Sclerotherapy needle injections can expand the subserosal and muscularis propria layers and cause a stable mucosal lift in ESD/EMR patients.

BACKGROUND: A mucosal lift is needed for ESD and EMR. Most lifts are made via sclerotherapy needle injection. The firm push needed to penetrate the mucosa often leaves the needle tip in the deep wall. The needle is next withdrawn and fluid injected until a sharp lift (due to submucosal expansion) begins to form; the needle is then held steady and the injection finished. The initial injection may result in a subtle deep lift that resolves quickly. It was the authors' belief that only submucosal expansion could lead to a stable mucosal lift. A colonic ESD case in which a polyp was inadvertently resected via needle knife in an expanded subserosal plane led to a questioning of this position. This study's purpose was to determine if stable deep wall mucosal lifts can be generated via bowel wall injection. METHODS: Transmucosal and intramural injections into bovine large bowel were carried out. Stable lifts and lift cross sections were made and examined grossly and histologically to determine the location of the lift fluid. Clinical ESD videos were also reviewed. RESULTS: Over 200 intact and cross-sectioned lifts were assessed. Gross inspection revealed two types of lifts (superficial and deep), whereas cross sections and histologic analyses revealed examples of stable expansion of the submucosal, muscularis propria, and subserosal layers post injection. Clinical "deep" lifts were also found. Superficial lifts are more focal and taller, whereas deep wall lifts are broader and less prominent. CONCLUSION: Stable deep wall mucosal lifts occur and are likely due to the deep starting point of the needle post insertion. If ESD/EMR are attempted with a deep lift, the chances of failure or perforation are high. Lifts must be carefully scrutinized before starting ESD/EMR. Other means of lift establishment should be evaluated and considered.

Plasma levels of the proangiogenic protein CXCL16 remains elevated for 1 month after minimally invasive colorectal cancer resection.

BACKGROUND: Inflammation-induced endothelial precursor cell recruitment and angiogenesis are thought to be associated with CXCL16-CXCR6 pair activity. This study's main purpose was to determine plasma CXCL16 levels after minimally invasive colorectal resection (MICR) for colorectal cancer (CRC); an adjunct study assessed wound fluid (WF) and plasma CXCL16 levels in a separate group of CRC patients. METHODS: CRC patients who had MICR and for whom plasma was available in a tissue bank were eligible. Plasma samples were collected preoperatively from all patients. Samples were also collected on postoperative days (POD) 1 and 3 and at various late postoperative time points (POD 7-34). In a separate study, blood and intra-abdominal wound fluid (WF) samples were collected from CRC MICR patients (pts). Samples were stored at - 80 °C. CXCL16 levels were determined via ELISA. The Wilcoxon signed-rank and Mann and Whitney tests were used for analysis. RESULTS: Main study: 86 CRC pts. were included. The mean preoperative plasma CXCL16 level was 2.36 ± 0.57 ng/ml. Elevated mean plasma levels (p <  0.0001 × first 4 time points) were noted on POD 1 (2.82 ± 0.81, n = 86), POD 3 (3.12 ± 0.77, n = 82), POD 7-13 (3.28 ± 0.88, n = 64), POD 14-20 (3.03 ± 0.62, n = 24), POD 21-27 (3.06 ± 0.67, n = 20, p = 0.0003), and POD 28-34 (3.17 ± 0.43, n = 11, p = 0.001) vs. preop levels. WF study: In the adjunct study, plasma and WF CXCL16 levels were determined for 23 CRC MICR pts. WF levels at all time points were significantly elevated over plasma levels. CONCLUSION: Plasma CXCL16 levels were elevated for 4 weeks after minimally invasive colorectal resection for cancer. Also, WF CXCL16 levels were 3-10 times greater than the corresponding plasma concentrations. The source of the late plasma elevations may be the healing wound. Increased plasma CXCL16 levels may promote tumor angiogenesis in the first month after MICR.

Risk factors for superficial surgical site infection after elective rectal cancer resection: a multivariate analysis of 8880 patients from the American College of Surgeons National Surgical Quality Improvement Program database.

BACKGROUND: Superficial surgical site infection (sSSI) is one of the most common complications after colorectal resection. The goal of this study was to determine the comorbidities and operative characteristics that place patients at risk for sSSI in patients who underwent rectal cancer resection. METHODS: The American College of Surgeons National Surgical Quality Improvement Program database was queried (via diagnosis and Current Procedural Terminology codes) for patients with rectal cancer who underwent elective resection between 2005 and 2012. Patients for whom data concerning 27 demographic factors, comorbidities, and operative characteristics were available were eligible. A univariate and multivariate analysis was performed to identify possible risk factors for sSSI. RESULTS: A total of 8880 patients met the entry criteria and were included. sSSIs were diagnosed in 861 (9.7%) patients. Univariate analysis found 14 patients statistically significant risk factors for sSSI. Multivariate analysis revealed the following risk factors: male gender, body mass index (BMI) >30, current smoking, history of chronic obstructive pulmonary disease (COPD), American Society of Anesthesiologists III/IV, abdominoperineal resection (APR), stoma formation, open surgery (versus laparoscopic), and operative time >217 min. The greatest difference in sSSI rates was noted in patients with COPD (18.9 versus 9.5%). Of note, 54.2% of sSSIs was noted after hospital discharge. With regard to the timing of presentation, univariate analysis revealed a statistically significant delay in sSSI presentation in patients with the following factors and/or characteristics: BMI <30, previous radiation therapy (RT), APR, minimally invasive surgery, and stoma formation. Multivariate analysis suggested that only laparoscopic surgery (versus open) and preoperative RT were risk factors for delay. CONCLUSIONS: Rectal cancer resections are associated with a high incidence of sSSIs, over half of which are noted after discharge. Nine patient and operative characteristics, including smoking, BMI, COPD, APR, and open surgery were found to be significant risk factors for SSI on multivariate analysis. Furthermore, sSSI presentation in patients who had laparoscopic surgery and those who had preoperative RT is significantly delayed for unclear reasons.

A multi-targeted approach to suppress tumor-promoting inflammation.

Cancers harbor significant genetic heterogeneity and patterns of relapse following many therapies are due to evolved resistance to treatment. While efforts have been made to combine targeted therapies, significant levels of toxicity have stymied efforts to effectively treat cancer with multi-drug combinations using currently approved therapeutics. We discuss the relationship between tumor-promoting inflammation and cancer as part of a larger effort to develop a broad-spectrum therapeutic approach aimed at a wide range of targets to address this heterogeneity. Specifically, macrophage migration inhibitory factor, cyclooxygenase-2, transcription factor nuclear factor-κB, tumor necrosis factor alpha, inducible nitric oxide synthase, protein kinase B, and CXC chemokines are reviewed as important antiinflammatory targets while curcumin, resveratrol, epigallocatechin gallate, genistein, lycopene, and anthocyanins are reviewed as low-cost, low toxicity means by which these targets might all be reached simultaneously. Future translational work will need to assess the resulting synergies of rationally designed antiinflammatory mixtures (employing low-toxicity constituents), and then combine this with similar approaches targeting the most important pathways across the range of cancer hallmark phenotypes.

Surgical Treatment of Diverticulitis: Hand-Assisted Laparoscopic Resection Is Predominantly Used for Complex Cases and Is Associated With Increased Postoperative Complications and Prolonged Hospitalization.

Introduction Laparoscopic (LAP) colectomy is now the "gold" standard for diverticulitis; the role of hand-assisted LAP (HAL) and Open methods today is unclear. This study assessed the elective use of these methods for diverticulitis. Methods A retrospective review of demographic, comorbidity (Carlson Comorbidity Index [CCI]), resection type, and short-term outcomes was carried out. Results There were 125 (44.5%) LAP, 125 (44.5%) HAL, and 31 (11%) Open cases (overall N = 281). The mean age, body mass index, and percentage of high-risk patients (CCI score >2) of the HAL group were greater (P < .05) than the LAP group (vs Open, P = ns). The Open group's mean age and percent with CCI >2 was greater when compared with the LAP group (P < .05). More Open (P < .05) and HAL patients had complex disease (Open, 63%; HAL, 40%, LAP, 22%) and were diverted (Open, 35%; HAL, 10%; LAP, 3%). Time to bowel movement was not different; however, there was a stepwise increase in median length of stay (LOS; days) from the LAP (5 days) to HAL (6 days) to Open group (7 days) (P < .05 for all). The LAP complication rate (22.4%) was lower (P < .05) than the HAL (42.4%) or Open groups' (45.2%) rates. The LAP surgical site infection rate (5.6%) was lower (P < .05) than the HAL (12.8%) or Open groups (19.6%). Conclusion The HAL and Open groups had more high risk, complex disease, diverted, and older patients than the LAP group; likewise, the overall complication rate and LOS was higher in the HAL and Open groups. Use of HAL methods likely contributed to the high minimally invasive surgery utilization rate (89%).

Minimally invasive colorectal resection for benign pathology is associated with persistent proangiogenic plasma compositional changes.

BACKGROUND: Minimally invasive colorectal resection for cancer is associated with increased plasma levels of numerous proangiogenic proteins for 3 to 4 weeks postoperatively, and plasma from postoperative weeks 2 and 3 stimulates proangiogenic endothelial cell behavior in vitro. It is unknown if similar plasma changes occur after minimally invasive colorectal resection for benign pathology. OBJECTIVE: The aim of this study is to assess 1) plasma levels of angiopoetin-2, placental growth factor, and soluble vascular cell adhesion molecule-1 after minimally invasive colorectal resection for benign pathology and 2) postoperative plasma's effects on in vitro endothelial cell proliferation (branch point formation), migration, and invasion. DESIGN: Prospectively gathered plasma samples taken from patients undergoing colorectal resection who consented to participate in an institutional review board-approved plasma and data bank were used for ELISAs and in vitro endothelial cell studies. SETTINGS: The plasma and clinical data used were collected at 3 hospitals. PATIENTS: Patients undergoing minimally invasive colorectal resection for benign indications who were enrolled in a plasma/data bank and for whom adequate samples and volumes of plasma were available were included in the study. MAIN OUTCOME MEASURES: Perioperative plasma levels of angiopoetin-2, placental growth factor, and soluble vascular cell adhesion molecule-1 were the primary outcomes measured. In vitro rates of endothelial cell branch point formation, migration, and invasion were determined after the addition of preoperative and postoperative plasma samples to endothelial cell cultures. RESULTS: Plasma from 86 patients undergoing minimally invasive colorectal resection for benign indications was assessed (diverticulitis, 30; benign polyps, 56). Plasma levels of angiopoetin-2, placental growth factor, and soluble vascular cell adhesion molecule-1 were significantly increased for 3 to 4 weeks postoperatively compared with preoperative levels. In regard to the endothelial cell culture assays, significantly increased endothelial cell branch point formation, invasion, and migration results were noted with plasma from the second and third weeks postoperatively in comparison with preoperative culture results. LIMITATIONS: The weaknesses of this study are the limited numbers of late postoperative plasma samples and the need to bundle late samples into 7- to 12-day time blocks. CONCLUSIONS: Minimally invasive colorectal resection for benign pathology is associated with persistent proangiogenic plasma alterations similar to those found in patients who have cancer. Surgical trauma and not the indication is the likely cause.

Minimally invasive colorectal resection is associated with significantly elevated levels of plasma matrix metalloproteinase 3 (MMP-3) during the first month after surgery which may promote the growth of residual metastases.

INTRODUCTION: MMP-3, a member of the matrix metalloproteinase (MMP) family, is involved in the breakdown of the extracellular matrix in tissue remodeling and may also play a role in cancer progression and metastasis. Minimally invasive colorectal resection (MICR) may increase plasma MMP-3 levels directly via surgical trauma or indirectly due to surgery-associated elevations in TNF-α and IL1 which are regulators of MMP-3. This study's purpose was to evaluate plasma MMP-3 levels during the first month after MICR for colorectal cancer. METHODS: Patients enrolled in an IRB approved data/plasma bank who underwent elective MICR for CRC. Blood plasma samples had been collected preoperatively, on postoperative day (POD) 1, 3 and at varying postoperative time points and were stored at -80 °C. The late samples (POD 7-41) were bundled into 7 day time blocks and considered as single time points. MMP-3 levels were analyzed in duplicate via ELISA and the results reported as mean ± SD. The paired t test was used for analysis (significance, p < 0.008 after Bonferroni's correction). RESULTS: A total of 73 CRC patients who underwent MICR met the inclusion criteria. The mean PreOp MMP-3 level was 14.9 ± 7.8 ng/ml (n = 73). Significantly elevated mean plasma levels were noted on POD 1 (21.4 ± 14.7 ng/ml, n = 73, p < 0.0001), POD 3 (37.9 ± 21.5 ng/ml, n = 72, p < 0.0001), POD 7-13 (22.0 ± 13.0 ng/ml, n = 56, p < 0.0001), POD 14-20 (21.9 ± 10.3 ng/ml, n = 20, p = 0.003), and on POD 21-27 (21.9 ± 11.43 ng/ml, n = 20, p = 0.002) when compared to PreOp levels. Plasma levels returned to the PreOp baseline at the POD 28-41 time point (n = 16, p = 0.07). CONCLUSION: Plasma MMP-3 levels remained significantly elevated from baseline for 4 weeks after MICR for CRC. The early postoperative increase in MMP-3 levels may be due to the surgery-related acute inflammatory response; the elevation noted during weeks 2-3 may be related to wound healing. Increased MMP-3 levels may promote metastases or the growth of residual cancer.

MAGE-A3 is highly expressed in a subset of colorectal cancer patients.

The expression of Cancer/Testis (CT) antigens in some tumors and restricted expression in normal tissue make CT antigens attractive vaccine targets. We evaluated the expression of MAGE-A3, PLAC1, GAGE, and CTAG2 in a series of colorectal cancers (CRC). CT mRNA expression was determined via quantitative PCR on paired tumors and normal tissue samples from 82 CRC patients. In addition, plasma antibody titers specific to MAGE-A3, PLAC1, GAGE, and CTAG2 were determined via ELISA. Tissue expression of MAGE-A3 was assessed via a standard IHC protocol. The Student's t-test was used for statistical analysis (significance p < 0.05). Tumor expression of MAGE-A3, CTAG2, and GAGE was compared to the levels of expression in testis. The percentage of samples that had a tumor vs. testis expression ratio above 0.1% was: MAGE-A3 (28%) and CTAG2 (17%) but no tumor presented GAGE expression levels above 0.1%. The expression levels of PLAC1 in tumors were compared to the levels in placenta, and in 12.8% of the samples analyzed, these levels were above 0.1%. Sero-reactivity specific for MAGE-A genes and PLAC1 was noted in 2.4% and 2.6% of patients, respectively. MAGE-A3 and PLAC1 may hold promise as vaccine targets for CRC. Further study is warranted.

CpG ODN, Toll like receptor (TLR)-9 agonist, inhibits metastatic colon adenocarcinoma in a murine hepatic tumor model.

BACKGROUND: Colorectal liver metastases (mets) are often refractory to conventional therapies. CpG oligodeoxynucleotide 1826 (CpG), a Toll like receptor (TLR)-9 agonist, inhibits murine tumor growth by augmenting Th1 immunity. The impact of CpG on metastatic colon tumors is unknown. The purpose of this study was to determine the effect of CpG on the growth of hepatic colon cancer mets. METHODS: Two studies with separate control groups were performed using 40 Balb/C mice (study A, CpG 50 µg/dose; study B, 100 µg/dose; n = 9-11/subgroup). Tumors were induced via portal vein injection of 2 × 10(4) CT26 colon tumor cells. After surgery, the mice were randomized; test groups were given 14 daily intraperitoneal (i.p.) CpG injections (50 or 100 µg/dose) while the control group received i.p. saline. On d 21 mice were sacrificed, the livers and spleens excised and weighed and the mets counted (reported as median ± 95% confidence interval [CI]) and histologically assessed. RESULTS: The CpG mice had significantly fewer hepatic mets/mouse (study A, median two nodules, 95% CI, 0-3; study B, 0 nodules, 95% CI 0-0) than the control mice (study A, 6 nodules, 95% CI, 3-9, P = 0.002; Study B, 6 nodules, 95% CI, 3-9, P < 0.001). In study B, there were no mets in 9/11 CpG mice (versus 2/10 for CpG 50 µg and 0/19 for control mice). The mean liver/spleen weights of the CpG mice in both studies were significantly greater than in control mice. Histologically, high mitotic rates were noted in control mets while fewer tumor cells and histiocytic and lymphocytic infiltrates were found in CpG livers. CONCLUSIONS: CpG inhibited liver tumor growth in this model (100 µg/dose more than 50 µg/dose). CpG was associated with increased liver and spleen weights not related to tumor burden. Increased lymphocytic and histiocytic infiltrates were noted in CpG-treated tumor nodules.

Plasma levels of angiopoietin-like protein 4 (ANGPTL4) are significantly lower preoperatively in colorectal cancer patients than in cancer-free patients and are further decreased during the first month after minimally invasive colorectal resection.

BACKGROUND: Surgery has been associated with proangiogenic plasma protein changes that may promote tumor growth. Angiopoietin-like protein 4 (ANGPTL4) is expressed by endothelial cells and other tissues in response to hypoxia. Both intact ANGPTL4 and its partly degraded C-terminal fragment may promote tumor angiogenesis. This study had two purposes: to measure and compare preoperative plasma ANGPTL4 levels in patients with colorectal cancer (CRC) and benign colorectal disease (BCD) and to determine plasma levels after minimally invasive colorectal resection (MICR) for CRC. METHODS: Plasma was obtained from an IRB-approved plasma/data bank. Preoperative plasma ANGPTL4 levels were measured for CRC and BCD patients, but postoperative levels were determined only for CRC patients for whom a preoperative, a postoperative day (POD) 3, and at least one late postoperative sample (POD 7-55) were available. Late samples were bundled into four time blocks and considered as single time points. ANGPTL4 levels (mean ± SD) were measured via ELISA and compared (significance, p < 0.01 after Bonferroni correction). RESULTS: Eighty CRC (71 % colon, 29 % rectal) and 60 BCD (62 % diverticulitis, 38 % adenoma) patients were studied. The mean preoperative plasma ANGPTL4 level in CRC patients (247.2 ± 230.7 ng/ml) was lower than the BCD group result (330.8 ± 239.0 ng/ml, p = 0.01). There was an inverse relationship between plasma levels and advanced CRC as judged by three criteria. In regard to the postoperative CRC analysis, the "n" for each time point varied: lower plasma levels (p < 0.001) were noted on POD 3 (161.4 ± 140.4 ng/ml, n = 80), POD 7-13 (144.6 ± 134.5 ng/ml, n = 46), POD 14-20 (139.0 ± 117.8 ng/ml, n = 27), POD 21-27 (138.9 ± 202.4, n = 20), and POD 28-55 (160.1 ± 179.0, n = 42) when compared to preoperative results. CONCLUSION: CRC is associated with lower preoperative plasma ANGPTL4 levels compared with BCD, and the levels may vary inversely with disease severity. After MICR for CRC, levels are significantly lower for over a month compared with the preoperative level; the cause for this persistent decrease is unclear. The implications of both the lower preoperative level and the persistently decreased postoperative levels are unclear. Further studies are needed.

Plasma from the second and third weeks after open colorectal resection for cancer stimulates in vitro endothelial cell growth, migration, and invasion.

INTRODUCTION: Angiogenesis is central to wound healing and tumor growth. Postoperative (postop) plasma from weeks 2 and 3 after minimally invasive colorectal resection (MICR) stimulates endothelial cell (EC) migration (MIG), invasion (INV), and proliferation (all vital to angiogenesis) compared with preoperative (preop) plasma results and may promote postop tumor growth. The purpose of this study was to determine whether plasma from open colorectal resection (OCR) patients has similar proangiogenic EC effects in vitro. METHODS: OCR cancer patient plasma from institutional review board-approved banks was used; patients with preop and one postop sample from postoperative days (POD) 7-33 were eligible. Samples were bundled into 7- to 13-day periods and considered as single time points. In vitro cultures of human umbilical venous ECs were used for the EC proliferation (BPF, Branch Point Formation), INV, and MIG assays performed with preop, POD 7-13, POD 14-20, and POD 21-33 plasma. Data were analyzed by paired t test and were reported as mean ± standard deviation (significance, P < 0.05). RESULTS: Plasma from 53 cancer patients (25 rectal and 28 colon) was used. Because of limited postop samples, the number for each time point varies: POD 7-13, n = 30; POD 14-20, n = 26; and POD 21-33, n = 17. In vitro EC BPF was significantly greater at the POD 7-13 (P < 0.0001) and POD 14-20 (P < 0.0001) time points versus preop results. Significantly greater EC INV and MIG were noted on POD 7-13 and POD 14-20 versus the preop plasma results (P < 0.0001). In regards to POD 21-33, a significantly greater result was noted only for the INV assay versus preop. CONCLUSIONS: Plasma from weeks 2 and 3 after OCR stimulates in vitro EC BPF, INV, and MIG. A significant difference from preop baseline was noted only for the INV assay in week 4. The OCR and previous MICR results were largely similar. Tumor angiogenesis may be stimulated after OCR and MICR for 3 weeks. Further studies are warranted.

Perioperative polyphenon E- and siliphos-inhibited colorectal tumor growth and metastases without impairment of gastric or abdominal wound healing in mouse models.

INTRODUCTION: Perioperative anticancer therapy that does not impair wound healing is needed to counter the persistent proangiogenic plasma compositional changes that occur after colorectal resection. Polyphenon E (PolyE), a green tea derivative (main component EGCG), and Siliphos (main component silibinin), from the milk thistle plant, both have antitumor effects. This study assessed the impact of PolyE/Siliphos (PES) on wound healing and the growth of CT-26 colon cancer in several murine models. METHODS: One wound healing and three tumor studies were performed. Tumor Study (TS)1 assessed the impact of PES on subcutaneous tumor growth, whereas TS2 assessed PES's impact on subcutaneous growth when given pre- and post-CO(2) pneumoperitoneum (pneumo), sham laparotomy, or anesthesia alone. TS3 determined the ability of PES to limit hepatic metastases (mets) after portal venous injection of tumor cells. In the final study, laparotomy and gastrotomy wound healing were assessed several ways. BALB/c mice were used for all studies. The drugs were given via drinking water (PolyE) and gavage (Siliphos), daily, for 7-9 days preprocedure and for 7-21 days postoperatively. Tumor mass, number/size of hepatic mets, and proliferation and apoptosis rates were assessed. The abdominal breaking strength and energy to failure were measured postmortem as was gastric bursting pressures. RESULTS: PES significantly inhibited subcutaneous growth in the nonoperative setting. PES also significantly decreased the number/size of liver mets when given perioperatively. Abdominal wound breaking strength, energy to wound failure, and collagen content were not altered by PES; gastrotomy bursting strength also was not affected by PES. Neither drug alone had a significant impact on tumor growth. CONCLUSIONS: The PES combination inhibited subcutaneous and hepatic tumor growth yet did not impair wound healing. PES holds promise as a perioperative anticancer therapy.

Plasma soluble vascular adhesion molecule-1 levels are persistently elevated during the first month after colorectal cancer resection.

INTRODUCTION: Plasma from the second and third weeks after minimally invasive colorectal resection (MICR) has high levels of the proangiogenic proteins VEGF and angiopoietin 2 and also stimulates, in vitro, endothelial cell (EC) proliferation and migration, which are critical to wound and tumor angiogenesis. Soluble vascular cell adhesion molecule-1 (sVCAM-1) stimulates EC chemotaxis and angiogenesis. The impact of MICR on blood levels of sVCAM-1 is unknown. This study's purpose was to determine plasma sVCAM-1 levels after MICR in colorectal cancer (CRC) patients. METHODS: Blood samples from 90 patients (26% rectal, 74% colon) were obtained preoperatively, on postoperative days (POD) 1 and 3, and at other points during the next 2 months. The late samples were bundled into 7-day time blocks. sVCAM-1 levels were determined in duplicate via ELISA and reported as ng/ml. Student's t test was used for data analysis (significance, P < 0.008 after Bonferroni correction). RESULTS: The mean incision length was 7.3 ± 3.1 cm, and the conversion rate was 3%. Compared with preoperative (PreOp) levels (811.3 ± 233.2), the mean plasma sVCAM-1 level was significantly higher on POD 1 (905.7 ± 292.4, P < 0.001) and POD 3 (977.7 ± 271.8, P < 0.001). Levels remained significantly elevated for the POD 7-13, POD 14-20, POD 21-27, and POD 28-67 time blocks. CONCLUSIONS: MICR for CRC is associated with a persistent increase in plasma sVCAM-1 levels during the first month. This sustained increase may promote angiogenesis and stimulate the growth of residual tumor cells early after surgery.

Plasma levels of angiostatin and endostatin remain unchanged for the first 3 weeks after colorectal cancer surgery.

INTRODUCTION: Angiostatin and endostatin are endogenous inhibitors of angiogenesis with anticancer effects. After minimally invasive colorectal resection (MICR), blood levels of the proangiogenic factors vascular endothelial growth factor (VEGF) and angiopoetin 2 (Ang-2) are elevated for 2-4 weeks. Also, postoperative human plasma from weeks 2 and 3 after MICR has been shown to stimulate endothelial cell proliferation and migration, which are critical to angiogenesis. This proangiogenic state may stimulate tumor growth early after MICR. Surgery's impact on angiostatin and endostatin is unknown. This study's purpose is to determine perioperative plasma levels of these two proteins in colorectal cancer (CRC) patients undergoing MICR. METHODS: Endostatin levels were assessed in 34 CRC patients and angiostatin levels in 30 CRC patients. Blood samples were taken preoperatively and on postoperative day (POD) 1 and 3 in all patients; in a subset, samples were taken between POD 7 and 20. The late samples were bundled into 7-day blocks (POD 7-13, POD 14-20) and considered as single time points. Angiostatin and endostatin plasma levels were determined via enzyme-linked immunosorbent assay (ELISA) in duplicate. Wilcoxon signed-rank test and Student's t test were used to analyze endostatin and angiostatin data, respectively. Significance was set at P<0.0125 (after Bonferroni correction). RESULTS: There was a significant decrease in median plasma endostatin levels on POD 1, which returned to the preoperative level by POD 3. There was no significant difference between pre- and postoperative plasma angiostatin levels. CONCLUSIONS: MICR has a very transient impact on plasma levels of endostatin and no impact on angiostatin during the first 21 days following surgery. Thus, angiostatin and endostatin do not likely contribute to or inhibit the persistent proangiogenic changes noted after MICR.

Minimally invasive colon resection is associated with a persistent increase in plasma PlGF levels following cancer resection.

BACKGROUND: Minimally invasive colorectal resection (MICR) is associated with persistently elevated plasma VEGF levels that may stimulate angiogenesis in residual tumor foci. Placenta growth factor (PlGF) stimulates neovascularization in tumors by modulating VEGF's effects. This study's purpose was to determine the impact of MICR on blood PlGF levels in cancer patients (Study A) and to compare PreOp levels in patients with cancer and benign (BEN) disease (Study B). METHODS: Blood samples were collected preoperatively, on postoperative day (POD) 1, POD 3, and at various time points 2-4 weeks after surgery. Samples from 7-day periods after POD 6 were bundled to allow analysis. Plasma PlGF levels were determined via ELISA, results reported as mean±SD, and data analyzed via t test. Significance was set at p<0.008 after Bonferroni correction. RESULTS: Study A: 76 colorectal cancer (CRC) patients had MICR (laparoscopic, 59%; hand-assisted, 41%). The mean length of stay was 5.8±2.1 days. The mean PreOp PlGF level was 15.4±4.3 pg/ml. Significantly increased levels were noted on POD 1 (25.8±7.7 pg/ml, p<0.001), POD 3 (22.9±6.7, p<0.001), POD 7-13 (19.2±5.1, p<0.001), and POD 14-20 (19.5±6.7, p<0.002). The mean POD 21-27 level was not significantly different from baseline. Study B included 126 CRC and 111 BEN patients. PreOp levels were higher in the CRC patients (15.6±5.3 pg/ml) than in the BEN group (13.5±5.5 pg/ml, p=0.001). CONCLUSIONS: PlGF levels are elevated for 3 weeks after MICR and PreOp plasma levels are higher in CRC patients than in BEN disease patients. The cause of the postoperative increase is unclear. The persistently higher blood levels of PlGF and VEGF after MICR may stimulate angiogenesis in residual tumor foci. Further studies regarding late blood protein alterations after surgery appear to be indicated.

Minimally invasive colorectal resection is associated with a transient increase in plasma hepatocyte growth factor levels early after surgery for colon cancer.

INTRODUCTION: Surgery's impact on blood levels of hepatocyte growth factor (HGF), a potent angiogenic factor, is unknown. Preoperative (PreOp) HGF blood levels are elevated in patients with colorectal cancer (CRC) and correlate with disease stage and prognosis. This study's purpose was to determine plasma HGF levels after minimally invasive colorectal resection (MICR) in patients with CRC. METHODS: Clinical and operative data were collected. Blood samples were obtained in all patients PreOp and on postoperative day (POD) 1 and 3; in some, samples were taken during weeks 2 and 3 after MICR. Late samples were bundled into 7-day time blocks. HGF levels were determined via enzyme-linked immunosorbent assay in duplicate. Student's t test was used to analyze the data (significance, P < .0125 after Bonferroni correction). RESULTS: A total of 28 CRC patients who underwent MICR were studied. Most had right, sigmoid, or left segmental colectomy. The mean plasma HGF level was higher on POD 1 (2417 ± 1476 pg/mL, P < .001) and POD 3 (2081 ± 1048 pg/mL, P < .001) when compared with PreOp levels (1045 ± 406 pg/mL). Plasma levels were back to baseline by the second (1100 ± 474 pg/mL, P = .64) and third postoperative weeks (1010 ± 327 pg/mL, P = .51). CONCLUSION: MICR for CRC is associated with a 1.9- to 2.3-fold increase in plasma HGF levels during the first 3 PODs after which levels normalize. This transient increase may briefly promote angiogenesis and the growth of residual tumor cells.

Plasma Levels of Keratinocyte Growth Factor Are Significantly Elevated for 5 Weeks After Minimally Invasive Colorectal Resection Which May Promote Cancer Recurrence and Metastasis.

Background: Human Keratinocyte Growth Factor (KGF) is an FGF family protein produced by mesenchymal cells. KGF promotes epithelial cell proliferation, plays a role in wound healing and may also support tumor growth. It is expressed by some colorectal cancers (CRC). Surgery's impact on KGF levels is unknown. This study's purpose was to assess plasma KGF levels before and after minimally invasive colorectal resection (MICR) for CRC. Aim: To determine plasma KGF levels before and after minimally invasive colorectal resection surgery for cancer pathology. Method: CRC MICR patients (pts) in an IRB approved data/plasma bank were studied. Pre-operative (pre-op) and post-operative (post-op) plasma samples were taken/stored. Late samples were bundled into 7 day blocks and considered as single time points. KGF levels (pg/ml) were measured via ELISA (mean ± SD). The Wilcoxon paired t-test was used for statistical analysis. Results: Eighty MICR CRC patients (colon 61%; rectal 39%; mean age 65.8 ± 13.3) were studied. The mean incision length was 8.37 ± 3.9 and mean LOS 6.5 ± 2.6 days. The cancer stage breakdown was; I (23), II (26), III (27), and IV (4). The median pre-op KGF level was 17.1 (95 %CI: 14.6-19.4; n = 80); significantly elevated (p < 0.05) median levels (pg/ml) were noted on post-op day (POD) 1 (23.4 pg/ml; 95% CI: 21.4-25.9; n = 80), POD 3 (22.5 pg/ml; 95% CI: 20.7-25.9; n = 76), POD 7-13 (21.8 pg/ml; 95% CI: 17.7-25.4; n = 50), POD 14-20 (20.1 pg/ml; 95% CI: 17.1-23.9; n = 33), POD 21-27 (19.6 pg/ml; 95% CI: 15.2-24.9; n = 15) and on POD 28-34 (16.7 pg/ml; 95% CI: 14.0-25.8; n = 12). Conclusion: Plasma KGF levels were significantly elevated for 5 weeks after MICR for CRC. The etiology of these changes is unclear, surgical trauma related acute inflammatory response and wound healing process may play a role. These changes, may stimulate angiogenesis in residual tumor deposits after surgery.

Minimally invasive colon resection for malignant colonic conditions is associated with a transient early increase in plasma sVEGFR1 and a decrease in sVEGFR2 levels after surgery.

INTRODUCTION: Plasma VEGF levels increase after minimally invasive colorectal resection (MICR) and remain elevated for 2-4 weeks. VEGF induces physiologic and pathologic angiogenesis by binding to endothelial cell (EC) bound VEGF-Receptor-1 (VEGFR1) and VEGFR2. Soluble forms of these receptors sequester plasma VEGF, decreasing the amount available to bind to EC-bound receptors. Ramifications of surgery-related plasma VEGF changes partially depend on plasma levels of sVEGFR1 and sVEGFR2. This study assessed perioperative sVEGFR1 and sVEGFR2 levels after MICR in patients with colorectal cancer. METHODS: Forty-five patients were studied; blood samples were taken from all patients preoperatively (preop) and on postoperative days (POD) 1 and 3; in most a fourth sample was drawn between POD 7-30. Late samples were bundled into two time points: POD 7-13 and POD 14-30. sVEGFR1 and sVEGFR2 levels were measured via ELISA. sVEGFR2 data are reported as mean +/- SD and were assessed with the paired samples t test. sVEGFR1 data were not normally distributed. They are reported as median and 95% confidence interval (CI) and were assessed with the Wilcoxon signed-Rank test (p < 0.05). RESULTS: Preoperatively, the mean plasma sVEGFR2 level (7583.9 pg/ml) was greater than the sVEGFR1 result (98.3 pg/ml). Compared with preop levels, sVEGFR2 levels were significantly lower on POD 1 (6068.2 pg/ml, +/-2034.5) and POD 3 (6227.6 pg/ml, +/-2007.0), whereas sVEGFR1 levels were significantly greater on POD 1 (237.5 pg/ml; 95% CI, 89.6-103.5), POD 3 (200.2 pg/ml; 95% CI, 159-253), and POD 7-13 (102.9 pg/ml; 95% CI, 189.7-253). No differences were found on POD 7-13 for sVEGFR2 or POD 14-30 for either protein. CONCLUSIONS: sVEGFR2 values decreased and sVEGFR1 levels increased early after MICR; sVEGFR2 changes dominate due to their much larger magnitude. The net result is less plasma VEGF bound by soluble receptors and more plasma VEGF available to bind to ECs early after surgery.

Minimally invasive colorectal resection is associated with a rapid and sustained decrease in plasma levels of epidermal growth factor (EGF) in the colon cancer setting.

BACKGROUND: Epidermal growth factor (EGF) stimulates tumor growth directly via tumor cell EGF receptors or indirectly via its proangiogenic effects. This study's purpose was to determine the impact of minimally invasive colorectal resection (MICR) on postoperative (postop) plasma EGF levels in the colorectal cancer (CRC) and benign disease settings and to see if preoperative (PreOp) EGF levels are altered in cancer patients. METHODS: MICR patients with benign pathology (n = 40) and CRC (n = 48) had blood samples taken PreOp and on postoperative days (POD) 1 and 3. In some patients, late samples were taken between POD7 and POD60; these were bundled into 7-day blocks and considered as single time points. EGF levels were determined by enzyme-linked immunosorbent assay (ELISA) and results were reported as mean ± SD after logarithmic transformation. The Student t test was used (p < 0.008 after Bonferroni correction). RESULTS: The cancer and benign groups were comparable except for age. The mean PreOp CRC plasma EGF level (122.9 ± 75.9 pg/ml) was significantly higher than that of the benign group (85.3 ± 38.5 pg/ml) (p = 0.015). The cancer group's EGF levels were significantly decreased on POD1 and POD3 and for the POD31-55 time point (mean EGF level = 63.1 ± 42.2 (n = 10). The benign group's POD3 and POD7-14 EGF levels were significantly lower than the PreOp level; later levels returned toward baseline. Small late sample size limited analysis. CONCLUSION: Plasma EGF levels are significantly higher in cancer patients. MICR is associated with a significant decrease in EGF levels early postop in both cancer and benign settings. Unlike the benign group, EGF blood levels in cancer patients remain low during the second postop month. A larger study with more late samples is needed to verify these results. EGF may have value as a tumor marker.

Minimally invasive colorectal resection for cancer is associated with a short-lived decrease in soluble Tie-2 receptor levels, which may transiently inhibit VEGF-mediated angiogenesis (via altered blood levels of free Ang-1 and Ang-2).

BACKGROUND: Angiopoetin- (Ang-) 1 inhibits and Ang-2 promotes VEGF-mediated angiogenesis via binding to endothelial cell-bound Tie-2 receptor (Tie-2). After minimally invasive colorectal resection (MICR), Ang-1 levels decrease and Ang-2 levels increase, which may stimulate angiogenesis in wounds and residual tumor foci. Soluble Tie-2 (sTie-2) modulates the effects of free Ang-1 and Ang-2 by binding to them. This study assessed perioperative MICR plasma sTie-2 levels. METHODS: Blood samples were taken preoperatively (PreOp) and on postoperative days (POD) 1 and 3 from 50 cancer and 53 benign disease MICR patients. In a subgroup, a fourth sample was taken between POD7 and POD13 and bundled as a single time point. sTie-2 levels (ng/ml) were determined via ELISA. The mean and SD were determined at each time point. The t test used for analysis. RESULTS: PreOp plasma sTie-2 levels were significantly higher in the benign group (27.6 ± 10.2) than in the cancer group (22.9 ± 7.9). A significant drop from PreOp occurred in sTie-2 levels in the cancer group on POD1 (20.0 ± 7.4) and POD3 (21.0 ± 6.6) and in the benign group on POD1 (24.8 ± 9.1). The benign group's POD3 and the cancer group's POD7-13 sTie-2 levels were statistically similar to the PreOp levels while the benign group's POD7-13 level was significantly higher. CONCLUSION: PreOp sTie-2 levels were significantly lower in cancer patients. MICR is associated with a significant short-lived decrease in plasma sTie-2 levels in cancer patients on POD1 and 3, which may briefly inhibit VEGF-mediated angiogenesis. The benign group's early results were similar.