Junjeong Choi

Perfusion MRI for the prediction of treatment response after preoperative chemoradiotherapy in locally advanced rectal cancer

ObjectivesTo evaluate the utility of perfusion MRI as a potential biomarker for predicting response to chemoradiotherapy (CRT) in locally advanced rectal cancer.MethodsThirty-nine patients with primary rectal carcinoma who were scheduled for preoperative CRT were prospectively recruited. Perfusion MRI was performed with a 3.0-T MRI system in all patients before therapy, at the end of the 2nd week of therapy, and before surgery. The Ktrans (volume transfer constant) and Ve (extracellular extravascular space fraction) were calculated.ResultsBefore CRT, the mean tumour Ktrans in the downstaged group was significantly higher than that in the non-downstaged group (P = 0.0178), but there was no significant difference between tumour regression grade (TRG) responders and TRG non-responders (P = 0.1392). Repeated-measures analysis of variance (ANOVA) showed significant differences for evolution of Ktrans values both between downstaged and non-downstaged groups (P = 0.0215) and between TRG responders and TRG non-responders (P = 0.0001). Regarding Ve, no significant differences were observed both between downstaged and non-downstaged groups (P = 0.689) or between TRG responders and TRG non-responders (P = 0.887).ConclusionPerfusion MRI of rectal cancer can be useful for assessing tumoural Ktrans changes by CRT. Tumours with high pre-CRT Ktrans values tended to respond favourably to CRT, particularly in terms of downstaging criteria.Key Points• Perfusion MRI can now assess therapeutic response of tumours to therapy.• Tumours with high initialKtransvalues responded favourably to chemoradiotherapy.• Perfusion MRI of rectal cancer may help with decisions about management.

PREDICTION OF SOLID-STATE AMORPHIZING REACTION USING EFFECTIVE DRIVING FORCE

It is proposed that the nucleation and growth of the amorphous phase through the solid‐state amorphizing reaction in thin‐film diffusion couples can be predicted by using the concept of effective driving force. The effective driving force consists of two factors: (i) the thermodynamic driving force given by maximum free‐energy difference between the physical mixture of binary elements and the amorphous phase (ΔGmax), and (ii) the kinetic factor given by a ratio of the effective radius of the interstitial site in the host matrix to the atomic radius of the diffusing species (Rm/d). From the comparison of reported experimental results, it is shown that the criterion of effective driving force holds well for predicting the nucleation of the amorphous phase in metal/silicon systems as well as that of metal/metal systems. In addition, the concept of effective driving force holds well for predicting the growth tendency of the amorphous phase in metal/silicon systems.

Thymidylate Synthase Gene Polymorphism Affects the Response to Preoperative 5-Fluorouracil Chemoradiation Therapy in Patients With Rectal Cancer

PURPOSE This study aims to correlate thymidylate synthase (TS) gene polymorphisms with the tumor response to preoperative 5-fluorouracil (5-FU)-based chemoradiation therapy (CRT) in patients with rectal cancer. METHODS AND MATERIALS Forty-four patients with rectal cancer treated with 5-FU-based preoperative CRT were prospectively enrolled in this study. Thymidylate synthase expression and TS gene polymorphisms were evaluated in tumor obtained before preoperative CRT and were correlated with the pathologic response, as assessed by histopathologic staging (pTNM) and tumor regression grade. RESULTS Patients exhibited 2R/3R and 3R/3R tandem repeat polymorphisms in the TS gene. With regard to TS expression in these genotypes, 2R/3RC and 3RC/3RC were defined as the low-expression group and 2R/3RG, 3RC/3RG, and 3RG/3RG as the high-expression group. There was no significant correlation between TS expression and tumor response. There was no significant difference in the tumor response between patients homozygous for 3R/3R and patients heterozygous for 2R/3R. However, 13 of 14 patients in the low-expression group with a G>C single-nucleotide polymorphism (SNP) (2R/3RC [n = 5] or 3RC/3RC [n = 9]) exhibited a significantly greater tumor downstaging rate, as compared with only 12 of 30 patients in the high-expression group without the SNP (2R/3RG [n = 10], 3RC/3RG [n = 9], or 3RG/3RG [n = 11]) (p = 0.001). The nodal downstaging rate was also significantly greater in this low-expression group, as compared with the high-expression group (12 of 14 vs. 14 of 30, p = 0.014). However, there was no significant difference in the tumor regression grade between these groups. CONCLUSIONS This study suggests that SNPs within the TS enhancer region affect the tumor response to preoperative 5-FU-based CRT in rectal cancer.

Efficient gene transfer of VSV-G pseudotyped retroviral vector to human brain tumor

A retroviral vector constructed from the murine leukemia virus (MLV) can only express transgenes in cells undergoing mitosis, indicating its suitability as a delivery vehicle for cancer gene therapy. However, the transduction efficiency (TE) of retroviruses embedding endogenous envelope proteins in human cancer cells was found to be unsatisfactory. Recently, several research groups have demonstrated the feasibility of a retroviral vector pseudotyped with a vesicular stomatitis virus G (VSV-G) protein. In this study, the potential of VSV-G pseudotyped MLV-based retrovirus was examined as a delivery vehicle in a variety of human cancer cells including brain tumor cells in vitro and in vivo. The transduction efficiency of the 293T/G/GP/LacZ retrovirus in cell culture was superior in most cancer cells, particularly in brain tumor cells, compared with that of other retroviruses, such as PA317- or PG13-derived. The relative growth rate and phosphatidylserine expression level on the plasma membrane of target cells mainly influenced the transduction efficiency of VSV-G pseudotyped retrovirus, which suggested that both the relative growth rate and phosphatidylserine expression level were major determinants of TE. Furthermore, 293T/G/GP/LacZ could efficiently transduce human cancer cells regardless of the presence of chemical additives, whereas in other retroviruses, cationic chemical additives such as polybrene or liposomes were essential during virus infection. Finally, an average of 10% gene expression was routinely obtained exclusively in the tumor mass when 293T/G/GP/LacZ concentrated by simple ultracentrifugation was directly administrated to pre-established brain tumors in animal models (U251-N nu/nu mice or C6 Wistar rats). All told, the present study suggests that the VSV-G pseudotyped retrovirus is a suitable vector for brain tumor gene therapy.

Preservation of lymphatic drainage from arm in breast cancer surgery: is it safe?.

Abstract #201 Purpose: Sentinel lymph node biopsy (SLNB) for breast cancer was introduced to prevent the high morbidity seen with Axillary lymph node dissection (ALND). Although multiple comparison studies have confirmed that SLNB consistently has lower morbidity and lymphedema rates than ALND; it is still clinically significant ranging from 0∼13%. The aim of this study was to confirm the feasibility of the technique, so called Axillary reverse mapping (ARM), and to test the hypothesis that arm lymphatics are never involved by the metastatic process of breast cancer.
 Methods: We reviewed prospectively maintained database of 129 patients who operated for primary breast cancer since June 2007. Sentinel lymph nodes (SLNs) were identified by using a radiolabeled isotope (TC99m-phytate or human serum albumin). Under general anesthesia, 2.5∼3 mL of blue dye was injected in the upper inner arm along the medial intramuscular groove of ipsilateral arm in order to locate the draining lymphatics or lymph node from the arm. We then proceeded as usual with the SLNB or ALND. During axillary procedure, we take the blue node (ARM node) and SLN (hot node), and both were sent to pathology department for frozen section analysis. If SLNs were positive, ALND was performed and axillary contents were sent to pathology. Histological results of ARM node were compared with that of the other nodes of the SLNB or ALND.
 Results: The mean age of patients was 48.3 years old (rang 27∼73). Surgeries included 41 mastectomies, 80 breast conserving surgeries and eight skin sparing mastectomies with immediate reconstruction. Of the 129 procedures, 81 were in SLNB (62.8%), 43 SLNB+ALND (33.3%), and five ALND. One hundred one of 129 (78.3%) blue ARM nodes were identified in the axilla. The average number of removed ARM node was 1.5 (range 1∼5). In 19 of 96 SLNB cases, the ARM nodes were hot, yielding 18.9% of concordance rate between ARM node and SLN. Among these 19 cases, seven ARM nodes contained metastasis. In one SLNB case, the metastatic ARM node was not hot. In all five ALND cases, ARM nodes were identified and one of five ARM nodes was positive for metastasis. Thus, ARM node metastasis rate of identified ARM node during ARM procedure was 8.9% (9/101).
 Conclusion: According to our study, it is thought that lymphatic drainage from arm share common lymphatic channel in axilla with lymphatic flow from breast. Therefore, intentional preservation of lymphatics or lymph node drained from arm during performing axillary surgery in breast cancer could be a dangerous one. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 201.

Perfusion Parameters of Dynamic Contrast-Enhanced Magnetic Resonance Imaging in Patients with Rectal Cancer: Correlation with Microvascular Density and Vascular Endothelial Growth Factor Expression

Objective To determine whether quantitative perfusion parameters of dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) correlate with immunohistochemical markers of angiogenesis in rectal cancer. Materials and Methods Preoperative DCE-MRI was performed in 63 patients with rectal adenocarcinoma. Transendothelial volume transfer (Ktrans) and fractional volume of the extravascular-extracellular space (Ve) were measured by Interactive Data Language software in rectal cancer. After surgery, microvessel density (MVD) and vascular endothelial growth factor (VEGF) expression scores were determined using immunohistochemical staining of rectal cancer specimens. Perfusion parameters (Ktrans, Ve) of DCE-MRI in rectal cancer were found to be correlated with MVD and VEGF expression scores by Spearmans rank coefficient analysis. T stage and N stage (negative or positive) were correlated with perfusion parameters and MVD. Results Significant correlation was not found between any DCE-MRI perfusion parameters and MVD (rs = -0.056 and p = 0.662 for Ktrans; rs = -0.103 and p = 0.416 for Ve), or between any DCE-MRI perfusion parameters and the VEGF expression score (rs = -0.042, p = 0.741 for Ktrans; r = 0.086, p = 0.497 for Ve) in rectal cancer. TN stage showed no significant correlation with perfusion parameters or MVD (p > 0.05 for all). Conclusion DCE-MRI perfusion parameters, Ktrans and Ve, correlated poorly with MVD and VEGF expression scores in rectal cancer, suggesting that these parameters do not simply denote static histological vascular properties.

Feasibility of Interstitial CT Lymphography Using Optimized Iodized Oil Emulsion in Rats

Objectives:To formulate an iodine-based contrast agent with an oil-in-water emulsion and to evaluate the feasibility of the agent for use as an interstitial computed tomographic (CT) lymphographic agent in a normal rat model. Materials and Methods:The effect of iodized oil (lipiodol) content and the type of surfactant/cosurfactant on the resultant emulsion size and polydispersity was investigated to obtain an optimized lipiodol emulsion for CT lymphography. Optimized emulsions (144 mg/mL) were injected in the hind paws of 6 rats, using 0.5 mL per paw. As control groups, iopamidol solution and lipiodol diluted with squalene to adjust the injection volume with iodine concentration equivalent to the emulsions were used. Precontrast and postcontrast CT images up to 1 week after contrast agent injection were obtained. Time-enhancement curves of the popliteal lymph nodes were obtained. Analysis of variance and post hoc analysis with the Dunn procedure were used for comparing mean peak enhancement, time to peak enhancement, and sustained duration of contrast enhancement. Results:Optimized emulsion formulations composed of 30% lipiodol and 282 mg/mL of 9:1 surfactant mixture (Tween 80:TPGS [alpha-tocopheryl polyethylene glycol succinate], Tween 80:Kollidon 12 PF, or Tween 80:Span 85) exhibited mean particle size less than 120 nm, and they were stable without significant particle size change up to 1 month. Targeted lymph nodes in all emulsion groups showed continuously increasing enhancement until 4 or 8 hours after injection, followed by continuous washout. Peak enhancement (time to peak enhancement) was 172.4 ± 54.5 HU (Hounsfield unit) (384.0 ± 131.5 minutes) for Tween 80:TPGS; 172.8 ± 28.0 HU (432.0 ± 107.3 minutes) for Tween 80:Kollidon 12 PF, and 177.2 ± 68.9 HU (294.0 ± 190.2 minutes) for Tween 80:Span 85. For iopamidol, peak enhancement of 153.0 ± 46.1 HU (0.5 ± 0.5 minutes) occurred early with rapid washout. For lipiodol as a reference agent, contrast enhancement continuously increased even 1 week after injection without washout (peak enhancement, 486.0 ± 97.4 HU). Peak enhancement among the emulsion groups and the iopamidol group was not statistically different (P = 0.95). All emulsion groups showed more prolonged enhancement than the iopamidol group; enhancement duration for the emulsion groups was 534.0 ± 481.1 minutes for Tween 80:TPGS; 957.0 ± 524.8 minutes for Tween 80:Kollidon 12 PF; and 750.0 ± 566.0 minutes for Tween 80:Span 85, and enhancement duration for iopamidol was 8.2 ± 12.3 minutes (all P < 0.05 in multiple comparisons). However, there was no significant difference in enhancement duration among the 3 emulsion groups (P > 0.05). Conclusions:Iodized oil emulsion made with a surfactant mixture (Tween 80 as the main surfactant and TPGS, Kollidon 12 PF, or Span 85 as the cosurfactant) provided sufficient and sustained contrast enhancement on CT of targeted lymph nodes with washout on delayed phase.

Concordant or Discordant? Imaging-Pathology Correlation in a Sonography-Guided Core Needle Biopsy of a Breast Lesion

An imaging-guided core needle biopsy has been proven to be reliable and accurate for the diagnosis of both benign and malignant diseases of the breast, and has replaced surgical biopsy. However, the possibility of a false-negative biopsy still remains. Imaging-pathology correlation is of critical importance in imaging-guided breast biopsies to detect such a possible sampling error and avoid a delay in diagnosis. We will review five possible categories and corresponding management after performing an imaging-pathology correlation in a sonography-guided core needle biopsy of a breast lesion, as well as illustrate the selected images for each category in conjunction with the pathologic finding. Radiologists should be familiar with the imaging features of various breast pathologies and be able to appropriately correlate imaging findings with pathologic results after a core needle biopsy.

The role of tumor-associated macrophage in breast cancer biology

Breast cancer is the most commonly diagnosed malignant tumor in women worldwide and contributes significantly as the primary cause of female cancer related mortality. Hence, research is focused on discovering new and effective treatment targets. The breast tumor microenvironment (TME) comprising of recruited host stromal cells and tumor cells, has recently emerged as an important player in tumor progression, with the potential for future treatment. The TME comprises immune system elements (such as macrophages and lymphocytes), cells composing blood vessel, fibroblast, myofibroblast, mesenchymal stem cells, adipocytes and extracellular matrix (ECM). Among these cells, tumor-associated macrophages (TAM) are the prominent components of TME in breast cancers. Macrophages exhibit a high plasticity in response to various external signals and participate in innate and adoptive immune responses to control numerous factors of TME. Depending on the microenvironmental signal present, macrophages are polarized into two distinct phenotypes, the classically activated (M1) or the alternative activated (M2) macrophages. Tumor-associated macrophages (TAMs) closely resemble the M2-polarized. Clinicopathological studies have suggested that TAM accumulation in tumors correlates with a poor clinical outcome. In human breast carcinomas, high TAM density correlates with poor prognosis. Over the years, studies into the role of TAMs in breast cancer progression have identified TAMs to be capable of inducing angiogenesis, remodelling the tumor extracellular matrix to aid invasion, modelling breast cancer cells to evade host immune system and recruiting immunosuppressive leukocytes to the tumor microenvironment. Along with these functions, the potential role for TAMs in activation of breast cancer stem cells (CSC) has also emerged. Thus, TAMs in breast cancer can enhance cancer cell invasion by degrading the ECM, stimulate tumor vascularization and angiogenesis and suppress the anti-tumor functions of cytotoxic T cells resulting in poor prognosis for patients. These observations make TAMs an attractive target for therapeutic intervention by targeting various aspects of their function. This review discusses the mechanisms responsible for TAM recruitment and highlights the roles of TAMs in regulating tumor angiogenesis, invasion, metastasis, immunosuppression, and chemotherapeutic resistance. Finally, the potential for TAM-targeted therapy as a promising novel strategy is also discussed.

Adipocyte biology in breast cancer: From silent bystander to active facilitator

Adipocytes account for the largest proportion among the cells that comprise breast tissue; therefore, they are considered to be a critical cell type in the tumor microenvironment of breast cancer. In breast cancer, adipocytes are not only found adjacent to cancer cells, but they also play an active role in the entire process of cancer development, progression, metastasis, and treatment response. Factors including the secretion of adipokines such as leptin and adiponectin, as well as autotaxin, interleukin 6, tumor necrosis factor alpha, and hepatic growth factor, metabolic remodeling that supports the growth of breast cancer by transfer of fatty acids to increase mitochondrial β-oxidation, extracellular matrix remodeling and endotrophin production from type IV collagen, and cancer-associated fibroblast phenotype changes have all been implicated in this comprehensive process. Moreover, adipocytes may act as obstacles to therapy, as they are involved in mechanisms of resistance against various breast cancer treatments. Adipose tissues may also be a reservoir for dormant tumor cells during postsurgical autologous fat grafting. Thus, adipocytes, and the processes and pathways in which they are involved, could be effective therapeutic targets for breast cancer. In this review, we focus on the current understanding of adipocyte biology as it affects breast cancer.