Locally advanced rectal cancer: is diffusion weighted MRI helpful for the identification of complete responders (ypT0N0) after neoadjuvant chemoradiation therapy?

OBJECTIVES: To determine retrospectively the additional value of DWI-MRI toT2-MRI for predicting complete response (ypT0N0 = CR) after chemoradiation-therapy (CRT) in locally advanced rectal cancer. METHODS: Seventy locally advanced rectal cancer patients underwent CRT followed by restaging MRI and resection. Two readers with different experience levels independently scored T2 images for CR and, in a second reading, combined T2 and DWI. A 5-point confidence-level score was used to generate ROC curves. Areas under the ROC curves (AUC) and interobserver agreement were compared for both readings. Histology served as reference standard. RESULTS: The interobserver agreement increased after addition of DWI from 0.35 to 0.58 but the AUC improved only for the experienced reader (0.77 to 0.89, p = 0.005 vs. 0.74 to 0.70, p > 0.05). Sensitivity and NPV improved from 20-30 % to 40-70 %, respectively 88 % to 91-95 %. Specificity and PPV improved only for the experienced reader (87 to 93 % respectively 27 to 63 %). CONCLUSION: Adding DWI to T2-MRI improves consistency between readers and has potential to improve readers' accuracy dependent on his/her experience. DWI could be of additional value, particularly in ruling out CR (high NPV), but considering the sub-optimal PPV one should be cautious about relying solely on MRI for the clinical decision to offer a wait-and-see strategy.

Lack of lymphangiogenesis despite coexpression of VEGF-C and its receptor Flt-4 in uveal melanoma.

PURPOSE: Because lymphatic vessels are absent from the normal eye and because uveal melanomas are presumed to spread by a hematogenous route in the absence of tumor exposure to conjunctival lymphatics, this study was undertaken to investigate the presence of lymphatic vessels in primary uveal melanomas. METHODS: The presence of lymphatics in 2 control eyes and in 33 primary uveal, 10 primary cutaneous, and 3 metastatic cutaneous melanomas was evaluated by using a double-immunostaining protocol that differentially highlights blood and lymphatic vasculature. In addition, 14 uveal melanomas were immunostained for the lymphatic growth factor vascular endothelial growth factor (VEGF)-C (with anti-VEGF-C polyclonal antibodies [pAbs]), its receptors Flt-4 (with monoclonal antibody [mAb] 9D9) and KDR (with anti-KDR mAb [Clone KDR-2]), and the hemangiogenic factor VEGF-A (with anti-VEGF pAbs). RESULTS: Lymphatics were not detected in normal eyes or in uveal melanoma. As a consequence, signs of lymphangiogenesis were not present. There was coexpression of VEGF-C with Flt-4 and KDR in 6 (43%) of the 14 melanomas. Staining for VEGF-A was completely negative in 25 uveal melanomas analyzed. CONCLUSIONS: The strictly hematogenous metastasis of primary uveal melanomas is explained by the absence of lymphatics in and around the tumor. The current data suggest that, in the presence of endothelial Flt-4, VEGF-C expression is not sufficient to induce lymphangiogenesis from preexisting blood vessels in human cancer.

Lymphangiogenesis in malignant tumours: Does it occur?

The development of a vascular bed is essential for solid tumour growth and metastasis. In many tumours, mean vascular density can be related to the rate of metastasis and, therefore, to prognosis. In other tumour types, such as cutaneous melanoma and head-and-neck squamous cell carcinoma, this relation is absent. Until now, the reason for this has been unclear, but since these particular tumour types are also known for their propensity to spread via the lymphatic system, it may be speculated that the presence of a pre-existing lymphatic bed and the formation of new lymphatics (lymphangiogenesis) are important factors. Growth factors involved in lymphangiogenesis during embryogenesis have been recently identified and these are also expressed in many tumour types, but the existence of tumour-induced lymphangiogenesis has not so far been reported. Partly, this could be due to the lack of reliable endothelial markers, thereby hampering a consistent evaluation of lymphatic vasculature. This editorial discusses the role of the lymphatic bed in mediating the metastasis of solid tumours, summarizes known methods to detect lymphatics, and proposes a hypothetical mechanism of tumour-induced lymphangiogenesis.

Relation of arterial geometry to luminal narrowing and histologic markers for plaque vulnerability: the remodeling paradox.

OBJECTIVE: To relate local arterial geometry with markers that are thought to be related to plaque rupture. BACKGROUND: Plaque rupture often occurs at sites with minor luminal stenosis and has retrospectively been characterized by colocalization of inflammatory cells. Recent studies have demonstrated that luminal narrowing is related with the mode of atherosclerotic arterial remodeling. METHODS: We obtained 1,521 cross section slices at regular intervals from 50 atherosclerotic femoral arteries. Per artery, the slices with the largest and smallest lumen area, vessel area and plaque area were selected for staining on the presence of macrophages (CD68), T-lymphocytes (CD45RO), smooth muscle cells (alpha-actin) and collagen. RESULTS: Inflammation of the cap or shoulder of the plaque was observed in 33% of all cross sections. Significantly more CD68 and CD45RO positive cells, more atheroma, less collagen and less alpha-actin positive staining was observed in cross sections with the largest plaque area and largest vessel area vs. cross sections with the smallest plaque area and smallest vessel area, respectively. No difference in the number of inflammatory cells was observed between cross sections with the largest and smallest lumen area. CONCLUSION: Intraindividually, pathohistologic markers previously reported to be related to plaque vulnerability were associated with a larger plaque area and vessel area. In addition, inflammation of the cap and shoulder of the plaque was a common finding in the atherosclerotic femoral artery.

The impact of atherosclerotic arterial remodeling on percentage of luminal stenosis varies widely within the arterial system. A postmortem study.

Luminal stenosis can be based on large atherosclerotic plaques in compensatory enlarged segments or on relatively little plaques in shrunken segments. In the present study, the contribution of plaque formation and remodeling to luminal narrowing was compared among six types of arteries prone to symptomatic atherosclerosis. Cross-sections (n = 5195) were obtained at regular intervals from 329 arteries. For each artery, the cross-section that contained the least amount of plaque was considered to be the reference. For each cross-section, the percentage of lumen area decrease was expressed as a percentage of the lumen area at the reference site (luminal stenosis). Similarly, the area encompassed by the internal elastic lamina (IEL area) was expressed as a percentage of the IEL area at the reference site (relative IEL area). All cross-sections were categorized in three groups: relative IEL area > 105% (enlargement), 95% to 105% (no remodeling), and < 95% (shrinkage). The prevalence of enlargement (50% to 75%) was significantly higher compared with shrinkage (8% to 25%). Shrinkage was observed most frequently in the femoral arteries (25%) and infrequently in the renal arteries (8%). For all types of arteries, the relative IEL area correlated negatively with luminal stenosis (P < .001). Regression analysis of relative IEL area on luminal stenosis, however, showed significant differences in the first-order regression coefficients among artery types. On average, plaque increase was more compensated for by enlargement in the coronary, common carotid, and renal arteries compared with the arteries obtained from the lower extremities. Anatomic regional differences were observed in the impact of arterial wall remodeling on percent luminal stenosis in de novo atherosclerotic lesions.

Remodeling of the atherosclerotic arterial wall: a determinant of luminal narrowing in human coronary arteries.

BACKGROUND: The type of remodeling of the human femoral artery (enlargement or shrinkage) is related to the percentage luminal stenosis. OBJECTIVE: To assess how local changes in vessel size, together with plaque load, determine luminal narrowing in atherosclerotic human coronary arteries. METHODS: We obtained 576 segments of 28 coronary arteries from 10 patients who had died from noncardiac causes. The lumen area and area circumscribed by the internal elastic lamina (IEL) area, a measure of local vessel size in each histologic cross-section were measured, and the mean lumen diameter and mean IEL diameter were calculated. To correct for arterial tapering, expected reference diameter values were calculated at the same location using linear regression of all data points along the artery. The IEL diameter and lumen diameter were expressed as percentages of the calculated IEL diameter and lumen diameter at the same location (percentage lumen diameter stenosis and relative IEL diameter, respectively). RESULTS: We found a negative relation between the relative IEL diameter and the percentage lumen diameter stenosis. On average, a narrower than expected lumen diameter was accompanied by a smaller than expected IEL diameter. A larger than expected lumen diameter was accompanied by a larger than expected IEL diameter. This relation was found for the left anterior descending, circumflex, and right coronary arteries (y = -0.60x + 105.33, r = 0.48; y = -0.45x + 100.69, r = 0.84; and y = -0.39x + 101.84, r = 0.61, respectively, all P < 0.05). CONCLUSIONS: Local luminal narrowing was correlated with a decrease in vessel size. Local remodeling of the artery is one of the determinants of luminal narrowing in the atherosclerotic human coronary artery.