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Long-term Survival and Propensity Score Matched Outcomes of Bilateral vs. Unilateral Diaphragm Interventions in Cytoreductive Surgery plus Intra-peritoneal Chemotherapy
Anticancer Research
Abstract
Background/aim:
To assess the impact of short- and long-term outcomes of bilateral vs. unilateral diaphragm interventions in cyto-reductive surgery (CRS) and intra-peritoneal chemotherapy (IPC).
Patients and methods:
A total of 652 CRS/IPC procedures, between 1996 and 2018, required diaphragm interventions. Among these, 388 underwent bilateral intervention. Preoperative heterogeneity was assessed in 6 parameters and addressed with propensity score matching. The association of each respective analysis was assessed with 11 outcomes. Overall survival was assessed based on histology.
Results:
CRS/IPC requiring bilateral diaphragmatic interventions illustrated significantly increased operative hours (9.6 vs. 8.6 hours, p<0.001). Postoperatively, there was significantly increased red blood cell (RBC) transfusion (6.37 units vs. 4.47 units, p=0.007) and grade III and IV complications (57.3% vs. 40.6%, p=0.004). No difference was noted in ICU stay, total length of stay, hospital death and return to OT. In terms of respiratory complications, an increased incidence of pneumothorax (16.5% vs. 6.2%, p<0.001) was noted whilst pleural effusions and pneumonia occurrences were non-significant. Overall survival, revealed bilateral interventions in low-grade appendiceal mucinous neoplasm conferred an increased relative risk (p=0.037, RR=2.230, 95%CI=1.052-4.730). They did not have an effect on OS in colorectal cancer and mesothelioma.
Conclusion:
Despite the increase in short-term morbidity, bilateral diaphragm interventions resulted in similar long-term survival to unilateral interventions.
... respectively [3,5e8,14e18]. A recent series showed a significative increased incidence of pneumothorax following bilateral diaphragmatic procedures, whereas the difference in pneumonia was not significant [27]. Higher rates of pneumothorax are usually reported without elective chest drain placement. ...
Introduction
Complete cytoreductive surgery with hyperthermic intraperitoneal chemotherapy is an effective treatment for improving prognosis of selected patients with peritoneal carcinomatosis. The addiction of diaphragmatic procedures may increase the incidence of postoperative respiratory complications. Our goal was to evaluate the early postoperative results following diaphragmatic surgery.
Methods
Prospectively collected data of patients undergoing diaphragmatic surgery between January 2000 and January 2020 were retrospectively analyzed. Chest drains were routinely placed in all cases. Demographics, clinical and perioperative features were evaluated.
Results
The study included 222 patients. Peritoneal stripping and full-thickness resections were performed in 165 and 57 cases, respectively. Women and ovarian tumours represented the vast majority of cases. Overall postoperative mortality and morbidity rates were 1.3% (3 patients) and 43.2% (96 patients), respectively. Specific diaphragmatic surgery-related complications was 9.4% (21 patients). No pleural effusion and pneumothotrax occurred. The incidence of pneumonia was 1.8% (4 patients), each due to systemic bacterial origin, 2 (0.9%) of which required Intensive Care Unit-readmission. Postoperative bleeding was observed in 15 (6.7%) cases, 12 (5.4%) of which required reoperation. A comparison with 105 patients who operated during the same period without diaphragmatic surgery was performed and by multivariate analysis, Peritoneal Cancer Index, histology and overall morbidity resulted significantly associated with diaphragmatic surgery.
Conclusion
Diaphragmatic surgery during cytoreductive surgery with hyperthermic intraperitoneal chemotherapy is often required in order to obtain complete resection. It may be associated with higher postoperative morbidity, especially bleeding, but routine placement of chest drains may reduce the incidence of adverse respiratory events.
... [8][9][10]18 Techniques such as diaphragmatic procedures, including peritonectomy or full-thickness resection, have been reported to be required in 29.6-50% of CRS/HIPEC surgeries. 19,20 We performed these procedures in 42.2% of our CRS/HIPEC cases. ...
Background
Cytoreductive surgery (CRS) provides a survival benefit when achieved without residual disease. As diaphragm is frequently affected in peritoneal malignancies, complete cytoreduction often requires surgical techniques over the diaphragm. The purpose of the study was to assess diaphragmatic resection impact on cytoreduction completeness, morbidity and mortality compared to less aggressive diaphragmatic peritonectomy in CRS and hyperthermic intraperitoneal chemotherapy (HIPEC) settings.Materials and Methods
Patients with peritoneal carcinomatosis and supramesocolic disease undergoing CRS/HIPEC from 2011 to 2019 were included in a prospectively collected database. We compared patients who underwent full-thickness diaphragmatic resection (DR) and diaphragmatic peritonectomy (DP). Epidemiological and clinical data, morbidity, and mortality within 90 days of surgery were documented.Results232 patients were initially selected. Inclusion criteria were met by 88 procedures. DR was performed on 32 patients and DP on 56. Number of resected organs was 5.21 in the DR cohort vs. 3.57 in the DP cohort (p<0.0001). Rate of Peritoneal Cancer Index (PCI) score >14 was higher in the DR group (75%) than in the DP group (50.9%) (p=0.027). Tumor invasion of diaphragmatic muscle after DR was confirmed in 89.3% patients. Postoperative pleural effusion was observed in 28 patients (50%) in the DP group and in 17 (53.1%) in the DR group.ConclusionsCRS/HIPEC requires specific surgical techniques over the diaphragm to achieve complete cytoreduction. As diaphragmatic muscle invasion is frequent, full-thickness resection may allow a cytoreduction completeness increase without an increased morbidity. Pleural drains are not systematically required as these procedures show low incidence of major respiratory complications.
BACKGROUND. Diaphragmatic resection (DR) is often required during cytoreductive surgery/hyperthermic intraperitoneal chemotherapy (CRS/HIPEC) to achieve complete cytoreduction (CC). While CC provides the best survival, requiring a DR may indicate unfavorable tumor biology. We assessed how DR during CRS/HIPEC affects outcomes.
METHODS. A retrospective cohort study was conducted using a prospective single-center database from October 1994–May 2020. Peritoneal surface malignancy patients who underwent CRS/HIPEC with CC-0/1/2 were assigned to DR and NoDR groups. Survival was measured using the Kaplan–Meier method. Subgroup analysis was performed for patients with peritoneal cancer index (PCI) ≥ 20 to eliminate confounding of more extensive disease in DR.
RESULTS. Of 824 CRS/HIPECs, 774 were included: 134 DR and 640 NoDR. PCI was significantly higher in DR: 29 versus 21, p < 0.001. CC-0/1 rate was 89% in DR and 95% in NoDR (p = 0.003). Neither 100-day morbidity nor mortality differed between the groups (p = 0.355 and p = 1.000). Median follow-up was 64 months. Median overall survival (OS) was significantly lower in DR (32 vs. 96 months, p < 0.001). Subgroup analysis by tumor type in patients with PCI ≥ 20 showed significantly shorter OS in DR than NoDR in appendiceal (40 vs. 196 months, p < 0.001) and colorectal (14 vs. 23 months, p = 0.003), but not in ovarian tumors (32 vs. 42 months, p = 0.893), whereas median PCI did not differ among subgroups.
CONCLUSIONS. DR during CRS/HIPEC does not increase morbidity and mortality. It is associated with worse survival in appendiceal and colorectal tumors, even after adjusting for tumor burden but does not appear to impact ovarian cancer survival.
Aim:
This study aimed to analyze diaphragmatic interventions and their complications in primary cytoreductive surgery (PCS) and to study their impact on attaining complete tumor resection (CTR) in advanced ovarian cancer (AOC), which is purportedly reflected in better disease-free and overall survival.
Patients and methods:
The study's collective consisted of 536 consecutive patients presenting a first diagnosis of AOC who underwent PCS between 2007 and 2013 at the Charité Medical University, Berlin. A total of 268 patients underwent diaphragmatic interventions, while 268 did not undergo any kind of diaphragmatic surgery.
Results:
Diaphragmatic interventions were indicated in 50% of cases with AOC. The surgical interventions varied between diaphragmatic partial resection (44.8%), stripping (53%) and only infrared coagulation (2.2%). The postoperative complication rate was higher in the diaphragm-intervention group in comparison to the group without any diaphragmatic intervention (49.6% vs. 38.8%), but most postoperative complications were not directly related to the diaphragmatic intervention itself but to the statically significant increase of other radical surgical procedures in this group. Pleura effusion was the only increased complication with a direct correlation with diaphragmatic surgery (25.4% vs. 14.2%). Preoperatively apparent stage IV (pleura effusion) disease, very high cancer antigen-125 value, serous papillary tumors and the presence of massive ascites (>500 ml) were statistically significant predictors of the need for diaphragmatic surgery in order to achieve CTR.
Conclusion:
Our current findings consider diaphragmatic surgery as being acceptable, feasible and in many cases as an essential intervention to achieve CTR or suboptimal debulking with an acceptable complication rate.
Pseudomyxoma peritonei (PMP) originating from an appendiceal mucinous neoplasm remains a biologically heterogeneous disease. The purpose of our study was to evaluate outcome and long-term survival after cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) consolidated through an international registry study.
A retrospective multi-institutional registry was established through collaborative efforts of participating units affiliated with the Peritoneal Surface Oncology Group International.
Two thousand two hundred ninety-eight patients from 16 specialized units underwent CRS for PMP. Treatment-related mortality was 2% and major operative complications occurred in 24% of patients. The median survival rate was 196 months (16.3 years) and the median progression-free survival rate was 98 months (8.2 years), with 10- and 15-year survival rates of 63% and 59%, respectively. Multivariate analysis identified prior chemotherapy treatment (P < .001), peritoneal mucinous carcinomatosis (PMCA) histopathologic subtype (P < .001), major postoperative complications (P = .008), high peritoneal cancer index (P = .013), debulking surgery (completeness of cytoreduction [CCR], 2 or 3; P < .001), and not using HIPEC (P = .030) as independent predictors for a poorer progression-free survival. Older age (P = .006), major postoperative complications (P < .001), debulking surgery (CCR 2 or 3; P < .001), prior chemotherapy treatment (P = .001), and PMCA histopathologic subtype (P < .001) were independent predictors of a poorer overall survival.
The combined modality strategy for PMP may be performed safely with acceptable morbidity and mortality in a specialized unit setting with 63% of patients surviving beyond 10 years. Minimizing nondefinitive operative and systemic chemotherapy treatments before definitive cytoreduction may facilitate the feasibility and improve the outcome of this therapy to achieve long-term survival. Optimal cytoreduction achieves the best outcomes.
Cytoreductive surgery (CRS) combined with perioperative intraperitoneal chemotherapy (PIC) has demonstrated improved survival in selected patients with pseudomyxoma peritonei (PMP). However, this aggressive treatment modality has been consistently associated with variable rates of perioperative mortality between 0% and 18% and morbidity between 30% and 70%. This study evaluates the clinical and treatment-related risk factors for perioperative morbidity and mortality in PMP patients who underwent CRS and PIC.
A total of 145 consecutive CRS and PIC procedures for PMP performed between January 1996 and March 2009 were evaluated. The association of 12 clinical and 20 treatment-related risk factors with grades III and IV/V morbidity were assessed by univariable and multivariable analysis.
The mortality (grade V) rate was 3%. The morbidity rates of grades III and IV were 23% and 22%, respectively. Eight factors were associated with grade IV/V morbidity on univariable analysis: peritoneal cancer index >or=21 (P = .034), ASA score >or=3 (P = .003), operation duration >or=10 h (P < .001), left upper quadrant peritonectomy procedure (P = .037), colonic resection (P = .012), ostomy (P = .005), ileostomy (P = .012), and transfusion >or=6 units (p = 0.011). Multivariable analysis showed 2 significant risk factors for grade IV/V morbidity: ASA >or= 3 (P = .006) and an operation length >or=10 h (P < .001).
CRS and PIC has an acceptable rate of perioperative mortality and morbidity in selected patients with PMP. Patients with bulky disease who undergo a long operation are at a particularly high risk of a severe adverse event.
This multi-institutional registry study evaluated cytoreductive surgery (CRS) combined with hyperthermic intraperitoneal chemotherapy (HIPEC) for diffuse malignant peritoneal mesothelioma (DMPM).
A multi-institutional data registry that included 405 patients with DMPM treated by a uniform approach that used CRS and HIPEC was established. The primary end point was overall survival. The secondary end point was evaluation of prognostic variables for overall survival.
Follow-up was complete in 401 patients (99%). The median follow-up period for the patients who were alive was 33 months (range, 1 to 235 months). The mean age was 50 years (standard deviation [SD], 14 years). Three hundred eighteen patients (79%) had epithelial tumors. Twenty-five patients (6%) had positive lymph nodes. The mean peritoneal cancer index was 20. One hundred eighty-seven patients (46%) had complete or near-complete cytoreduction. Three hundred seventy-two patients (92%) received HIPEC. One hundred twenty-seven patients (31%) had grades 3 to 4 complications. Nine patients (2%) died perioperatively. The mean length of hospital stay was 22 days (SD, 15 days). The overall median survival was 53 months (1 to 235 months), and 3- and 5-year survival rates were 60% and 47%, respectively. Four prognostic factors were independently associated with improved survival in the multivariate analysis: epithelial subtype (P < .001), absence of lymph node metastasis (P < .001), completeness of cytoreduction scores of CC-0 or CC-1 (P < .001), and HIPEC (P = .002).
The data suggest that CRS combined with HIPEC achieved prolonged survival in selected patients with DMPM.
Objectives:
To establish the positive predictive values of pre-operative identification with CT imaging of metastatic diaphragm disease in surgically managed cases of advanced ovarian cancer (AOC). Additionally, we have assessed the post-operative morbidity and survival following diaphragmatic surgical intervention in a large regional cancer centre in the United Kingdom.
Study design:
A retrospective review of all cases of AOC with metastatic diaphragm disease surgically treated at the Pan-Birmingham Gynaecological Cancer Centre, UK between 1st August 2007 and 29th February 2016.
Results:
A total of 536 women underwent surgery for primary AOC. Diaphragm disease was evident intra-operatively in 215/536 (40.1%) and 85/536 women (15.9%) underwent a procedure involving their diaphragm. Of these 85 cases, 38 peritoneal strippings (38/85, 44.7%), 31 partial diaphragmatic resections (31/85, 35.6%) and 16 electro-surgical ablations (16/85, 18.9%) were performed. There were no significant differences in post-operative complications between the three different diaphragmatic surgical groups. Of those patients who underwent peritoneal stripping or partial diaphragm resection, 12% were upstaged to stage 4A by virtue of pleural invasion. The positive predictive value for pre-operative radiological identification of diaphragmatic disease was 78.6%. CT imaging failed to detect diaphragmatic involvement despite obvious diaphragm disease during surgery in 29.4% of cases, giving a low negative predictive value of 64.8%. The sensitivity and specificity for CT imaging in detecting diaphragm disease was 44.3% and 93.8%, respectively.
Conclusions:
Diaphragmatic disease is often discovered in AOC. However, pre-operative assessment with CT imaging is not reliable in accurately detecting diaphragm involvement. Therefore, all patients with AOC should be regarded as in potential need for diaphragm surgery and their operation undertaken in cancer centres with adequate expertise in upper abdominal surgery. If there is a suspicion of diaphragm muscle invasion during diaphragmatic peritonectomy, the muscle should be partially resected. This will lead to potential upstaging of disease to stage 4A and therefore, to suitability for targeted therapy. In our Centre, the surgical removal of diaphragmatic disease did not significantly increase surgical morbidity.
Purpose
The purpose of this study is to assess the short-term morbidity and mortality in patients undergoing cytoreductive surgery with hyperthermic intraperitoneal chemotherapy (CRS/HIPEC) with diaphragmatic involvement.
Methods
All patients undergoing CRS/HIPEC at a tertiary care institution from April 2007 to October 2013 were retrospectively reviewed. Patients with diaphragmatic disease (Group 1) were compared to those who did not (Group 2). Univariate, propensity score analysis, and multivariate analysis were used to compare groups focusing on postoperative complications.
Results
A total of 199 patients underwent CRS/HIPEC. Diagnoses included appendiceal/colorectal cancers (56 %), pseudomyxoma peritoneii (12 %), and gastric cancer (7 %). Group 1 was composed of 89 patients (44.7 %) with diaphragmatic involvement, of which 37.1 % underwent diaphragm stripping and 62.9 % required a full-thickness diaphragmatic resection. Group 1 had longer operative times (p = 0.009), increased transfusion requirements (p = 0.007), less optimal cytoreduction (p = 0.010), longer ICU stay (p = 0.003), and overall hospital stay (p = 0.039). Major complications were significantly higher in Group 1: 26 (29 %) versus 16 (15 %), p = 0.020. Rate of respiratory complications was not different between groups (G1: 14/26, 53.8 % and G2: 6/16, 37.5 %, p = NS). Ninety-day mortality was not significantly different. Diaphragmatic involvement (Estimate 1.235, SE 0.387, p = 0.017) was an independent predictor of 30-day morbidity in patients with
Standard approach for medically stable advanced ovarian cancer patients should be primary cytoreduction following platinum-based chemotherapy. The aim of surgical effort should be the complete removal of all visible disease. Our objective was to compare perioperative features, postoperative complications, and secondarily oncological outcomes of patients who underwent diaphragmatic stripping with those who underwent diaphragmatic resection for advanced ovarian cancer.
One hundred twelve cases were identified, among them 79 underwent diaphragmatic stripping and 33 underwent diaphragmatic full-thickness resection. Data collected included patients' age, all perioperative details and pathological findings, International Federation of Gynecology and Obstetrics stage, adjuvant therapy, and follow-up data.
Larger residual tumors (mean, 5.1 vs 1.6 mm, respectively; P < 0.01) but shorter operating time (25 minutes shorter operative time, P = 0.07) were observed in the stripping group. Higher postoperative pleural effusions rates (63.6% vs 37.9%, P = 0.01), but no differences in the remaining complications, were observed in the resection group. After a mean of 31 months of follow-up, disease-free survival rates were 27.8% in the stripping group and 39.4% in the resection group (P = 0.04). No significant differences were observed for overall survival.
Diaphragmatic surgery at the time of primary cytoreductive surgery for advanced ovarian cancer may contribute to the achievement of complete cytoreduction with low perioperative complication rate; full-thickness resection is preferable if peritoneum stripping will not achieve a complete removal of the disease.
Cytoreductive surgery (CRS) combined with perioperative intraperitoneal chemotherapy (PIC) is a treatment option for peritoneal surface malignancy. Despite the survival benefits, this treatment was previously associated with a high morbidity and mortality rates and the perception of the poor perioperative outcomes associated with this regimen remains. The aim of this study was to report the perioperative outcomes of CRS and PIC from a single institution to review factors that are associated with a poor perioperative outcome.
The clinical- and treatment-related data of 243 consecutive procedures performed were prospectively collected and retrospectively reviewed. Adverse events were rated according to the National Cancer Institute's Common Toxicity Criteria (grade I-V). Univariate and multivariate analyses were performed to identify significant clinical and treatment-related factors for a poor perioperative outcome (grades III/IV/V morbidity).
The perioperative mortality rate was 3%. The rate of severe morbidity was 43%. Multivariate analysis demonstrated that left upper quadrant peritonectomy (P < 0.001) and small bowel resection (P < 0.01) were factors that predicted for a poor perioperative outcome.
The morbidity and mortality rates of CRS and PIC are within an acceptable range for a major gastrointestinal surgery which is performed with a curative intent. Patient selection is important in ensuring that suitable patients receive this treatment. A new perspective of this treatment needs to be sought.
Gastrointestinal and ovarian malignancies frequently recur with metastatic disease limited to the abdominal cavity. Due to full thickness penetration of tumor through bowel wall, spillage of tumor from lymphatic channels by surgical trauma or perforation of the tumor through the ovarian capsule, tumor cells are disseminated throughout the peritoneal surfaces either prior to or at the time of surgical removal of the primary tumor. In the past, diagnosis of recurrent cancer was difficult because no sensitive diagnostic test was available by which to image a small tumor volume present on peritoneal surfaces. Computerized tomography with intraperitoneal infusion of contrast can demonstrate tumor nodules not otherwise detectable. Intraperitoneal installation of I-131 labeled monoclonal antibody has allowed visualization of mucinous tumor on peritoneal surfaces not seen by any other radiologic test. Intraperitoneal chemotherapy has been shown to provide palliation in patients with small volume disease confined to peritoneal surfaces. Because of limited penetration of chemotherapy into large tumor nodules this treatment strategy has not been effective for bulky intraabdominal recurrent cancer. Cytoreductive surgery utilizing high voltage electrocautery and CO2 laser evaporation of tumor can make patients relatively disease free. These surgical technologies combined with postoperative intraperitoneal chemotherapy have been shown to be of benefit for selected patients with recurrent intraabdominal cancer. The wider application of these intraperitoneal chemotherapy treatments for patients in an adjuvant setting may be of value in preventing the occurrence of peritoneal carcinosis and in improving survival.
To confirm the findings from uncontrolled studies that aggressive cytoreduction in combination with hyperthermic intraperitoneal chemotherapy (HIPEC) is superior to standard treatment in patients with peritoneal carcinomatosis of colorectal cancer origin.
Between February 1998 and August 2001, 105 patients were randomly assigned to receive either standard treatment consisting of systemic chemotherapy (fluorouracil-leucovorin) with or without palliative surgery, or experimental therapy consisting of aggressive cytoreduction with HIPEC, followed by the same systemic chemotherapy regime. The primary end point was survival.
After a median follow-up period of 21.6 months, the median survival was 12.6 months in the standard therapy arm and 22.3 months in the experimental therapy arm (log-rank test, P =.032). The treatment-related mortality in the aggressive therapy group was 8%. Most complications from HIPEC were related to bowel leakage. Subgroup analysis of the HIPEC group showed that patients with 0 to 5 of the 7 regions of the abdominal cavity involved by tumor at the time of the cytoreduction had a significantly better survival than patients with 6 or 7 affected regions (log-rank test, P <.0001). If the cytoreduction was macroscopically complete (R-1), the median survival was also significantly better than in patients with limited (R-2a), or extensive residual disease (R-2b; log-rank test, P <.0001).
Cytoreduction followed by HIPEC improves survival in patients with peritoneal carcinomatosis of colorectal origin. However, patients with involvement of six or more regions of the abdominal cavity, or grossly incomplete cytoreduction, had still a grave prognosis.
Although quality assessment is gaining increasing attention, there is still no consensus on how to define and grade postoperative complications. This shortcoming hampers comparison of outcome data among different centers and therapies and over time.
A classification of complications published by one of the authors in 1992 was critically re-evaluated and modified to increase its accuracy and its acceptability in the surgical community. Modifications mainly focused on the manner of reporting life-threatening and permanently disabling complications. The new grading system still mostly relies on the therapy used to treat the complication. The classification was tested in a cohort of 6336 patients who underwent elective general surgery at our institution. The reproducibility and personal judgment of the classification were evaluated through an international survey with 2 questionnaires sent to 10 surgical centers worldwide.
The new ranking system significantly correlated with complexity of surgery (P < 0.0001) as well as with the length of the hospital stay (P < 0.0001). A total of 144 surgeons from 10 different centers around the world and at different levels of training returned the survey. Ninety percent of the case presentations were correctly graded. The classification was considered to be simple (92% of the respondents), reproducible (91%), logical (92%), useful (90%), and comprehensive (89%). The answers of both questionnaires were not dependent on the origin of the reply and the level of training of the surgeons.
The new complication classification appears reliable and may represent a compelling tool for quality assessment in surgery in all parts of the world.
There is controversy about the effect of the influence of hyperthermia and chemotherapeutic agents on the healing of intestinal anastomosis. The effects of hyperthermic intraperitoneal chemoperfusion (HIPEC) of wound healing after colonic anastomosis were investigated in a rat model.
Thirty-six Wag/Rija rats were randomized into three groups of 12 animals each: group I: control (only colonic anastomosis was performed) (n = 12); group II: HIPEC (mitomycin C in a concentration of 20 mg/m(2) (n = 12) colonic anastomosis was performed before HIPEC; group III: HIPEC (mitomycin C in a concentration of 20 mg/m(2) (n = 12) colonic anastomosis was performed after HIPEC. Bursting pressure and bursting sites were recorded 4 and 10 days after intervention. Collagen deposits, inflammation and foreign body reactions were evaluated.
Lower bursting pressure and lost of collagen were found in both HIPEC groups and compared with the control group. There was almost no difference between both HIPEC groups. They were noted overwhelmingly at the anastomosis in the HIPEC group. The degree of collagen accumulation was well-correlated with bursting pressure.
These results have shown that hyperthermic intraperitoneal chemoperfusion (HIPEC) impairs wound healing in colonic anastomosis in rats.
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