Safety and Efficacy of Oxaliplatin Pressurized Intraperitoneal Aerosolized Chemotherapy (PIPAC) in Colorectal and Appendiceal Cancer with Peritoneal Metastases: Results of a Multicenter Phase I Trial in the USA.

BACKGROUND: Pressurized intraperitoneal aerosolized chemotherapy (PIPAC) is a laparoscopic locoregional treatment for peritoneal metastases (PM) from colorectal cancer (CRC) or appendiceal cancer (AC) in patients who cannot undergo cytoreductive surgery (CRS). While PIPAC has been studied in Europe and Asia, it has not been investigated in the USA. PATIENTS AND METHODS: We evaluated PIPAC with 90 mg/m2 oxaliplatin alone (cycle 1) and preceded by systemic chemotherapy with fluorouracil (5-FU) and leucovorin (LV) (cycle 2-3) as a multicenter prospective phase I clinical trial (NCT04329494). The primary endpoint was treatment-related adverse events (AEs). Secondary endpoints included survival and laparoscopic, histologic, and radiographic response. RESULTS: 12 patients were included: 8 with CRC and 4 with AC. Median prior chemotherapy cycles was 2 (interquartile range (IQR) 2-3). All patients were refractory to systemic oxaliplatin-based chemotherapy. Median peritoneal carcinomatosis index (PCI) was 28 (IQR 19-32). Six (50%) of twelve patients completed three PIPAC cycles. No surgical complications or dose-limiting toxicities were observed. Two patients developed grade 3 treatment-related toxicities (one abdominal pain and one anemia). Median overall survival (OS) was 12.0 months, and median progression-free survival (PFS) was 2.9 months. OS was correlated with stable disease by Response Evaluation Criteria in Solid Tumors (RECIST) criteria but not with laparoscopic response by PCI or histologic response by peritoneal regression grading system (PRGS). CONCLUSIONS: This phase I trial in the USA demonstrated safety, feasibility, and early efficacy signal of PIPAC with oxaliplatin and chemotherapy in patients with PM from AC or CRC who are refractory to standard lines of systemic chemotherapy.

Compared to preoperative plasma levels post-operative urokinase-type plasminogen activator-1 levels are persistently elevated for 6 weeks after minimally invasive colorectal resection.

Background: Urokinase-type plasminogen activator-1 (uPA) is a serine protease that converts plasminogen to plasmin after binding to uPA receptor (uPAR). Plasmin catalyzes the regeneration of basement membrane, extracellular matrix, and other tissues. uPA alone and with plasmin leads to activation of angiogenic growth factors that impact tumor cell proliferation, adhesion, and migration. uPA over expression has been noted in colorectal cancer (CRC) and high tissue levels have been correlated with prognosis. uPA/uPAR promotes immune cell activation in healing surgical wounds and may alter perioperative uPA plasma levels. Postoperative (postop) plasma levels, if elevated, may impact the early growth of residual metastases. The impact of minimally invasive colorectal resection (MICR) surgery for CRC on plasma uPA levels is unknown. This study's aim was to measure plasma uPA levels during the first postop month. Methods: CRC patients undergoing MICR who enrolled in an Institutional Review Board (IRB) approved data/plasma bank for whom adequate plasma was available were included in the study. Patients who had chemotherapy or radiotherapy within 4 weeks, those who received blood transfusions perioperatively and immunosuppressed patients were excluded. Clinical and pathological data were prospectively collected as were blood samples preoperatively, postop day (POD) 1, 3 and at least 1 late time point between POD 7-41. Plasma was isolated and stored at -80 ℃. Late samples were bundled into 7-day blocks and considered as single time points. Total uPA levels (ng/mL) were analyzed in duplicate via enzyme-linked immunosorbent assay (ELISA) and results reported as mean ± standard deviation (SD). The Wilcoxon paired t-test was used for analysis. Results: Ninety-three patients undergoing MICR for CRC [colonic 68%; rectal 32%; average age 65.6 years, laparoscopic 63%, hand-assisted minimally invasive surgery (MIS) 37%] who met criteria were studied. Cancer stage breakdown was; stage I, 30%, stage II, 29%, stage III, 34%, stage IV, 7%. The median preoperative (preop) uPA plasma level (ng/mL) was 529.8 [95% confidence interval (CI): 462.8, 601.1] (n=93). Significant elevations in median levels vs. preop were present during POD 3 (542.8, 95% CI: 518.8, 597.3, n=86, P=0.003), POD 7-13 (688.1, 95% CI: 591.7, 753.0, n=72, P<0.001), POD 14-20 (764.9, 95% CI: 704.1, 911.6, n=27, P<0.001), POD 21-27 (685.6, 95% CI: 443.8, 835.8, n=15, P<0.001), and on POD 28-41 (800.3, 95% CI: 626.9, 940.6, n=21, P<0.001). The colon cancer subgroup's preop and POD 14-20 median results were significantly higher than the corresponding rectal cancer results; otherwise, at the other 5 postop time points there were no significant differences between the rectal and colon cancer subgroups. In addition, no association was found between cancer stage and preop uPA levels and no significant differences were found in postop uPA levels between the hand-assisted laparoscopic group and the lap assisted subgroup at any of the postop time points. Conclusions: Persistently elevated plasma uPA levels at 5/6 postop time point (P<0.05), in combination with other previously demonstrated long duration proangiogenic plasma protein changes, may render the plasma proangiogenic within the period of the first month post-surgery and may promote angiogenesis within the residual tumor foci. The clinical significance pertaining to these changes, if any, is uncertain and remains to be proven.

Osteopontin Levels Are Persistently Elevated for 4 weeks Following Minimally Invasive Colorectal Cancer Resection.

INTRODUCTION: Osteopontin (OPN) is an integrin binding phosphorylated glycoprotein secreted by macrophages and leukocytes that is found in extracellular fluids and sites of inflammation; various forms of CD44 serve as receptors. Osteopontin, expressed by numerous cancers, enhances tumor progression and angiogenesis via the PI3K/AKT and ERK mediated pathways in concert with Vascular Endothelial Growth Factor (VEGF); OPN also plays a role in wound healing. The impact of minimally invasive colorectal resection (MICR) for colorectal cancer (CRC) on plasma OPN levels is unknown. This study's goal was to assess blood levels during the first month after MICR. METHOD: Patients undergoing MICR for CRC who were enrolled in an IRB approved tissue/prospective data bank for whom preoperative, postop Day (POD) 1, POD 3, and at least 1 late postop plasma sample (POD 7-34) were available were studied. Osteopontin levels were determined in duplicate via enzyme linked immunosorbent assay (ELISA) (results reported as mean ± SD). The Wilcoxon signed rank test was used for analysis (significance P < .05). RESULTS: A total of 101 CRC patients (63% colon and 37% rectal) met study criteria. The mean preop OPN level was 89.2 ± 36.8 (ng/ml) for the entire group. Significantly elevated (P < .001) mean plasma levels were detected, vs preop, on POD1 (198.0 ± 67.4; n = 101), POD 3 (186.0 ± 72.6, n = 101), POD 7-13 (154.1 ± 70.2, n = 70), POD14-20 (146.7 ± 53.4, n=32), and POD 21-27 (123.0 ± 56.9, n = 25). No difference was noted at the POD 27-34 timepoint (P > .05). CONCLUSION: Plasma OPN levels are significantly elevated over baseline for a month after MICR for CRC. The early rise in OPN levels may be related to the postop acute inflammatory response. The persistent elevation noted in weeks 2-4, however, may be a manifestation of wound healing in which OPN plays a role. Similar persistent plasma elevations of VEGF, angiopoietin 2 (ANG 2), and 11 other proangiogenic proteins have been noted and, collectively, may promote angiogenesis in residual tumors.

Multicenter dose-escalation Phase I trial of mitomycin C pressurized intraperitoneal aerosolized chemotherapy in combination with systemic chemotherapy for appendiceal and colorectal peritoneal metastases: rationale and design.

Objectives: Peritoneal metastasis (PM) from appendiceal cancer or colorectal cancer (CRC) has significant morbidity and limited survival. Pressurized intraperitoneal aerosolized chemotherapy (PIPAC) is a minimally invasive approach to treat PM. We aim to conduct a dose-escalation trial of mitomycin C (MMC)-PIPAC combined with systemic chemotherapy (FOLFIRI) in patients with PM from appendiceal cancer or CRC. Methods: This is a multicenter Phase I study of MMC-PIPAC (NCT04329494). Inclusion criteria include treatment with at least 4 months of first- or second-line systemic chemotherapy with ineligibility for cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS-HIPEC). Exclusion criteria are: progression on chemotherapy; extraperitoneal metastases; systemic chemotherapy intolerance; bowel obstruction; or poor performance status (ECOG>2). Escalating MMC-PIPAC doses (7-25 mg/m2) will be administered in combination with standard dose systemic FOLFIRI. Safety evaluation will be performed on 15 patients (dose escalation) and six expansion patients: 21 evaluable patients total. Results: The primary endpoints are recommended MMC dose and safety of MMC-PIPAC with FOLFIRI. Secondary endpoints are assessment of response (by peritoneal regression grade score; Response Evaluation Criteria in Solid Tumors [RECIST 1.1], and peritoneal carcinomatosis index), progression free survival, overall survival, technical failure rate, surgical complications, conversion to curative-intent CRS-HIPEC, patient-reported outcomes, and functional status. Longitudinal blood and tissue specimens will be collected for translational correlatives including pharmacokinetics, circulating biomarkers, immune profiling, and single-cell transcriptomics. Conclusions: This Phase I trial will establish the recommended dose of MMC-PIPAC in combination with FOLFIRI. Additionally, we expect to detect an early efficacy signal for further development of this therapeutic combination.

A colonoscopic overtube system that creates a 'therapeutic zone' and permits retraction facilitates endoscopic submucosal dissection, was associated with fewer deep bowel wall injuries and instrument exchanges, and required less lifting solution vs classic endoscopic submucosal dissection in an ex vivo bovine model.

INTRODUCTION: Endoscopic submucosal dissection (ESD) is the 'gold standard' for large flat polyps; nevertheless, the rate of adoption in the USA is low. In ESD, the polyp is 'surgically' detached with a needle knife after a submucosal lift; gravity and the dissection cap are used for retraction. ESD would be easier if active retraction were possible. In an ex vivo bovine colon model, this study assessed an overtube system (Boston Scientific ORISE Tissue Retraction System, TRS) that permits retraction and creates 'an operative field' for removal of rectal/sigmoid lesions. METHOD: Classic ESD (C-ESD) was compared to TRS-facilitated ESD (TRS-ESD). Cleaned/preserved bovine large bowel was used, and two 2-cm 'lesions'/colon were branded onto the mucosal surface 25 and 35 cm from the anus. Submucosal saline lifts were made using a thin catheter and a standard needle knife. We tracked case length, number of instrument exchanges (to refresh lift), the volume of lift solution, the fullness of resection, and deep muscle injuries. RESULTS: Fifty ESDs were carried out in 25 colons (25 C-ESD, 25 TRS-ESD). Complete resections were noted in all cases. The TRS method required fewer instrument exchanges (median 5) vs C-ESD (median 9, p < 0.0001) and less lift solution (median 39 ml) than the C-ESD cases (median 55 ml, p = 0.0003). TRS-ESD was associated with fewer deep muscle injuries (median 2) than C-ESD (median 3, p = 0.0191). Finally, the TRS group's median case length (34.5 min) was shorter than that of C-ESD (41 min, p = 0.0543). CONCLUSION: The TRS system provides retraction and facilitates ESD regarding the number of lift injections, the volume of lift solution needed, and avoidance of muscle injuries. Of note, there is an apparent TRS learning curve, and the device mandates a distal-to-proximal approach and initial 360 degree mucosal incision. Further study is warranted.

Sustained postoperative plasma elevations of plasminogen activator inhibitor-1 following minimally invasive colorectal cancer resection.

Plasminogen activator inhibitor-1 (PAI-1) is a serine protease inhibitor that inhibits urokinase-type plasminogen activator and tissue-type plasminogen activator. PAI-1 participates in angiogenesis, wound healing and tumor invasion, and additionally regulates endothelial cell proliferation, angiogenesis and tumor growth. The purpose of the present study was to measure plasma PAI-1 levels perioperatively in patients with colorectal cancer (CRC) undergoing minimally invasive colorectal resection (MICR). Patients with CRC who underwent elective MICR were eligible for the study. All patients were enrolled in an approved data/plasma bank. Patients with preoperative, postoperative day (POD) 1, POD 3, and at least one POD 7-34 plasma sample collection were studied. Plasma PAI-1 levels were determined in duplicate using ELISA, and the medians and 95% confidence intervals (CIs) were determined. The correlations between postoperative plasma PAI-1 levels and length of surgery were evaluated. PAI-1 levels were compared between patients who underwent laparoscopic-assisted vs. hand-assisted surgery. The preoperative PAI-1 levels of stage I, II, III and IV pathological stage subgroups were also compared. A total of 91 patients undergoing MICR for CRC were studied. The mean incision length was 8.0±3.9 cm, and the length of stay was 6.8±4.3 days. Compared with the median preoperative levels (17.30; 95% CI: 15.63-19.78 ng/ml), significantly elevated median levels were observed on POD 1 (28.86; 95% CI: 25.46-31.22 ng/ml; P<0.001), POD 3 (18.87; 95% CI: 17.05-21.78 ng/ml; P=0.0037), POD 7-13 (26.97; 95% CI: 22.81-28.74 ng/ml; P<0.001), POD 14-20 (25.92; 95% CI: 17.85-35.89 ng/ml; P=0.001) and POD 21-27 (22.63; 95% CI: 20.03-30.09 ng/ml; P<0.001). The PAI-1 levels in the hand-assisted group were higher compared with those in the laparoscopic-assisted group for 4 weeks after surgery; however, a significant difference was found only on POD 1. Therefore, plasma PIA-1 levels were found to be significantly elevated for 4 weeks after MICR, and the surgery-related acute inflammatory response may account for the early postoperative PIA-1 increase. Furthermore, PAI-1-associated VEGF-induced angiogenesis in the healing wounds may account for the late postoperative elevations, and increased PAI-1 levels may promote angiogenesis in residual tumor deposits.

PIPAC for the Treatment of Gynecologic and Gastrointestinal Peritoneal Metastases: Technical and Logistic Considerations of a Phase 1 Trial.

BACKGROUND: Peritoneal metastases (PM) from ovarian, gastric, appendiceal, or colorectal origin can be treated via cytoreductive surgery with or without the addition of hyperthermic intraperitoneal chemotherapy (HIPEC) for selected patients. Unfortunately, not all patients are candidates for aggressive surgical debulking. For these patients, pressurized intraperitoneal aerosolized chemotherapy (PIPAC) has emerged as an alternative method for intraperitoneal (IP) chemotherapy administration. This report presents the design and implementation of the first phase 1 trial to evaluate the safety and efficacy of PIPAC in the United States. METHODS: This is an ongoing prospective phase 1 clinical trial of PIPAC for patients who have histologically confirmed ovarian, uterine, gastric, appendiceal, or colorectal cancer with PM and have progressed to at least one evidence-based chemotherapeutic regimen. The trial has two clinical arms. The patients in arm 1 have gynecologic and gastric malignancies treated with IP cisplatin and doxorubicin, and the arm 2 patients have colorectal and appendiceal malignancies treated with intravenous fluorouracil and leucovorin followed by IP oxaliplatin. All the patients are monitored for dose-limiting toxicities and adverse events. RESULTS: Practical and technical considerations for the phase 1 PIPAC trial are presented. These considerations include patient selection, operating room setup, and technical details for successful aerosolized chemotherapy delivery. The phase 1 study results will be reported separately at completion of the trial. CONCLUSIONS: The PIPAC treatment is a feasible, minimally invasive approach that permits IP delivery of chemotherapy. Once completed, the ongoing phase 1 trial will help to provide safety and initial efficacy data.

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.

Plasma MMP-2 and MMP-7 levels are elevated first month after surgery and may promote growth of residual metastases.

BACKGROUND: MMP-2 also known as gelatinase A and MMP-7 (matrilysin) are members of the zinc-dependent family of MMPs (Matrix metalloproteinase). MMP-2 and MMP-7 are remodeling enzymes that digest extracellular matrix; MMP-2 is extensively expressed during development and is upregulated at sites of tissue damage, inflammation, and in stromal cells of metastatic tumors. MMP-7 is expressed in the epithelial cells and in a variety of cancers including colon tumors. Plasma MMP-2 and MMP-7 levels were assessed before and after minimally invasive colorectal resection for cancer pathology. AIM: To determine plasma MMP-2 and MMP-7 levels before and after minimally invasive colorectal resection for cancer pathology. METHODS: Patients enrolled in a plasma bank for whom plasma was available were eligible. Plasma obtained from preoperative (Preop) and postoperative blood samples was used. Only colorectal cancer (CRC) patients who underwent elective minimally invasive cancer resection with preop, post-operative day (POD) 1, 3 and at least 1 late postop sample (POD 7-34) were included. Late samples were bundled into 7 d blocks (POD 7-13, 14-20, etc.) and treated as single time points. Plasma MMP-2 and MMP-7 levels were determined via enzyme-linked immunosorbent assay in duplicate. RESULTS: Total 88 minimally invasive CRC resection CRC patients were studied (right colectomy, 37%; sigmoid, 24%; and LAR/AR 18%). Cancer stages were: 1, 31%; 2, 30%; 3, 34%; and 4, 5%. Mean Preop MMP-2 plasma level (ng/mL) was 179.3 ± 40.9 (n = 88). Elevated mean levels were noted on POD1 (214.3 ± 51.2, n = 87, P < 0.001), POD3 (258.0 ± 63.9, n = 80, P < 0.001), POD7-13 (229.9 ± 62.3, n = 65, P < 0.001), POD 14-20 (234.9 ± 47.5, n = 25, P < 0.001), POD 21-27 (237.0 ± 63.5, n = 17, P < 0.001,) and POD 28-34 (255.4 ± 59.7, n = 15, P < 0.001). Mean Preop MMP-7 level was 3.9 ± 1.9 (n = 88). No significant differences were noted on POD 1 or 3, however, significantly elevated levels were noted on POD 7-13 (5.7 ± 2.5, n = 65, P < 0.001), POD 14-20 (5.9 ± 2.5, n = 25, P < 0.001), POD 21-27 (6.1 ± 3.6, n = 17, P = 0.002) and on POD 28-34 (6.8 ± 3.3, n = 15 P < 0.001,) vs preop levels. CONCLUSION: MMP-2 levels are elevated for 5 wk and MMP-7 levels elevated for weeks 2-6. The etiology of these changes in unclear, trauma and wound healing likely play a role. These changes may promote residual tumor growth and metastasis.

The cancer testis antigens CABYR-a/b and CABYR-c are expressed in a subset of colorectal cancers and hold promise as targets for specific immunotherapy.

INTRODUCTION: Calcium-binding tyrosine phosphorylation-regulated protein (CABYR) is expressed in the human germ line but not in adult human tissues, thus, it is considered a cancer testis protein. The aim of this study is to evaluate the CABYR isoforms: a/b and c mRNA expression in colorectal cancer (CRC) and to determine if these proteins hold promise as vaccine targets. MATERIALS AND METHODS: CABYR mRNA expression in a set of normal human tissues, including the testis, were determined and compared using semi-quantitative PCR. As regards the tumor and normal mucosal samples from study patients, RNA was extracted and cDNA generated after which quantitative PCR was carried out. Analysis of CABYR protein expressions by immunohistochemistry in tumor and normal colon tissues was also performed. RESULTS: A total of 47 paired CRC and normal tissue specimens were studied. The percent of patients with a relative expression ratio of malignant to normal (M/N) tissues over 1 was 70% for CABYR a/b and 72% for CABYR c. The percent with both a M/N ratio over 1 and expression levels over 0.1% of testis was 23.4% for CABYR-a/b and 25.5% for CABYR c. CABYR expression in tumors was further confirmed by immunohistochemistry. CONCLUSIONS: CABYR a/b and c hold promise as specific immunotherapy targets, however, a larger and more diverse group of tumors (Stage 1-4) needs to be assessed and evaluation of blood for anti-CABYR antibodies is needed to pursue this concept.

Pressurized Intraperitoneal Aerosol Chemotherapy, a Palliative Treatment Approach for Patients With Peritoneal Carcinomatosis: Description of Method and Systematic Review of Literature.

BACKGROUND: Peritoneal metastases arise in patients with a variety of primary cancers, and are associated with a poor prognosis. Systemic chemotherapy is the mainstay of treatment; however, the morbidity is considerable and the survival benefit is modest. Cytoreductive surgery and heated intraperitoneal chemotherapy is a potentially curative treatment available to a minority of patients; however, most develop recurrent disease. A novel palliative treatment for peritoneal metastases, pressurized intraperitoneal aerosol chemotherapy, has recently been introduced. Pressurized intraperitoneal aerosol chemotherapy utilizes an aerosol of chemotherapy in carbon dioxide gas. It is instilled into the abdomen under pressure via laparoscopic ports. No cytoreduction is performed. Pressurized intraperitoneal aerosol chemotherapy can be repeated at 6-week intervals. Oxaliplatin or cis-platinum and doxorubicin have been used to date. OBJECTIVE: This study aims to systematically review and evaluate the method, and the preclinical and early clinical results of pressurized intraperitoneal aerosol chemotherapy. DATA SOURCES: Medline and the Cochrane Library were the data sources for the study. STUDY SELECTION: Peer-reviewed series of greater than 10 patients, with sufficient patient data, through April 2019, were selected. INTERVENTION: Patients with peritoneal metastases underwent pressurized intraperitoneal aerosol chemotherapy. MAIN OUTCOME MEASURES: Patient dropout, histologic tumor response, adverse events, and 30-day mortality were the primary outcomes measured. RESULTS: A total of 921 patients with peritoneal metastases were brought to the operating room for pressurized intraperitoneal aerosol chemotherapy. The number of pressurized intraperitoneal aerosol chemotherapy treatments administered was as follows: 1 treatment, 862 (94%); 2 treatments, 645 (70%); and 3 treatments, 390 patients (42%). Initial laparoscopic access was not possible in 59 patients (6.4%). Common Terminology Criteria for Adverse Events grade 3 or higher were noted in 13.7% of the patients who, collectively, underwent a total of 2116 treatments. The 30-day mortality was 2.4% (22/921). LIMITATIONS: This study was limited by the heterogeneity of reported data and primary tumor types and by the lack of long-term survival data. CONCLUSIONS: Early clinical results are encouraging, but tumor-specific, prospective, randomized trials are needed to compare pressurized intraperitoneal aerosol chemotherapy to systemic chemotherapy. This method has yet to be introduced to the United States. It is another therapeutic option for patients with peritoneal metastases and will broaden the patient base for future clinical trials.

Splenic flexure mobilization for sigmoid and low anterior resections in the minimally invasive era: How often and at what cost?

BACKGROUND: Splenic flexure mobilization (SFM) increases left colonic reach for a better vascularized and tension-free anastomosis. Open SFM is challenging due to anatomic position. Minimally invasive SFM improves visualization and minimizes splenic traction. METHODS: We retrospectively reviewed all sigmoid and low anterior resections (LAR) by a colorectal surgical group over 10-year period. We analyzed indications, surgical methods and perioperative outcomes of open and MIS SFM cohorts. RESULTS: 793 patients were included; 122 (15.5%) open, 671 (84.5%) MIS (60% laparoscopic-assisted (LA), 40% hand-assisted (HA)). Overall, indications were cancer (56%), diverticulitis (31%), and other benign diseases (13%). Compared to MIS, open cases had more complex disease (45% vs. 18%, p < 0.01), with fewer SFM performed (40% vs. 86%, p < 0.01), required more frequent diversion (30% vs. 21%, p = 0.02) and were complicated by higher leak/abscess (7% vs. 3%, p = 0.06) and reoperation rates (10% vs. 6%, p = 0.11). 1% of SFM required conversion (LA to HA 0.5%, MIS to open 0.5%). There were no open SFM complications. There were 26 (5%) MIS SFM complications; bleeding (18; 12 splenic capsular tears (0 splenectomy/splenorraphy), 6 mesenteric) and organ injury (bowel (3), pancreatic (4), renal (1)). CONCLUSIONS: Our SFM rate was high in the MIS group, with a low overall complication rate. Of note, the anastomotic leak/abscess rate was 3%, and may be related to the high SFM rate. It is the authors' opinion that a major advantage of MIS is to facilitate SFM, hence SFM is more likely to be performed with these methods compared to open procedures.

Plasma and wound fluid levels of eight proangiogenic proteins are elevated after colorectal resection.

BACKGROUND: Colorectal resection is associated with 3-5 wk long elevations in the plasma levels of at least 11 proangiogenic proteins that may stimulate tumor angiogenesis post-surgery. The increases during the first week after surgery may be related to the acute inflammatory response; the cause(s) of the week 2-5 increases is unknown. The wounds are a possible source because of the important role that angiogenesis plays in the healing process. The main hypothesis of the study is that wound fluid levels of the proteins studied will be elevated well beyond plasma levels which, in turn, are elevated from preoperative baseline levels. AIM: To determine plasma and wound fluid levels of 8 proangiogenic proteins after colorectal resection for cancer and benign pathology. METHODS: Blood and wound fluid samples were taken simultaneously on postoperative (postop) day 1, 3, and later time points until wound drain removal in 35 colorectal cancer patients and 31 benign disease patients undergoing colorectal resection in whom closed wound drains had been placed in either the pelvis or the subcutaneous space of the abdominal incision. Postop plasma levels were compared to preop plasma and postop wound fluid levels (separate analyses for cancer and benign groups). RESULTS: Sixty-six colorectal disease patients were studied (35 cancer, 31 benign pathology). Most patients underwent minimally invasive surgery (open surgery in 11% of cancer and 6% of benign patients). The majority in the cancer group had rectal resections while in the benign group sigmoid or right colectomy predominated. Plasma levels of all 8 proteins were significantly elevated from baseline (P < 0.05) at all post-operative time points in the cancer group and at 90% of time points (29/32) in the benign group. Wound levels of all 8 proteins were 3-106 times higher (P < 0.05) than plasma levels at 87-90 percent of postop time points; of note, wound levels were more than 10 times higher at 47-50% of time points. CONCLUSION: Plasma protein levels were elevated for 3 weeks after surgery; wound fluid levels were much greater than corresponding blood levels. Healing wounds may be the source of the plasma increases.

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.

Plasma interleukin-8 levels are persistently elevated for 1 month after minimally invasive colorectal resection for colorectal cancer.

Minimally invasive colorectal resection (MICR) for colorectal cancer (CRC) is associated with elevated levels of seven proangiogenic proteins that persist for 2-4 weeks after surgery. The proangiogenic plasma may promote tumor growth postoperatively in patients with residual cancer. To the best of our knowledge, the impact of surgery on interleukin 8 (IL-8) levels is unknown. The aim of the present study was to evaluate plasma IL-8 levels after MICR for CRC. Patients with CRC enrolled in an institutional review board-approved plasma/data bank who underwent MICR were eligible. Blood samples were taken preoperatively (preop) and at multiple postoperative (postop) time points, and were stored at -80°C. Only patients for whom preop, postop day (POD) 1, POD 3 and at least 1 late postop plasma samples (POD7-34) available were enrolled. Clinical, demographical and pathological data were collected. IL-8 levels were determined via ELISA and results were reported as the mean and ± standard deviation. The Wilcoxon signed rank test was used for analysis with P<0.05 used as the significance threshold. A total of 73 CRC patients (colon, 62%; rectal, 38%) who underwent MICR (laparoscopic-assisted, 60%; hand-assisted, 40%) were studied. The mean preop IL-8 level was 20.4±10.6 pg/ml. Significant elevations in plasma IL-8 levels were noted compared with preop levels on POD1 (43.1±38.6; n=72; P<0.0001), POD 3 (33.0±30.1; n=71; P<0.0001), POD7-13 (29.9±21.9; n=50; P<0.0001), POD14-20 (33.1±18.3; n=24; P=0.002), and for the POD21-27 time point (24.0±9.2; n=16; P=0.002). In conclusion, plasma IL-8 levels were significantly elevated from baseline for 4 weeks after MICR for CRC. In conjunction with the other proangiogenic MICR-associated blood compositional changes, increased IL-8 levels may promote tumor angiogenesis and growth postop.

P-Cadherin (CDH3) is overexpressed in colorectal tumors and has potential as a serum marker for colorectal cancer monitoring.

INTRODUCTION: Placental-Cadherin (CDH3) is a cell adhesion molecule vital to cellular localization and tissue integrity. It is highly expressed in the placenta (PLC)and is overexpressed by many types of cancer. P-cadherin levels in colorectal cancer (CRC) remains poorly characterized. This study's purpose was to determine P-cadherin expression in CRC and normal tissues and to assess plasma CDH3 levels in order to determine the relationship, if any, between cancer stage, P-cadherin expression and plasma CDH3 levels. METHODS: An IRB approved plasma, tumor, and prospective data bank was utilized. CRC patients for whom tumor and normal colon tissue samples were available were enrolled. Tumor samples were OCT embedded and stored at -80C°. Total purified RNA was isolated from tissue samples and cDNA synthesized. CDH3 expression was analyzed by quantitative PCR (QPCR) using the SYBR Green platform. Tumor expression levels were determined and compared to levels in normal colonic tissue and PLC. Expression in 22 different normal tissues was also assessed by RT-PCR. Plasma CDH3 levels were determined via ELISA in patients for whom preoperative blood samples were available. Results: A total of 77 paired CRC and normal colon specimens (36 M/ 41 F, age 67.3±14.5) were assessed (82% colon, 18% rectal; Cancer Stage 2, 44; Stage 3, 33). All tested tumors had CDH3 expression levels over 0.1% of the PLC level and tumor to normal colon ratios greater than 1. CDH3 expression was noted in 14/22 normal organ tissues. There was a positive correlation between tumor CDH3 QPCR and preoperative CDH3 blood levels (n=57, P= 0.038). Expression levels were significantly higher in rectal vs. colon tumors (p=0.019). Conclusion: CDH3 expression was elevated in CRC tumors as compared to normal tissue. CDH3 was expressed by numerous normal organs and, thus, is not a viable vaccine target, however, the correlation between plasma and tumor CDH3 levels suggests CDH3 may have value as a diagnostic or prognostic marker.

Warm and Humidified Versus Cold and Dry CO2 Pneumoperitoneum in Minimally Invasive Colon Resection: A Randomized Controlled Trial.

INTRODUCTION: Peritoneal insufflation with warm-humidified (WH) CO2 gas during minimally invasive surgical procedures is purported to prevent hypothermia and peritoneal desiccation and is associated with decreased postoperative IL-6 levels. This randomized study's purpose was to determine the clinical impact of WH versus cold-dry (CD) CO2 in minimally invasive colon resection (MICR), and to assess perioperative plasma levels of IL-6, TIMP-1, sVEGF-R1, and HSP-70 after MICR. METHODS: Operative and short-term clinical data plus perioperative blood samples were collected on MICR patients randomized to receive either WH (36.7°C, 95% humidity) or CD (room temperature, 0% humidity) CO2 perioperatively. Peritoneal biopsies were taken at the start and end of surgery. Outcomes tracked included core temperature, postoperative in-hospital pain levels, analgesia requirements, and standard recovery parameters. Preoperative and postoperative days (PODs) 1 and 3 plasma protein levels were determined via ELISA. RESULTS: A total of 101 patients were randomized to WH CO2 (50) or CD CO2 (51). The WH group contained more diabetics ( P = .03). There were no differences in indication, minimally invasive surgical method used, or core temperature. Pain scores were similar; however, the WH patients required less narcotics on PODs 1 to 3 ( P < .05), and less ketorolac on PODs 1 and 2 ( P < .03). No differences in length of stay, complication rates, or time to flatus/diet tolerance were noted. Plasma levels of the 4 proteins were similar postoperatively. Though insignificant, the WH group had less marked histologic changes on "end-of-case" peritoneal biopsies. CONCLUSION: This study found significantly lower pain medication requirements for PODs 1 to 3 for the WH group; however, because there were no differences in the pains scores between the groups, firm conclusions regarding WH CO2 cannot be made.