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Perioperative Systemic Therapy vs Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy Alone for Resectable Colorectal Peritoneal Metastases: A Phase 2 Randomized Clinical Trial.
Rovers, KP, Bakkers, C, Nienhuijs, SW, Burger, JWA, Creemers, GM, Thijs, AMJ, Brandt-Kerkhof, ARM, Madsen, EVE, van Meerten, E, Tuynman, JB, et al
JAMA surgery. 2021;(8):710-720
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Abstract
IMPORTANCE To date, no randomized clinical trials have investigated perioperative systemic therapy relative to cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS-HIPEC) alone for resectable colorectal peritoneal metastases (CPM). OBJECTIVE To assess the feasibility and safety of perioperative systemic therapy in patients with resectable CPM and the response of CPM to neoadjuvant treatment. DESIGN, SETTING, AND PARTICIPANTS An open-label, parallel-group phase 2 randomized clinical trial in all 9 Dutch tertiary centers for the surgical treatment of CPM enrolled participants between June 15, 2017, and January 9, 2019. Participants were patients with pathologically proven isolated resectable CPM who did not receive systemic therapy within 6 months before enrollment. INTERVENTIONS Randomization to perioperative systemic therapy or CRS-HIPEC alone. Perioperative systemic therapy comprised either four 3-week neoadjuvant and adjuvant cycles of CAPOX (capecitabine and oxaliplatin), six 2-week neoadjuvant and adjuvant cycles of FOLFOX (fluorouracil, leucovorin, and oxaliplatin), or six 2-week neoadjuvant cycles of FOLFIRI (fluorouracil, leucovorin, and irinotecan) and either four 3-week adjuvant cycles of capecitabine or six 2-week adjuvant cycles of fluorouracil with leucovorin. Bevacizumab was added to the first 3 (CAPOX) or 4 (FOLFOX/FOLFIRI) neoadjuvant cycles. MAIN OUTCOMES AND MEASURES Proportions of macroscopic complete CRS-HIPEC and Clavien-Dindo grade 3 or higher postoperative morbidity. Key secondary outcomes were centrally assessed rates of objective radiologic and major pathologic response of CPM to neoadjuvant treatment. Analyses were done modified intention-to-treat in patients starting neoadjuvant treatment (experimental arm) or undergoing upfront surgery (control arm). RESULTS In 79 patients included in the analysis (43 [54%] men; mean [SD] age, 62 [10] years), experimental (n = 37) and control (n = 42) arms did not differ significantly regarding the proportions of macroscopic complete CRS-HIPEC (33 of 37 [89%] vs 36 of 42 [86%] patients; risk ratio, 1.04; 95% CI, 0.88-1.23; P = .74) and Clavien-Dindo grade 3 or higher postoperative morbidity (8 of 37 [22%] vs 14 of 42 [33%] patients; risk ratio, 0.65; 95% CI, 0.31-1.37; P = .25). No treatment-related deaths occurred. Objective radiologic and major pathologic response rates of CPM to neoadjuvant treatment were 28% (9 of 32 evaluable patients) and 38% (13 of 34 evaluable patients), respectively. CONCLUSIONS AND RELEVANCE In this randomized phase 2 trial in patients diagnosed with resectable CPM, perioperative systemic therapy seemed feasible, safe, and able to induce response of CPM, justifying a phase 3 trial. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT02758951.
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Microparticles vs. Macroparticles as Curcumin Delivery Vehicles: Structural Studies and Cytotoxic Effect in Human Adenocarcinoma Cell Line (LoVo).
Wezgowiec, J, Tsirigotis-Maniecka, M, Saczko, J, Wieckiewicz, M, Wilk, KA
Molecules (Basel, Switzerland). 2021;(19)
Abstract
This study aimed to characterize the hydrogel micro- and macro-particles designed to deliver curcumin to human colon cancer cells (LoVo). Six series of vehicles based on sodium alginate (micro- and macro-particles, uncoated, coated with chitosan or gelatin) were synthesized. The uncoated microparticles were fabricated using an emulsion-based technique and the uncoated macroparticles with an extrusion technique, with both coupled with ionotropic gelation. The surface morphology of the particles was examined with scanning electron microscopy and the average size was measured. The encapsulation efficiency, moisture content, and swelling index were calculated. The release of curcumin from the particles was studied in an experiment simulating the conditions of the stomach, intestine, and colon. To evaluate the anticancer properties of such targeted drug delivery systems, the cytotoxicity of both curcumin-loaded and unloaded carriers to human colon cancer cells was assessed. The microparticles encapsulated much less of the payload than the macroparticles and released their content in a more prolonged manner. The unloaded carriers were not cytotoxic to LoVo cells, while the curcumin-loaded vehicles impaired their viability-more significantly after incubation with microparticles compared to macroparticles. Gelatin-coated or uncoated microparticles were the most promising carriers but their potential anticancer activity requires further thorough investigation.
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Free Fatty Acids Signature in Human Intestinal Disorders: Significant Association between Butyric Acid and Celiac Disease.
Baldi, S, Menicatti, M, Nannini, G, Niccolai, E, Russo, E, Ricci, F, Pallecchi, M, Romano, F, Pedone, M, Poli, G, et al
Nutrients. 2021;(3)
Abstract
Altered circulating levels of free fatty acids (FFAs), namely short chain fatty acids (SCFAs), medium chain fatty acids (MCFAs), and long chain fatty acids (LCFAs), are associated with metabolic, gastrointestinal, and malignant diseases. Hence, we compared the serum FFA profile of patients with celiac disease (CD), adenomatous polyposis (AP), and colorectal cancer (CRC) to healthy controls (HC). We enrolled 44 patients (19 CRC, 9 AP, 16 CD) and 16 HC. We performed a quantitative FFA evaluation with the gas chromatography-mass spectrometry method (GC-MS), and we performed Dirichlet-multinomial regression in order to highlight disease-specific FFA signature. HC showed a different composition of FFAs than CRC, AP, and CD patients. Furthermore, the partial least squares discriminant analysis (PLS-DA) confirmed perfect overlap between the CRC and AP patients and separation of HC from the diseased groups. The Dirichlet-multinomial regression identified only strong positive association between CD and butyric acid. Moreover, CD patients showed significant interactions with age, BMI, and gender. In addition, among patients with the same age and BMI, being male compared to being female implies a decrease of the CD effect on the (log) prevalence of butyric acid in FFA composition. Our data support GC-MS as a suitable method for the concurrent analysis of circulating SCFAs, MCFAs, and LCFAs in different gastrointestinal diseases. Furthermore, and notably, we suggest for the first time that butyric acid could represent a potential biomarker for CD screening.
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[Meta-analysis of laparoscopic versus open surgery for palliative resection of the primary tumor in stage IV colorectal cancer].
Tan, SJ, Jiang, Y, Xi, QL, Meng, QY, Zhuang, QL, Han, YS, Wu, GH
Zhonghua wei chang wai ke za zhi = Chinese journal of gastrointestinal surgery. 2020;(6):589-596
Abstract
Objective: To systematically evaluate the safety and efficacy of laparoscopic versus open surgery for palliative resection of the primary tumor in stage IV colorectal cancer. Methods: The databases of CNKI, Wanfang, VIP, PubMed, EMBASE and Cochrane Library were searched to retrieve randomized controlled trials (RCT) or clinical controlled trials (CCT) comparing laparoscopic surgery with open surgery for palliative resection of the primary tumor in stage IV colorectal cancer published from January 1991 to May 2019. Chinese search terms included "colorectum/colon/rectum" , "cancer/malignant tumor" , "laparoscopy" , "metastasis" , " IV" ; English search terms included "laparoscop*" , "colo*" , "rect*" , "cancer/tumor/carcinoma/neoplasm" , " IV" , "metasta*" . Inclusion criteria: (1) RCT or CCT, with or without allocation concealment or blinding; (2) patients with stage IV colorectal cancer that was diagnosed preoperatively and would receive resection of the primary tumor; (3) the primary tumor that was palliatively resected by laparoscopic or open procedure. Exclusion criteria: (1) no valid data available in the literature; (2) single study sample size ≤20; (3) subjects with colorectal benign disease; (4) metastatic resection or lymph node dissection was performed intraoperatively in an attempt to perform radical surgery; (5) duplicate publication of the literature. Two researchers independently evaluated the quality of the included studies. In case of disagreement, the evaluation was performed by discussion or a third researcher was invited to participate. The data were extracted from the included studies, and the Cochrane Collaboration RevMan 5.1.0 version software was used for this meta-analysis. Results: Four CCTs with a total of 864 patients were included in this study, including 216 patients in the laparoscopic group and 648 patients in the open group. Compared with the open group, except for longer operation time (WMD=37.60, 95% CI: 26.11 to 49.08, P<0.05), laparoscopic group had less intraoperative blood loss (WMD=-74.89, 95% CI: -144.78 to -5.00, P<0.05), earlier first flatus and food intake after surgery (WMD=-1.00, 95% CI: -1.12 to -0.87, P<0.05; WMD=-1.61, 95%CI: -2.16 to -1.06, P<0.05), shorter hospital stay (WMD=-2.01, 95% CI: -2.21 to -1.80, P<0.05) and lower morbidity of postoperative complication (OR=0.52, 95% CI: 0.35 to 0.77, P<0.05). However, no significant differences were found in time to start postoperative chemotherapy, postoperative chemotherapy rate, and mortality (P > all 0.05). Conclusion: Laparoscopic surgery for palliative resection of the primary tumor is safe and feasible to enhance recovery after surgery by promoting postoperative bowel function recovery, shortening hospital stay and reducing postoperative complication in stage IV colorectal cancer.
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1L- vs. 4L-Polyethylene glycol for bowel preparation before colonoscopy among inpatients: A propensity score-matching analysis.
Frazzoni, L, Spada, C, Radaelli, F, Mussetto, A, Laterza, L, La Marca, M, Piccirelli, S, Cortellini, F, Rondonotti, E, Paci, V, et al
Digestive and liver disease : official journal of the Italian Society of Gastroenterology and the Italian Association for the Study of the Liver. 2020;(12):1486-1493
Abstract
BACKGROUND Inpatients are at risk for inadequate colon cleansing. Experts recommend 4L-polyethylene-glycol (PEG) solution. A higher colon cleansing adequacy rate for a hyperosmolar 1L-PEG plus ascorbate prep has been recently reported. AIMS We aimed to determine whether 1L-PEG outperforms 4L-PEG among inpatients. METHODS post-hoc analysis of a large Italian multicenter prospective observational study among inpatients (QIPS study). We performed a propensity score matching between 1L-PEG and 4L-PEG group. The primary outcome was the rate of adequate colon cleansing as assessed by unblinded endoscopists through Boston scale. Secondary outcome was the safety profile. RESULTS Among 1,004 patients undergoing colonoscopy, 724 (72%) were prescribed 4L-PEG and 280 (28%) 1L-PEG. The overall adequate colon cleansing rate was 69.2% (n = 695). We matched 274 pairs of patients with similar distribution of confounders. The rate of patients with adequate colon cleansing was higher in 1L-PEG than in 4L-PEG group (84.3% vs. 77.4%, p = 0.039). No different shift in serum concentration of electrolytes (namely Na+, K+, Ca2+), creatinine and hematocrit were observed for both preparations. CONCLUSION We found a higher rate of adequate colon cleansing for colonoscopy with the 1L-PEG bowel prep vs. 4L-PEG, with apparent similar safety profile, among inpatients. A confirmatory randomized trial is needed. (ClinicalTrials.gov no: NCT04310332).
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Repeat hepatectomy with systemic chemotherapy might improve survival of recurrent liver metastasis from colorectal cancer-a retrospective observational study.
Matsuoka, H, Morise, Z, Tanaka, C, Hayashi, T, Ikeda, Y, Maeda, K, Masumori, K, Koide, Y, Katsuno, H, Tanahashi, Y, et al
World journal of surgical oncology. 2019;(1):33
Abstract
BACKGROUND Although hepatectomy for metastatic colorectal cancer (mCRC) prolongs survival in up to 40% of people, recurrence rates approach 70%. We used a multidisciplinary approach to treat recurrent liver metastases, including chemotherapy, surgery, and palliative care. On the other hand, development of chemotherapeutic agents is remarkable and improves long-term survival. However, whether chemotherapy and repeat hepatectomy combination therapy improve survival or not is still unclear. The aim of this study was to analyze the outcomes of repeat hepatectomy with systemic chemotherapy for mCRC. METHODS Following Institutional Review Board approval, we reviewed the records of all patients who underwent hepatectomy for mCRC between 1974 and 2015 at Fujita Health University Hospital. We used the Kaplan-Meier method to estimate overall survival from the first and last hepatectomy in multi hepatectomy cases after 2005 and compared outcomes between groups using the log-rank test. RESULTS A total of 426 liver resections were performed for mCRC; of these, 236 cases were performed after 2005 (late group). In 118 (50%) cases, the site of recurrence was the liver, 59 (50%) underwent repeat hepatectomy, and 14 cases had ≥ 2 repeat hepatectomies. Overall survival (OS) before and after 2005 was 42.2 and 64.1 months, respectively, with the late group having better OS compared to the early (1974-2004) group. OS for single hepatectomy cases was 83.2 months, for two hepatectomies was 42.9 months, and for three hepatectomies was 35.3 months. In total, 59 patients did not undergo surgery after recurrence with an OS of 28.7 months. Mortality of the second and third repeat hepatectomy was 1.7% and 15.3%, respectively. CONCLUSION Repeat hepatectomy with systemic chemotherapy for mCRC is feasible and might achieve improved survival in carefully selected patients.
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Comparison of prognostic models to predict the occurrence of colorectal cancer in asymptomatic individuals: a systematic literature review and external validation in the EPIC and UK Biobank prospective cohort studies.
Smith, T, Muller, DC, Moons, KGM, Cross, AJ, Johansson, M, Ferrari, P, Fagherazzi, G, Peeters, PHM, Severi, G, Hüsing, A, et al
Gut. 2019;(4):672-683
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OBJECTIVE To systematically identify and validate published colorectal cancer risk prediction models that do not require invasive testing in two large population-based prospective cohorts. DESIGN Models were identified through an update of a published systematic review and validated in the European Prospective Investigation into Cancer and Nutrition (EPIC) and the UK Biobank. The performance of the models to predict the occurrence of colorectal cancer within 5 or 10 years after study enrolment was assessed by discrimination (C-statistic) and calibration (plots of observed vs predicted probability). RESULTS The systematic review and its update identified 16 models from 8 publications (8 colorectal, 5 colon and 3 rectal). The number of participants included in each model validation ranged from 41 587 to 396 515, and the number of cases ranged from 115 to 1781. Eligible and ineligible participants across the models were largely comparable. Calibration of the models, where assessable, was very good and further improved by recalibration. The C-statistics of the models were largely similar between validation cohorts with the highest values achieved being 0.70 (95% CI 0.68 to 0.72) in the UK Biobank and 0.71 (95% CI 0.67 to 0.74) in EPIC. CONCLUSION Several of these non-invasive models exhibited good calibration and discrimination within both external validation populations and are therefore potentially suitable candidates for the facilitation of risk stratification in population-based colorectal screening programmes. Future work should both evaluate this potential, through modelling and impact studies, and ascertain if further enhancement in their performance can be obtained.
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Comparing adenoma and polyp miss rates for total underwater colonoscopy versus standard CO2: a randomized controlled trial using a tandem colonoscopy approach.
Anderson, JC, Kahi, CJ, Sullivan, A, MacPhail, M, Garcia, J, Rex, DK
Gastrointestinal endoscopy. 2019;(3):591-598
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BACKGROUND AND AIMS Although water exchange may improve adenoma detection compared with CO2, it is unclear whether water is a better medium to fill the lumen during withdrawal and visualize the mucosa. Total underwater colonoscopy (TUC) involves the use of water exchange with the air valve off during insertion followed by the inspection of the mucosa under water. Our goal was to compare miss rates for TUC with standard CO2 for polyps and adenomas using a tandem colonoscopy design. METHODS We randomized participants to undergo tandem colonoscopies using TUC or CO2 first. In TUC, water exchange was performed during insertion, and withdrawal was performed under water. For the CO2 colonoscopy, both insertion and withdrawal were performed with CO2. The main outcomes were miss rates for polyps and adenomas for the first examination calculated as the number of additional polyps/adenomas detected during the second examination divided by the total number of polyps/adenomas detected for both examinations. Inspection times were calculated by subtracting the time for polypectomy, and care was taken to keep the times equal for both examinations. RESULTS A total of 121 participants were randomized with 61 having CO2 first. The overall miss rate for polyps was higher for the TUC-first group (81/237; 34%) compared with the CO2-first cohort (57/264; 22%) (P = .002). In addition, the overall miss rate for all adenomas was higher for the TUC-first group (52/146; 36%) compared with the CO2 group (37/159; 23%) (P = .025). However, 1 of the 3 endoscopists had higher polyp/adenoma miss rates for CO2, but these were not statistically significant differences. The insertion time was longer for TUC than for CO2. After adjusting for times, participant characteristics, and bowel preparation, the miss rate for polyps was higher for TUC than for CO2. CONCLUSIONS We found that TUC had an overall higher polyp and adenoma miss rate than colonoscopy performed with CO2, and TUC took longer to perform. However, TUC may benefit some endoscopists, an issue that requires further study. (Clinical trial registration number: NCT03231917.).
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Water exchange colonoscopy decreased adenoma miss rates compared with literature data and local data with CO2 insufflation: an observational study.
Cheng, CL, Kuo, YL, Hsieh, YH, Tang, JH, Leung, FW
BMC gastroenterology. 2019;(1):143
Abstract
BACKGROUND Reports showed adenoma miss rates (AMRs) of 22.5-27% in the right colon and 23.4-33.3% in the proximal colon. Missed lesions could contribute to postcolonoscopy cancers. Water exchange (WE) with near-complete removal of infused water during insertion increased adenoma detection rate but the impact on AMR had not been reported. We hypothesized that WE could reduce AMRs. Study 1 compared the AMRs of WE with literature data. Study 2 developed local AMR data with CO2 insufflation. METHODS The lead author attended a research seminar in 2017 on WE colonoscopy. For performance improvement, study 1 was undertaken. When data in study 1 confirmed WE produced a considerably lower AMRs in the right and proximal colon, study 2 with CO2 insufflation was performed. RESULTS Eighty-six patients completed each study. In study 1, WE removed 89% of infused water upon arrival to the cecum. The AMRs of right colon (17.5%) and proximal colon (15.5%) were considerably lower than those in the literature. Upon completion of study 2, compared with local data of CO2 insufflation, WE showed a significantly lower AMR in the right (17.5% vs. 33.8%, P = 0.034) and proximal (15.5% vs. 30.4%, P = 0.018) colon, respectively. The major limitation was that the investigation consisted of two consecutive observational studies, not a randomized controlled trial (RCT). CONCLUSIONS WE with near-complete (89%) removal of infused water during insertion significantly decreased AMRs in the right and proximal colon compared with literature data and those of CO2 insufflation in our hands. The provocative data warrant confirmation in a RCT. TRIAL REGISTRATION NCT03832322 (Retrospectively registered on February 2, 2019).
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Single dose of intravenous ferric carboxymaltose infusion versus multiple fractionated doses of intravenous iron sucrose in the treatment of postoperative anaemia in colorectal cancer patients: study protocol for a randomised controlled trial.
Laso-Morales, MJ, Vives, R, Vallejo-Tarrat, A, Caló, N, Valle-Beltran, A, Pontes, C
Trials. 2019;(1):23
Abstract
BACKGROUND Patients with colorectal cancer (CRC) often present with associated anaemia which is usually present at the time of diagnosis and is aggravated during the postoperative period due to blood loss during the surgery process. Several guidelines advocate for the treatment of postoperative anaemia in these patients in order to prevent complications and allogeneic blood transfusions. However, there are no publications to shed light on the effectiveness of intravenous iron (IVI) administration after CRC surgery and the optimal dose and regimen. We have started a clinical trial with the objective of comparing the effectiveness of 1000 mg of ferric carboxymaltose with fractionated iron sucrose 200 g/48 h for the treatment of postoperative anaemia, by measuring the change of haemoglobin (Hb) levels from postoperative day (POD) 1 to POD 30. METHODS We designed an open label randomised controlled trial to compare two postoperative IVI treatment regimens. Patients aged > 18 years undergoing CRC surgery, with Hb < 11 g/dL on POD 1 are randomly assigned to receive either 1000 mg of ferric carboxymaltose (single dose) or 200 g/48 h of iron sucrose. The main study endpoint will be the change from POD 1 to POD 30 in Hb levels and the key secondary endpoint the percentage of patients with Hb levels ≥ 13 g/dL at POD 30. Other secondary endpoints include: changes in iron metabolism parameters (Fe, ferritin, transferrin, % saturated trasferrin) at POD 30; total doses of iron received; number of postoperative transfusions; compliance with oral iron treatment; number of medical and surgical complications; adverse reactions reported by the patient; use of health resources after surgery; and changes in quality of life (QoL). It has been estimated that a sample of 48 patients per group will allow detecting a difference of 0.75 g/dL in Hb in the change in Hb levels from POD 1 to POD 30. DISCUSSION The results of this study will confirm if the single dose of 1000 mg ferric carboxymaltose should be preferred in front of the fractionated doses and in which type of patients this regimen should be used preferably. TRIAL REGISTRATION European Union Clinical Trials Register, EudraCT 2015-001005-13 . Registered on 6 January 2015.