Age alone is not a barrier to efficacy of cytoreductive surgery and hyperthermic intraperitoneal chemotherapy for colorectal peritoneal metastases: analysis of 1138 patients from the UK and Ireland Colorectal Peritoneal Metastases Registry.

BACKGROUND: The management of colorectal peritoneal metastases continues to be a challenge but recent evidence suggests cytoreductive surgery (CRS) with hyperthermic intraperitoneal chemotherapy (HIPEC) can improve survival. Uncertainty about the relationship between age and tumour biology makes patient selection challenging particularly when reported procedure related morbidity is high and impact on survival outcomes unknown. The UK and Ireland Colorectal Peritoneal Metastases Registry was reviewed to assess the influence of age on efficacy of CRS and HIPEC. METHODS: A review of outcomes from the UK and Ireland Colorectal Peritoneal Metastases Registry was performed. Data from 2000 to 2021 were included from five centres in the UK and Ireland, and the cohort were sub-divided into three age groups; <45 years, 45-65 years and >65 years old. Primarily, we examined post-operative morbidity and survival outcomes across the three age groups. In addition, we examined the impact that the completeness of cytoreduction, nodal status, or adverse pathological features had on long-term survival. RESULTS: During the study period, 1138 CPM patients underwent CRS HIPEC. 202 patients(17.8%) were <45 years, 549 patients(48.2%) aged 45-65 years and 387 patients(34%) >65 years. Overall, median length of surgery (CRS and HIPEC), median PCI score and rate of HIPEC administration was similar in all three groups, as was overall rates of major morbidity and/or mortality. Complete cytoreduction rates (CC0) were similar across the three cohorts; 77%, 80.6% and 81%, respectively. Median overall survival for all patients was 38 months following complete cytoreduction. CONCLUSION: Age did not appear to influence morbidity or long-term survival following CRS and HIPEC. When complete cytoreduction is achieved survival outcomes are good. The addition of HIPEC can be performed safely and may reduce local recurrence within the peritoneum.

Malnutrition is associated with adverse postoperative outcome in patients undergoing elective colorectal cancer resections.

PURPOSE: Malnutrition results in a significant increase in postoperative morbidity and mortality after abdominal surgery. Apart from the anthropometric assessments, malnutrition can be also assessed using laboratory scores, with the most widely used being Onodera's Prognostic Nutritional Index (PNI). The purpose of our study was to assess if the presence of malnutrition as calculated by the Onodera's PNI was associated with higher postoperative morbidity after elective colorectal cancer resection. METHODS: We performed a retrospective analysis of our institutional database including the patients who underwent elective colorectal cancer resection over a 24-month period. PNI scores were calculated and correlated amongst other parameters, such as cancer stage, severity of postoperative complications, unplanned transfusion of blood products, need for unplanned level 2/3 care after surgery and overall length of hospitalization. RESULTS: A total of 213 patients were included in this analysis, with 22.5% being classified as malnourished based on the preoperative PNI. Of note, PNI values were inversely associated with advanced-stage disease, severity of postoperative complications and unplanned intensive care unit (ICU) admission postoperatively. Also, malnourished patients had a statistically significant prolonged length of in-hospital stay. No difference in PNI scores was identified between groups requiring unplanned blood products' transfusions. CONCLUSIONS: Preoperative malnutrition status as defined by PNI is associated with greater postoperative morbidity after elective surgery for colorectal cancer. Routine nutritional assessment and ad hoc nutritional support prior to surgery could contribute to an improvement of postoperative outcome after colorectal cancer resections.

The Role of Neoadjuvant and Adjuvant Systemic Chemotherapy with Cytoreductive Surgery and Heated Intraperitoneal Chemotherapy for Colorectal Peritoneal Metastases: A Systematic Review.

BACKGROUND: Cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) is an effective treatment for colorectal peritoneal metastases (CPM), increasing overall survival in selected patients. The aim of this systematic review was to assess the effect of neoadjuvant and adjuvant systemic chemotherapy on overall survival in patients with CPM undergoing CRS and HIPEC, compared with those who receive CRS and HIPEC alone. METHODS: A systematic literature review was performed using the PubMed database, and the preferred reporting items for systematic reviews and meta-analyses guidelines formed the structure of the review. Data regarding publication details, study design, patient pathology, treatments received, follow-up periods, overall survival and safety were collected and tabulated, and study quality was assessed using the MINORS score for non-randomized studies. RESULTS: Sixteen of 288 studies met the inclusion criteria. Seven publications related to the role of neoadjuvant chemotherapy, and there was no strong evidence for the efficacy of neoadjuvant chemotherapy. Of note, one study observed worse survival outcomes when neoadjuvant therapy was used. Fourteen studies investigated the role of adjuvant chemotherapy and there was limited evidence that adjuvant systemic chemotherapy improves survival following CRS and HIPEC. CONCLUSIONS: Systemic adjuvant chemotherapy may be associated with improved overall survival, but the role of systemic neoadjuvant chemotherapy cannot be determined by the currently available evidence. The delivery of a combination of the two modes of systemic chemotherapy has not been investigated in a randomized controlled trial to date. Further research designed to investigate the role of these modalities in the patient's treatment is required.

Urinary tract involvement in peritoneal metastatic disease: Is this a contraindication to cytoreductive surgery and hyperthermic intraperitoneal chemotherapy?

Urinary tract involvement in resectable peritoneal malignancies might require extensive resections and reconstructions in the genitourinary tract during the performance of cytoreductive surgery (CRS) with hyperthermic intraperitoneal chemotherapy (HIPEC), a fact which could impair the postoperative course and survival of these patients. We performed a review of the literature to assess whether urinary tract involvement in patients with peritoneal metastases undergoing CRS and HIPEC could affect the postoperative outcomes with respect to morbidity, mortality and survival rates, identifying a total of 6 retrospective studies addressing these clinical questions. Despite their heterogeneity, the existing studies demonstrate that despite a possible increase in postoperative complications when urological procedures are required as part of cytoreduction, survival outcomes do not seem to be affected. This review therefore concludes that urinary tract 6 in peritoneal metastatic disease is not a contraindication to CRS and HIPEC.

Hypercoagulation in colorectal cancer: what can platelet indices tell us?

Colorectal cancer, as all solid malignancies, is accompanied by changes in the haemostatic mechanism favoring the establishment of a thrombotic potential, with platelets playing a key-role in this framework; they further link colorectal cancer progression and hypercoagulation with the immune-response against the neoplastic spread. Under this rationale, various studies have assessed the use of platelet indices as prognostic markers of the biological behavior of colorectal cancer, demonstrating significant results. We herein attempt to summarize in a narrative and critical approach the relevant available data and the underlying pathophysiology, stressing the necessity of a more thorough understanding and future implementation of platelet indices in all stages of care we deliver to colorectal cancer patients.

Management of colorectal cancer patients at high risk of peritoneal metastases.

PURPOSE: Colorectal cancer (CRC) has potential to spread within the peritoneal cavity, and this transcoelomic dissemination is termed "peritoneal metastases" (PM). Cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) is a radical strategy to treat selected CRC patients with PM. Studies suggest that identification of CRC patients at high risk of PM may lead to earlier treatment strategies and improve survival in this subset of patients. The aim of this article was to summarise the current evidence regarding CRC patients at high risk of PM. METHODS: A retrospective review of articles on CRC patients with high risk of PM published up to December 2014 in PubMed, Medline, Embase, and Ovid search engines was conducted. The following combination of search terms were used: "intraperitoneal chemotherapy", "HIPEC", "colorectal cancer", "peritoneal carcinomatosis", "peritoneal metastases", "high risk", "peritoneal recurrence". RESULTS: Although opinions differ, CRC patients identified as "high risk" of PM included: limited, synchronous PM completely resected with the primary tumor, ovarian metastases (synchronous or metachronous) and spontaneous or iatrogenic perforation of the bowel by the primary tumor. Aggressive early treatment strategies currently used are: CRS and HIPEC for high-risk primary tumors and second-look CRS and HIPEC often following systematic chemotherapy for the primary resection. Positive results have been shown with both approaches in a number of studies. With CRS/HIPEC for the primary tumor, the overall survival in the two groups (25 patients treated with CRS/HIPEC vs 50 treated with conventional surgery) was significantly improved (p<0.03), as was disease-free survival (p<0.04). For second look surgery, in 29 patients treated with CRS and HIPEC, this resulted in 14% morbidity and 0% mortality and a 2-year disease-free survival rate in excess of 50%. CONCLUSIONS: We are progressively moving to an era of individualised treatment strategies. The management of CRC patients with high risk of PM is ever evolving, with early detection and early treatment strategies showing promising results. The optimal timing of early surgery remains unclear and requires further evaluation. Should current and future randomized trials demonstrate long-term survival benefit, we may potentially see a change in treatment paradigm from current conventional surgery to a more aggressive, early radical approach as the standard of care.

Systematic review of the clinical effectiveness of wound-edge protection devices in reducing surgical site infection in patients undergoing open abdominal surgery.

OBJECTIVE: Assess the existing evidence on the clinical effectiveness of wound-edge protection devices (WEPDs) in reducing the surgical site infection (SSI) rate in patients undergoing open abdominal surgery. BACKGROUND: Surgical site infections are a common postoperative complication associated with considerable morbidity, extended hospital stay, increased health care costs, and reduced quality of life. Wound-edge protection devices have been used in surgery to reduce SSI rates for more than 40 years; however, they are yet to be cited in major clinical guidelines addressing SSI management. METHODS: A review protocol was prespecified. A variety of sources were searched in November 2010 for studies containing primary data on the use of WEPDs in reducing SSI compared with standard care in patients undergoing open abdominal surgery. The outcome of interest was a well-specified, clinically based definition of an SSI. No language or time restrictions were applied. The quality assessment of the studies and the quantitative analyses were performed in line with the principles of the Cochrane Collaboration. RESULTS: Twelve studies reporting primary data from 1933 patients were included in the review. The quality assessment found all of them to be at considerable risk of bias. An exploratory meta-analysis was performed to provide a quantitative indication on the effect of WEPDs. The pooled risk ratio under a random effects model was 0.60 (95% confidence interval, 0.41-0.86), indicating a potentially significant benefit from the use of WEPDs. No indications of significant between-study heterogeneity or publication bias, respectively, were identified. CONCLUSIONS: Evidence to date suggests that WEPDs may be efficient in reducing SSI rates in patients undergoing open abdominal surgery. However, the poor quality of the existing studies and their small sample sizes raise the need for a large, good quality randomized controlled trial to validate this indication.

Operative findings, early complications, and long-term survival in 456 patients with pseudomyxoma peritonei syndrome of appendiceal origin.

BACKGROUND: Pseudomyxoma peritonei syndrome is a clinical entity characterized by mucinous ascites usually originating from a perforated mucinous appendiceal tumor. Currently optimal therapy is considered complete macroscopic tumor removal (complete cytoreduction) combined with heated intraperitoneal chemotherapy. When complete cytoreduction is not achievable, major tumor debulking is undertaken. The long-term follow-up of patients undergoing surgery for perforated appendiceal tumors in a national pseudomyxoma center is reported. METHODS: Between March 1994 and July 2009, 456 patients with pseudomyxoma peritonei syndrome from perforated appendiceal tumors underwent surgery. The treatment strategy involved a combination of cytoreductve surgery aiming for macroscopic tumor removal, combined with hyperthermic intraperitoneal chemotherapy with mitomycin C. Where complete tumor removal was not possible, maximal tumor debulking was performed. Perioperative outcomes and predicted 5- and 10-year survival are reported. RESULTS: Overall 15 of 456 (3%) tumors were not resectable at laparotomy. Of the 441 patients who had resection, 289 (66%) had complete cytoreduction and 152 (34%) had major tumor debulking. Postoperative in-hospital mortality was 1.6% and grade 3/4 morbidity was 7%. The Kaplan-Meier method predicted 5- and 10-year overall survival of 69% and 57%, respectively. Five- and 10-year predicted survival was 87% and 74% for the 289 patients who had complete cytoreduction compared with 34% and 23% for the 152 who had major tumor debulking. CONCLUSION: Complete tumor removal was achieved in 289 of 441 (66%) patients with peritoneal dissemination from perforated appendiceal tumors with good long-term survival and probable cure in more than two-thirds.

Low Preoperative Serum Albumin Levels Are Associated With Impaired Outcome After Cytoreductive Surgery and Perioperative Intraperitoneal Chemotherapy for Peritoneal Surface Malignancies.

Preoperative hypoalbuminemia is known to be associated with postoperative morbidity and mortality, as well as with poor survival after gastrointestinal cancer surgery. However, limited data exist regarding the prognostic significance of hypoalbuminemia in patients with peritoneal metastases undergoing cytoreductive surgery, combined with perioperative intraperitoneal chemotherapy. We performed a systematic literature review of the previously published studies addressing the potential association between preoperative albumin levels and overall surgical outcomes after the performance of cytoreductive surgery and perioperative intraperitoneal chemotherapy for peritoneal surface malignancies. Our research yielded a total of nine retrospective studies which met our inclusion criteria, and despite their heterogeneity; and we can conclude that preoperatively low albumin levels are associated with greater likelihood of overall and major morbidity, as well as less favorable oncological outcome after the performance of cytoreductive surgery and perioperative intraperitoneal chemotherapy.

The transition from primary colorectal cancer to isolated peritoneal malignancy is associated with an increased tumour mutational burden.

Colorectal Peritoneal metastases (CPM) develop in 15% of colorectal cancers. Cytoreductive surgery and heated intraperitoneal chemotherapy (CRS & HIPEC) is the current standard of care in selected patients with limited resectable CPM. Despite selection using known prognostic factors survival is varied and morbidity and mortality are relatively high. There is a need to improve patient selection and a paucity of research concerning the biology of isolated CPM. We aimed to determine the biology associated with transition from primary CRC to CPM and of patients with CPM not responding to treatment with CRS & HIPEC, to identify those suitable for treatment with CRS & HIPEC and to identify targets for existing repurposed or novel treatment strategies. A cohort of patients with CPM treated with CRS & HIPEC was recruited and divided according to prognosis. Molecular profiling of the transcriptome (n = 25), epigenome (n = 24) and genome (n = 21) of CPM and matched primary CRC was performed. CPM were characterised by frequent Wnt/ ß catenin negative regulator mutations, TET2 mutations, mismatch repair mutations and high tumour mutational burden. Here we show the molecular features associated with CPM development and associated with not responding to CRS & HIPEC. Potential applications include improving patient selection for treatment with CRS & HIPEC and in future research into novel and personalised treatments targeting the molecular features identified here.

Colorectal cancer: seed and soil hypothesis revisited.

The local growth and metastatic potential of colorectal cancer is the outcome of a dynamic balance between cancer cells and the immune system, at both a local and systemic level, summarized as the "seed and soil" hypothesis. Until recently, the staging and treatment approaches for colorectal cancer appeared to be orientated predominantly to the 'seed' component, virtually neglecting, in daily clinical practice, the impact of the 'soil' in the natural course of the disease. We are currently witnessing an increasing amount of evidence, spanning from clinical to laboratory research, which highlight that cancer growth and metastasis is the result of the dynamic balance between the disease itself and the impaired function of the immune system. Herein, we attempt to elucidate the vicious circle between impaired immune response and colorectal cancer progression, highlighting the urgent need for a qualitive turn in confronting cancer, which is based on two pillars with regulation of both the seed and the soil.

Impact of wound edge protection devices on surgical site infection after laparotomy: multicentre randomised controlled trial (ROSSINI Trial).

OBJECTIVE: To determine the clinical effectiveness of wound edge protection devices in reducing surgical site infection after abdominal surgery. DESIGN: Multicentre observer blinded randomised controlled trial. PARTICIPANTS: Patients undergoing laparotomy at 21 UK hospitals. INTERVENTIONS: Standard care or the use of a wound edge protection device during surgery. MAIN OUTCOME MEASURES: Surgical site infection within 30 days of surgery, assessed by blinded clinicians at seven and 30 days and by patient's self report for the intervening period. Secondary outcomes included quality of life, duration of stay in hospital, and the effect of characteristics of the patient and operation on the efficacy of the device. RESULTS: 760 patients were enrolled with 382 patients assigned to the device group and 378 to the control group. Six patients in the device group and five in the control group did not undergo laparotomy. Fourteen patients, seven in each group, were lost to follow-up. A total of 184 patients experienced surgical site infection within 30 days of surgery, 91/369 (24.7%) in the device group and 93/366 (25.4%) in the control group (odds ratio 0.97, 95% confidence interval 0.69 to 1.36; P=0.85). This lack of benefit was consistent across wound assessments performed by clinicians and those reported by patients and across all secondary outcomes. In the secondary analyses no subgroup could be identified in which there was evidence of clinical benefit associated with use of the device. CONCLUSIONS: Wound edge protection devices do not reduce the rate of surgical site infection in patients undergoing laparotomy, and therefore their routine use for this role cannot be recommended. TRIAL REGISTRATION: Current Controlled Trials ISRCTN 40402832.

Reduction of surgical site infection using a novel intervention (ROSSINI): study protocol for a randomised controlled trial.

BACKGROUND: Surgical site infection (SSI) is a common complication following abdominal surgery. It is associated with considerable morbidity and mortality, and its management results in significant cost to health services within both primary and secondary care. Some surgeons believe that the use of a wound-edge protection device may reduce the incidence of SSI. Whilst there is some encouraging evidence showing that such devices may lead to a reduction in SSI, there are no controlled trials of sufficient size or quality to support their routine use. METHODS/DESIGN: 750 patients will be recruited from around 20 surgical units within the United Kingdom. Patients undergoing laparotomy through any major abdominal incision for any indication, elective or emergency, are eligible. Patients under the age of 18, those undergoing a laparoscopic assisted procedure or who have undergone laparotomy within the previous 3 months, and those who are unable to give informed consent will be excluded. Patients will be randomised (1:1 ratio) to the use of a wound-edge protection device or no wound-edge protection device during surgery. Follow up will consist of blinded clinical wound reviews at 5-7 days and 30-33 days postoperatively with a self-completed questionnaire covering the intervening period. Quality of life questionnaires will be completed prior to surgery and at the subsequent wound review points and information on resource usage will also be captured.The primary outcome measure is SSI within 30 days of surgery. Secondary outcomes include the impact of the degree of wound contamination, patient comorbidity, and operative characteristics on the efficacy of a wound-edge protection device in reducing SSI and whether the use of a wound-edge protection device has an effect on health-related quality of life or length of hospital stay and is cost-effective. DISCUSSION: Rossini is the first multicentre observer-blinded randomised controlled trial of sufficient size and quality to establish whether the use of a wound-edge protection device in adult patients undergoing abdominal surgery leads to a lower rate of SSI. The results of this study will be used to inform current surgical practice and may potentially benefit patients undergoing surgery in the future. TRIAL REGISTRATION NUMBER: Current Controlled Trials ISRCTN: ISRCTN40402832.

Small bowel volvulus in a patient with chronic idiopathic intestinal pseudo-obstruction.

Chronic idiopathic intestinal pseudo-obstruction (CIIP) is a rare syndrome of ineffectual gut motility associated with clinical, endoscopic and radiological exclusion of mechanical causes, as well as evidence of air-fluid levels in distended bowel loops. A case of small bowel volvulus in a patient with an established diagnosis of CIIP is presented. The case is illustrated by images of operative findings and computed tomography scan reconstruction, showing the classical appearances of small bowel volvulus. The patient recovered well after surgery and is maintained on parenteral nutrition. CIIP is a heterogeneous disorder in which the primary aims of management are nutrition, pain control and the avoidance of unnecessary repeated laparotomies. However, even in the presence of an established diagnosis of CIIP, surgeons should be vigilant to the possibility that an operable mechanical obstruction may still occur.