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18-Fluorodeoxyglucose positron emission tomography has limited sensitivity for colonic adenoma and early stage colon cancer.

BACKGROUND: 18-Fluorodeoxyglucose positron emission tomography (PET) is used clinically to detect recurrent colon cancer after surgical resection, but the sensitivity of PET for premalignant colon lesions and early stage colon cancer is not well defined. METHODS: In a prospective study, 45 patients with a total of 58 colonic neoplasms, including premalignant polyps, premalignant, flat lesions, and early stage cancers, were evaluated by PET. RESULTS: The sensitivity of PET for cancer was 62% (8/13). PET detected 100% (7/7) of cancers 2 cm or larger but only 17% (1/6) of cancers smaller than 2 cm. PET detected 23% (3/13) of flat, premalignant lesions; 70% (7/10) of protruded, premalignant lesions 3 cm or larger; 38% (3/8) of protruded, premalignant lesions between 2 and 2.9 cm; and 14% (2/14) of protruded, premalignant lesions between 1 and 1.9 cm. There was no false-positive PET reading. CONCLUSIONS: PET has limited sensitivity for flat, premalignant lesions; protruded, premalignant lesions smaller than 3 cm; and colon cancers smaller than 2 cm.

Adenoma↗

Sulphated bile acid per se inhibits colonic carcinogenesis in mice.

Peroral sulpholithocholic acid (SLC) promoted colonic tumorigenesis in conventional rats. We then tested this compound in the mouse, a species with different bile acid metabolism from the rat. Female conventional ICR mice received 0.5 mg of N-methyl-N-nitrosourea (MNU) three times in one week intrarectally or 16 mg/kg body weight of 1,2-dimethylhydrazine (DMH) subcutaneously once a week for 10 weeks, followed by a basal diet (CE-2), or CE-2 containing SLC or lithocholic acid (LC) (both at 0.5 mmol/100 g CE-2) for 40 weeks. At autopsy, numbers of mice bearing colonic neoplasms were 4/26 (15%) in the MNU + CE-2, 4/23 (17%) in the MNU + SLC, 5/28 (18%) in the MNU + LC, 12/24 (50%) in the DMH + CE-2, 6/23 (26%) in the DMH + SLC and 11/27 (41%) in the DMH + LC group. The DMH + SLC group had less adenocarcinomas than did the DMH + CE-2 and the DMH + LC group (P < 0.05). Total faecal bile acids in the mice fed on bile salts showed threefold increases compared with those on the basal diet. Sulphates constituted an average 7% and 19% of faecal bile acids in the MNU + SLC and DMH + SLC group, respectively. These results indicated that effects of peroral SLC on colonic carcinogenesis correlated with the degree of desulphation of SLC in the intestine and sulphates per se inhibited colonic carcinogenesis.

1,2-Dimethylhydrazine↗

[The single-stage surgery of perforated colon carcinoma. Our experience of 46 cases].

BACKGROUND: 46 cases of perforated colonic neoplasm (4.6% of the entire series): 11 (24%) of the right colon, 35 (76%) of the left colon; 19 males (41%) and 27 females (59%); mean age 67 years old, range 32-92 years. pTNM: stage II, 1 case (2%); stage III: 27 cases (59%); stage IV, 18 cases (39%). The aim of this study was to resolve the perforation and to treat the neoplasm in a single operation. METHODS: The various types of perforation included: 35/46 = 76% perforations in situ; 6/47 = 13% recent perforations upstream; and 5/46 = 11% at a distance from the neoplasia. The following types of peritonitis were observed: purulent localised 10/46 = 22%, purulent generalised 12/46 = 26%, fecaloid 18/46 = 39%, fecal 6/46 = 13%. In 24 cases/46 = 52% the perforation had occurred in an occluded colon. The preoperative finding of pneumoperitoneum in 12/46 = 26% indicated generalised fecaloid-fecal peritonitis. Surgery commenced by suturing the perforation followed wherever possible by standard colectomy: on the right in all 11 cases = 100%, on the left in 15/35 = 43%; only in the event of prohibitive local or in particular general conditions was Hartmann's segmentary colectomy used in 10 cases/35 = 29%, or a definitive preternatural anus in 10/35 = 29%. The following aspects are essential in this single-stage surgery: the emergency nature of the operation; massive dose antibiotic treatment limited to the pre- and perioperative stages and above all peritoneal cleansing using accurate, methodical, repeated and abundant lavage with 8-10-20 or more litres of polysaline isotonic solution at 37 degrees C, but only used 500 ml at a time. This lavage is essential to reduce bacterial load contributes to the rapid hydroelectrolytic re-equilibrium in severe conditions of peritonitis. When necessary, colonic preparation was carried out using direct colostomic perioperative lavage. The peritonisation of the retroperitoneum with the omentum is important, as is the protection of the anastomosis using omental wrapping and active lavage and aspiration of the colorectal anastomosis, even using the 3-way tube, in a transanal trans- or subanastomotic position. Total parenteral feeding is useful and almost indispensable for 6-8 days. RESULTS: Postoperative morbidity was negligible and mortality occurred in 14/46 cases = 30%, of whom 13/32 = 41% were over 60 and 1/14 = 7% under 60; if the cases are divided into two periods, pre-Gullino tube (1974-84) mortality was 8/22 = 36% and with Gullino's tube (1985-95) it was 6/24 = 25%; postoperative stay was 18 days in the first period and only 11 days in the second. The 11 cases at stage IV who survived the operation all died following the spread of neoplasms within 2-30 months, mean 10 months; the over-5-year survival rate for the only case at stage II and the 19 at stage III was 38% (Kaplan-Meier). CONCLUSIONS: By using this courageous single-stage surgery and operating patients at such a severe stage, both the immediate and long-term results appear to be more than satisfactory. It is important to underline, however, that not all neoplastic perforations appeared to be caused by endoluminal hypertension-ischemia; in those cases with non-occluded colon, about half might have been the consequence of biological problems of immune hyperreactivity of a rejection reaction type (Arthus, Snarelli-Shwartzman phenomenon and similar).

Adult↗

Overexpression of cyclin D1 mRNA in colorectal carcinomas and relationship to clinicopathological features: an in situ hybridization analysis.

Increased expression of a key cell cycle regulator, cyclin D1, may have relevance to carcinogenesis and clinicopathological characteristics of some cancers. This study represents the first application of in situ hybridization, ISH, to detect cyclin D1 mRNA in tissue sections from colorectal carcinomas. This approach was selected because of its unique potential to clarify whether increased expression of cyclin D1 mRNA correlates with clinical and pathological parameters. The ISH ofa non-radioactive oligonucleotide probe (Biogenex) was immunocytochemically detected in paraffin embedded sections from biopsy or resection specimens. Tumors ranged from well to poorly differentiated, and from stages A, B, C, and D. Ten year survival data were available on the majority of patients. Intensity of tumor and background (smooth muscle) signals were independently scored from 0 to 3. Overexpressed cyclin D1 mRNA was seen in 86% of cases compared to background. This frequency is similar to that reported for pancreatic carcinoma. The average signal intensity score in tumor foci was 1.9 with a background score of 0.05 (p<001). All cases showed specific staining judged by the cytoplasmic localization and a tumor signal:background ratio >1. Expression did not differentiate cancers based on grade, stage or survival (p>1), but did differentiate carcinoma and severe dysplasia from mild dysplasia. We conclude that ISH of cyclin D1 mRNA is an effective and relatively specific means of detecting activity of this gene in colonic neoplasms. The high frequency of overexpression implies that gene activity by itself is not likely to predict a tumor s biological or clinical behavior. On the other hand, these data suggest that increased cyclin D1 gene activity may be an early event in colorectal carcinogenesis. They also are consistent with findings showing cyclin D1 is inducible by a variety of oncogene products.

Adenocarcinoma↗

Chemopreventive effect of N-(2-cyclohexyloxy-4-nitrophenyl)methane sulfonamide (NS-398), a selective cyclooxygenase-2 inhibitor, in rat colon carcinogenesis induced by azoxymethane.

Non-steroidal anti-inflammatory drugs (NSAIDs) such as sulindac and indomethacin inhibit colon carcinogenesis, and selective cyclooxygenase (COX)-2 inhibitors are considered to be potential chemopreventive agents without the side effects of usual NSAIDs. We reported that NS-398, N-(2-cyclohexyloxy-4-nitrophenyl)methane sulfonamide, suppressed the formation of preneoplastic lesions, aberrant crypt foci (ACF), induced by azoxymethane (AOM) in a short-term assay of rat colon carcinogenesis. In this study, we examined the effects of long-term NS-398 administration on rat colon carcinogenesis. After three AOM treatments at weekly intervals, a dose of 10 mg/kg of NS-398 in 5% Arabic gum solution was administered by gavage three times per week in group 2 until the termination of the experiment. Rats in group 1 were fed in a basal diet and given 5% Arabic gum solution alone after AOM treatment. At 40 weeks after the first AOM treatment, all rats were killed and the whole intestines including colon were examined. While the incidences of whole intestinal and colon neoplasms in group 1 were 84.6% and 80.8%, respectively, those in group 2 (given NS-398) were 51.9% and 44.4% respectively (P=0.0177 and P=0.0103 by Fisher's exact test, respectively). The multiplicities in group 2 (0.67+/-0.78 and 0.48+/-0.58) were also decreased significantly compared with those (1.39+/-1.10 and 1.08+/-0.74) in group 1 (P<0.01 by Welch's method and P<0.002 by Student's t test, respectively). In immunohistochemistry for proliferative cell nuclear antigen (PCNA), the PCNA-stained cell index (7.40+/-0.5) in group 2 was significantly decreased from that in group 1 (14.03+/-0.82) (P<0.001 by Welch's method). The results suggest that NS-398, a selective COX inhibitor, has a chemopreventive activity against colon carcinogenesis without side-effects such as gastric ulceration.

Animals↗

The value of pre-operative ultrasound of the liver in colonic and gastric neoplasia.

In a series of 50 patients presenting with gastric or colonic neoplasms ultrasound scans of the liver were performed during the pre-operative assessment. The radiologist who performed the scan was informed that the patient had gastro-intestinal malignancy but was unaware of the clinical or biochemical findings that might suggest hepatic metastases. The ultrasound findings were then compared with the results of laparotomy, laparoscopy or the clinical course of the patient. The overall accuracy of ultrasound in this small series was 88%.

Colonic Neoplasms↗

Multicentre prospective controlled study of Barrett's oesophagus and colorectal adenomas. Groupe d'Etude de l'Oesophage de Barrett.

Previous studies have suggested that patients with Barrett's oesophagus may be at increased risk of colorectal neoplasia, though the association is disputed. In a multicentre prospective study we compared the prevalence of colorectal adenomas in patients with Barrett's oesophagus and controls. Barrett's oesophagus patients (n = 104) had histological confirmation of columnar epithelium extending more than 3 cm above the gastro-oesophageal junction. The 537 controls were patients with symptoms suggesting irritable bowel syndrome. No participant had a personal history of colonic neoplasm. Each patient underwent colonoscopy. Histologically proven adenomas were found in 26 Barrett's patients (25%) and 75 controls (14%). Three colorectal cancers were discovered in each group. The prevalence of adenomas was greater in the Barrett's oesophagus group than in the control group (p < 0.01) but the relation became non-significant after adjustment for age and sex and control for other known risk factors by a logistic regression model (odds ratio 1.4 [0.7-2.7]). The relative risk of adenoma was significantly higher in patients older than 59 than in younger patients (2.2 [1.3-3.5]) and in men than in women (3.4 [2.0-5.7]). Other factors contributing significantly to the risk of adenoma were a family history of colorectal cancer (2.3 [1.1-4.8]), rectal bleeding (2.1 [1.1-3.9]), previous colonic investigation (0.3 [0.1-0.7]), and complete as opposed to partial colonoscopy (6.4 [0.8-48.3]). We conclude that Barrett's oesophagus is not an independent risk factor for colorectal neoplasia and, therefore, is not, in itself an indication for colorectal screening.

Adenoma↗

Epidemiology of colonic aberrant crypt foci: review and analysis of existing studies.

Since first described in a rodent model in 1987, aberrant crypt foci (ACF) in the colon have been shown to exhibit many of the molecular features of the more advanced colonic neoplasms including cancer. Therefore, they may be early lesions with potential for progression, and be valuable biomarkers for reduction of risk of colorectal cancer (CRC). For this review, we searched PubMed, and reference lists of recent publications, for studies which reported on associations of features of ACF in humans, such as number or size, with subject characteristics, such as age or family history of CRC. Over 150 papers have reported on ACF in humans. However, the vast majority of these publications are concerned with molecular and morphological features of biopsied lesions, and not their epidemiology. None of the epidemiological studies were of optimum design, primarily due to their absence of a well-defined subject sampling frame or method. Given their 'first-generation' nature, consistent findings were of increased ACF number with age and with synchronous advanced colonic neoplasia. One study reported a higher mean number of ACF in subjects with a family history of CRC than in those without. The strongest evidence on the ability of ACF to predict a diagnosis of CRC will be from prospective studies with baseline ACF assessment in a large sample of disease-free persons (many thousands) who are followed carefully for many years. In the interim, because ACF are asymptomatic, well-designed cross-sectional studies are feasible and will yield valuable information on the relation of ACF to the known risk factors for CRC. This information can then be used to improve the design of prospective studies, and of clinical intervention trials that use ACF as an intermediate endpoint.

Colonic Neoplasms↗

Significance of distal polyps detected with flexible sigmoidoscopy in asymptomatic patients.

BACKGROUND: Colorectal cancer is a frequent cause of death from cancer. To reduce the mortality associated with this disease, regular flexible sigmoidoscopy is recommended. However, the significance of diminutive polyps (adenomatous or hyperplastic) detected during flexible sigmoidoscopy remains controversial, as does the appropriate endoscope length (35 vs 60 cm) for colorectal cancer screening. METHODS: One hundred one consecutive patients with no history of colonic disease, gastrointestinal tract symptoms, or positive results of fecal occult blood testing underwent flexible sigmoidoscopy as part of a colorectal cancer screening program. All patients with distal polyps detected during flexible sigmoidoscopy underwent colonoscopy. RESULTS: More than 25% of these asymptomatic, predominantly male subjects had colonic neoplasms or polyps detected. Fifty percent more lesions could be detected with a 60-cm sigmoidoscope than with a 35-cm sigmoidoscope, and detection of any distal polyp, whether adenomatous or hyperplastic, was associated with at least one proximal colon adenoma in 20% of patients. "Extended flexible sigmoidoscopy" for colorectal cancer screening was well tolerated by patients, as evidenced by insertion to the hepatic flexure in 25% of patients, and provided significantly more information than could be obtained with a 35-cm sigmoidoscope. CONCLUSIONS: Colorectal cancer screening should be performed with a 60-cm flexible sigmoidoscope, and distal colonic polyps or neoplasms will be detected in 25% of asymptomatic patients.

Aged↗

Infective endocarditis due to Streptococcus bovis in a series of nonaddict patients: clinical and morphological characteristics of 20 cases and review of the literature.

BACKGROUND AND OBJECTIVES: Controversy frequently exists about the actual frequency of Streptococcus bovis infective endocarditis (IE), its incidence of malignancy and its outcome. Consequently, the characteristics of S bovis IE were examined in an unselected population of nondrug-addicted patients. The literature was also reviewed. METHODS: Nondrug-addicted patients with S bovis IE were retrospectively reviewed. Clinically definite IE was diagnosed according to the Duke classification criteria at the single reference hospital for a defined population in northwestern Spain over a 13-year period. The clinical features, need for surgery and mortality rate of these patients were compared with those of other nondrug-addicted patients with IE examined during the same time period. RESULTS: Between 1987 and 1999, S bovis IE was diagnosed in 20 consecutive patients. This pathogen was responsible for 16.8% of the cases of definite IE in nondrug-addicted patients. Underlying conditions and embolic septic events were common. The aortic valve was the most common site of IE. Simultaneous involvement of two cardiac valves and moderate to severe regurgitation were more common in patients with S bovis IE. Colonic neoplasms were observed in 77% of patients. However, in-hospital mortality rate, need for in-hospital surgery and surgery during follow-up did not differ between patients with S bovis IE and the other nondrug-addicted patients with IE. CONCLUSIONS: In unselected patients, the rate of mortality due to S bovis IE is similar to that observed in IE due to other microorganisms. However, colonoscopic evaluation during admission and follow-up is required.

Aged↗

Evaluation of a monoclonal antibody to ras peptide, RAP-5, claimed to bind preferentially to cells of infiltrating carcinomas.

RAP-5, a monoclonal antibody raised against a p21ras peptide, has been claimed to show immunohistochemical localisation of cells with infiltrative properties in human tumours. We confirmed that this antibody reveals pronounced cellular heterogeneity in human colonic neoplasms but could find no obvious relationship to infiltrative activity. RAP-5 bound to many different cell types, neoplastic and normal. In order to clarify the specificities of RAP-5 we applied it to two cell lines: nontumorigenic hamster fibroblasts in which ras expression is barely detectable, and a vigorously tumorigenic line derived from these fibroblasts by insertion of the human mutated Ha-ras oncogene in a high expression vector. Another antibody to p21ras, Y13-259, clearly distinguished between these cell lines both on immunoblots and immunocytochemically, but RAP-5 did not. Rather, it bound to proteins of a variety of molecular weights in both cell lines. The results show that RAP-5 is unlikely to be a useful reagent for detection of ras associated proteins in human tissues.

Adenocarcinoma↗

Colon cancer-associated DNA mutations: marker selection for the detection of proximal colon cancer.

This study evaluates the potential ability of a specific panel of DNA mutations to identify right-sided colorectal carcinomas (CRCs) that would be missed by a flexible sigmoidoscopy (FS) screening program. This panel could then be applied to stool DNA analysis for noninvasive proximal CRC detection. A series of resected right-sided CRCs from 101 patients who had no left-sided advanced colonic neoplasms distal to the splenic flexure were analyzed. Tumor DNA was isolated from microdissected tumor sections. Deletions in the BAT-26 locus, a marker of microsatellite instability, and mutations at 19 loci spread among the p53, K-ras, and Apc genes were detected following PCR amplification. Mutations were identified in 83% of successfully amplified samples and were variably present in each of the target sites: p53 (42%), Apc (37%), K-ras (28%), and BAT-26 (24%). Mutations were identified across all Dukes stages (CIS/A 6/8 [75%], B 41/51[80%], C 30/32 (94%), and D 6/9 [67%]). Our data suggest that this 20-marker mutation panel may be associated with more than 80% of cancers undetectable by FS. The adjunctive use of stool DNA mutation analysis using this marker panel in FS CRC screening programs may significantly increase the detection of proximal CRC.

Adenocarcinoma↗

Long-term inhalation toxicity of hydrazine.

Year-long intermittent exposures of rats, mice, hamsters, and dogs to hydrazine were conducted using concentrations of 0.05, 0.25, 1.0, and 5.0 ppm. Rats were held 18 months postexposure; hamsters, 1 year postexposure; mice, 15 months postexposure; and dogs, 38 months postexposure. Male and female rats exhibited dose-dependent incidences of benign nasal adenomatous polyps and smaller numbers of malignant nasal epithelial tumors after 1 year of exposure to hydrazine and 18 months postexposure holding. Nasal tumors were often associated with chronic irritation and were most frequent in male rats, with an incidence of greater than 50% in the highest exposure group. Hamsters exposed to 0.25-ppm and higher concentrations showed pathologic changes characteristic of degenerative disease, including amyloidosis. After exposure to 0.5 ppm hydrazine, hamsters developed a 10% incidence of benign nasal polyps compared to 0.5% in controls. Small numbers of colon neoplasms and thyroid parafollicular cell adenomas were found in hamsters, but only in the highest concentrations tested. Lung adenomas appeared to be marginally increased in mice exposed to 1.0 ppm hydrazine, the highest concentration tested in this species. No consistent clinical or pathological effects were seen in dogs during or after exposure to hydrazine at any concentration. Using amyloidosis as a criterion, a no-effect level was not achieved in hamsters. In rats, there appeared to be a marginal production of nasal tumors at 0.05 ppm, while mice showed no effects at 0.25 ppm. This study has demonstrated that the nasal respiratory epithelia of rats and hamsters are the most sensitive tissues to the tumorigenic action of hydrazine following inhalation exposures. This is similar to the reaction of rats to formaldehyde, another highly reactive water-soluble compound.

Animals↗

Gamma-amino-butyric acid immunoreactivity in intramucosal colonic tumors.

BACKGROUND AND AIM: The level of gamma-amino-butyric acid (GABA) is reported to be increased in colon cancer. Moreover, data suggests that GABA plays a role in the proliferation or maturation of some types of cells. We examined the expression of GABA in intramucosal colonic tumors to clarify the relation between GABA and the degree of atypia. METHODS: Paraffin sections were prepared from 56 protruded-type colonic neoplasms, which were classified as intramucosal adenocarcinoma (AC), adenoma with severe atypia (ASA), or adenoma with mild to moderate atypia (AMA). Expression of GABA was investigated immunohistochemically, and GABA immunoreactivity was compared to the staining patterns of carcinoembryonic antigen (CEA) and cancer-associated antigen (CA19-9) which were classified into three categories. RESULTS: Intense GABA immunoreactivity was observed in 73.7%, 54.6%, 13.3%, and 5.4% of AC, ASA, AMA, and normal mucosa specimens, respectively. Kendall's correlation coefficient between GABA immunoreactivity and the degree of atypia was 0.447. Strong, positive CEA staining (pattern 3) was observed in 57.9%, 36.3%, and 13.3% of AC, ASA, and AMA specimens, respectively. Strong, positive CA19-9 staining was observed: 26.3%, 9.1% and 0%, respectively. In AC and ASA, the proportion of glands with strong GABA immunoreactivity was greater than the proportion of glands that were strongly positive for CA19-9. CONCLUSION: GABA may be useful as a tumor marker in combination with other tumor markers such as CEA and CA19-9.

Adenocarcinoma↗

Mitogen responsiveness and inhibitory activity of mesenteric lymph node cells. Conditioned medium containing T cell growth factor reverses suppressor function.

Blood-, lymph node-, and tumour-infiltrating lymphocytes (PBL, LNC, and TIL, respectively) from patients with colonic neoplasms were tested for responsiveness to phytohaemagglutinin (PHA). All populations responded, with LNC and PBL showing comparable reactivities while TIL were less reactive as assessed by incorporation of 3H-thymidine. Increased mitogen responsiveness was observed for T cells enriched by SRBC rosette formation or passage through nylon columns. Mitomycin C-treated LNC and TIL inhibited PHA induced 3H-thymidine incorporation of admixed autologous PBL, suggesting the presence of suppressor cells. Suppressor activity resided primarily in the SRBC rosetting population and was dose-dependent, with increasing numbers of LNC giving greater diminution of PHA response. Suppression by LNC was apparent only when they were added to PBL responders within 6 h of the initiation of stimulation assays, in common with the effects of Concanavalin A (Con A)-induced suppressors on PBL phytomitogen responsiveness. Con A-induced and LNC-suppressor activity could be reversed by addition of lymphocyte-conditioned medium (CM) containing T cell growth factor (TCGF; interleukin IL-2). These data provide further evidence that the suppressor phenomena observed in this system are a function of activated T cells present both in drainage lymph nodes and at the tumour site.

Cells, Cultured↗

Acute phase response in laparoscopic and open colectomy in colon cancer: randomized study.

PURPOSE: All types of trauma to the organism produce a systemic response that is proportional to the severity of the lesion caused. The more rapid clinical recovery during the postoperative period of patients undergoing laparoscopic-assisted colectomy vs. patients receiving conventional surgery suggests that laparoscopic surgery produces less surgical trauma. The aim of this randomized, prospective study was to compare acute phase postoperative response in patients diagnosed with colon neoplasm undergoing open segmentary colectomy vs. laparoscopic-assisted colectomy. METHODS: From June 1994 to July 1997 the results of 97 patients (58 submitted to open colectomy and 39 undergoing laparoscopic-assisted colectomy) were analyzed. Blood determinations of cortisol, prolactin, C-reactive protein and interleukin-6 were performed before surgery and at 4, 12, 24, and 72 hours after surgery. RESULTS: The plasma levels of cortisol and prolactin were higher in the postoperative period with both surgical techniques with no significant differences being observed. The levels of interleukin-6 achieved a maximum peak at 4 hours after surgery, later showing a decrease and practically achieving basal levels at 72 hours in both groups. The levels of interleukin-6 were higher with significant differences at 4, 12, and 24 hours in the patients undergoing open colectomy. The plasma levels of C-reactive protein were significantly lower at 72 hours in patients receiving laparoscopic-assisted colectomy. CONCLUSIONS: The results obtained in this randomized, prospective study suggest that acute phase systemic response is attenuated in patients undergoing laparoscopic-assisted colectomy in comparison with patients receiving open colectomy.

Acute-Phase Reaction↗