Karolin Isaksson

Prevention of abdominal adhesions--present state and what's beyond the horizon?

Intra-abdominal adhesions are normally found after most surgical procedures. Many of the adhesions are asymptomatic, but in about 5% they will lead to readmission due to adhesion-related disorders, such as small bowel obstruction, pelvic pain and infertility. This review discusses possible ways to prevent abdominal adhesions and provides an update as comes to where we stand today in research regarding experimental and clinical use of various antiadhesive agents.

Multiregion whole-exome sequencing uncovers the genetic evolution and mutational heterogeneity of early-stage metastatic melanoma

Cancer genome sequencing has shed light on the underlying genetic aberrations that drive tumorigenesis. However, current sequencing-based strategies, which focus on a single tumor biopsy, fail to take into account intratumoral heterogeneity. To address this challenge and elucidate the evolutionary history of melanoma, we performed whole-exome and transcriptome sequencing of 41 multiple melanoma biopsies from eight individual tumors. This approach revealed heterogeneous somatic mutations in the range of 3%-38% in individual tumors. Known mutations in melanoma drivers BRAF and NRAS were always ubiquitous events. Using RNA sequencing, we found that the majority of mutations were not expressed or were expressed at very low levels, and preferential expression of a particular mutated allele did not occur frequently. In addition, we found that the proportion of ultraviolet B (UVB) radiation-induced C>T transitions differed significantly (P < 0.001) between early and late mutation acquisition, suggesting that different mutational processes operate during the evolution of metastatic melanoma. Finally, clinical history reports revealed that patients harboring a high degree of mutational heterogeneity were associated with more aggressive disease progression. In conclusion, our multiregion tumor-sequencing approach highlights the genetic evolution and non-UVB mutational signatures associated with melanoma development and progression, and may provide a more comprehensive perspective of patient outcome. Cancer Res; 76(16); 4765-74. ©2016 AACR.

Clinical impact of abdominal adhesions: What is the magnitude of the problem?

Abdominal adhesions occur after almost every intraabdominal surgical procedure. Research during recent years has brought about vast health-care costs. The purpose of this educational review is to bring the reader up to date in the field of clinical intra-abdominal adhesions and includes discussions concerning the problems following abdominal adhesions including small-bowel obstruction, reoperations, female infertility and pain, pelvic and abdominal, as well as financial aspects. The development of adhesions could be considered as a normal reaction of the peritoneal surface following injury. Adhesion formation is a consequence of the inflammatory response and the subsequent healing process [1]. Adhesion formation per se and the greater omentum have a beneficial role in the peritoneal defence by trapping bacteria and thereby diminishing bacteraemia and generalized peritonitis [2,3]. Together with diaphragmatic lymphatic uptake, the peritoneal membrane, peritoneal macrophages and overall peripheral immune functions, the formation of intra-abdominal adhesions will represent an important defence mechanism provided in the peritoneum [4]. Intra-abdominal adhesions are found in as many as 93% of patients who have undergone intraabdominal surgery [5,6]. Close to 10% of the population has intra-abdominal adhesions without any prior laparotomies owing to, for example, inflammatory disease in the abdomen and/or congenital defects [6,7]. Normally, most adhesions are asymptomatic, but will, however, cause problems in a small proportion of patients. These postsurgical, adhesion-related problems include smallbowel obstruction (SBO), female infertility, as well as pelvic pain and abdominal pain. The formation of adhesions also causes secondary problems such as the prolongation and endangering of future intraabdominal operations [8,9].

Toxicity and Dose Response of Intra-Abdominally Administered Poly-L-alpha-Lysine and Poly-L-Glutamate for Postoperative Adhesion Protection.

Background/Aims: Two differently charged polypeptides, poly-L-lysine (PL) and poly-L-glutamate (PG), have previously been shown to reduce postoperative intra-abdominal adhesions. This study aims to investigate the possible toxic effects and to establish a lowest effective antiadhesive dose. Methods: 152 mice were investigated with a well-known adhesion model and given different concentrations of the two differently charged polypeptides as well as only the cationic PL. Results: For the first time, a probable toxic level of PL given intraperitoneally (40 mg/kg) and the lowest significant concentration of PL and PG for antiadhesive purposes (1.6 mg/kg) could be established. Conclusion: The gap between the possible toxicity level of PL and the lowest efficient antiadhesive dose is probably too narrow, and the shape and charge of PL warrant continuous research for another polycation in the concept of differently charged polypeptides used as antiadhesive agents.

Effects of Polylysine and Polyglutamate on Inflammation and the Normal Process of Peritoneal Healing After Surgery

Introduction: Intraperitoneal adhesions are common after abdominal surgery and may lead to serious clinical complications. Previous studies have investigated the possible effects of the polypeptides poly-L-lysine (αPL) and poly-L-glutamate (PG) forming a polymer complex that prohibits local peritoneal adhesions after surgery. The aim of this study was to examine whether the normal process of peritoneal healing was affected by PL/PG polymer matrix. Material and methods: Male rats (Sprague Dawley) (n=84) underwent abdominal wall surgery and suturing. Rats were randomized in groups according to evaluation time (2, 4, 6, 8, 24 hours and 7 days) with corresponding control groups. Controls received saline (0.9%) and the experimental groups received PL/PG on the surgery site. tPA, PAI-1, IL-6 and active TGFb1 were analyzed at given time points postoperatively in peritoneal lavage. Adhesions were evaluated after seven days. Significant differences were considered to be p<0.05. Results: At a few individual time points small differences were seen between the groups (control and experiment) comparing levels of tPA, PAI-1, IL-6 and active TGFb1. When comparing levels of substances from all time points no statistical differences were seen between the groups as a total. Adhesions were significantly decreased on day 7, p=0.002. Conclusion: Despite significant reduction in adhesions PL/PG administered intraperitoneally as an anti-adhesion agent locally on surgically traumatized area does not seem to affect the normal process of peritoneal healing.

Prevention of pleural adhesions by bioactive polypeptides - a pilot study.

Objective: Postoperative pleural adhesions lead to major problems in repeated thoracic surgery. To date, no antiadhesive product has been proven clinically effective. Previous studies of differently charged polypeptides, poly-L-lysine (PL) and poly-L-glutamate (PG) have shown promising results reducing postoperative abdominal adhesions in experimental settings. This pilot study examined the possible pleural adhesion prevention by using the PL+PG concept after pleural surgery and its possible effect on key parameters; plasmin activator inhibitor-1 (PAI-1) and tissue growth factor beta 1 (TGFb) in the fibrinolytic process. Methods: A total of 22 male rats were used in the study, one control group (n=10) and one experimental group (n=12). All animals underwent primary pleural surgery, the controls receiving saline in the pleural cavity and the experimental group the PL+PG solution administered by spray. The animals were evaluated on day 7. Macroscopic appearance of adhesions was evaluated by a scoring system. Histology slides of the adhesions and pleural biopsies for evaluation of PAI-1 and TGFb1 were taken on day 7. Results: A significant reduction of adhesions in the PL+PG group (p<0.05) was noted at day 7 both regarding the length and severity of adhesions. There were no significant differences in the concentration of PAI-1 and TGFb1 when comparing the two groups. Conclusions: PL+PG may be used to prevent pleural adhesions. The process of fibrinolysis, and fibrosis was though not affected after PLPG administration.

Prevention of Adhesions by PL/PG after Adhesiolysis

Background: Previous studies of differently charged polypeptides, Poly-L-lysine (PL) and Poly-L-Glutamate (PG) have shown promising results, reducing postoperative adhesions. This study aimed to investigate the possible anti adhesion effect of those combined polypeptides, after adhesiolys. The concentration of tPA, PAI-1 and active TGFb1 in biopsies from adhesions, unharmed peritoneum before and after adhesiolysis, was also investigated. Materials and methods: A total of 24 male rats were divided in three groups A (N=8), B (N=8) and C (N=8). All rats underwent primary adhesion creating surgery at day 0, and adhesiolysis at day 7. Adhesions were evaluated at day 7 and 14, where group B received PL/PG after surgery at day 0 and after adhesiolysis at day 7, and group C received PL/PG after adhesiolysis at day 7. Tissue plasminogen activator (tPA), Plasminogen activator inhibitor 1(PAI-1) and active transforming growth factor beta 1(TGF-β1) were collected from biopsies of adhesions and normal peritoneum at day 0, 7 and 14. Results: Significant reduction of adhesions p<0.05 was seen in group B at day 7 after primary surgery, and at day 14 after adhesiolysis. Significantly p<0.05 reduction of adhesions was seen at day 14 after adhesiolysis in group C. Some variations were seen in tPA, PAI-1 and active TGFb1. Conclusions: PL/PG may be used to prevent adhesion formation after adhesiolysis. The process of fibrinolysis and fibrosis was not affected, after PL/PG prophylaxis and adhesiolysis.

Sentinel lymph node biopsy in patients with thin melanomas: Frequency and predictors of metastasis based on analysis of two large international cohorts: ISAKSSON et al.

Sentinel lymph node (SLN) metastasis in patients with thin melanomas (≤1 mm) is uncommon but adverse prognostic factors may indicate an increased risk. We sought to determine how often SLN biopsy (SLNB) was performed in patients with thin melanomas, establish the frequency of SLN metastasis and evaluate the predictive value of ulceration, tumor mitotic rate, and thickness for SLN involvement.

Circulating insulin-like growth factor I in relation to melanoma risk in the European Prospective Investigation into Cancer and Nutrition: Circulating IGF-I concentrations and melanoma risk

Insulin‐like growth factor‐I (IGF‐I) regulates cell proliferation and apoptosis, and is thought to play a role in tumour development. Previous prospective studies have shown that higher circulating concentrations of IGF‐I are associated with a higher risk of cancers at specific sites, including breast and prostate. No prospective study has examined the association between circulating IGF‐I concentrations and melanoma risk. A nested case–control study of 1,221 melanoma cases and 1,221 controls was performed in the European Prospective Investigation into Cancer and Nutrition cohort, a prospective cohort of 520,000 participants recruited from 10 European countries. Conditional logistic regression was used to estimate odds ratios (ORs) for incident melanoma in relation to circulating IGF‐I concentrations, measured by immunoassay. Analyses were conditioned on the matching factors and further adjusted for age at blood collection, education, height, BMI, smoking status, alcohol intake, marital status, physical activity and in women only, use of menopausal hormone therapy. There was no significant association between circulating IGF‐I concentration and melanoma risk (OR for highest vs lowest fifth = 0.93 [95% confidence interval [CI]: 0.71 to 1.22]). There was no significant heterogeneity in the association between IGF‐I concentrations and melanoma risk when subdivided by gender, age at blood collection, BMI, height, age at diagnosis, time between blood collection and diagnosis, or by anatomical site or histological subtype of the tumour (Pheterogeneity≥0.078). We found no evidence for an association between circulating concentrations of IGF‐I measured in adulthood and the risk of melanoma.