Photodynamic therapy of established prostatic adenocarcinoma with TOOKAD: a biphasic apparent diffusion coefficient change as potential early MRI response marker

The goal of this study was to examine the use of diffusion-weighted magnetic resonance imaging (DW-MRI) for the assessment of early progression of photodamage induced by Pd-bacteriopheophorbide (TOOKAD)-based photodynamic therapy (PDT). TOOKAD is a novel second-generation photosensitizer for PDT of solid tumors developed in our laboratory and presently under clinical trials for prostate cancer (PC) therapy. Using the subcutaneous human prostate adenocarcinoma WISH-PC14 xenografts in nude mice as a model, a unique biphasic change in the apparent diffusion coefficient (ADC) was observed within the first 24 hours post-PDT, with initial decrease followed by an increase in ADC. Using DW-MRI, this phenomenon enables the detection of successful tumor response to PDT within 7 hours posttreatment. This process was validated by direct, histological, and immunohistochemical examinations and also by evaluation of serum prostate-specific antigen (PSA) levels that decreased significantly already 7 hours posttreatment. In vitro studies of multicellular cell spheroids confirmed a PDT-induced decrease in ADC, suggesting that lipid peroxidation (LPO) significantly contributes to ADC decline observed after PDT. These results demonstrate that TOOKAD-based PDT successfully eradicates prostate adenocarcinoma xenografts and suggests DW-MRI to be useful for the detection of early tumor response and treatment outcome in the clinical setting.     

Apparent diffusion coefficient from magnetic resonance imaging as a biomarker in oncology drug development

Magnetic resonance imaging (MRI) can be made sensitive to diffusion of water molecules in biological tissues: this phenomenon can be quantitated to provide a biomarker, the apparent diffusion coefficient (ADC). Over the past decade, evidence has accumulated from numerous clinical and animal studies that ADC is abnormal in tumours; that elevated ADC reflects an elevated non-cellular fraction; and that acute increases in ADC following therapy can indicate that tumour cells have been killed. However there remain substantial challenges in ensuring robust and valid ADC measurements, particularly in multicentre studies in common sites of metastasis such as lung and liver. Moreover, there is uncertainty about how best to select the timing of observation post-therapy to avoid false-negatives, and how to minimise the confounding factors which could decouple drug-induced ADC increase from drug-induced cell kill. In this review we summarise the physical basis of the biomarker, the evidence that it reflects non-viable fraction, particularly in extracranial tumours, and suggest a roadmap for validation and qualification.     

Noninvasive monitoring of radiation-induced treatment response using proton magnetic resonance spectroscopy and diffusion-weighted magnetic resonance imaging in a colorectal tumor model.

BACKGROUND AND PURPOSE: To examine whether in vivo proton magnetic resonance spectroscopy ((1)H MRS) and diffusion-weighted magnetic resonance imaging (DW-MRI) can monitor radiation-induced changes in HT29 xenografts in mice. MATERIALS AND METHODS: HT29 xenografts in mice received a dose of 15Gy. In vivo(1)H MRS and DW-MRI were acquired pretreatment and 1, 3, 6 and 10 days post-irradiation. After imaging, tumors were excised for histological analysis. The amounts of necrosis, fibrosis and viable cells in the cross sections were scored and compared to changes in apparent diffusion coefficient (ADC) and choline/water ratio. RESULTS: Radiation-induced necrosis in the xenografts was observed as increased tumor ADC. In-growth of fibrosis three days post-irradiation restricting water mobility was accompanied by decreased tumor ADC. Choline/water ratio correlated with metabolic activity and tumor growth. CONCLUSIONS: ADC and choline/water ratio assessed by in vivo DW-MRI and (1)H MRS depicts radiation-induced changes in HT29 xenografts following irradiation.     

磁共振弥散加权成像在肺癌中的应用

磁共振弥散加权成像(DWI)作为一种无辐射、无创伤的检查手段,对肺癌的诊断及分期有很大帮助,其表观弥散系数(ADC)的测定对肺癌的疗效评估也显示出较高的临床应用价值.作为CT的补充手段,MRI-CT图像融合使肺癌放疗靶区勾画更为准确.     

Early response of prostate carcinoma xenografts to docetaxel chemotherapy monitored with diffusion MRI

For many anticancer therapies, it would be desirable to accurately monitor and quantify tumor response early in the treatment regimen. This would allow oncologists to continue effective therapies or discontinue ineffective therapies early in the course of treatment, and hence, reduce morbidity. This is especially true for second-line therapies, which have reduced response rates and increased toxicities. Previous works by others and ourselves have shown that water mobility, measured by diffusion-weighted magnetic resonance imaging (DW-MRI), increases early in tumors destined to respond to therapies. In the current communication, we further characterize the utility of DW-MRI to predict response of prostate cancer xenografts to docetaxel in SCID mice in a preclinical setting. The current data illustrate that tumor volumes and secreted prostate-specific antigen both respond strongly to docetaxel in a dose-responsive manner, and the apparent diffusion coefficient of water (ADC(w)) increases significantly by 2 days even at the lowest doses (10 mg/kg). The ADCw data were parsed by histogram analyses. Our results indicate that DW-MRI can be used for early detection of prostate carcinoma xenograft response to docetaxel chemotherapy.     

New vaccine targeting EGF receptor offers hope for glioma patients

Diffusion-weighted MRI (DW-MRI) has received more attention recently, especially from uroradiologists, owing to its role in the characterization of renal lesions. Moreover, the apparent diffusion coefficient (ADC), a value calculated based on DW-MRIs, has been used to analyze renal lesions quantitatively. However, many factors influence the accuracy of the ADC value calculation during the DW-MRI procedure. In addition, it is of great interest whether DW-MRI is superior to more conventional dynamic contrast-enhanced (DCE)-MRI for the characterization of renal lesions, or whether DW-MRI combined with DCE-MRI may provide more valuable information. Here we review state-of-the-art DW-MRI for the evaluation of renal cell carcinomas, discuss factors that influence the calculation of ADC maps, examine the impact of field strength on ADC values and, finally, compare DW-MRI and DCE-MRI for imaging renal lesions.     

Apparent diffusion coefficient by diffusion-weighted magnetic resonance imaging as a sole biomarker for staging and prognosis of gastric cancer

Objective:To investigate the role of apparent diffusion coefficient (ADC) from diffusion-weighted magnetic resonance imaging (DW-MRI) when applied to the 7th TNM classification in the staging and prognosis of gastric cancer (GC).Methods:Between October 2009 and May 2014,a total of 89 patients with non-metastatic,biopsy proven GC underwent 1.ST DW-MRI,and then treated with radical surgery.Tumor ADC was measured retrospectively and compared with final histology following the 7th TNM staging (local invasion,nodal involvement and according to the different groups — stage Ⅰ,Ⅱ and Ⅲ).Kaplan-Meier curves were also generated.The follow-up period is updated to May 2016.Results:Median follow-up period was 33 months and 45/89 (51％) deaths from GC were observed.ADC was significantly different both for local invasion and nodal involvement (P＜0.001).Considering final histology as the reference standard,a preoperative ADC cut-off of 1.80×10-3 mm2/s could distinguish between stages Ⅰ and Ⅱ and an ADC value of≤1.36×10-3 mm2/s was associated with stage Ⅲ (P＜0.001).Kaplan-Meier curves demonstrated that the survival rates for the three prognostic groups were significantly different according to final histology and ADC cut-offs (P＜0.001).Conclusions:ADC is different according to local invasion,nodal involvement and the 7th TNM stage groups for GC,representing a potential,additional prognostic biomarker.The addition of DW-MRI could aid in the staging and risk stratification of GC.     

A Prospective Study of Diffusion-weighted Magnetic Resonance Imaging as an Early Prognostic Biomarker in Chemoradiotherapy in Squamous Cell Carcinomas of the Anus

AimsThe use of diffusion-weighted magnetic resonance imaging (DW-MRI) as a prognostic marker of treatment response would enable early individualisation of treatment. We aimed to quantify the changes in mean apparent diffusion coefficient (ΔADC_mean) between a DW-MRI at diagnosis and on fraction 8–10 of chemoradiotherapy (CRT) as a biomarker for cellularity, and correlate these with anal squamous cell carcinoma recurrence.Materials and methodsThis prospective study recruited patients with localised anal cancer between October 2014 and November 2017. DW-MRI was carried out at diagnosis and after fraction 8–10 of radical CRT. A region of interest was delineated for all primary tumours and any lymph nodes >2 cm on high-resolution T₂-weighted images and propagated to the ADC map. Routine clinical follow-up was collected from Nation Health Service electronic systems.ResultsTwenty-three of 29 recruited patients underwent paired DW-MRI scans. Twenty-six regions of interest were delineated among the 23 evaluable patients. The median (range) tumour volume was 13.6 cm³ (2.8–84.9 cm³). Ten of 23 patients had lesions with ΔADC_mean ≤ 20%. With a median follow-up of 41.2 months, four patients either failed to have a complete response to CRT or subsequently relapsed. Three of four patients with disease relapse had lesions demonstrating ΔADC_mean <20%, the other patient with persistent disease had ΔADC_mean of 20.3%.ConclusionsWe demonstrated a potential correlation between patients with ΔADC_mean <20% and disease relapse. Further investigation of the prognostic merit of DW-MRI change is needed in larger, prospective cohorts.     

Acute tumour response to the MEK1/2 inhibitor selumetinib (AZD6244, ARRY-142886) evaluated by non-invasive diffusion-weighted MRI

Background:

Non-invasive imaging biomarkers underpin the development of molecularly targeted anti-cancer drugs. This study evaluates tumour apparent diffusion coefficient (ADC), measured by diffusion-weighted magnetic resonance imaging (DW-MRI), as a biomarker of response to the MEK1/2 inhibitor selumetinib (AZD6244, ARRY-142886) in human tumour xenografts.

Methods:

Nude mice bearing human BRAF^V600D WM266.4 melanoma or BRAF^V600E Colo205 colon carcinoma xenografts were treated for 4 days with vehicle or selumetinib. DW-MRI was performed before and 2 h after the last dose and excised tumours analysed for levels of phospho-ERK1/2, cleaved caspase 3 (CC3) and necrosis.

Results:

Selumetinib treatment induced tumour stasis and reduced ERK1/2 phosphorylation in both WM266.4 and Colo205 tumour xenografts. Relative to day 0, mean tumour ADC was unchanged in the control groups but was significantly increased by up to 1.6-fold in selumetinib-treated WM266.4 and Colo205 tumours. Histological analysis revealed a significant increase in necrosis in selumetinib-treated WM266.4 and Colo205 xenografts and CC3 staining in selumetinib-treated Colo205 tumours relative to controls.

Conclusion:

Changes in ADC following treatment with the MEK1/2 inhibitor selumetinib in responsive human tumour xenografts were concomitant with induction of tumour cell death. ADC may provide a useful non-invasive pharmacodynamic biomarker for early clinical assessment of response to selumetinib and other MEK-ERK1/2 signalling-targeted therapies.     

Comparison of noninvasive MRT procedures for temperature measuremnt for the application of medical heat therapies

Novel methods for hyperthermia tumor therapy, such as high-intensity focused ultrasound (HIFU) or laser-induced thermotherapy (LITT), require accurate non-invasive temperature monitoring. Non-invasive temperature measurement using magnetic resonance imaging (MRI) is based on the analysis of changes in longitudinal relaxation time (T1), diffusion coefficient (D), or water proton resonance frequency (PRF). The purpose of this study was the development and comparative analysis of the three different approaches of MRI temperature monitoring (T1, D, and PRF). Measurements in phantoms (e.g., ultrasound gel) resulted in the following percent changes: T1-relaxation time: 1.98%/degree C; diffusion coefficient: 2.22%/degree C; and PRF: -0.0101 ppm/degree C. All measurements were in good agreement with the literature. Temperature resolutions could also be measured from the inverse correlation of the data over the whole calibration range: T1: 2.1 +/- 0.6 degrees C; D: 0.93 +/- 0.2 degree C; and PRF: 1.4 +/- 0.3 degrees C. The diffusion and PRF methods were not applicable in fatty tissue. The use of the diffusion method was restricted due to prolonged echo time and anisotropic diffusion in tissue. Initial tests with rabbit muscle tissue in vivo indicated that MR thermometry via T1 and PRF procedures is feasible to monitor the local heating process induced by HIFU. The ultrasound applicators in the MR scanner did not substantially interfere with image quality.     

Applications of diffusion-weighted magnetic resonance imaging in renal cell carcinoma

Diffusion-weighted MRI (DW-MRI) has received more attention recently, especially from uroradiologists, owing to its role in the characterization of renal lesions. Moreover, the apparent diffusion coefficient (ADC), a value calculated based on DW-MRIs, has been used to analyze renal lesions quantitatively. However, many factors influence the accuracy of the ADC value calculation during the DW-MRI procedure. In addition, it is of great interest whether DW-MRI is superior to more conventional dynamic contrast-enhanced (DCE)-MRI for the characterization of renal lesions, or whether DW-MRI combined with DCE-MRI may provide more valuable information. Here we review state-of-the-art DW-MRI for the evaluation of renal cell carcinomas, discuss factors that influence the calculation of ADC maps, examine the impact of field strength on ADC values and, finally, compare DW-MRI and DCE-MRI for imaging renal lesions.     

Detection of head and neck squamous cell carcinoma with diffusion weighted MRI after (chemo)radiotherapy: correlation between radiologic and histopathologic findings

PURPOSE: To investigate the value of diffusion weighted magnetic resonance imaging (DW-MRI) in differentiating persistent or recurrent head and neck squamous cell carcinoma (HNSCC) from nontumoral postradiotherapeutic alterations. METHODS AND MATERIALS: In 26 patients with suspicion of persistent or recurrent HNSCC, MRI of the head and neck was performed, including routine turbo spin-echo (TSE) sequences and an additional echo-planar DW-MRI sequence, using a large range of b-values (0-1000 s/mm(2)). Apparent diffusion coefficient (ADC) maps were calculated. In the suspect areas at the primary site and in the suspect lymph nodes, signal intensity was measured on the native b0 and b1000 images and ADC values were calculated for these tissues. The same was done for surrounding irradiated normal tissue. Imaging results were correlated to histopathology. RESULTS: Signal intensity on native b0 images was significantly lower for HNSCC than for nontumoral postradiotherapeutic tissue (p < 0.0001), resulting in a sensitivity of 66.2%, specificity of 60.8%, and accuracy of 62.4%. Signal intensity on native b1000 images was significantly higher for HNSCC than for nontumoral tissue (p < 0.0001), resulting in a sensitivity of 71.6%, specificity of 71.3%, and accuracy of 71.4%. ADC values were significantly lower for HNSCC than for nontumoral tissue (p < 0.0001), resulting in a sensitivity of 94.6%, specificity of 95.9%, and accuracy of 95.5%. When compared with computed tomography, TSE-MRI and fluorodeoxyglucose-positron emission tomography, DW-MRI yielded fewer false-positive results in persistent primary site abnormalities and in persistent adenopathies, and aided in the detection of subcentimetric nodal metastases. CONCLUSIONS: Diffusion weighted-MRI accurately differentiates persistent or recurrent HNSCC from nontumoral tissue changes after (chemo)radiotherapy.     

Diffusion-weighted magnetic resonance imaging allows noninvasive in vivo monitoring of the effects of combretastatin a-4 phosphate after repeated administration

The noninvasive assessment of anticancer treatment efficacy is very important for the improvement of therapeutic window. The purpose of the present study was to evaluate the antitumoral effects of the vascular targeting agent, combretastatin A-4 phosphate (CA-4-P), at selected time points after repeated intraperitoneal drug administrations (25 mg/kg), using diffusion-weighted magnetic resonance imaging (DW-MRI). The experiments were performed during an overall follow-up period of 3 weeks on WAG/Rij rats with subcutaneously growing rhabdomyosarcomas. Each animal served as its own baseline. The DW-MRI studies were quantified by calculating the apparent diffusion coefficient (ADC) for different low and high b-values to separate the effects on tumor vasculature and cellular integrity. The changes in ADC as well as the extent of necrosis development (proportional to the tumor volume), measured on the MR images, were of comparable magnitude after each treatment. All ADC values showed a significant decrease at 6 hours, followed by a significant increase at 2 days for various CA-4-P administrations. DW-MRI allowed us to monitor both reduction in perfusion and changes in the extent of tumor necrosis after CA-4-P injection. Repeated CA-4-P administration retains efficacy in rat rhabdomyosarcomas, with similar findings after each drug administration.     

Assessing response to treatment of bone metastases from breast cancer: what should be the standard of care?

Bone is the most common site for breast cancer metastases, occurring in up to 70% of those with metastatic disease. In order to effectively manage these patients, it is essential to have consistent, reproducible and validated methods of assessing response to therapy. We present current clinical practice of imaging response assessment of bone metastases. We also review the biology of bone metastases and measures of response assessment including clinical assessment, tumour markers and imaging techniques; bone scans (BSs), computed tomography (CT), positron emission tomography, magnetic resonance imaging (MRI) and whole-body diffusion-weighted MRI (WB DW-MRI). The current standard of care of BSs and CT has significant limitations and are not routinely recommended for the purpose of response assessment in the bones. WB DW-MRI has the potential to address this unmet need and should be evaluated in clinical trials.     

Developments in nuclear magnetic resonance imaging and spectroscopy: application to radiation oncology

Nuclear magnetic resonance techniques have advanced to the point where functional, physiologic, and biochemical information may be obtained from patients. Magnetic resonance imaging of tissue water can be used to measure perfusion and diffusion with submillimeter resolution. Magnetic resonance spectroscopy may be applied to the assessment of tissue metabolites that contain protons, phosphorus, fluorine, or other nuclei. The combination of imaging and spectroscopy technologies has lead to spectroscopic imaging techniques that are capable of mapping proton metabolites at resolutions as small as 0.25 cm(3) within the time constraints of a clinical imaging study. This article provides a brief review of magnetic resonance techniques for imaging of tissue physiological function and addresses possible applications in the realm of radiation oncology.     

Correlation of diffusion MRI with the Ki-67 index in non-small cell lung cancer

Background

The primary objective of the study was to evaluate the association between the minimum apparent diffusion coefficient (ADC_min) and Ki-67, an index for cellular proliferation, in non-small cell lung cancers. Also, we aimed to assess whether ADC_min values differ between tumour subtypes and tissue sampling method.

Methods

The patients who had diffusion weighted magnetic resonance imaging (DW-MRI) were enrolled retrospectively. The correlation between ADC_min and the Ki-67 index was evaluated.

Results

Ninety three patients, with a mean age 65 ± 11 years, with histopathologically proven adenocarcinoma and squamous cell carcinoma of the lungs and had technically successful DW-MRI were included in the study. The numbers of tumour subtypes were 47 for adenocarcinoma and 46 for squamous cell carcinoma. There was a good negative correlation between ADC_min values and the Ki-67 proliferation index (r = −0.837, p < 0.001). The mean ADC_min value was higher and the mean Ki-67 index was lower in adenocarcinomas compared to squamous cell carcinoma (p < 0.0001). There was no statistical difference between tissue sampling methods.

Conclusions

Because ADC_min shows a good but negative correlation with Ki-67 index, it provides an opportunity to evaluate tumours and their aggressiveness and may be helpful in the differentiation of subtypes non-invasively.     

Diffusion-weighted MRI for imaging cell death after cytotoxic or apoptosis-inducing therapy

Background:

Non-invasive serial imaging is desirable to detect processes such as necrotic and apoptotic cell death in cancer patients undergoing treatment. This study investigated the use of diffusion-weighted (DW-) magnetic resonance imaging (MRI) for imaging cell death induced by either a cytotoxic drug (irinotecan), or the apoptosis-inducing agent birinapant, in human tumour xenografts in vivo.

Methods:

Nude mice bearing human SW620 colon carcinoma xenografts were treated with vehicle, irinotecan (50 mg kg⁻¹) or birinapant (30 mg kg⁻¹) for up to 5 days. DW-MRI was performed prior to and on days 1, 3 and 5 during treatment. Assessment of tumour apoptosis and necrosis ex vivo was used to validate the imaging findings.

Results:

Both irinotecan and birinapant induced significant tumour growth delay. Irinotecan induced a small increase in the tumour apparent diffusion coefficient (ADC) after 1 day, with a 20 and 30% increase at days 3 and 5 respectively. ADC was unchanged in the vehicle- and birinapant-treated tumours despite a growth delay in the latter. Histological analysis showed that irinotecan increased necrosis at days 3 and 5, and induced apoptosis after 1 day, compared with vehicle. Birinapant induced apoptosis after day 3, but had no effect on tumour necrosis.

Conclusions:

Tumour ADC changes after irinotecan treatment were associated with the induction of a mixture of necrotic and apoptotic cell death, whereas induction of apoptosis alone with birinapant was not sufficient to induce changes in tissue microstructure that were detectable with DW-MRI. ADC is a useful non-invasive biomarker for early detection of response to cytotoxic drugs, but false negatives may arise while detecting apoptotic response to birinapant.     

Utility of functional diffusion maps to monitor a patient diagnosed with gliomatosis cerebri

Diffusion-weighted magnetic resonance imaging (DWI) is a sensitive imaging biomarker for tumor cellularity. Functional diffusion maps (fDMs), which examine voxel-by-voxel changes in the apparent diffusion coefficient (ADC) calculated from serial DWIs, have previously been applied to regions of contrast-enhancement; however, application of fDMs to non-enhancing brain tumors has not been pursued. In this case study we demonstrate the utility of applying fDMs to regions of abnormal FLAIR signal intensity in a patient diagnosed with gliomatosis cerebri: a relatively rare, infiltrative, non-enhancing brain tumor. The absolute volume of hypercellularity extracted from fDMs was useful in tracking tumor growth, which correlated in time with a progressive decline in neurological status despite no change in traditional magnetic resonance images. Results of this study demonstrate the value of fDMs, applied to regions of FLAIR abnormal signal intensity, for localizing regions of hypercellularity and for monitoring overall tumor status.     

Technology insight: water diffusion MRI--a potential new biomarker of response to cancer therapy

Diffusion-weighted MRI (DW-MRI) is a functional imaging technique that displays information about the extent and direction of random water motion in tissues. Water movement in tissues is modified by interactions with hydrophobic cellular membranes, intracellular organelles and macromolecules. DW-MRI provides information on extracellular-space tortuosity, tissue cellularity and the integrity of cellular membranes. Images can be sensitive to large or small displacements of water, therefore, macroscopic water flows and microscopic water displacements in the extracellular space can be depicted. Preclinical and clinical data indicate a number of potential roles of DW-MRI in the characterization of malignancy, including determination of lesion aggressiveness and monitoring response to therapy. This Review outlines the biological basis of observations made on DW-MRI and describes how measurements are acquired and quantified, and discusses the interpretation of images and limitations of the technique. The strength of evidence for adoption of DW-MRI as a biomarker for the assessment of tumor response is presented.