Efficacy of hyperthermic intraperitoneal chemotherapy in colorectal cancer: A phase I and III open label randomized controlled registry-based clinical trial protocol.

Standard treatment for patient with peritoneal metastases from colorectal cancer is cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC). In recent years, the efficacy of oxaliplatin-based HIPEC has been challenged. An intensified HIPEC (oxaliplatin+irinotecan) in combination with early postoperative intraperitoneal chemotherapy (EPIC) has shown increased recurrence-free survival in retrospective studies. The aim of this trial is to develop a new HIPEC/EPIC regimen and evaluate its effect on morbidity, oncological outcome, and quality-of-life (QoL). This study is designed as a combined phase I/III multicenter randomized trial (RCT) of patients with peritoneal metastases from colorectal cancer eligible for CRS-HIPEC. An initial phase I dose escalation study, designed as a 3+3 stepwise escalation, will determine the maximum tolerable dose of 5-Fluorouracil (5-FU) as 1-day EPIC, enrolling a total of 15-30 patients in 5 dose levels. In the phase III efficacy study, patients are randomly assigned intraoperatively to either the standard treatment with oxaliplatin HIPEC (control arm) or oxaliplatin/irinotecan-HIPEC in combination with single dose of 1-day 5-FU EPIC (experimental arm). 5-FU is administered intraoperatively after CRS-HIPEC and closure of the abdomen. The primary endpoint is 12-month recurrence-free survival. Secondary endpoints include 5-year overall survival, 5-year recurrence-free survival (registry based), postoperative complications, and QoL up to 3 years after study treatment. This phase I/III trial aims to identify a more effective treatment of colorectal peritoneal metastases by combination of HIPEC and EPIC.

Identifying a common data dictionary across colorectal cancer outcome registries: A mapping exercise to identify opportunities for data dictionary harmonisation.

IMPORTANCE: The development of colorectal cancer outcome registries internationally has been organic, with differing datasets, data definitions and infrastructure across registries which has limited data pooling and international comparison. Currently there is no comprehensive data dictionary identified as a standard. This study is part of an international collaboration that aims to identify areas of data capture and usage which may be optimised to improve understanding of colorectal cancer outcomes. OBJECTIVE: This study aimed to compare and identify commonalities and areas of difference across major colorectal cancer registries. We sought to establish datasets comprising of mutually collected common fields, and a combined comprehensive dataset of all collected fields across major registries to aid in establishing a future colorectal cancer registry database standard. DESIGN AND METHODS: This mixed qualitative and quantitative study compared data dictionaries from three major colorectal cancer outcome registries: Bowel Cancer Outcomes Registry (BCOR) (Australia and New Zealand), National Bowel Cancer Audit (NBOCA) (United Kingdom) and Dutch ColoRectal Audit (DCRA) (Netherlands). Registries were compared and analysed thematically, and a common dataset and combined comprehensive dataset were developed. These generated datasets were compared to data dictionaries from Sweden (SCRCR), Denmark (DCCG), Argentina (BNCCR-A) and the USA (NAACCR and ACS NSQIP). Fields were assessed against prominent quality indicator metrics from the literature and current case-use. RESULTS: We developed a combined comprehensive dataset of 225 fields under seven domains: demographic, pre-operative, operative, post-operative, pathology, neoadjuvant therapy, adjuvant therapy, and follow up/recurrence. A common dataset was developed comprising 38 overlapping fields, showing a low degree of mutually collected data, especially in preoperative, post operative and adjuvant therapy domains. The BNCCR-A, SCRCR and DCCG databases all contained a high percentage of common dataset fields. Fields were poorly comparable when viewed form current quality indicator metrics. CONCLUSION: This study mapped data dictionaries of prominent colorectal cancer registries and highlighted areas of commonality and difference The developed common field dataset provides a foundation for registries to benchmark themselves and work towards harmonisation of data dictionaries. This has the potential to enable meaningful large-scale international outcomes research.

Transanal formation of anastomosis using C-REX device is feasible and effective in high anterior resection.

PURPOSE: C-REX is a novel instrument for creating stapleless colorectal anastomosis by compression. The aim of this study was to evaluate the feasibility and effectiveness of C-REX in open and laparoscopic high anterior resections. METHODS: A prospective clinical safety study on 21 patients reconstructed with C-REX colorectal anastomosis following high anterior resection of the sigmoid colon using two different devices for intraabdominal (n = 6) or transanal (n = 15) placement of the anastomotic rings. Any signs of complications were prospectively monitored by a predefined protocol. Anastomotic contact pressure (ACP) was measured via a catheter-based system, and time for evacuation of the anastomotic rings by the natural route was noted. Blood samples were collected daily, and flexible endoscopy was performed postoperatively to examine macroscopic appearance of the anastomoses. RESULTS: One of six patients operated with the intraabdominal anastomosis technique with an ACP of 50 mBar had to be reoperated because of anastomotic leakage. None of the 15 patients operated with the transanal technique (5 open and 10 laparoscopic procedures) had anastomotic complications, and their ACP ranged between 145 and 300 mBar. C-REX rings were uneventfully expelled by the natural route in all patients after a median of 10 days. Flexible endoscopy showed well-healed anastomoses without stenosis in 17 patients and a moderate subclinical stricture in one patient. CONCLUSION: These results indicate that the novel transanal C-REX device is a feasible and effective method for colorectal anastomosis following high anterior resections, irrespective of open or laparoscopic approach. Moreover, C-REX allows measurement of intraoperative ACP and thereby a quantitative evaluation of the anastomotic integrity.

Risk Factors for Postoperative Complications Following Resection of Colorectal Liver Metastases and the Impact on Long-Term Survival: A Population-Based National Cohort Study.

BACKGROUND: Postoperative complications (POCs) following resection of colorectal liver metastases (CRLM) are common. The objective of this study was to evaluate risk factors for developing complications and their impact on survival considering prognostic factors of the primary tumor, metastatic pattern and treatment in a well-defined national cohort. METHODS: Patients treated with resection for CRLM that was also radically resected for their primary colorectal cancer (diagnosed in 2009-2013) were identified in Swedish national registers. Liver resections were categorized according to extent of surgery (Category I-IV). Risk factors for developing POCs as well as prognostic impact of POCs were evaluated in multivariable analyses. A subgroup analysis of minor resections was performed to evaluate POCs after laparoscopic surgery. RESULTS: POCs were registered for 24% (276/1144) of all patients after CRLM resection. Major resection was a risk factor for POCs in multivariable analysis (IRR 1.76; P = 0.001). Comparing laparoscopic and open resections in the subgroup analysis of small resections, 6% (4/68) in the laparoscopic group developed POCs compared to 18% (51/289) after open resection (IRR 0.32; P = 0.024). POCs were associated with a 27% increased excess mortality rate (EMRR 1.27; P = 0.044). However, primary tumor characteristics, tumor burden in the liver, extrahepatic spread, extent of liver resection and radicality had higher impact on survival. CONCLUSION: Minimal invasive resections were associated with a decreased risk of POCs following resection of CRLM which should be considered in surgical strategy. Postoperative complications were associated with a moderate risk for inferior survival.

CRCBaSe: a Swedish register-based resource for colorectal adenocarcinoma research.

OBJECTIVES: To facilitate high-quality register-based research on colorectal cancer (CRC) in Sweden by constructing a database consisting of CRC patients, matched comparators, and relatives. MATERIAL AND METHODS: Patients with adenocarcinoma in the colon and/or rectum were identified in the Swedish Colorectal Cancer Register, a nationwide quality-of-care register. For each patient, six comparators from the general population were matched on birth year, sex, year of CRC diagnosis, and county. Comparators were free from CRC at the time of matching, but could later become cases. For both patients and comparators, first-degree relatives (parents, siblings, and children) were identified. Information from nationwide population-based registers was retrieved and linked to each individual in the database using the personal identification number unique to all Swedish residents. RESULTS: A total of 76,831 CRC patients diagnosed between 1995 and 2016 were identified (51% colon, 49% rectal; before 2007 only rectal cancer patients were included). Among all patients, 37% were stage I-II, 22% stage III, and 22% stage IV. The median follow-up time was 11.9 years (inter-quartile range, IQR: 8.6-15.3). Together with comparators and relatives, the database contains 2,413,139 individuals with information on demographics, dates and causes of death, in- and outpatient healthcare records, cancer diagnoses, prescribed and dispensed drugs, childbirths (among women), and social security information (such as sick leave and early retirement). CONCLUSION: The Colorectal Cancer Database Sweden (CRCBaSe) is a large and unique register-based data research platform, which opens up for clinically important, large epidemiological studies with innovative design in the field of colorectal adenocarcinoma.

High resection rates of colorectal liver metastases after standardized follow-up and multimodal management: an outcome study within the COLOFOL trial.

BACKGROUND: Outcome after colorectal liver metastases (CRLM) resection has improved over time, despite increased resection rates. Hence, it's crucial to identify all patients possible to treat with curative intent. The objectives of this study were to map recurrence pattern, treatment strategy and survival depending on treatment and follow-up strategy. METHODS: In the COLOFOL-trial, patients with radically resected stage II-III colorectal cancer were randomized to high-frequency (6, 12, 18, 24 and 36 months; HF) or low-frequency (12 and 36 months; LF) follow-up. In this study, all CRLM within 5 years were identified and medical files scrutinized. Overall survival (OS) was analysed in uni- and multivariable analyses. Primary endpoint was 5-year OS. RESULTS: Of 2442 patients, 235 (9.6%) developed metachronous CRLM of which 123 (52.3%) underwent treatment with curative intent, resulting in 5-year OS of 58%. Five-year OS for patients with CRLM was 43% after HF versus 24% after LF. The survival benefit was confirmed for HF 8 years from resection of the primary tumour, HR 0.63 (CI 0.46-0.85). CONCLUSION: A high proportion of metachronous CRLM was possible to treat with curative intent, yielding high survival rates. More intense follow-up after colorectal cancer resection might be of value in high-risk patients.

Treatment and survival of patients with metachronous colorectal lung metastases.

INTRODUCTION: The lungs are the second most common site for metachronous metastases in colorectal cancer. No treatment algorithm is established, and the role of adjuvant chemotherapy is unclear. This study aimed to map pulmonary recurrences in a modern multimodal treated population, and to evaluate survival depending on management. METHODS: Retrospective study based on the COLOFOL-trial population of 2442 patients, radically resected for colorectal cancer stage II-III. All recurrences within 5 years were identified and medical records were scrutinized. RESULTS: Of 165 (6.8%) patients developing lung metastases as first recurrence, 89 (54%) were confined to the lungs. Potentially curative treatment was possible in 62 (37%) cases, of which 33 with surgery only and 29 with surgery and chemotherapy combined. The 5-year overall survival (5-year OS) for all lung recurrences was 28%. In patients treated with chemotherapy only the 5-year OS was 7.5%, compared with 55% in patients treated with surgery, and 72% when surgery was combined with chemotherapy. Hazard ratio for mortality was 2.9 (95% confidence interval 1.40-6.10) for chemotherapy only compared to surgery. CONCLUSION: A high proportion of metachronous lung metastases after colorectal surgery were possible to resect, yielding good survival. The combination of surgery and chemotherapy might be advantageous for survival.

Who should operate patients presenting with emergent colon cancer? A comparison of short- and long-term outcome depending on surgical sub-specialization.

BACKGROUND: Colorectal cancer presents as emergencies in 20% of the cases. Emergency resection is associated with high postoperative morbidity and mortality. The specialization of the operating team in the emergency settings differs from the elective setting, which may have an impact on outcome. The aim of this study was to evaluate short- and long-term outcomes following emergent colon cancer surgery depending on sub-specialization of the operating team. METHODS: This is a retrospective population study based on data from the Swedish Colorectal Cancer Registry (SCRCR). In total, 656 patients undergoing emergent surgery for colon cancer between 2011 and 2016 were included. The cohort was divided in groups according to specialization of the operating team: (1) colorectal team (CRT); (2) emergency surgical team (EST); (3) general surgical team (GST). The impact of specialization on short- and long-term outcomes was analyzed. RESULTS: No statistically significant difference in 5-year overall survival (CRT 48.3%; EST 45.7%; GST 42.5%; p = 0.60) or 3-year recurrence-free survival (CRT 80.7%; EST 84.1%; GST 77.7%21.1%; p = 0.44) was noted between the groups. Neither was any significant difference in 30-day mortality (4.4%; 8.1%; 5.5%, p = 0.20), 90-day mortality (8.8; 11.9; 7.9%, p = 0.37) or postoperative complication rate (35.5%, 35.9 30.7, p = 0.52) noted between the groups. Multivariate analysis adjusted for case-mix showed no difference in hazard ratios for long-term survival or postoperative complications. The rate of permanent stoma after 3 years was higher in the EST group compared to the CRT and GST groups (34.5% vs. 24.3% and 23.9%, respectively; p < 0.0.5). CONCLUSION: Surgical sub-specialization did not significantly affect postoperative complication rate, nor short- or long-term survival after emergent operation for colon cancer. Patients operated by emergency surgical teams were more likely to have a permanent stoma after 3 years.

Low-dose aspirin use and colorectal cancer survival in 32,195 patients-A national cohort study.

BACKGROUND: Results from previous studies indicate that use of aspirin may improve colorectal cancer (CRC) survival. The aim of this study was to assess whether use of aspirin influences overall survival or CRC-specific survival in an unselected cohort of patients diagnosed with CRC. METHODS: The study was performed using the Colorectal Cancer Data Base Sweden (CRCBaSe), a mega-linkage originating from the Swedish Colorectal Cancer Register, with additional linkages to other national health care registers. All patients diagnosed with primary CRC stage I-III treated with curative surgery, aged 18-85 years at diagnosis, from 2007 through 2016 were identified. Information on low-dose aspirin use was extracted from the Swedish Prescribed Drug Register. Exposure was defined as dispensed prescription for at least 6 months. Aspirin exposure was analyzed at the time of surgery (yes/no) and as a time-varying exposure during follow-up. Follow-up was restricted to a maximum 6 years, to model 5-year survival. Cox regression models were fitted to estimate hazard ratios (HRs) with 95% confidence intervals (CIs). Adjustments were performed for sex, age, year of diagnosis, Charlson comorbidity index, hypertension, and ASA score as potential confounders. RESULTS: A total of 32,195 patients diagnosed with CRC were included. 6764 (21%) were exposed to aspirin at the time of CRC surgery. The median time of follow-up was 4.2 years. Aspirin use at the time of surgery was not associated with all-cause (adjusted HR = 1.03, 95% CI: 0.97-1.08) nor CRC-specific mortality (adjusted HR = 0.99, 95% CI: 0.91-1.07). Aspirin use during follow-up was associated with increased all-cause (adjusted HR = 1.09, 95% CI: 1.04-1.15) but not CRC-specific mortality (adjusted HR = 0.98, 95% CI: 0.91-1.06). A CRC-specific effect associated with aspirin was noted from approximately 3 years following surgery. CONCLUSIONS: In this large nation-wide cohort study there was no convincing association between aspirin use after CRC and OS or CRC-specific survival.

Short- and long-term outcomes following bridge to surgery and emergency resection in acute malignant large bowel obstruction.

AIM: Bridge to surgery (BtS) aims to decrease perioperative morbidity and mortality in emergency resection (ER) of the colon. Previous results are inconsistent, and long-term comparisons are scarce. The aim of this study was to compare the short- and long-term outcomes of BtS and ER. METHOD: This retrospective study examined data from the Swedish Colorectal Cancer Registry for patients treated for acute malignant large bowel obstruction from 2007 to 2009. Patients were grouped by treatment strategy: BtS (using a self-expanding metallic stent or diverting stoma) or ER. Medical records were scrutinized for all patients in the BtS group. The primary endpoints were 5-year overall survival (OS) and 3-year recurrence-free survival (RFS). The secondary endpoints were postoperative mortality and morbidity rates and stoma permanence. RESULTS: Overall, 143 patients were treated using BtS versus 1302 patients treated with ER. The 5-year OS was higher in the BtS group than in the ER group (53.8% vs. 37.4%; p < 0.05). No difference was noted in the 3-year RFS (75.7% vs. 75.0%; p = 0.38). The postoperative mortality rate was lower in the BtS group than in the ER group (0.7% vs. 7.3%; p < 0.05). Complications occurred in 46.9% of patients in the BtS group (both procedures) versus 35.9% of patients in the ER group (p < 0.05); the rate of severe complications was 23.1% and 16.9%, respectively (p = 0.07). CONCLUSION: This retrospective population-based registry study showed higher long-term survival and lower postoperative mortality rates among patients treated with BtS versus ER for acute malignant large bowel obstruction.

Abdominal Closure With Reinforcing Suture Decreases Incisional Hernia Incidence After CRS/HIPEC.

Background: Cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) entails several risk factors for incisional hernia (IH). A few reports available showing incidences between 7% and 17%. At our institution fascia closure has been performed in a 4:1 suture to wound length manner, with a continuous 2-0 polydiaxanone suture (PDS-group) or with a 2-0 polypropylene suture preceded by a reinforced tension line (RTL) suture (RTL-group). Our hypothesis was that these patients might benefit from reinforcing the suture line with a lower IH incidence in this group. The aim was to evaluate the 1-year IH-incidence of the two different closures. Methods: Patients eligible for inclusion were treated with CRS/HIPEC between 2004 and 2019. IH was diagnosed by scrutinizing CT-scans 1 year ±3 months after surgery. Additional data was retrieved from clinical records and a prospective CRS/HIPEC-database. Results: Of 193 patients, 129 were included, 82 in the PDS- and 47 in the RTL-group. RTL-patients were 5 years younger, had less blood loss and more frequent postoperative neutropenia. No difference regarding sex, BMI, recent midline incisions, excision of midline scars, peritoneal cancer index score, complications (≥Clavien-Dindo 3b), or chemotherapy. Ten IH (7.8%) were found, 9 (11%) in the PDS- and 1 (2.1%) in the RTL-group (p = 0.071). Conclusion: An IH incidence of 7.8% in patients undergoing CRS/HIPEC is not higher than after laparotomies in general. The IH incidence in the PDS-group was 11% compared to 2% in the RTL-group. Even though significance was not reached, the difference is clinically relevant, suggesting an advantage with RTL suture.

Risk of recurrence after endoscopic resection of nonpedunculated T1 colorectal cancer.

BACKGROUND: The long-term outcome after local excision of T1 colorectal cancer (CRC) remains unknown. The aim of this study was to examine clinical and histopathological risk factors for recurrence in patients with T1 CRC undergoing endoscopic resection. METHODS: This was a retrospective registry-based population study on prospectively collected data of all patients with nonpedunculated T1 CRC undergoing only local excision (no salvage surgery) in Sweden between 2009 and 2018. Potential risk factors for recurrence, including age, sex, tumor location, resection margins, lymphovascular, perineural, and submucosal invasion, grade of differentiation, and mucinous subtype, were analyzed using univariate and multivariate cox regression. RESULTS: Median follow-up time was 60 months, and 28 /602 patients (4.7 %) had a recurrence (13 local and 18 distant). Recurrence rate stratified by submucosal invasion was: Sm1 3.5 % (14 /397), Sm2 6.0 % (8 /133), and Sm3 8.3 % (6 /72), with no significant differences. Resection margins, lymphovascular and perineural invasion, grade of differentiation, mucinous subtype, and age were not significant risk factors for recurrence. In contrast, rectal location was found to be a significant risk factor for tumor recurrence in multivariate analysis (hazard ratio 3.08, P = 0.006). The 3- and 5-year disease-free survival was 96.2 % and 91.1 %, respectively, in T1 CRC patients undergoing endoscopic resection. CONCLUSION: Tumor recurrence was rare (4.7 %) in this large population-based study on recurrence after local excision of nonpedunculated T1 CRC. Rectal location was an independent risk factor for recurrence, suggesting the need for strict surveillance after endoscopic resection of early rectal cancer.

Delineating the intra-patient heterogeneity of molecular alterations in treatment-naïve colorectal cancer with peritoneal carcinomatosis.

In a non-negligible number of patients with metastatic colorectal cancer (mCRC), the peritoneum is the predominant site of dissemination. Cure can be achieved by cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC), but this procedure is associated with long-term morbidity and high relapse rates. Thus, there is a pressing need for improved therapeutic strategies and complementary biomarkers. The present study explored the molecular heterogeneity in mCRC with peritoneal carcinomatosis (PC), and the potential clinical implications thereof. Multi-region immunohistochemical profiling and deep targeted DNA-sequencing was performed on chemotherapy-naïve tumours from seven patients with synchronous colorectal PC who underwent CRS and HIPEC. In total, 88 samples (5-19 per patient) were analysed, representing primary tumour, lymph node metastases, tumour deposits, PC and liver metastases. Expression of special AT-rich sequence-binding protein 2 (SATB2), a marker of colorectal lineage, was lacking in the majority of cases, and a conspicuous intra-patient heterogeneity was denoted for expression of the proposed prognostic and predictive biomarker RNA-binding motif protein 3 (RBM3). Loss of mismatch repair proteins MLH1 and PSM2, observed in one case, was concordant with microsatellite instability and the highest tumour mutational burden. When present in a patient, mutations in key CRC driver genes, i.e., KRAS, APC and TP53, were homogenously distributed across all samples, while less common mutations were more heterogenous. On the same note, copy number variations showed intra-patient as well inter-patient heterogeneity. In two out of seven cases, hierarchical clustering revealed that samples from the PC and lymph node metastases were more similar to each other than to the primary tumour. In summary, these findings should encourage additional studies addressing the potential distinctiveness of mCRC with PC, which might pave the way for improved personalized treatment of these patients.

Lymphovascular Infiltration, Not Depth of Invasion, is the Critical Risk Factor of Metastases in Early Colorectal Cancer: Retrospective Population-based Cohort Study on Prospectively Collected Data, Including Validation.

OBJECTIVE: To identify clinical and histopathological risk factors of LNM in T1 CRC. SUMMARY OF BACKGROUND DATA: The requisite of additional surgery after locally resected T1 CRC is dependent on the risk of LNM. Depth of submucosal invasion is used as a key predictor of lymphatic metastases although data are conflicting on its actual impact. METHODS: Retrospective population-based cohort study on prospectively collected data on all patients with T1 CRC undergoing surgical resection in Sweden, 2009-2017 and Denmark 2016-2018. The Danish cohort was used for validation. Potential risk factors of LNM investigated were; age, sex, tumor location, submucosal invasion, grade of differentiation, mucinous subtype, lymphovascular, and perineural invasion. RESULTS: One hundred fifty out of the 1439 included patients (10%) had LNM. LVI (P < 0.001), perineural invasion (P < 0.001), mucinous subtype (P = 0.006), and age <60 years (P < 0.001) were identified as independent risk factors whereas deep submucosal invasion was only a dependent (P = 0.025) risk factor and not significant in multivariate analysis (P = 0.075). The incidence of LNM was 51/882 (6%) in absence of the independent risk factors. The Danish validation cohort, confirmed our findings regarding the role of submucosal invasion, LVI, and age. CONCLUSIONS: This is a large study on LNM in T1 CRC, including validation, showing that LVI and perineural invasion, mucinous subtype, and low age constitute independent risk factors, whereas depth of submucosal invasion is not an independent risk factor of LNM. Thus, our findings provide a useful basis for management of patients after local excision of early CRC.

Cost comparisons of endoscopic and surgical resection of stage T1 rectal cancer.

Background and study aims Management of T1 rectal cancer is complex and includes several resection methods, making cost comparisons challenging. The aim of this study was to compare costs of endoscopic and surgical resection and to investigate hypothetical cost scenarios for the treatment of T1 rectal cancer. Patients and methods Retrospective population-based cost minimization study on prospectively collected data on T1 rectal cancer patients treated using endoscopic submucosal dissection (ESD), transanal endoscopic microsurgery (TEM), open, laparoscopic, or robotic resection, in Skåne County, Sweden (2011-2017). The hypothetical cost scenarios were based on the distribution of high-risk features of lymph node metastases in a national cohort (2009-2017). Results Eighty-five patients with T1 RC undergoing ESD (n = 16), TEM (n = 17), open (n = 35), laparoscopic (n = 9), and robotic (n = 8) resection were included. ESD had a total 1-year cost of 5165 €â€Šand was significantly ( P  < 0.05) less expensive compared to TEM (14871€), open (21 453 €), laparoscopic (22 488 €) and robotic resection (26 562 €). Risk factors for lymph node metastases were seen in 68 % of 779 cases of T1 rectal cancers included in the national cohort. The hypothetical scenario of performing ESD on all T1 RC had the lowest total 1-year per patient cost compared to all other alternatives. Conclusions This is the first study analyzing total 1-year costs of endoscopic and surgical methods to resect T1 rectal cancer, which showed that the cost of ESD was significantly lower compared to TEM and surgical resection. In fact, based on hypothetical cost scenarios, ESD is still justifiable from a cost perspective even when all high-risk cases are followed by surgery in accordance to guidelines.

CXCL2-CXCR2 axis mediates αV integrin-dependent peritoneal metastasis of colon cancer cells.

Peritoneal metastasis is an insidious aspect of colorectal cancer. The aim of the present study was to define mechanisms regulating colon cancer cell adhesion and spread to peritoneal wounds after abdominal surgery. Mice was laparotomized and injected intraperitoneally with CT-26 colon carcinoma cells and metastatic noduli in the peritoneal cavity was quantified after treatment with a CXCR2 antagonist or integrin-αV-antibody. CT-26 cells expressed cell surface chemokine receptors CXCR2, CXCR3, CXCR4 and CXCR5. Stimulation with the CXCR2 ligand, CXCL2, dose-dependently increased proliferation and migration of CT-26 cells in vitro. The CXCR2 antagonist, SB225002, dose-dependently decreased CXCL2-induced proliferation and migration of colon cancer cells in vitro. Intraperitoneal administration of CT-26 colon cancer cells resulted in wide-spread growth of metastatic nodules at the peritoneal surface of laparotomized animals. Laparotomy increased gene expression of CXCL2 at the incisional line. Pretreatment with CXCR2 antagonist reduced metastatic nodules by 70%. Moreover, stimulation with CXCL2 increased CT-26 cell adhesion to extracellular matrix (ECM) proteins in a CXCR2-dependent manner. CT-26 cells expressed the αV, ß1 and ß3 integrin subunits and immunoneutralization of αV abolished CXCL2-triggered adhesion of CT-26 to vitronectin, fibronectin and fibrinogen. Finally, inhibition of the αV integrin significantly attenuated the number of carcinomatosis nodules by 69% in laparotomized mice. These results were validated by use of the human colon cancer cell line HT-29 in vitro. Our data show that colon cancer cell adhesion and growth on peritoneal wound sites is mediated by a CXCL2-CXCR2 signaling axis and αV integrin-dependent adhesion to ECM proteins.

No benefit of more intense follow-up after surgery for colorectal cancer in the risk group with elevated CEA levels - An analysis within the COLOFOL randomized clinical trial.

BACKGROUND: Patients with colorectal cancer were examined to determine (1) whether elevated carcinoembryonic antigen (CEA) levels, either before treatment or after surgery, was associated with an increased risk of overall or colorectal cancer-specific mortality or recurrence, and (2) whether high intensity follow-up would benefit those patients. MATERIALS AND METHODS: Post-hoc analysis based on 2509 patients that underwent surgery for colorectal cancer, stage II or III, in the COLOFOL randomized trial with 5-year follow-up. Serum CEA levels were ascertained before treatment and one month after surgery. Follow-up examinations included computed tomography of the thorax and abdomen and serum CEA sampling. Patients were randomized to examinations at either 6, 12, 18, 24, and 36 months (high-intensity group) or at 12 and 36 months after surgery (low-intensity group). Levels of CEA >5 µg/l were defined as elevated. RESULTS: Elevated CEA levels before treatment were associated with increased risk of recurrence (hazard ratio [HR], 1.49; 95% confidence interval [CI]: 1.22-1.83), colorectal cancer-specific mortality (HR, 1.44; 95% CI: 1.08-1.91), and overall mortality (HR, 1.38; 95% CI: 1.07-1.78). Elevated CEA levels after surgery were associated with increased colorectal cancer-specific mortality (HR, 1.68; 95% CI: 1.08-2.61) and overall mortality (HR, 1.79; 95% CI: 1.22-2.63). The intensity of the follow-up regimen had no effect on 5-year outcomes in patients with elevated CEA levels. CONCLUSION: Both pre-treatment and post-surgery elevated serum CEA levels were associated with increased overall and cancer-specific mortality. Intensified follow-up showed no benefit over low-intensity follow-up in this high-risk group of patients with elevated CEA levels.

Impact of patient, primary tumor and metastatic pattern including tumor location on survival in patients undergoing ablation or resection for colorectal liver metastases: A population-based national cohort study.

INTRODUCTION: Selecting the optimal treatment strategy for patients with colorectal liver metastases (CRLM) aim to improve survival for the total cohort. Following the introduction of laparoscopic resections and ablation, localization may direct choice of method. The aim with this study was to re-evaluate prognostic factors that should be considered at the preoperative multidisciplinary tumor board, based on a national population cohort. MATERIALS AND METHODS: A national cohort with radically operated colorectal cancer in 2009-2013, also treated for CRLM was identified in Swedish national registries. Prognostic factors were identified and evaluated in multivariable analyses. RESULTS: 1200 patients treated with resection and 125 with ablation only were included in the study cohort. Relative five-year survival was 54.7% (50.9%-58.4%) and 32.0% (22.4%-41.9%), respectively). High age, acute surgery and complications at time of primary tumor resection remained important risk factors at liver surgery, as well as the primary tumor characteristics; vascular invasion and high lymph node ratio. As for metastatic pattern; tumor size, location in segment 4, 6, 7 or 8, multiple metastatic sites and progress after preoperative chemotherapy were significant risk factors. In multivariate analyses, ablation therapy doubled the risk of death within 5 years. This strong negative impact was confirmed in a weighted propensity score analysis (HR = 2.1 (95 % CI 1.5 -3.0)). CONCLUSION: Segmental localization and tumor size were prognostic factors but also patient and primary tumor factors significantly impacted survival after intervention for CRLM. Long-term survival was significantly lower after ablation therapy compared to surgical resection.