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CT of Non-Small Cell Lung Cancer (NSCLC): Histopathological Correlates for Texture Parameters
Abstract
PURPOSE
To correlate CT texture with histopathological markers for angiogenesis and hypoxia.
METHOD AND MATERIALS
Following IRB approval and informed consent, 13 patients (8 male, 5 female, mean age 65.2 years, mean tumor size 5.1 cm) with primary NSCLC underwent CT followed by IV administration of Pimonidazole (0.5mg/m2), an exogenous marker of hypoxia, 24hours prior to surgery. Texture was assessed for the unenhanced and contrast-enhanced CT images using TexRAD, a software algorithm that selectively filters and extracts texture at different anatomical scales between σ=0.5 (fine detail) and σ=2.5 (coarse features) with quantification of mean gray-level intensity. Following surgery, matched tumor sections underwent immunohistochemical staining using the avidin-biotin complex method for angiogenesis, CD34, and for intrinsic and extrinsic markers of hypoxia, GLUT-1 and Pimonidazole respectively. The fraction of the tumor stained for each marker was assessed.
RESULTS
Texture parameters significantly correlated with intrinsic and extrinsic markers of hypoxia for unenhanced and enhanced CT. Particularly CT texture correlated inversely with GLUT-1 (unenhanced CT relative texture i.e. σ=1.0/σ=1.5, r = -0.56, p <0.001) and positively with Pimonidazole (contrast-enhanced CT texture i.e. σ=1.0, r = 0.60, p <0.0005). There were no significant correlations between texture and angiogenesis.
CONCLUSION
Texture parameters derived from CT images on NSCLC have the potential to act as imaging correlates for tumour hypoxia.
CLINICAL RELEVANCE/APPLICATION
As hypoxia is an adverse feature associated with treatment resistance and reduced survival, texture analysis could provide prognostic information for patients with NSCLC.
... The feasibility of combining medical imaging parameters to predict KRAS mutations has been proven in some previous studies. [17][18][19] In the study by Lovinfosse et al, 20 showed that KRAS mutations were associated with N stage, gross tumor pattern, axial length of the tumor, and the ratio of the axial to the longitudinal dimensions of the tumor on MRI. So far as we know, there is no study that focuses on the correlation between CT image features and KRAS status of rectal cancer. ...
Background:
The purpose of this study was to investigate the feasibility of CT parameters to predict the presence of KRAS mutations in rectal cancer patients. The relationship between the presence of a KRAS mutation and pathological findings was evaluated simultaneously.
Methods:
Eighty-nine patients (29 females, 60 males, age 27-90, mean 59.7±12 years) with pathologically proven rectal cancer were enrolled. A KRAS mutation test was completed following surgery. Parameters evaluated on CT included the tumor location, the diameter of the superior rectal vein (SRV) and inferior mesenteric vein (IMV), the presence of calcification, ulceration, lymph node enlargement (LNE), distant metastasis, tumor shape (intraluminal polypoid mass, infiltrative mass, or bulky), circumferential extent (C0-C1/4, C1/4-C1/2, C1/2-C3/4, or C3/4-C1), enhanced pattern (homogeneous or heterogeneous), CT ratio, and the length of the tumor (LOT). Pathological findings included lymphovascular emboli, signet ring cell, peripheral fat interval infiltration, focal ulcer, lymph node metastasis, tumor pathological type, and differentiation extent. The correlations between KRAS status and CT parameters, and KRAS status and pathological findings were investigated. The accuracy of CT characteristics for predicting KRAS mutation was evaluated.
Results:
A KRAS mutation was detected in 42 cases. On CT image, the diameter of the SRV was significantly increased in the KRAS mutation group compared to in the KRAS wild-type group (4.6±0.9 mm vs 4.2±0.9 mm, p=0.02), and LNE was more likely to occur in the KRAS mutation group (73.3% vs 26.7%, p=0.03). There was no significant difference between the KRAS mutation group and the KRAS wild-type group on the other CT parameters (location, IMV, calcification, ulcer, distant metastasis, tumor shape, enhanced pattern, circumferential extent, CT ratio, and LOT). In the pathological findings, a KRAS mutation was more likely to occur in the middle differentiation group (p=0.03). No significant difference was found between the KRAS mutation group and the KRAS wild-type group in the presence of lymphovascular emboli, signet ring cell, peripheral fat interval infiltration, focal ulcer, lymph node metastasis, and tumor pathological type. With the best cut-off value of 4.07 mm, the AUC of the SRV to predict a KRAS mutation was 0.63 with a sensitivity of 76.2% and a specificity of 48.9%.
Conclusion:
It was feasible to use the diameter of the SRV to predict a KRAS mutation in rectal cancer patients, and LNE also can be regarded as an important clue on preoperative CT images.
... However, medical imaging methods may disclose certain features associated with KRAS mutation. The feasibility of combining medical imaging parameters to predict KRAS mutation has been proven in some previous studies [16,17,18]. ...
Background The purpose of this study was to investigate the feasibility of CT parameters to predict the presence of KRAS mutation in rectal cancer patients. The relationship between KRAS mutation and pathological findings was evaluated simultaneously.
Methods 89 patients (29 females, 60 males, age 27–90, mean 59.7 ± 12 years) with pathologically proven rectal cancer were enrolled. KRAS mutation test was completed following surgery. Parameters evaluated on CT included the diameter of superior rectal vein (SRV) and inferior mesenteric vein (IMV), the presence of calcification, ulceration, lymph node enlargement (LNE), distant metastasis, tumor growth pattern (single nodule or annular thickening), enhanced pattern (homogeneous or heterogeneous), CT ratio and the length of tumor (LOT). Pathological findings included lymphovascular emboli, signet ring cell, peripheral fat interval infiltration, focal ulcer, lymph node metastasis, tumor pathological type and differentiation extent. The correlations between KRAS status and CT parameters, KRAS status and pathological findings were investigated. The accuracy of CT characteristics for predicting KRAS mutation was evaluated.
Results KRAS mutation was detected in 42 cases. On CT image, the diameter of SRV was significantly increased in KRAS mutation group than in KRAS wild-type group (4.6 ± 0.9 mm vs. 4.2 ± 0.9 mm, p = 0.02). And LNE was more likely to occur in KRAS mutation group (73.3% vs. 26.7%, p = 0.03). There was no significant difference between KRAS mutation group and KRAS wild-type group on the other CT parameters (IMV, calcification, ulcer, distant metastasis, tumor growth pattern, enhanced pattern, CT ratio and LOT). In pathological findings, KRAS mutation was more likely to occur in middle differentiation group (p = 0.03). No significant difference was found between KRAS mutation group and KRAS wild-type group in the presence of lymphovascular emboli, signet ring cell, peripheral fat interval infiltration, focal ulcer, lymph node metastasis, tumor pathological type. The AUC of SRV to predict KRAS mutation was 0.63.
Conclusion It was feasible to use the diameter of SRV to predict KRAS mutation in rectal cancer patients, and LNE also can be regarded as an important clue on preoperative CT images.
... CT texture analysis (CTTA) was performed using TexRAD (TexRAD Ltd, www.texrad.com, Cambridge, UK part of Feedback Plc www.fbk.com), a proprietary commercial research software algorithm [15][16][17]. The texture within lymphoma tumours was assessed by a physician by constructing tumour ROIs on CT, under the supervision of an imaging researcher (with > 9 years' of experience in CTTA) and a dual accredited Radiologist/Nuclear Medicine specialist (with > 10 years' of PET-CT experience). ...
Objectives:
The purpose of this study was to investigate the ability of computed tomography texture analysis (CTTA) to provide additional prognostic information in patients with Hodgkin's lymphoma (HL) and high-grade non-Hodgkin's lymphoma (NHL).
Methods:
This retrospective, pilot-study approved by the IRB comprised 45 lymphoma patients undergoing routine 18F-FDG-PET-CT. Progression-free survival (PFS) was determined from clinical follow-up (mean-duration: 40 months; range: 10-62 months). Non-contrast-enhanced low-dose CT images were submitted to CTTA comprising image filtration to highlight features of different sizes followed by histogram-analysis using kurtosis. Prognostic value of CTTA was compared to PET FDG-uptake value, tumour-stage, tumour-bulk, lymphoma-type, treatment-regime, and interim FDG-PET (iPET) status using Kaplan-Meier analysis. Cox regression analysis determined the independence of significantly prognostic imaging and clinical features.
Results:
A total of 27 patients had aggressive NHL and 18 had HL. Mean PFS was 48.5 months. There was no significant difference in pre-treatment CTTA between the lymphoma sub-types. Kaplan-Meier analysis found pre-treatment CTTA (medium feature scale, p=0.010) and iPET status (p<0.001) to be significant predictors of PFS. Cox analysis revealed that an interaction between pre-treatment CTTA and iPET status was the only independent predictor of PFS (HR: 25.5, 95% CI: 5.4-120, p<0.001). Specifically, pre-treatment CTTA risk stratified patients with negative iPET.
Conclusion:
CTTA can potentially provide prognostic information complementary to iPET for patients with HL and aggressive NHL.
Key points:
• CT texture-analysis (CTTA) provides prognostic information complementary to interim FDG-PET in Lymphoma. • Pre-treatment CTTA and interim PET status were significant predictors of progression-free survival. • Patients with negative interim PET could be further stratified by pre-treatment CTTA. • Provide precision surveillance where additional imaging reserved for patients at greatest recurrence-risk. • Assists in risk-adapted treatment strategy based on interim PET and CTTA.
Rationale and objectives:
The aim of our study was to assess the relationships between textural features extracted from contrast enhanced (CE) and noncontrast enhanced (NCE) computed tomography (CT) images of primary colorectal cancer, in order to identify radiomics features more likely to provide potential complementary information regarding outcome.
Materials and methods:
Sixty-one patients with primary colorectal cancer underwent both CE-CT and NCE-CT scans within the same acquisition. First-order and textural features (with three different methods for grey-level discretization) were extracted from the tumor volume in both modalities and their correlation was assessed with Spearman's rank correlation (rs). Significance was assessed at p < 0.05 with correction for multiple comparisons. Kaplan-Meier estimation and log-rank tests were used to identify features associated with long term patient survival.
Results:
Moderate positive correlations were observed between CE-CT and NCE-CT histogram-derived entropy (EntropyHist) and area under the curve (CHAUC) (rs = 0.49, p < 0.001 and rs= 0.45, p < 0.001, respectively). Some second and third order textural features were found highly correlated between CE-CT and NCE-CT, such as small zone-size emphasis SZSE (rs = 0.729, p < 0.001) and zone-size percentage (rs = 0.770, p < 0.001). Grey-levels discretization methods influenced these correlations. A few of the third order NCE-CT and CE-CT features were significantly associated with survival.
Conclusion:
Some radiomics features with moderate correlations between nonenhanced and enhanced CT images were found to be associated with survival, thus suggesting that complementary prognostic value may be extracted from both modalities when available.
Unlabelled:
There is evidence in some solid tumors that textural features of tumoral uptake in (18)F-FDG PET images are associated with response to chemoradiotherapy and survival. We have investigated whether a similar relationship exists in non-small cell lung cancer (NSCLC).
Methods:
Fifty-three patients (mean age, 65.8 y; 31 men, 22 women) with NSCLC treated with chemoradiotherapy underwent pretreatment (18)F-FDG PET/CT scans. Response was assessed by CT Response Evaluation Criteria in Solid Tumors (RECIST) at 12 wk. Overall survival (OS), progression-free survival (PFS), and local PFS (LPFS) were recorded. Primary tumor texture was measured by the parameters coarseness, contrast, busyness, and complexity. The following parameters were also derived from the PET data: primary tumor standardized uptake values (SUVs) (mean SUV, maximum SUV, and peak SUV), metabolic tumor volume, and total lesion glycolysis.
Results:
Compared with nonresponders, RECIST responders showed lower coarseness (mean, 0.012 vs. 0.027; P = 0.004) and higher contrast (mean, 0.11 vs. 0.044; P = 0.002) and busyness (mean, 0.76 vs. 0.37; P = 0.027). Neither complexity nor any of the SUV parameters predicted RECIST response. By Kaplan-Meier analysis, OS, PFS, and LPFS were lower in patients with high primary tumor coarseness (median, 21.1 mo vs. not reached, P = 0.003; 12.6 vs. 25.8 mo, P = 0.002; and 12.9 vs. 20.5 mo, P = 0.016, respectively). Tumor coarseness was an independent predictor of OS on multivariable analysis. Contrast and busyness did not show significant associations with OS (P = 0.075 and 0.059, respectively), but PFS and LPFS were longer in patients with high levels of each (for contrast: median of 20.5 vs. 12.6 mo, P = 0.015, and median not reached vs. 24 mo, P = 0.02; and for busyness: median of 20.5 vs. 12.6 mo, P = 0.01, and median not reached vs. 24 mo, P = 0.006). Neither complexity nor any of the SUV parameters showed significant associations with the survival parameters.
Conclusion:
In NSCLC, baseline (18)F-FDG PET scan uptake showing abnormal texture as measured by coarseness, contrast, and busyness is associated with nonresponse to chemoradiotherapy by RECIST and with poorer prognosis. Measurement of tumor metabolic heterogeneity with these parameters may provide indices that can be used to stratify patients in clinical trials for lung cancer chemoradiotherapy.
To establish the potential for tumour heterogeneity in non-small cell lung cancer (NSCLC) as assessed by CT texture analysis (CTTA) to provide an independent marker of survival for patients with NSCLC.
Tumour heterogeneity was assessed by CTTA of unenhanced images of primary pulmonary lesions from 54 patients undergoing (18)F-fluorodeoxyglucose (FDG) PET-CT for staging of NSCLC. CTTA comprised image filtration to extract fine, medium and coarse features with quantification of the distribution of pixel values (uniformity) within the filtered images. Receiver operating characteristics identified thresholds for PET and CTTA parameters that were related to patient survival using Kaplan-Meier analysis.
The median (range) survival was 29.5 (1-38) months. 24, 10, 14 and 6 patients had tumour stages I, II, III and IV respectively. PET stage and tumour heterogeneity assessed by CTTA were significant independent predictors of survival (PET stage: Odds ratio 3.85, 95% confidence limits 0.9-8.09, P = 0.002; CTTA: Odds ratio 56.4, 95% confidence limits 4.79-666, p = 0.001). SUV was not a significantly associated with survival.
Assessment of tumour heterogeneity by CTTA of non-contrast enhanced images has the potential for to provide a novel, independent predictor of survival for patients with NSCLC.
Computed tomography is a routine staging procedure in non-small cell lung cancer. CT texture analysis (CTTA) can quantify heterogeneity within these lung tumours. CTTA seems to offer a novel independent predictor of survival for NSCLC. CTTA could contribute to disease risk-stratification for patients with NSCLC.
The application of a cost-effective spectral imager to spatially segmenting absorptive
and fluorescent chemical probes on the basis of their spectral characteristics has been demonstrated. The imager comprises a computer-controlled spectrally selective element that allows random access to a bandwidth of 15 nm between 400 and 700 nm. Further, the use of linear un-mixing of the spectral response of a sample at a single pixel has been facilitated using non-negative least squares fitting. Examples are givenshowing the separation of dye distributions, such as immunohistochemical markersfor tumour hypoxia, from multiply stained thin tissue sections, imaged by trans-illuminationmicroscopy. A quantitative study is also presented that shows a correlation between staining intensity and normal versus tumour tissue, and the advantage of reducing the amount of data captured for a particular study is also demonstrated. An example of the application to fluorescence microscopy is also given, showing the separation of green fluorescent protein, Cy3 and Cy5 at a single pixel. The system has been validated against samples of known optical density and of known overlapping combinations of coloured filters. These results confirm the ability of this technique to separate spectral responses that cannot be resolved with conventional colour imaging.
To establish the potential for tumour heterogeneity in non-small cell lung cancer (NSCLC) as assessed by CT texture analysis (CTTA) to provide an independent marker of survival for patients with NSCLC.
Tumour heterogeneity was assessed by CTTA of unenhanced images of primary pulmonary lesions from 54 patients undergoing (18)F-fluorodeoxyglucose (FDG) PET-CT for staging of NSCLC. CTTA comprised image filtration to extract fine, medium and coarse features with quantification of the distribution of pixel values (uniformity) within the filtered images. Receiver operating characteristics identified thresholds for PET and CTTA parameters that were related to patient survival using Kaplan-Meier analysis.
The median (range) survival was 29.5 (1-38) months. 24, 10, 14 and 6 patients had tumour stages I, II, III and IV respectively. PET stage and tumour heterogeneity assessed by CTTA were significant independent predictors of survival (PET stage: Odds ratio 3.85, 95% confidence limits 0.9-8.09, P = 0.002; CTTA: Odds ratio 56.4, 95% confidence limits 4.79-666, p = 0.001). SUV was not a significantly associated with survival.
Assessment of tumour heterogeneity by CTTA of non-contrast enhanced images has the potential for to provide a novel, independent predictor of survival for patients with NSCLC.
Computed tomography is a routine staging procedure in non-small cell lung cancer. CT texture analysis (CTTA) can quantify heterogeneity within these lung tumours. CTTA seems to offer a novel independent predictor of survival for NSCLC. CTTA could contribute to disease risk-stratification for patients with NSCLC.
The aim was to undertake an initial study of the relationship between texture features in computed tomography (CT) images of non-small cell lung cancer (NSCLC) and tumour glucose metabolism and stage. This retrospective pilot study comprised 17 patients with 18 pathologically confirmed NSCLC. Non-contrast-enhanced CT images of the primary pulmonary lesions underwent texture analysis in 2 stages as follows: (a) image filtration using Laplacian of Gaussian filter to differentially highlight fine to coarse textures, followed by (b) texture quantification using mean grey intensity (MGI), entropy (E) and uniformity (U) parameters. Texture parameters were compared with tumour fluorodeoxyglucose (FDG) uptake (standardised uptake value (SUV)) and stage as determined by the clinical report of the CT and FDG-positron emission tomography imaging. Tumour SUVs ranged between 2.8 and 10.4. The number of NSCLC with tumour stages I, II, III and IV were 4, 4, 4 and 6, respectively. Coarse texture features correlated with tumour SUV (E: r = 0.51, p = 0.03; U: r = -0.52, p = 0.03), whereas fine texture features correlated with tumour stage (MGI: rs = 0.71, p = 0.001; E: rs = 0.55, p = 0.02; U: rs = -0.49, p = 0.04). Fine texture predicted tumour stage with a kappa of 0.7, demonstrating 100% sensitivity and 87.5% specificity for detecting tumours above stage II ( p = 0.0001). This study provides initial evidence for a relationship between texture features in NSCLC on non-contrast-enhanced CT and tumour metabolism and stage. Texture analysis warrants further investigation as a potential method for obtaining prognostic information for patients with NSCLC undergoing CT.
To assess the utility of texture analysis of liver computed tomographic (CT) images by determining the effect of acquisition parameters on texture and by comparing the abilities of texture analysis and hepatic perfusion CT to help predict survival for patients with colorectal cancer.
The study comprised a phantom test and a clinical evaluation of 48 patients with colorectal cancer who had consented to retrospective analysis of hepatic perfusion CT data acquired during a research study approved by the institutional review board. Both components involved texture analysis to quantify the relative contribution of CT features between 2 and 12 pixels wide to overall image brightness and uniformity. The effect of acquisition factors on texture was assessed on CT images of a cylindric phantom filled with water obtained by using tube currents between 100 and 250 mAs and voltages between 80 and 140 kVp. Texture on apparently normal portal phase CT images of the liver and hepatic perfusion parameters were related to patient survival by using Kaplan-Meier survival analysis.
A texture parameter that compared the uniformity of distribution of CT image features 10 and 12 pixels wide exhibited the least variability with CT acquisition parameters (maximum coefficient of variation, 2.6%) and was the best predictor of patient survival (P < .005). There was no significant association between survival and hepatic perfusion parameters.
The study provides preliminary evidence that analysis of liver texture on portal phase CT images is potentially a superior predictor of survival for patients with colorectal cancer than CT perfusion imaging. Supplemental material: http://radiology.rsnajnls.org/cgi/content/full/2502071879/DC1.
Several parameters of the tumor microenvironment, such as hypoxia, inflammation and angiogenesis, play a critical role in tumor aggressiveness and treatment response. A major question remains if these markers can be used to stratify patients to certain treatment protocols. The purpose of this study was to investigate the inter-relationship and the prognostic significance of several biological and clinicopathological parameters in patients with head and neck squamous cell carcinoma (HNSCC) treated by radiotherapy +/- chemotherapy.
We used two subgroups of a retrospective series for which CT-determined tumoral perfusion correlated with local control. In the first subgroup (n = 67), immunohistochemistry for carbonic anhydrase IX (CA IX) and glucose transporter-1 (GLUT-1) was performed on the pretreatment tumor biopsy. In the second subgroup (n = 34), enzyme linked immunosorbent assay (ELISA) was used to determine pretreatment levels of the cytokines vascular endothelial growth factor (VEGF) and interleukin-6 (IL-6) in serum. Correlation was investigated between tumoral perfusion and each of these biological markers, as well as between the markers mutually. The prognostic value of these microenvironmental parameters was also evaluated.
For CA IX and GLUT-1, the combined assessment of patients with both markers expressed above the median showed an independent correlation with local control (p = 0.02) and disease-free survival (p = 0.04) with a trend for regional control (p = 0.06). In the second subgroup, IL-6 pretreatment serum level above the median was the only independent predictor of local control (p = 0.009), disease-free survival (p = 0.02) and overall survival (p = 0.005).
To our knowledge, we are the first to report a link in HNSCC between IL-6 pretreatment serum levels and radioresistance in vivo. This link is supported by the strong prognostic association of pretreatment IL-6 with local control, known to be the most important parameter to judge radiotherapy responses. Furthermore, the combined assessment of CA IX and GLUT-1 correlated independently with prognosis. This is a valuable indication that a combined approach is important in the investigation of prognostic markers.
The microenvironment of solid tumors is a heterogeneous, complex milieu for tumor growth and survival that includes features
such as acidic pH, low nutrient levels, elevated interstitial fluid pressure (IFP) and chronic and fluctuating levels of oxygenation
that relate to the abnormal vascular network that exists in tumors. The metastatic potential of tumor cells is believed to
be regulated by interactions between the tumor cells and their extracellular environment (extracellular matrix (ECM)). These
interactions can be modified by the accumulation of genetic changes and by the transient alterations in gene expression induced
by the local tumor microenvironment. Clinical and experimental evidence suggests that altered gene expression in response
to the hypoxic microenvironment is a contributing factor to increased metastatic efficiency. A number of genes that have been
implicated in the metastatic process, involving angiogenesis, intra/extravasation, survival and growth, have been found to
be hypoxia-responsive. The various metastatic determinants, genetic and epigenetic, somatic and inherited may serve as precedents
for the future identification of more genes that are involved in metastasis. Much research has focused on genetic and molecular
properties of the tumor cells themselves. In the present review we discuss the epigenetic and physiological regulation of
metastasis and emphasize the need for further studies on the interactions between the pathophysiologic tumor microenvironment
and the tumor extracellular matrix.
Angiogenesis, a key process for the growth of human cancers, has recently been exploited for the development of a novel class of cancer therapeutics that was thought to have wide applications and not to induce resistance in the clinical setting. Indeed, anti-angiogenic therapy has become an important option for the management of several human malignancies. However, a significant number of patients either do not respond to anti-angiogenic agents or fairly rapidly develop resistance. In addition, the benefit of anti-angiogenic therapy is relatively short-lived and the majority of patients eventually relapses and progresses. Several mechanisms of resistance to anti-angiogenic therapy have been recently proposed. The current review focuses on the role of intra-tumor hypoxia as a mechanism of resistance to anti-angiogenic agents and speculates on therapeutic approaches that might circumvent resistance and thereby improve clinical outcome.
Background:
Assessment of the change in tumour burden is an important feature of the clinical evaluation of cancer therapeutics: both tumour shrinkage (objective response) and disease progression are useful endpoints in clinical trials. Since RECIST was published in 2000, many investigators, cooperative groups, industry and government authorities have adopted these criteria in the assessment of treatment outcomes. However, a number of questions and issues have arisen which have led to the development of a revised RECIST guideline (version 1.1). Evidence for changes, summarised in separate papers in this special issue, has come from assessment of a large data warehouse (>6500 patients), simulation studies and literature reviews. HIGHLIGHTS OF REVISED RECIST 1.1: Major changes include: Number of lesions to be assessed: based on evidence from numerous trial databases merged into a data warehouse for analysis purposes, the number of lesions required to assess tumour burden for response determination has been reduced from a maximum of 10 to a maximum of five total (and from five to two per organ, maximum). Assessment of pathological lymph nodes is now incorporated: nodes with a short axis of 15 mm are considered measurable and assessable as target lesions. The short axis measurement should be included in the sum of lesions in calculation of tumour response. Nodes that shrink to <10mm short axis are considered normal. Confirmation of response is required for trials with response primary endpoint but is no longer required in randomised studies since the control arm serves as appropriate means of interpretation of data. Disease progression is clarified in several aspects: in addition to the previous definition of progression in target disease of 20% increase in sum, a 5mm absolute increase is now required as well to guard against over calling PD when the total sum is very small. Furthermore, there is guidance offered on what constitutes 'unequivocal progression' of non-measurable/non-target disease, a source of confusion in the original RECIST guideline. Finally, a section on detection of new lesions, including the interpretation of FDG-PET scan assessment is included. Imaging guidance: the revised RECIST includes a new imaging appendix with updated recommendations on the optimal anatomical assessment of lesions.
Future work:
A key question considered by the RECIST Working Group in developing RECIST 1.1 was whether it was appropriate to move from anatomic unidimensional assessment of tumour burden to either volumetric anatomical assessment or to functional assessment with PET or MRI. It was concluded that, at present, there is not sufficient standardisation or evidence to abandon anatomical assessment of tumour burden. The only exception to this is in the use of FDG-PET imaging as an adjunct to determination of progression. As is detailed in the final paper in this special issue, the use of these promising newer approaches requires appropriate clinical validation studies.
Changes in tumor area and the attenuation value determined from computed tomography (CT) slice section of the tumor at its maximum size were investigated in 18 patients with hepatocellular carcinoma who were studied by CT after arterial embolization therapy. The tumor area was reduced in all cases after embolization therapy. Greater than 50% reduction of the tumor area occurred during the follow-up period in 13 cases (87%). In cases evaluated by follow-up CT, the relative attenuation value of tumor to nontumor regions decreased during the initial stage after embolization therapy, but showed a tendency towards greater elevation than in the initial stage, despite tumor reduction. This change in the attenuation value was considered to reflect necrosis and shrinkage of the tumor after embolization therapy. The absence of such changes in nontumor regions supports the use of arterial embolization therapy as an effective, conservative treatment for hepatocellular carcinoma. Follow-up examination by CT of hepatocellular carcinoma after embolization therapy contributes to the post-therapeutic evaluation of tumors and to the determination of the appropriate time for reembolization therapy.
Tumor hypoxia may be associated with treatment resistance, cell proliferation, and metastatic potential, which contribute to poor prognosis. Complementary techniques for detecting hypoxia, cell growth, and metastases are required to study these relationships.
The purpose of this study was to demonstrate the clinical feasibility of quantitative hypoxia detection with pimonidazole, a novel hypoxia marker, and to correlate hypoxia with S-phase markers of tumor proliferation.
Pimonidazole binds to thiol-containing proteins specifically in hypoxic cells. Ten patients with cervical carcinoma received 0.5 g/m2 pimonidazole intravenously followed by biopsy of the cervical carcinoma the next day. Hypoxic cells were recognized by immunohistochemical detection of pimonidazole using a mouse monoclonal antibody. Cell proliferation was detected with a commercially available monoclonal antibody for proliferating cell nuclear antigen (PCNA). Assessment of hypoxia and cell proliferation was made qualitatively with light microscopy and quantitatively using point counting and image analysis software methods.
No clinical toxic effects were associated with pimonidazole administration. Immunostaining with pimonidazole antibody was observed in 9 of 10 tumors, suggesting that hypoxia is a common occurrence in cervical carcinoma. Quantitatively, tumors that had large numbers of hypoxic cells had the greatest percentage of S-phase cells, but some tumors with smaller amounts of hypoxia also had substantial numbers of S-phase cells.
Pimonidazole can be used for qualitative and quantitative assessment of tumor hypoxia.