Synchronous "skip" facial metastases from colorectal adenocarcinoma: a case report and review of literature.

BACKGROUND: Skin metastases from colorectal adenocarcinoma are rare conditions that are metachronous in most of cases and may represent the first sign of a recurrence. These lesions are usually located to the abdominal wall on postoperative scars, perineum and chest due to direct spread from the tumor or to the lymphatic and venous dissemination. We describe a rare case of synchronous skin metastases in a patient affected by sigmoid adenocarcinoma with no sign of liver and lung repetitive lesions. CASE PRESENTATION: We admitted a 59 years old male, with no relevant medical history. He was evaluated by our tertiary center of colorectal surgery complaining diarrhoea and abdominal pain. The physical examination revealed a palpable mass in left flank of the abdomen. The colonoscopy showed a sub-stenosis of the sigmoid colon (G2 adenocarcinoma). No repetitive lesions were detected by the preoperative CT scan. The patient reported a rapid grow of a soft supralabial and chin nodules in the last 2 months, which he believed to be related to the use of the mask due to COVID-19 pandemic. A laparoscopic left hemicolectomy with complete mesocolic excision and a local excision of both facial nodules were performed. The histological examination revealed a poorly differentiated signet ring cell colorectal adenocarcinoma with metastases in seven pericolic lymphonodes. The excisional biopsy of the skin nodules revealed a subcutaneous metastases from primary colorectal tumour. CONCLUSIONS: As far as we know, synchronous facial metastases from colorectal cancer in the absence of any other metastases has never been described before. The onset of new skin nodules in patients affected by colorectal cancer should raise-up the clinical suspicion of metastatic lesions even when repetitive lesions are not detected in the liver or lungs.

Ageing with sacral nerve modulation for fecal incontinence: how many patients get benefit after more than 10 years?

Sacral nerve modulation (SNM) has represented a major advancement in the minimally invasive management of patients with fecal incontinence (FI). Although the success rate in the short-medium term has widely been demonstrated, the very long-term outcomes are poorly investigated. This study aims to assess the effectiveness of SNM in a cohort of patients with a follow-up longer than 10 years. Clinical records of patients submitted to SNM for FI in our tertiary referral colorectal Unit between 1998 and 2010 were retrospectively reviewed looking for status of the implantable pulse generator (IPG), follow-up duration, severity of FI by the St Marks' score and quality of life. 58 patients fulfilled the entry criteria and 36 (58%, median follow-up, 12 years) accepted to take part to the telephone interview, while 22 (38%) were lost to the follow-up. Nineteen patients had their IPG removed (Group A) while 17 (27%) had the SNM still active after a median follow-up of 13 years (Group B). In the group A, the median baseline St Marks' score was 13 and did not change after the IPG removal. In group B, the median baseline St Marks' score was 14, at last IPG substitution, it was of 7 and at the last follow-up dropped to 4. In the group A, the median SF-12 physical and mental scores did not change significantly while they improved significantly in group B. A progressive deterioration of the success rate of SNM with the time has been documented after a very long-term follow-up.

The REALISE score: a new statistically validated scoring system to assess the severity of anal fissures.

BACKGROUND: Anal fissure (AF) is a common, painful disease that strongly affects patients' quality of life, however, no scoring system to assess the severity of AF is available in the literature. The aim of this study was to set up and validate a reliable scoring system to quantify the severity of AF, to be used in prospective trials comparing the efficacy and the outcomes of surgical or medical treatments. METHODS: The study was conducted on patients with acute or chronic AF and a control group in a tertiary centre for coloproctology in June 2020-September 2020. Two researchers independently carried out a structured interviewer-led questionnaire at two different time points (T1/T2). The questionnaire consisted of five items selected according to the most commonly reported symptoms for AF: the item pain, was scored from 0 to 10 using a visual analogue scale, and quality of life, duration of pain, use of painkillers, and bleeding were scored from 1 to 5 using Likert-scale questions. The scoRing systEm for AnaL fIsSurE (REALISE) score was the sum of the points. Patients with AF and a control group of patients with haemorrhoids, anal fistula, or obstructed defecation syndrome entered the study. Main outcome measures were reliability, inter-/intraobserver agreement, and repeatability. RESULTS: One hundred and fifty well-matched patients (75 with AF and 75 controls) were enrolled. A significant difference was found between the mean REALISE score for patients with AF and controls (p < 0.001). The two REALISE scores were highly correlated (r = 0.99). The coefficient of repeatability was 1.45 in T1 and 1.18 in T2. CONCLUSIONS: The REALISE score may have an important role in the assessment and management of AF, in grading the severity of AF and comparing results of different treatments.

GLI2 induces genomic instability in human keratinocytes by inhibiting apoptosis.

Abnormal Sonic Hedgehog signalling leads to increased transcriptional activation of its downstream effector, glioma 2 (GLI2), which is implicated in the pathogenesis of a variety of human cancers. However, the mechanisms underlying the tumorigenic role of GLI2 remain elusive. We demonstrate that overexpression of GLI2-ß isoform, which lacks the N-terminal repressor domain (GLI2ΔN) in human keratinocytes is sufficient to induce numerical and structural chromosomal aberrations, including tetraploidy/aneuploidy and chromosomal translocations. This is coupled with suppression of cell cycle regulators p21(WAF1/CIP1) and 14-3-3σ, and strong induction of anti-apoptotic signalling, resulting in a reduction in the ability to eliminate genomically abnormal cells. Overexpression of GLI2ΔN also rendered human keratinocytes resistant to UVB-mediated apoptosis, whereas inhibition of B-cell lymphoma 2 (BCL-2) restored endogenous (genomic instability (GIN)) and exogenous (UVB) DNA damage-induced apoptosis. Thus, we propose that ectopic expression of GLI2 profoundly affects the genomic integrity of human epithelial cells and contributes to the survival of progenies with genomic alterations by deregulating cell cycle proteins and disabling the apoptotic mechanisms responsible for their elimination. This study reveals a novel role for GLI2 in promoting GIN, a hallmark of human tumors, and identifies potential mechanisms that may provide new opportunities for the design of novel forms of cancer therapeutic strategies.

ASPP1 and ASPP2 are new transcriptional targets of E2F.

The E2F family of transcription factors regulates the expression of a number of genes whose products are involved in cell cycle control, DNA replication and apoptosis. We show here that E2F-1 binds in vivo the promoters of ASPP1 and ASPP2 genes, two activators of p53-mediated apoptosis, E2F-1, E2F-2 and E2F-3 all activate the isolated ASPP1 and ASPP2 promoters. Overexpression or deregulation of E2F-1 increased the expression levels of ASPP1 and ASPP2 mRNA and proteins. The identification of ASPP1 and ASPP2 genes as transcriptional targets of E2F provides another mechanism by which E2F cooperates with p53 to induce apoptosis.

ASPP proteins specifically stimulate the apoptotic function of p53.

We identified a family of proteins termed ASPP. ASPP1 is a protein homologous to 53BP2, the C-terminal half of ASPP2. ASPP proteins interact with p53 and specifically enhance p53-induced apoptosis but not cell cycle arrest. Inhibition of endogenous ASPP function suppresses the apoptotic function of endogenous p53 in response to apoptotic stimuli. ASPP enhance the DNA binding and transactivation function of p53 on the promoters of proapoptotic genes in vivo. Two tumor-derived p53 mutants with reduced apoptotic function were defective in cooperating with ASPP in apoptosis induction. The expression of ASPP is frequently downregulated in human breast carcinomas expressing wild-type p53 but not mutant p53. Therefore, ASPP regulate the tumor suppression function of p53 in vivo.

Selective virus-mediated intracellular delivery of membrane-impermeant compounds by means of plasma membrane vesicles.

The impermeability of the cell plasma membrane is a major obstacle to intracellular delivery of large hydrophilic molecules, such as many kinds of drugs. This contribution describes a general-purpose delivery system that employs the membrane fusion capacity of enveloped viruses to circumvent cell impermeability. Vesicles were generated from the plasma membrane of HEp-2 cells, a human cell line host for the Newcastle disease virus (NDV). They could be loaded with a fluorescent, high molecular weight dye (FITC/dextran, MW 70 KDa) or with the enzyme ribonuclease A (MW 14 KDa). These vesicles were found to fuse and deliver their lumen contents to cultured HEp-2 cells in the presence of NDV virions. When ribonuclease was employed as the encapsulated solute, viral replication was inhibited and death of the infected cells was accelerated. Implications and possible applications of this technique in antiviral therapy are discussed.

Pseudo First-Order Cleavage of an Immobilized Substrate by an Enzyme Undergoing Two-Dimensional Surface Diffusion.

In this paper we study the reaction kinetics of an enzyme adsorbed on a peptide substrate surface. Although the adsorption is effectively irreversible, the enzyme is able to diffuse on the surface. Our reaction system consisted of the enzyme collagenase and the oligopeptide FALGPA, a substrate for the enzyme. A quartz surface was coated with covalently bound substrate molecules. The extent of reaction was monitored continuously in a flow cell via UV absorption. The data are compatible with a kinetic model based on a pseudo first-order diffusion/orientation rate-limiting step followed by a relatively fast chemical cleavage step. This model was validated by examining the pH dependence of the rate constant. Copyright 1999 Academic Press.