The effect of intravenous iron therapy on long-term survival in anaemic colorectal cancer patients: Results from a matched cohort study.

INTRODUCTION: Intravenous iron therapy has been shown to be advantageous in treating anaemia and reducing the need for blood transfusions. Iron treatment, however, may also be hazardous by supporting cancer growth. Present clinical study explores, for the first time, the effect of preoperative intravenous iron therapy on tumour prognosis in anaemic colorectal cancer patients. METHODS: A retrospective cohort study was performed on consecutive patients who underwent surgery for colorectal cancer between 2010 and 2016 in a single teaching hospital. The primary outcomes were 5-year overall survival (OS) and disease-free survival (DFS). Survival estimates were calculated using the Kaplan-Meier method and patients were matched based on propensity score. RESULTS: 320 (41.0%) of all eligible patients were anaemic, of whom 102 patients received preoperative intravenous iron treatment (31.9%). After propensity score matching 83 patients were included in both intravenous and non-intravenous iron group. The estimated 1-, 3-, and 5-year OS (91.6%, 73.1%, 64.3%, respectively) and DFS (94.5%, 86.7%, 83.4%, respectively) in the intravenous iron group were comparable with the non-intravenous iron group (p = 0.456 and p = 0.240, respectively). In comparing patients with an event (death or recurrence) and no event in the intravenous iron group, a distinct trend was found for decreased transferrin in the event group (median 2.53  g/L vs 2.83  g/L, p = 0.052). CONCLUSION: The present study illustrates that a dose of 1000-2000 mg preoperative intravenous iron therapy does not have a profound effect on long-term overall and disease-free survival in anaemic colorectal cancer patients. Future randomised trials with sufficient power are required to draw definite conclusions on the safety of intravenous iron therapy.

Iron therapy as treatment of anemia: A potentially detrimental and hazardous strategy in colorectal cancer patients.

In colorectal cancer patients, iron therapy, and especially intravenous iron therapy, is increasingly used to treat anemia and reduce the use of blood transfusions. However, iron has also been shown to be an essential nutrient for rapidly proliferating tissues and cells. In this respect, anemia of inflammation, characterized by limited duodenal iron uptake and sequestration of iron into the reticuloendothelial system, might be regarded as a potentially effective defense strategy of the human body against tumor growth. We therefore hypothesize that iron therapy, by supporting colorectal tumor growth and increasing the metastatic potential, may worsen tumor prognosis in colorectal cancer patients. This hypothesis is particularly supported for colorectal cancer by laboratory, epidemiological and animal studies, demonstrating the role of iron in all aspects of tumor development growth. Compared to non-malignant colon cells, tumor cells differ in the levels and activity of many iron import and export proteins, resulting in an increase in intracellular iron level and enhanced proliferation. In addition, it is demonstrated that iron is able to amplify Wnt signaling in tumors with Apc mutation, a critical mutation in the development of colorectal cancer. If our hypothesis is to be confirmed, current practice of iron administration, as treatment for anemia and as replacement of blood transfusions, can be hazardous and should be completely reconsidered.

The role of preoperative iron deficiency in colorectal cancer patients: prevalence and treatment.

BACKGROUND: In preoperative blood management of colorectal cancer patients, intravenous iron therapy is increasingly used to treat anaemia and prevent red blood cell transfusions. However, while iron deficiency is the most common cause of anaemia, little is known about the prevalence and namely type of iron deficiency in this population, whereas both types of iron deficiency (i.e. absolute and functional iron deficiency) are recommended to be treated differently by international cancer guidelines. OBJECTIVE: The aim of present study is to investigate the prevalence and namely type of iron deficiency in colorectal cancer patients, and to assess its clinical relevance. METHODS: Preoperative iron status, clinical parameters (i.e. age, ASA classification, tumour location, tumour stage) and postoperative complications were retrospectively collected for all newly diagnosed colorectal cancer patients in our institution over a 3-year period. RESULTS: Iron deficiency was observed in 163 (48.1%) of 339 patients. Of these iron-deficient patients, 3.7% had an isolated absolute iron deficiency (AID) and 15.3% a functional iron deficiency (FID), while the rest had a combination of AID and FID. Anaemia was present in 66.1% of iron-deficient patients. Iron deficiency was significantly associated with an increased postoperative complication rate (univariable OR 1.94, p = 0.03, multivariable OR 1.84, p = 0.07), with right-sided tumours (p < 0.001), high ASA classification (p = 0.002), advanced tumour stage (p = 0.01) and advanced age (p = 0.04). In comparing clinical parameters between patients with AID and FID, advanced age was significantly associated with FID (p = 0.03), and the presence of anaemia with AID (p = 0.02). CONCLUSION: In preoperative colorectal cancer patients, there is a high prevalence of iron deficiency, including a high percentage of patients with-a component of-functional iron deficiency, associated with the increased postoperative complication rate. As both types of iron deficiency require a different treatment strategy, our results illustrate the therapeutic potential of especially intravenous iron supplementation in patients with severe iron deficiency and stress the urgency of routinely monitoring preoperative iron status and differentiation between types of iron deficiency. As iron therapy may also be potentially harmful in respect to stimulation of tumour growth, future clinical trials assessing the long-term effect of iron therapy are necessary.

Advanced glycation end products as a biomarker for incisional hernia.

BACKGROUND: Incisional hernia is one of the most frequent complications after abdominal surgery, with incidences up to 30%. A reliable biomarker for the prediction of this complication is lacking. Advanced glycosylation end products (AGEs), also known as non-enzymatic collagen crosslinks, are correlated with aging, smoking, hyperglycemia, hyperlipidemia and oxidative stress. In this study the accumulation of AGEs and the relation between AGEs and incisional hernia were investigated. MATERIALS AND METHODS: In an exploratory case-control study, 23 patients with incisional hernia after midline incision were compared with 17 patients without clinical or radiological signs of incisional hernia after midline incision, AGEs were measured using a Skin Auto Fluorescence (SAF)-reader. RESULTS: Twenty-three patients with a clinically significant incisional hernia and 17 control patients were included. The study groups had significant differences in mean BMI. There was a significant difference between mean AGEs in patients with and without incisional hernia after midline incision (3.00 ± 0.15 vs. 2.56 ± 0.11, T test p = 0.03). CONCLUSION: AGE accumulation measured in the skin indirectly with autofluorescence might be associated with incisional hernia. Prospective larger trials should confirm this finding.

The 'AbdoMAN': an artificial abdominal wall simulator for biomechanical studies on laparotomy closure techniques.

PURPOSE: Incisional hernia remains a frequent complication after abdominal surgery associated with significant morbidity and high costs. Animal and clinical studies have exhibited some limitations. The purpose of this study was to develop an artificial human abdominal wall (AW) simulator in order to enable investigations on closure modalities. We hypothesized that a physical model of the human AW would give new insight into commonly used suture techniques representing a substantial complement or alternative to clinical and animal studies. METHODS: The 'AbdoMAN' was developed to simulate human AW biomechanics. The 'AbdoMAN' capacities include measurement and regulation of intra-abdominal pressure (IAP), generation of IAP peaks as a result of muscle contraction and measurements of AW strain patterns analyzed with 3D image stereo correlation software. Intact synthetic samples were used to test repeatability. A laparotomy closure was then performed on five samples to analyze strain patterns. RESULTS: The 'AbdoMAN' was capable of simulating physiological conditions. AbdoMAN lateral muscles contract at 660 N, leading the IAP to increase up to 74.9 mmHg (range 65.3-88.3). Two strain criteria were used to assess test repeatability. A test with laparotomy closure demonstrated closure testing repeatability. CONCLUSIONS: The 'AbdoMAN' reveals as a promising enabling tool for investigating AW surgery-related biomechanics and could become an alternative to animal and clinical studies. 3D image correlation analysis should bring new insights on laparotomy closure research. The next step will consist in evaluating different closure modalities on synthetic, porcine and human AW.

Long-term prognostic value of preoperative anemia in patients with colorectal cancer: A systematic review and meta-analysis.

OBJECTIVE: To evaluate the long-term prognostic factor of preoperative anemia in colorectal cancer patients. BACKGROUND: Anemia is frequently observed in colorectal cancer patients, with a case incidence of 30 to 67 percent. Besides an indicator of tumor-induced blood loss and inflammation, anemia in cancer is also suggested to be a cause of inferior outcome, possibly via worsening of tumor hypoxia. As surgery is likely to enhance anemia, the long-term prognostic value of preoperative anemia seems most interesting. METHODS: Comprehensive searches were carried out in all relevant databases, including MEDLINE, Embase and Web-of-Science. To include studies addressing overall survival, follow-up had to be at least 24 months or till death. For pooling of survival results, a mixed-linear (fixed-effects) model was fit to the reported hazard ratios (HRs) to calculate a pooled estimate and confidence interval. RESULTS: We included 12 studies comprising 3588 patients to estimate the association between preoperative anemia and overall survival (OS) and disease-free survival (DFS). In a fixed-effects meta-analysis of eight studies, including both colon and rectal cancer, preoperative anemia was significantly associated with poor OS (HR 1.56; 95% CI 1.30 to 1.88; p < 0.001). A meta-analysis of seven studies also showed that preoperative anemia was significantly associated with poor DFS (HR 1.34; 95% CI 1.11 to 1.61; p = 0.002). Restricted to studies exclusively on colon cancer or rectal cancer, HRs for OS were 1.25 (95% CI 1.00 to 1.55; p = 0.05) and 2.59 (95% CI 1.68 to 4.01; p < 0.001), respectively, while HRs for DFS were 1.21 (95% CI 0.96 to 1.52; p = 0.11) and 1.61 (95% CI 1.18 to 2.21; p = 0.003). CONCLUSION: The present meta-analysis reveals that preoperative anemia is significantly associated with decreased long-term OS and DFS in rectal cancer, but not in colon cancer patients, although this meta-analysis is mainly based on retrospective studies with high heterogeneity. These results justify raised awareness about the impact of preoperative anemia on long-term survival.

Development of incisional herniation after midline laparotomy.

BACKGROUND: Incisional herniation is a common complication after abdominal surgery associated with considerable morbidity. The aim of this study was to determine whether incisional hernia is an early complication, in order to understand better the aetiology of incisional hernia formation. METHODS: This study involved the secondary analysis of a subset of patients included in a large RCT comparing small and large tissue bites (5 mm every 5 mm, or 1 cm every 1 cm) in patients scheduled to undergo elective abdominal surgery by midline laparotomy. The distance between the rectus abdominis muscles (RAM distance) was measured by standardized ultrasound imaging 1 month and 1 year after surgery. The relationship between the 1-year incidence of incisional hernia and the RAM distance at 1 month was investigated. RESULTS: Some 219 patients were investigated, 113 in the small-bites and 106 in the large-bites group. At 1 month after surgery the RAM distance was smaller for small bites than for large bites (mean(s.d.) 1·90(1·18) versus 2·39(1·34) cm respectively; P = 0·005). At 1 year, patients with incisional hernia had a longer RAM distance at 1 month than those with no incisional hernia (mean(s.d.) 2·43(1·48) versus 2·03(1·19) cm respectively; relative risk 1·14, 95 per cent c.i. 1·03 to 1·26, P = 0·015). CONCLUSION: A RAM distance greater than 2 cm at 1 month after midline laparotomy is associated with incisional hernia. Closure with small bites results in a smaller distance between the muscles.

Biologic meshes are not superior to synthetic meshes in ventral hernia repair: an experimental study with long-term follow-up evaluation.

BACKGROUND: In laparoscopic incisional hernia repair, direct contact between the prosthesis and the abdominal viscera is inevitable, which may lead to an inflammatory reaction resulting in abdominal adhesion formation. This study compared five different synthetic and biologic meshes in terms of adhesion formation, shrinkage, incorporation, and histologic characteristics after a period of 30 and 90 days. METHODS: In 85 rats, a mesh was positioned intraperitoneally in direct contact with the viscera. Five different meshes were implanted: Prolene (polypropylene), Parietex composite (collagen-coated polyester), Strattice (porcine dermis, non-cross-linked), Surgisis (porcine small intestine submucosa, non-cross-linked), and Permacol (porcine dermis, cross-linked). The meshes were tested in terms of adhesion formation, shrinkage, and incorporation after a period of 30 and 90 days. Additionally, collagen formation after 90 days was determined. RESULTS: Significantly less adhesion formation was observed with Parietex composite (5 %; interquartile range [IQR], 2-5 %) and Strattice (5 %; IQR, 4-10 %) in the long term. In contrast, organs were attached to Permacol with four of seven meshes (57 %), and adhesion coverage of Surgisis mesh was present in 66 % (IQR, 0-100 %) of the cases. After 90 days, the best incorporation was seen with the Parietex composite mesh (79 %; IQR, 61-83 %). After 90 days, major alterations in adhesion formation were seen compared with 30 days. Histologically, Strattice and Parietex composite showed a new mesothelial layer on the visceral side of the mesh. Microscopic degradation and new collagen formation were seen in the Surgisis group. CONCLUSIONS: Parietex composite mesh demonstrated the best long-term results compared with all the other meshes. The biologic non-cross-linked mesh, Strattice, showed little adhesion formation and moderate shrinkage but poor incorporation. Biologic meshes are promising, but varying results require a more detailed investigation and demonstrate that biologic meshes are not necessarily superior to synthetic meshes. The significant changes that take place between 30 and 90 days should lead to careful interpretation of short-term experimental results.

Long-term follow-up evaluation of chronic pain after endoscopic total extraperitoneal repair of primary and recurrent inguinal hernia.

BACKGROUND: Long-term data on chronic pain after endoscopic total extraperitoneal (TEP) hernia repair are hardly available. METHODS: Between January 1997 and December 1998, 416 patients with consecutive primary and recurrent inguinal hernia underwent endoscopic TEP hernia repair. Long-term follow-up evaluation was carried out from June 2007 to June 2008. The primary outcome measure was persistent pain and discomfort interfering with daily activity. RESULTS: The overall response rate was 66% (273 of 416 patients). Of the 416 patients, 85 (20%) had died of causes unrelated to hernia repair and 58 (14%) were lost to follow-up. A total of 177 patients were physically examined in the outpatient clinic. Because 96 patients were not able to visit the outpatient' clinic, they completed the survey by telephone. The median follow-up period was 10 years (range, 9-11 years). After TEP repair, 16 patients (6%) reported chronic groin pain, and 10 patients (4%) still experience pain at this writing after the 10-year follow-up period. One of the patients has experienced persistent pain and discomfort interfering with daily activity. Patients with preoperative pain have reported significantly more chronic pain (P = 0.03). CONCLUSIONS: Chronic groin pain after TEP repair of primary and recurrent inguinal hernia seems to have a low incidence after a 10-year follow-up period.

The anatomical limits of the posterior vaginal vault toward its use as route for intra-abdominal procedures.

BACKGROUND: The use of natural openings for abdominal surgery started at the beginning of the 21st century. A trans-Douglas endoscopic device has been designed to perform most of the intra-abdominal operations in women through the pouch of Douglas. The posterior vaginal vault is limited in size and could be damaged by an oversized instrument. This study investigates the optimal dimensions of the instrument by measuring the limiting factor in the passage. METHODS: In ten female embalmed bodies the transversal and sagittal diameter of the fornix posterior vaginalis was measured by two observers. The pouch of Douglas was filled to its maximal capacity with mouldable latex through an open abdomen. By internal vaginal examination the connective tissue borders of the fornix posterior were palpated and the impression in the cast was measured. The mean value of these two diameters was evaluated in this study. The level of agreement between the observers was calculated. RESULTS: The mean fornix posterior diameter was 2.6 cm (standard deviation, SD 0.5 cm) with a range of 2.0-3.4 cm. The mean difference between the two observers of all measurements was 0.08 cm (not significant). Both observers had an acceptable intraobserver variation. The interobserver agreement was excellent. CONCLUSION: Instruments with dimensions within the measured limits can be used safely for intra-abdominal operations via the natural orifice of the vagina.