Loss of Primary Cilia Potentiates BRAF/MAPK Pathway Activation in Rhabdoid Colorectal Carcinoma: A Series of 21 Cases Showing Ciliary Rootlet CoiledCoil (CROCC) Alterations.

A rhabdoid colorectal tumor (RCT) is a rare cancer with aggressive clinical behavior. Recently, it has been recognized as a distinct disease entity, characterized by genetic alterations in the SMARCB1 and Ciliary Rootlet Coiled-Coil (CROCC). We here investigate the genetic and immunophenotypic profiling of 21 RCTs using immunohistochemistry and next-generation sequencing. Mismatch repair-deficient phenotypes were identified in 60% of RCTs. Similarly, a large proportion of cancers exhibited the combined marker phenotype (CK7-/CK20-/CDX2-) not common to classical adenocarcinoma variants. More than 70% of cases displayed aberrant activation of the mitogen-activated protein kinase (MAPK) pathway with mutations prevalently in BRAF V600E. SMARCB1/INI1 expression was normal in a large majority of lesions. In contrast, ciliogenic markers including CROCC and γ-tubulin were globally altered in tumors. Notably, CROCC and γ-tubulin were observed to colocalize in large cilia found on cancer tissues but not in normal controls. Taken together, our findings indicate that primary ciliogenesis and MAPK pathway activation contribute to the aggressiveness of RCTs and, therefore, may constitute a novel therapeutic target.

Gastro-intestinal metastasis from Melanoma: Clinico-pathological clues.

INTRODUCTION: Metastasis from melanoma in the gastro-intestinal tract is a frequent event but, in the absence of an adequate clinical context and oncological anamnesis, it could be misdiagnosed by the pathologists. Moreover, amelanotic and/or poorly differentiated metastasis from melanoma in the gastro-intestinal tract can be easily underestimated. MATERIALS AND METHODS: We describe the histological features of gastro-intestinal metastasis from melanoma in a multi-centric cohort of 49 patients. In 24/49 patients, we were able to compare histological findings such as the growth pattern and the melanotic pigment also in the primary melanoma. RESULTS: The epithelioid pattern is the most common growth pattern observed in gastro-intestinal metastasis (57 %), followed by the mixed pattern (41 %) and the spindled pattern (2 %). We documented a discordant growth pattern between metastasis and primary in 9/24 cases and the absence of melanotic pigment in 8/49 cases. DISCUSSION: Our experience highlights that pathologists should take into account the possibility of gastro-intestinal metastasis from melanoma also in cases with spindled-cells/amelanotic lesions, without a previous anamnesis of melanoma asportation, and in cases of a discordant growth pattern with the primary. A correct clinical integration and an aware immunohistochemical approach are imperative to best manage the bioptic sample in order to investigate the biological profiling and therefore plan a personalizated therapy.

Comparison of surgery and compression with compression alone in chronic venous ulceration (ESCHAR study): randomised controlled trial.

BACKGROUND: Chronic venous leg ulceration can be managed by compression treatment, elevation of the leg, and exercise. The addition of ablative superficial venous surgery to this strategy has not been shown to affect ulcer healing, but does reduce ulcer recurrence. We aimed to assess healing and recurrence rates after treatment with compression with or without surgery in people with leg ulceration. METHODS: We did venous duplex imaging of ulcerated or recently healed legs in 500 consecutive patients from three centres. We randomly allocated those with isolated superficial venous reflux and mixed superficial and deep reflux either compression treatment alone or in combination with superficial venous surgery. Compression consisted of multilayer compression bandaging every week until healing then class 2 below-knee stockings. Primary endpoints were 24-week healing rates and 12-month recurrence rates. Analysis was by intention to treat. FINDINGS: 40 patients were lost to follow-up and were censored. Overall 24-week healing rates were similar in the compression and surgery and compression alone groups (65% vs 65%, hazard 0.84 [95% CI 0.77 to 1.24]; p=0.85) but 12-month ulcer recurrence rates were significantly reduced in the compression and surgery group (12% vs 28%, hazard -2.76 [95% CI -1.78 to -4.27]; p<0.0001). Adverse events were minimal and about equal in each group. INTERPRETATION: Surgical correction of superficial venous reflux reduces 12-month ulcer recurrence. Most patients with chronic venous ulceration will benefit from the addition of simple venous surgery.

Echogenicity of B-mode sonographic images of the carotid artery: work in progress.

OBJECTIVE: The echogenicity of the carotid atheromatous plaque estimated from B-mode sonographic images may be related to plaque content and has been analyzed with a number of techniques. The purpose of this study was to compare plaque with surrounding muscle tissue echogenicity and to validate the use of first-order mathematical descriptors as determinants of tissue echogenicity. METHODS: We estimated echogenicity descriptors for regions in the following 3 distinct areas of a typical B-mode sonographic image of a diseased carotid artery: plaque, blood, and sternocleidomastoid muscle. Two-dimensional B-mode sonographic images from 19 symptomatic and asymptomatic plaques (17 subjects) were interrogated, in which the following estimators were calculated: minimal, maximal, mean, and median gray levels, SD of gray levels, coefficient of variation, and gray level skewness, kurtosis, entropy, and energy. Plaque echogenicity was estimated at systole and diastole for studying the effect of the phase of the cardiac cycle. To assess the effect of different fascial tissue-muscle fiber composition on the first-order mathematical descriptors, we estimated echogenicity at 3 different sites within the muscle tissue. RESULTS: Compared with the echogenicity of surrounding muscle tissue, plaque echogenicity was characterized by (1) significantly lower (Student t test, P < .05) gray level mean, median, SD, and entropy; (2) significantly higher (Student t test, P < .05) coefficient of variation, gray level skewness, and kurtosis; and (3) similar minimal and maximal gray levels and gray level energy. The phase of the cardiac cycle, systole or diastole, did not affect the estimation of plaque echogenicity. Echogenicity was found to vary within the muscle tissue. The coefficient of variation was significantly higher in the asymptomatic plaques in the small group that was investigated. CONCLUSIONS: First-order statistical descriptors may be used to characterize atheromatous plaques and the surrounding muscle tissue.

Carotid artery wall motion estimated from B-mode ultrasound using region tracking and block matching.

The motion of the carotid atheromatous plaque relative to the adjacent wall may be related to the risk of cerebral events. A quantitative method for motion estimation was applied to analyse arterial wall movement from sequences of 2-D B-mode ultrasound (US) images. Image speckle patterns were tracked between successive frames using the correlation coefficient as the matching criterion. The size of the selected region-of-interest (ROI) was shown to affect the motion analysis results; an optimal size of 3.2 x 2.5 mm(2) was suggested for tracking a region at the wall-lumen interface and of 6.3 x 2.5 mm(2) for one within the tissue. The results showed expected cyclical motion in the radial direction and some axial movement of the arterial wall. The method can be used to study further the axial motion of the carotid artery wall and plaque and, thus, provide useful insight into the mechanisms of atherosclerosis.

The impact of arteriovenous fistula formation on central hemodynamic pressures in chronic renal failure patients: a prospective study.

BACKGROUND: The presence of an arteriovenous (AV) fistula creates permanently high cardiac output. This may cause an imbalance between available cardiac oxygen supply in response to greater demand and increased arterial stiffness. METHODS: Surrogate markers of subendocardial perfusion (subendocardial viability ratio [SEVR]) and arterial stiffness (augmentation index [AIx]) can be measured noninvasively by using pulse wave analysis on the radial pulse to obtain central pressures. We prospectively followed up nine patients with chronic renal failure (CRF) undergoing creation of an AV fistula for vascular access at regular intervals over 6 months. RESULTS: After surgery, blood pressure and heart rate remained unchanged throughout the study period. AIx stayed the same (baseline versus 6 months, 20% +/- 11% versus 22% +/- 15%), but there was a decrease in SEVR immediately after surgery (-9% +/- 5%; P < 0.05) that persisted for at least 3 months (-14% +/- 7%; P < 0.01). At 6 months, SEVR remained below baseline values in all but one patient (mean SEVR at baseline, 166% +/- 22% versus 6 months, 150% +/- 20%; P < 0.05; -9% +/- 7%). CONCLUSION: Creation of an AV fistula may directly predispose patients with CRF to a risk for myocardial ischemia caused by an adverse imbalance between subendocardial oxygen supply and increased oxygen demand consequent to a greater cardiac output.