The value of histology, tumor infiltrating lymphocytes, and mismatch repair status as risk factors of nodal metastasis in screening detected and endoscopically removed pT1 colorectal cancers.

BACKGROUND The number of patients with colorectal cancers (CRCs) invading the submucosa (pT1) resected during colonoscopy is increasing due to the screening. Such tumors are potentially metastatic, but only 15% of patients have nodal involvement. Histologic criteria currently used for selecting patients needing resection are imprecise and most patients are overtreated. Tumor infiltrating lymphocytes (TILs) and mismatch repair (MMR) status impact on CRC prognosis and could be risk factors of nodal metastasis. AIM To identify patients requiring completion surgery, the value of histologic variables, TILs, and MMR status as risk factors of nodal metastasis was investigated in screening detected and endoscopically removed pT1 CRCs. MATERIALS AND METHODS Histologic variables, CD3+ and CD8+ TILs, and MMR status were assessed in 102 endoscopically removed pT1 CRC. Univariate and multivariate analyses were used to evaluate the correlation with nodal metastasis. RESULTS Positive resection margin, evidence of vascular invasion and tumor budding, wide area of submucosal invasion, and high number of CD3+ TILs were associated with nodal metastasis in univariate analyses. Vascular invasion was statistically independent in multivariate analysis. Evidence of neoplastic cells in the vessels and/or at the excision border featured 5 out of 5 metastatic tumors and 13 out of 97 non-metastatic ones. CONCUSIONS Completion surgery should be mandatory only for patients with pT1 CRC with vascular invasion or with tumor cells reaching the margin. In all other cases, the treatment choice should be entrusted to the evaluation of the risk-benefit ratio of each patient considering the rarity of nodal metastasis

Methylation status of Vitamin D receptor gene promoter in benign and malignant adrenal tumors

We previously showed a decreased expression of vitamin D receptor (VDR) mRNA/protein in a small group of adrenocortical carcinoma (ACC) tissues, suggesting the loss of a protective role of VDR against malignant cell growth in this cancer type. Downregulation of VDR gene expression may result from epigenetics events, that is, methylation of cytosine nucleotide of CpG islands in VDR gene promoter. We analyzed methylation of CpG sites in the VDR gene promoter in normal adrenals and adrenocortical tumor samples. Methylation of CpG-rich 5' regions was assessed by bisulfite sequencing PCR using bisulfite-treated DNA from archival microdissected paraffin-embedded adrenocortical tissues. Three normal adrenals and 23 various adrenocortical tumor samples (15 adenomas and 8 carcinomas) were studied. Methylation in the promoter region of VDR gene was found in 3/8 ACCs, while no VDR gene methylation was observed in normal adrenals and adrenocortical adenomas. VDR mRNA and protein levels were lower in ACCs than in benign tumors, and VDR immunostaining was weak or negative in ACCs, including all 3 methylated tissue samples. The association between VDR gene promoter methylation and reduced VDR gene expression is not a rare event in ACC, suggesting that VDR epigenetic inactivation may have a role in adrenocortical carcinogenesi

Lumican is overexpressed in lung adenocarcinoma pleural effusions.

Adenocarcinoma (AdC) is the most common lung cancer subtype and is often associated with pleural effusion (PE). Its poor prognosis is attributable to diagnostic delay and lack of effective treatments and there is a pressing need in discovering new biomarkers for early diagnosis or targeted therapies. To date, little is known about lung AdC proteome. We investigated protein expression of lung AdC in PE using the isobaric Tags for Relative and Absolute Quantification (iTRAQ) approach to identify possible novel diagnostic/prognostic biomarkers. This provided the identification of 109 of lung AdC-related proteins. We further analyzed lumican, one of the overexpressed proteins, in 88 resected lung AdCs and in 23 malignant PE cell-blocks (13 lung AdCs and 10 non-lung cancers) using immunohistochemistry. In AdC surgical samples, lumican expression was low in cancer cells, whereas it was strong and diffuse in the stroma surrounding the tumor. However, lumican expression was not associated with tumor grade, stage, and vascular/pleural invasion. None of the lung cancer cell-blocks showed lumican immunoreaction, whereas those of all the other tumors were strongly positive. Finally, immunoblotting analysis showed lumican expression in both cell lysate and conditioned medium of a fibroblast culture but not in those of A549 lung cancer cell line. PE is a valid source of information for proteomic analysis without many of the restrictions of plasma. The high lumican levels characterizing AdC PEs are probably due to its release by the fibroblasts surrounding the tumor. Despite the role of lumican in lung AdC is still elusive, it could be of diagnostic value

Genetic Features of Metachronous Esophageal Cancer Developed in Hodgkin's Lymphoma or Breast Cancer Long-Term Survivors: An Exploratory Study.

Background Development of novel therapeutic drugs and regimens for cancer treatment has led to improvements in patient long-term survival. This success has, however, been accompanied by the increased occurrence of second primary cancers. Indeed, patients who received regional radiotherapy for Hodgkin's Lymphoma (HL) or breast cancer may develop, many years later, a solid metachronous tumor in the irradiated field. Despite extensive epidemiological studies, little information is available on the genetic changes involved in the pathogenesis of these solid therapy-related neoplasms. Methods Using microsatellite markers located in 7 chromosomal regions frequently deleted in sporadic esophageal cancer, we investigated loss of heterozygosity (LOH) and microsatellite instability (MSI) in 46 paired (normal and tumor) samples. Twenty samples were of esophageal carcinoma developed in HL or breast cancer long-term survivors: 14 squamous cell carcinomas (ESCC) and 6 adenocarcinomas (EADC), while 26 samples, used as control, were of sporadic esophageal cancer (15 ESCC and 11 EADC). Results We found that, though the overall LOH frequency at the studied chromosomal regions was similar among metachronous and sporadic tumors, the latter exhibited a statistically different higher LOH frequency at 17q21.31 (p = 0.018). By stratifying for tumor histotype we observed that LOH at 3p24.1, 5q11.2 and 9p21.3 were more frequent in ESCC than in EADC suggesting a different role of the genetic determinants located nearby these regions in the development of the two esophageal cancer histotypes. Conclusions Altogether, our results strengthen the genetic diversity among ESCC and EADC whether they occurred spontaneously or after therapeutic treatments. The presence of histotype-specific alterations in esophageal carcinoma arisen in HL or breast cancer long-term survivors suggests that their transformation process, though the putative different etiological origin, may retrace sporadic ESCC and EADC carcinogenesis

Calcific Myonecrosis of the Leg: A Rare Entity

Calcific myonecrosis is a rare disease that has been shown to be a late sequela of trauma. This article presents a 68-year-old man with calcific myonecrosis of the leg 40 years after a tibial fracture complicated with peroneal nerve palsy. The soft tissue mass increased in size after another injury to the leg that occurred two years before his presentation. Physical examination at presentation showed a palpable extra-osseous mass at the anterior aspect of the left leg; the mass was not adherent to adjacent soft-tissues and bone, and it was painless but tender to palpation. Radiographs of the left leg showed extensive calcification at the soft-tissue of the anterior and posterior leg. An ultrasonography-guided trocar biopsy was done; histological findings were indicative of calcific myonecrosis. Given the benign entity of the lesion and known high rate of complications, he was recommended for no further treatment except for clinical and imaging observation. Located at the site of the biopsy, he experienced infection with drainage that eventually healed after six months with antibiotics and wound dressing changes. During the last follow-up examination, two years after diagnosis, the patient was asymptomatic without progression of the mass

Oncofetal gene SALL4 and prognosis in cancer: A systematic review with meta-analysis

The Spalt-Like Transcription Factor 4 (SALL4) oncogene plays a central function in embryo-fetal development and is absent in differentiated tissues. Evidence suggests that it can be reactivated in several cancers worsening the prognosis. We aimed at investigating the risk associated with SALL4 reactivation for all-cause mortality and recurrence in cancer using the current literature. A PubMed and SCOPUS search until 1st September 2016 was performed, focusing on perspective studies reporting prognostic parameters in cancer data. In addition, 17 datasets of different cancer types from The Cancer Genome Atlas were considered. A total of 9,947 participants across 40 cohorts, followed-up for about 5 years on average, were analyzed comparing patients showing SALL4 presence (SALL4+, n = 1,811) or absence (SALL4-, n = 8,136). All data were summarised using risk ratios (RRs) for the number of deaths/recurrences and hazard ratios (HRs) for the time-dependent risk related to SALL4+, adjusted for potential confounders. SALL4+ significantly increased overall mortality (RR = 1.34, 95% confidence intervals (CI)=1.21-1.48, p<0.0001, I2=66%; HR=1.4; 95%CI: 1.19-1.65; p<0.0001; I2=63%) and recurrence of disease (RR = 1.25, 95% CI = 1.1-1.42, p=0.0006, I2=62%); HR=1.52; 95% CI: 1.22-1.89, p=0.0002; I2=69%) compared to SALL4-. Moreover, SALL4 remained significantly associated with poor prognosis even using HRs adjusted for potential confounders (overall mortality: HR=1.4; 95%CI: 1.19-1.65; p<0.0001; I2=63%; recurrence of disease: HR=1.52; 95% CI: 1.22-1.89, p=0.0002; I2=69%). These results suggest that SALL4 expression increases both mortality and recurrence of cancer, confirming this gene as an important prognostic marker and a potential target for personalized medicine

β-Arrestin-1 expression and epithelial-to-mesenchymal transition in laryngeal carcinoma.

Aim: The novel primary end-point of the present study was to ascertain β-arrestin-1 expression in a cohort of consecutive patients with laryngeal squamous cell carcinoma (LSCC) with information available on their cigarette-smoking habits. A secondary end-point was to conduct a preliminary clinical and pathological investigation into the possible role of β-arrestin-1 in the epithelial-to-mesenchymal transition (EMT), identified by testing for E-cadherin, Zeb1, and Zeb2 expression, in the setting of LSCC. Methods: The expression of β-arrestin-1, E-cadherin, zeb1, and zeb2 was ascertained in 20 consecutive LSCCs. Results: Statistical analysis showed no significant associations between β-arrestin-1 and EMT (based on the expression of E-cadherin, Zeb1, and Zeb2). The combined effect of nicotine and β-arrestin-1 was significantly associated with a shorter disease-free survival ( P=0.01) in our series of LSCC. This latter result was also confirmed in an independent, publicly available LSCC cohort ( P=0.047). Conclusions: Further investigations on larger series (ideally in prospective settings) are needed before we can consider closer follow-up protocols and/or more aggressive treatments for patients with LSCC and a combination of nicotine exposure and β-arrestin-1 positivity in tumor cells at the time of their diagnosis. Further studies on how β-arrestin functions in cancer via different signaling pathways might reveal potential targets for the treatment of even advanced laryngeal malignancies

The immune cell landscape of metastatic uveal melanoma correlates with overall survival

Uveal melanoma (UM) represents the most common primary intra-ocular malignancy in adults. Up to 50% of the patients develop distant metastases within 10\u2009years from diagnosis, with the liver as the most common site. Upon metastatization, life expectancy strongly reduces and immune checkpoint inhibitors that prove effective in cutaneous melanoma do not modify clinical outcome. To date, few studies have focused on deciphering the immunomodulatory features of metastatic UM microenvironment, and there are no prognostic models for clinical use. This highlights the urgent need to understand the delicate interplay between tumor and immune cells acting at the site of metastasis

A Therapeutic and Diagnostic Multidisciplinary Pathway for Merkel Cell Carcinoma Patients

Merkel Cell Carcinoma (MCC) is a highly aggressive neuroendocrine neoplasm of the skin. Due to its rarity, the management of MCC is not standardized across centers. In this article, we present the experience of the Veneto region in the North-East of Italy, where a committee of skin cancer experts has proposed a clinical pathway for the diagnosis and treatment of MCC. Putting together the evidence available in the international literature, we outlined the best approach to the management of patients affected with this malignancy step- by- step for each possible clinical situation. Crucial in this pathway is the role of the multidisciplinary team to deal with the lack of robust information on each aspect of the management of this disease