Prognostic Value of p27, p53, and Vascular Endothelial Growth Factor in Dukes A and B Colon Cancer Patients Undergoing Potentially Curative Surgery

PURPOSE Early-stage colon cancer patients (Dukes A or B; pT1–T3 pNO pMO) are excluded from adjuvant chemotherapy following potentially curative surgery because they are expected to have good long-term survival. However, 20 percent to 30 percent of these patients ultimately succumb from recurrent disease. This indicates that the conventional staging procedures may be unable to precisely predict cancer prognosis.METHODS In 65 early-stage colon cancers, we investigated by immunohistochemistry the role of molecular markers such as p27, p53, and vascular endothelial growth factor in identifying high-risk patients who may benefit from adjuvant treatments.RESULTS No clinicopathologic factor, namely Dukes stage, t parameter, number of resected nodes, and vascular or lymphatic invasion, was found be an independent significant predictor of disease-specific and disease-free survival. In contrast, each molecular marker predicted survival and recurrence rates much better than the conventional Dukes staging system. The best combination of variables for prediction of long-term outcome and recurrence rate included p27, p53, and vascular endothelial growth factor. Interestingly, the greater the number of molecular alterations, the lower the five-year estimated survival function. Nearly all cancer-related deaths were observed among patients whose colon cancers expressed all three molecular alterations. Regardless of Dukes stage, the recurrence rate was found to increase with the increase in the number of molecular alterations. Early-stage colon cancers expressing p27 down-regulation and high p53 and vascular endothelial growth factor immunoreactivity showed a 100 percent actuarial four-year recurrence rate.CONCLUSIONS Assessment of molecular alterations may be useful to identify a higher-risk group of early-stage colon cancer patients who may benefit from adjuvant chemotherapy.     

Factors affecting long-term changes of liver stiffness in direct-acting anti-hepatitis C virus therapy: A multicentre prospective study

The long-term changes of liver stiffness (LS) in patients who achieve viral clearance after direct-acting anti-HCV therapy remain undefined. We conducted a multicentre prospective study to investigate this aspect. Patients with HCV infection treated with DAAs were enrolled from six Italian centres; they underwent clinical, biochemical, ultrasound and transient elastography evaluations before treatment (T0), 12 weeks (SVR12) and 24 months (T24) after the end of therapy. Among the 516 consecutive patients enrolled, 301 had cirrhosis. LS significantly decreased from T0 to SVR (14.3 vs 11.1 kPa, p = .002), with a progressive reduction until T24 (8.7 kPa, p < .001). However, only patients with steatosis and those who developed HCC did not experience a late improvement in LS. Multivariate analysis of baseline and follow-up variables identified steatosis as the only independent predictor of failure of LS improvement (OR 1.802, p = .013). ROC curve analysis of the association of LS with the risk of developing HCC showed that SVR12 ≥14.0 kPa had the highest accuracy (sensitivity 82%, specificity 99%; AUC: 0.774). Multivariate analysis revealed that LS was the only variable independently associated with an increased risk of developing HCC (OR 6.470, p = .035). Achieving an SVR was associated with a progressive, long-term decline of LS, suggesting a late improvement in liver fibrosis, besides the resolution of inflammation. Fatty liver and the development of HCC interfered with late reduction of LS. Patients with an LS ≥14 kPa at 12 weeks after the end of treatment were at higher risk for developing HCC.     

Thyroid function tests in acute viral hepatitis: relative reduction in serum thyroxine levels due to T4-TBG binding inhibitors in patients with severe liver cell necrosis

Thyroid function tests were evaluated in 34 patients with acute viral hepatitis (AVH) and in 38 healthy controls (C). As expected, AVH patients displayed a significant increase in T4, rT3 and TBG serum levels with respect to C, while FT4 and TSH concentrations were similar. A positive correlation between TBG and T4 was evident in C, but not in AVH. In this group there was, instead, an inverse correlation between the sum of serum levels of GOT + GPT and T4 concentrations. When AVH patients were divided in "high necrosis" (HN, serum GOT + GPT greater than 2000 UI/l) and "low necrosis" (LN, serum GOT + GPT less than 2000 UI/ml) groups, we found a significant reduction in both T4 and T3 serum concentrations in HN with respect to LN, despite similar levels of TBG, albumin, FT4 and TSH. The hypothesis that thyroid-hormone binding inhibitors (THBI), released during severe liver cell injury, accounted for an impaired serum binding capacity in HN-AVH, was confirmed by the significant increase in FT4/T4 ratio and by the demonstration of THBI activity in pooled sera of these patients, with respect to LN subgroup. Our present finding may clarify the unexplained observation of reduced T4 levels in patients with fulminant hepatitis and the ominous prognostic significance of a "low T4 syndrome" in subjects with severe liver disease and/or other systemic illnesses.     

Pre-Menopausal Breast Fat Density Might Predict MACE During 10 Years of Follow-Up: The BRECARD Study

ObjectivesThis study sought to determine whether the breast gland adipose tissue is associated with different rates of major adverse cardiac events (MACEs) in pre-menopausal women.BackgroundTo our knowledge, no study investigated the impact of breast adipose tissue infiltration on MACEs in pre-menopausal women.MethodsProspective multicenter cohort study conducted on pre-menopausal women >40 years of age without cardiovascular disease and breast cancer at enrollment. The study started in January 2000 and ended in January 2009, and the end of the follow-up for the evaluation of MACEs was in January 2019. Participants underwent mammography to evaluate breast density and were divided into 4 groups according to their breast density. The primary endpoint was the probability of a MACE at 10 years of follow-up in patients staged for different breast deposition/adipose tissue deposition.ResultsThe propensity score matching divided the baseline population of 16,763 pre-menopausal women, leaving 3,272 women according to the category of breast density from A to D. These women were assigned to 4 groups of the study according to baseline breast density. At 10 years of follow-up, we had 160 MACEs in group 1, 62 MACEs in group 2, 27 MACEs in group 3, and 16 MACEs in group 4. MACEs were predicted by the initial diagnosis of lowest breast density (hazard ratio: 3.483; 95% confidence interval: 1.476 to 8.257). Further randomized clinical trials are needed to translate the results of the present study into clinical practice. The loss of ex vivo breast density models to study the cellular/molecular pathways implied in MACE is another study limitation.ConclusionsAmong pre-menopausal women, a higher evidence of adipose tissue at the level of breast gland (lowest breast density, category A) versus higher breast density shows higher rates of MACEs. Therefore, the screening mammography could be proposed in overweight women to stage breast density and to predict MACEs. (Breast Density in Pre-menopausal Women Is Predictive of Cardiovascular Outcomes at 10 Years of Follow-Up [BRECARD]; NCT03779217)     

Immunomodulation of atherosclerosis: myth and reality

Atherosclerosis is an inflammatory disease which displays features of immune activation both locally and systemically. In the present review, we discuss the evidence for immune activation in human disease and experimental models, and survey candidate antigens associated with atherosclerosis. Studies of atherosclerosis in genetic models of immunodeficiency are analysed, as well as immunomodulating therapies and immunization protocols. Based on recent research, it is concluded that immunomodulation represents an interesting approach to the development of new prevention and treatment methods for atherosclerosis.     

A novel MEIS2 mutation explains the complex phenotype in a boy with a typical NF1 microdeletion syndrome

Concurrence of distinct genetic conditions in the same patient is not rare. Several cases involving neurofibromatosis type 1 (NF1) have recently been reported, indicating the need for more extensive molecular analysis when phenotypic features cannot be explained by a single gene mutation. Here, we describe the clinical presentation of a boy with a typical NF1 microdeletion syndrome complicated by cleft palate and other dysmorphic features, hypoplasia of corpus callosum, and partial bicoronal craniosynostosis caused by a novel 2bp deletion in exon 2 of Meis homeobox 2 gene (MEIS2) inherited from the mildly affected father. This is only the second case of an inherited MEIS2 intragenic mutation reported to date. MEIS2 is known to be associated with cleft palate, intellectual disability, heart defects, and dysmorphic features. Our clinical report suggests that this gene may also have a role in cranial morphogenesis in humans, as previously observed in animal models.     

Reconstruction of a complex pelvic perineal defect with pedicled anterolateral thigh flap combined with bilateral lotus petal flap: A case report

Reconstructing extensive perineal defects represents a challenge, and reconstructive choice requires a careful physical assessment of previous radiotherapy, pre‐existing scars, the presence of stomas, and the availability of donor sites. We report a case of a patient affected by an anal carcinoma who underwent a pelvic exenteration and bilateral inguinal iliac obturator lymph node dissection. We performed a pedicled anterolateral thigh flap (ALT) combined with bilateral lotus petal flaps (LPF) to reconstruct the pelvic–perineal area. The result was good, and no major post‐operative complications were reported. Bilateral LPF, combined with a pedicled ALT, may represent a valid option in pelvic–perineal reconstruction following a wide oncological resection. © 2014 Wiley Periodicals, Inc. Microsurgery 35:154–157, 2015.