-based chemotherapy agents to improve efficiency. Here, we will primarily review principles of thermal ablation to provide a framework for understanding the mechanisms of combination therapy, and review the studies on combination therapy, including presenting preliminary data on the role of such variables as nanoparticle size and thermal dose on improving combination therapy outcome. We will discuss how thermal ablation can also be used to improve overall intratumoral drug accumulation and nanoparticle content release. Finally, in this article we will further describe the appealing off-shoot approach of utilizing thermal ablation techniques not as the primary treatment, but rather, as a means to improve efficiency of intratumoral nanoparticle drug delivery.     

Selective adipose tissue ablation by localized,sustained drug delivery

The reduction of adipose depots is widely considered to be the optimal approach to limit pathologies associated with obesity. While many current antiobesity strategies are centered on regulating satiety, these approaches typically attempt an overall weight loss and are unable to target distinct adipose depots specifically associated with disease risk. The authors report a novel therapeutic modality utilizing localized and sustained delivery of drugs to provide for the selective ablation of adipose tissue. Using the epididymal fat pad of Sprague-Dawley rats as a model, they injected into the tissue poly(lactide-co-glycolide) microspheres encapsulating tumor necrosis factor-alpha, a well-known regulator of adipose tissue mass. The utility of this approach was investigated in vivo by measuring the fat pad mass relative to the contralateral control within the same animal (n = 4 at each time point) and in vitro by measuring apoptosis in adipose organ cultures. The authors demonstrated control over the localization of tumor necrosis factor-alpha by performing blood analysis. This is the first report of localized drug delivery for adipose tissue ablation, and these results indicate the potential utility of the general tissue ablation approach for treatment of numerous pathologies.     

Nano-assisted radiofrequency ablation of clinically extracted irregularly-shaped liver tumors

Radiofrequency ablation (RFA) for liver tumors is a minimally invasive procedure that uses electrical energy and heat to destroy cancer cells. One of the critical factors that impedes its successful outcome is the use of inappropriate radiofrequency levels that will not completely destroy the target tumor tissues, resulting in therapy failure. Additionally, the surrounding healthy tissues may suffer from serious damage due to excessive ablation. To address these challenges, this work proposes the employment of injected nanoparticles to thermally promote the ablation efficacy of conventional RFA. A three-dimensional finite difference analysis is employed to simulate the RFA treatment. Based on the data acquired from measured experiments, the simulation results have demonstrated close agreement with experimental data with a maximum discrepancy of within ±8.7%. Several types of nanoparticles were selected to evaluate their influences on liver tissue's thermal and electrical properties. We analysed the effects of nanoparticles on liver RFA via a tumor rending process incorporating several clinically-extracted tumor profiles and vascular systems. Simulations were conducted to explore the temperature difference responses between conventional RFA treatment and one with the inclusion of assisted nanoparticles on several irregularly-shaped tumors. Results have indicated that applying selected nanoparticles with high thermal conductivity and electrical conductivity on the targeted tissue zone promotes heating rate while sustaining a similar ablation zone that experiences lower maximum temperature when compared with the conventional RFA treatment. In sum, incorporating thermally-enhancing nanoparticles promotes heat transfer during the RFA treatment, resulting in improved ablation efficiency.     

Gd-EOB-DTPA-Enhanced MR Guidance in Thermal Ablation of Liver Malignancies

Objective

To evaluate the potency of Gd-EOB-DTPA to support hepatic catheter placement in laser ablation procedures by quantifying time-dependent delineation effects for instrumentation and target tumor within liver parenchyma. Monitoring potential influence on online MR thermometry during the ablation procedure is a secondary aim.

Materials and Methods

30 cases of MR-guided laser ablation were performed after i.v. bolus injection of gadoxetic acid (0.025 mmol/Kg Gd-EOB-DTPA; Bayer Healthcare, Berlin, Germany). T₁-weighted GRE sequences were used for applicator guidance (FLASH 3D) in the catheter placement phase and for therapy monitoring (FLASH 2D) in the therapy phase. SNR and consecutive CNR values were measured for elements of interest plotted over time both for catheter placement and therapy phase and compared with a non-contrast control group of 19 earlier cases. Statistical analysis was realized using the paired Wilcoxon test.

Results

Sustainable signal elevation of liver parenchyma in the contrast-enhanced group was sufficient to silhouette both target tumor and applicator against the liver. Differences in time dependent CNR alteration were highly significant between contrast-enhanced and non-contrast interventions for parenchyma and target on the one hand (p = 0.020) and parenchyma and instrument on the other hand (p = 0.002). Effects lasted for the whole procedure (monitoring up to 60 min) and were specific for the contrast-enhanced group. Contrasting maxima were seen after median 30 (applicator) and 38 (tumor) minutes, in the potential core time of a multineedle procedure. Contrast influence on T1 thermometry for real-time monitoring of thermal impact was not significant (p = 0.068–0.715).

Conclusion

Results strongly support anticipated promotive effects of Gd-EOB-DTPA for MR-guided percutaneous liver interventions by proving and quantifying the delineating effects for therapy-relevant elements in the procedure. Time benefit, cost effectiveness and oncologic outcome of the described beneficiary effects will have to be part of further investigations.     

IgG and IgM glycosylation patterns in patients undergoing image-guided tumor ablation

BackgroundImage-guided tumor ablation is a technique whereby needle-like applicators are placed directly into solid tumors under guidance typically with computed tomography or ultrasound. Changes in IgG and IgM antibody glycosylation were studied during ablation-induced immune response to cancer, and the use of glycosylation as a biomarker for diagnosis, prognosis and disease treatment was examined.MethodsPlasma from 27 tumor patients was collected immediately before, after and for 6 months following ablation. IgG and IgM antibodies were isolated by use high-throughput chromatography, and analyzed by hydrophilic liquid chromatography. Thorough identification of glycan structures in each chromatography peak was performed by nano-liquid chromatography electrospray ionization mass spectrometry.ResultsAlthough antibody glycosylation was found to vary with cancer type, discernable patterns of change based on the successful treatment of tumors by ablation were not identified. One patient with renal clear cell carcinoma and poor disease outcome had unexpectedly high amount of oligomannose IgG glycans during the whole period of monitoring. In contrast, IgM antibodies did not follow the same pattern.ConclusionsThese findings suggest that glycosylation patterns are indicative of an immune system that is unable to prevent different types of cancer, rather than products of the immunostimulatory response to the ablation of tumor itself. Analyses of the outcome effect suggested that IgG glycosylation and IgM glycosylation are not associated with tumor ablation.General significancePresent work opens a new way for parallel determination of glycosylation changes of both IgG and IgM antibodies by use of high-throughput methods, and their future use as biomarkers for disease diagnosis and prognosis. This article is part of a Special Issue entitled "Glycans in personalised medicine" Guest Editor: Professor Gordan Lauc.     

Androgens as therapy for androgen receptor-positive castration-resistant prostate cancer

Prostate cancer is the most frequently diagnosed non-cutaneous tumor of men in Western countries. While surgery is often successful for organ-confined prostate cancer, androgen ablation therapy is the primary treatment for metastatic prostate cancer. However, this therapy is associated with several undesired side-effects, including increased risk of cardiovascular diseases. Shortening the period of androgen ablation therapy may benefit prostate cancer patients. Intermittent Androgen Deprivation therapy improves quality of life, reduces toxicity and medical costs, and delays disease progression in some patients. Cell culture and xenograft studies using androgen receptor (AR)-positive castration-resistant human prostate cancers cells (LNCaP, ARCaP, and PC-3 cells over-expressing AR) suggest that androgens may suppress the growth of AR-rich prostate cancer cells. Androgens cause growth inhibition and G1 cell cycle arrest in these cells by regulating c-Myc, Skp2, and p27^Kip via AR. Higher dosages of testosterone cause greater growth inhibition of relapsed tumors. Manipulating androgen/AR signaling may therefore be a potential therapy for AR-positive advanced prostate cancer.     

Therapeutic advances for patients with intermediate hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is the fifth most common malignant tumor and constitutes a major health threat globally. Intermediate HCC (Barcelona Clinic Liver Cancer Staging, stage B) encompasses a wide range of patients and is characterized by substantial heterogeneity with varying tumor burdens and liver functions. Therefore, it is paramount to evaluate the patient's overall conditions and to select the most appropriate therapy based on available evidence. Transarterial chemoembolization is the recommended first-line therapy for intermediate HCC patients. However, in clinical practice, other treatment options are also used as alternative therapies, such as hepatic resection, percutaneous thermal ablation, radiotherapy (RT), systemic treatment, immunotherapy, and so forth. In this review, we will introduce current treatment strategies for intermediate HCC, discuss their advantages and disadvantages, and propose future directions.     

Prognostic value of rectal cancer regression after preoperative chemoradiation therapy

Despite the international experience enriched in the number of observations of combination treatment in patients with rectal cancer, many issues remain to be the subject-matter of the discussion. This also applies to the estimation of the value of tumor regression after neoadjuvant chemoradiation therapy in order to develop indications for sphincter-sparing operations depending on the site of a tumor in the organ and their impact on long-term treatment results. The authors have gained experience with combination treatment in 157 patients with rectal cancer (T2-4 N0-2 M0) receiving neoadjuvant chemoradiation therapy in a cumulative radiation dose of 39.5-47 Gy and radical surgery 4-6 weeks after radiation. The direct effect of chemoradiation therapy has been investigated using a set of studies involving ultrasonography, magnetic resonance imaging, endoscopic diagnosis, as well as the data of a postoperative morphological study of primary tumor and lymph nodes. The authors have evaluated the impact of preoperative chemoradiation therapy on the rate and degree of resorption of a primary tumor, including the depth of its invasion through the intestinal wall and exit into the cellular tissue, its localization in the organ and the distance to the anus, a difference in the preoperative estimation of stages and according to the data of pathomorphological studies of intraoperative specimens, etc. The degree of tumor resorption was comparatively analyzed with the long-term results and the rate of sphincter-sparing operations.     

Treatment options after failure of radiation therapy-a review

Radioresistant or recurrent prostate cancer represents a serious health risk for approximately 20%-30% of patients treated with primary radiation therapy for clinically localized prostate cancer. The majority of patients exhibit large volume and poorly differentiated disease at the time of diagnosis, which limits the ability of salvage therapy to eradicate the cancer. Early detection with serum PSA monitoring and prostate needle biopsy following primary radiation therapy may identify residual adenocarcinoma at an earlier stage and increase the likelihood of successful salvage therapy. Radical prostatectomy, prostate cryoablation, and brachytherapy comprise the options for salvage treatment available for radiorecurrent prostate cancer. The goal of disease eradication must be balanced against the potential for serious treatment-related side effects. As a result, many patients receive noncurative therapy with androgen ablation despite the real risk of disease progression and mortality.     

In vivo immunological antitumor effect of OK-432-stimulated dendritic cell transfer after radiofrequency ablation

Radiofrequency ablation therapy (RFA) is a radical treatment for liver cancers and induces tumor antigen-specific immune responses. In the present study, we examined the antitumor effects of focal OK-432-stimulated dendritic cell (DC) transfer combined with RFA and analyzed the functional mechanisms involved using a murine model. C57BL/6 mice were injected subcutaneously with colon cancer cells (MC38) in their bilateral flanks. After the establishment of tumors, the subcutaneous tumor on one flank was treated using RFA, and then OK-432-stimulated DCs were injected locally. The antitumor effect of the treatment was evaluated by measuring the size of the tumor on the opposite flank, and the immunological responses were assessed using tumor-infiltrating lymphocytes, splenocytes and draining lymph nodes. Tumor growth was strongly inhibited in mice that exhibited efficient DC migration after RFA and OK-432-stimulated DC transfer, as compared to mice treated with RFA alone or treatment involving immature DC transfer. We also demonstrated that the antitumor effect of this treatment depended on both CD8-positive and CD4-positive cells. On the basis of our findings, we believe that combination therapy for metastatic liver cancer consisting of OK-432-stimulated DCs in combination with RFA can proceed to clinical trials, and it is anticipated to be markedly superior to RFA single therapy.     

Radiofrequency ablation as locoregional therapy for unresectable hepatic malignancies: initial results in 24 patients with 5-years follow-up

Radiofrequency ablation (RFA) is one treatment modality for unresectable liver metastases. Patients with hepatic malignancies (n = 24) underwent elective RFA. All tumors were ablated with a curative intent, with a margin of 1 cm, in a single session of RFA. The median diameter of tumor was 3.1 cm (range 1.7-6.9 cm). Studied patients were not candidates for resection due to multifocal hepatic disease, extrahepatic disease, proximity to major vascular structures or presence of cirrhosis with functional hepatic reserve inadequate to tolerate major hepatic resection. Complete tumor necrosis was achieved in 87.5% and tumor recurred in 3 patients (12.5%) with lesions larger than 5 cm. Distant intrahepatic recurrence was diagnosed in another 4 (16.7%). Distant metastases were found in 7 (29.2%) patients. Four of these 7 patients had also distant intrahepatic recurrence of disease. Two and 5-years survival rates were 41.7% (10 patients) and 8.3% (2 patients) respectively. RFA is safe and effective option for patients with unresectable hepatic malignancies smaller than 5 cm without distant metastatic disease. RF ablation resulted in complete tumor necrosis in 87.5% with 2 and 5-years survival rates much higher than with chemotherapy alone or only supportive therapy, when survival is measured in weeks or months. If RFA is unavailable, percutaneous ethanol injection therapy can be done but with inferior survival rates.     

Optimization of 131I ablation in patients with differentiated thyroid carcinoma: comparison of early outcomes of treatment with 100 mCi versus 60 mCi

INTRODUCTION: The aim of this study was to compare the early outcomes between two groups of patients with differentiated thyroid carcinoma (DTC) who received 60 or 100 mCi of (131)I for remnant ablation. MATERIAL AND METHODS: 224 DTC patients with primary tumor > 1 cm of diameter or multifocal were randomised into prospective clinical trial. Patients with extrathyroideal extension of primary tumor and nodal metastases or M1 were not enrolled. 99 patients received 60 mCi, and 125--100 mCi of radioiodine as the first ablative dose. RESULTS: The effectiveness of thyroid ablation was evaluated after one year, during endogenous TSH (thyroid stimulating hormone) stimulation, and after two years during Lthyroxine therapy. Whole body scintigraphy (WBS) was performed under thyroxine withdrawal and thyroglobulin serum level was assessed. Distant micrometastases were detected in 9.8% of patients by post-therapy WBS, 11 patients in group A treated with 60 mCi and 11 in group B treated with 100 mCi. In other patients no symptoms of persistent disease were detected. At one year follow up full remission was diagnosed in 176 patients: 76 in group A and 100 in group B. The remaining ones, 13.3% and 11.2% respectively, received the second course of (131)I for remnant ablation. There were no statistically significant differences in Tg (thyroglobulin) serum level either 12 or 24 months after 131I treatment. CONCLUSIONS: Our evaluation of early efficacy of adjuvant radioiodine treatment in low risk DTC patients shows no differences between two radioiodine activities - 60 and 100 mCi in relation to thyroid ablation. Thus, the activity of 60 mCi is recommended.     

Glioblastoma therapy with cytotoxic mesenchymal stromal cells optimized by bioluminescence imaging of tumor and therapeutic cell response

Genetically modified adipose tissue derived mesenchymal stromal cells (hAMSCs) with tumor homing capacity have been proposed for localized therapy of chemo- and radiotherapy resistant glioblastomas. We demonstrate an effective procedure to optimize glioblastoma therapy based on the use of genetically modified hAMSCs and in vivo non invasive monitoring of tumor and therapeutic cells. Glioblastoma U87 cells expressing Photinus pyralis luciferase (Pluc) were implanted in combination with hAMSCs expressing a trifunctional Renilla reniformis luciferase-red fluorescent protein-thymidine kinase reporter in the brains of SCID mice that were subsequently treated with ganciclovir (GCV). The resulting optimized therapy was effective and monitoring of tumor cells by bioluminescence imaging (BLI) showed that after 49 days GCV treatment reduced significantly the hAMSC treated tumors; by a factor of 10(4) relative to controls. Using a Pluc reporter regulated by an endothelial specific promoter and in vivo BLI to image hAMSC differentiation we gained insight on the therapeutic mechanism. Implanted hAMSCs homed to tumor vessels, where they differentiated to endothelial cells. We propose that the tumor killing efficiency of genetically modified hAMSCs results from their association with the tumor vascular system and should be useful vehicles to deliver localized therapy to glioblastoma surgical borders following tumor resection.     

肠内营养联合复方氨基酸在恶性肿瘤患者化疗中的应用

为了观察肠内营养(EN)支持治疗联合复方氨基酸在恶性肿瘤化疗患者中的临床疗效及并建立相关护理方法,将68例恶性肿瘤化疗患者随机分为治疗组和对照组,每组34例,治疗组给予肠内营养支持治疗联合复方氨基酸治疗,对照组给予常规处理。对两组病人治疗前后进行生化指标监测、记录不良反应以及进行营养评估。研究结果显示,治疗组与对照组比较,人体测量值增加,血清清蛋白升高,两组比较有显著性差异(p<0.05)。本研究表明,肠内营养(EN)支持治疗联合复方氨基酸对于改善恶性肿瘤化疗病人的营养状况效果明显,并且可以提高患者对化疗的耐受力、增强免疫功能。