Cytoreductive surgery in combination with hyperthermic intraperitoneal chemotherapy improves survival in patients with colorectal peritoneal metastases compared with systemic chemotherapy alone

Background: Colorectal cancer peritoneal metastasis (CPM) confers an exceptionally poor prognosis, and traditional treatment involving systemic chemotherapy (SC) is largely ineffective. Cytoreductive surgery (CRS) combined with hyperthermic intraperitoneal chemotherapy (HIPEC) is increasingly advocated for selected patients with CPM; however, opinions are divided because of the perceived lack of evidence, high morbidity, mortality, and associated costs for this approach. As there is no clear consensus, the aim of this study was to compare outcomes following CRS+HIPEC vs SC alone for CPM using meta-analytical methodology, focusing on survival outcomes. Secondary outcomes assessed included morbidity, mortality, quality of life (QOL), and health economics (HE).Methods: An electronic literature search was conducted to identify studies comparing survival following CRS+HIPEC vs SC for CPM. The odds ratio (OR) was calculated using the Mantel–Haenszel method with corresponding 95% confidence intervals (CI) and P-values. Heterogeneity was examined using the Q-statistic and quantified with I2. The fixed-effect model (FEM) was used in the absence of significant heterogeneity. For included studies, 2- and 5-year survival was compared for CRS+HIPEC vs SC alone.Results: Four studies (three case–control, one RCT) provided comparative survival data for patients undergoing CRS+HIPEC (n=187) vs SC (n=155) for CPM. Pooled analysis demonstrated superior 2-year (OR 2.78; 95% CI 1.72–4.51; P=0.001) and 5-year (OR 4.07; 95% CI 2.17–7.64; P=0.001) survival with CRS+HIPEC compared with SC. Mortality ranged from 0 to 8%. No data were available for the assessment of QOL or HE.Conclusions: Although limited by between-study heterogeneity, the data support the assertion that in carefully selected patients, multimodal treatment of CPM with CRS+HIPEC has a highly positive prognostic impact on medium- and long-term survival compared with SC alone. There is a paucity of comparative data available on morbidity, QOL, and HE

miR-19-mediated inhibition of transglutaminase-2 leads to enhanced invasion and metastasis in colorectal cancer

Transglutaminase-2 (TG2) is a critical cross-linking enzyme in the extracellular matrix (ECM) and tumor microenvironment (TME). Although its expression has been linked to colorectal cancer, its functional role in the processes that drive disease appears to be context dependent. There is now considerable evidence of a role for microRNAs (miRNA) in the development and progression of cancer, including metastasis. A cell model of metastatic colon adenocarcinoma was used to investigate the contribution of miRNAs to the differential expression of TG2, and functional effects on inflammatory and invasive behavior. The impact of TG2 in colorectal cancer was analyzed in human colorectal tumor specimens and by manipulations in SW480 and SW620 cells. Effects on invasive behavior were measured using Transwell invasion assays, and cytokine production was assessed by ELISA. TG2 was identified as a target for miR-19 by in silico analysis, which was confirmed experimentally. Functional effects were evaluated by overexpression of pre-miR-19a in SW480 cells. Expression of TG2 correlated inversely with invasive behavior, with knockdown in SW480 cells leading to enhanced invasion, and overexpression in SW620 cells the opposite. TG2 expression was observed in colorectal cancer primary tumors but lost in liver metastases. Finally, miR-19 overexpression and subsequent decreased TG2 expression was linked to chromosome-13 amplification events, leading to altered invasive behavior in colorectal cancer cells.IMPLICATIONS: Chromosome-13 amplification in advanced colorectal cancer contributes to invasion and metastasis by upregulating miR-19, which targets TG2.<br/

miR-153 supports colorectal cancer progression via pleiotropic effects that enahance invasion and chemotherapeutic resistance

Although microRNAs (miRNA) have been broadly studied in cancer, comparatively less is understood about their role in progression. Here we report that miR-153 has a dual role during progression of colorectal cancer by enhancing cellular invasiveness and platinum-based chemotherapy resistance. miRNA profiling revealed that miR-153 was highly expressed in a cellular model of advanced stage colorectal cancer. Its upregulation was also noted in primary human colorectal cancer compared with normal colonic epithelium and in more advanced colorectal cancer stages compared with early stage disease. In colorectal cancer patients followed for 50 months, 21 of 30 patients with high levels of miR-153 had disease progression compared with others in this group with low levels of miR-153. Functional studies revealed that miR-153 upregulation increased colorectal cancer invasiveness and resistance to oxaliplatin and cisplatin both in vitro and in vivo. Mechanistic investigations indicated that miR-153 promoted invasiveness indirectly by inducing matrix metalloprotease enzyme 9 production, whereas drug resistance was mediated directly by inhibiting the Forkhead transcription factor Forkhead box O3a (FOXO3a). In support of the latter finding, we found that levels of miR-153 and FOXO3a were inversely correlated in matched human colorectal cancer specimens. Our findings establish key roles for miR-153 overexpression in colorectal cancer progression, rationalizing therapeutic strategies to target expression of this miRNA for colorectal cancer treatment

A prospective case–control study of extralevator abdominoperineal excision (ELAPE) of the rectum versus conventional laparoscopic and open abdominoperineal excision: comparative analysis of short-term outcomes and quality of life

Background: Conventional abdominoperineal excision (APE) of the rectum is associated with higher circumferential resection margin (CRM) involvement, increased local recurrence, and reduced survival compared to anterior resection. A more radical extralevator APE (ELAPE) technique may improve oncological outcome. However, this technique may confer additional morbidity, and little comparative data on short-term outcomes have been reported. This study compares short-term outcomes and quality of life (QOL) after open and laparoscopic ELAPE, laparoscopic APE (LAPE), and open APE (OAPE).Methods: Data on all ELAPE and 10 consecutive LAPE and OAPE were extracted from a prospective database. Perioperative care and follow-up were standardized. QOL was assessed using EORTC questionnaires.Results: Sixteen ELAPE (14 laparoscopic), 10 LAPE, and 10 OAPE were included. Demographics, tumour stage, and neoadjuvant therapy use were comparable. Operative time was higher with ELAPE than LAPE and OAPE (295, 207.5, and 157.5 min, respectively, p = 0.01). A porcine collagen perineal mesh was used in 9 patients undergoing ELAPE but in no LAPE or OAPE patients. No difference in 30-day complications, re-admission, or length of stay was noted. ELAPE and LAPE were associated with earlier removal of urinary catheter (p = 0.02), yet other enhanced recovery after surgery (ERAS) parameters were equivalent. All ELAPE resections were R0 with no positive CRM identified. One LAPE and 2 OAPE were R1 resections. Analysis revealed no deterioration in QOL with ELAPE, with equivalent global health status.Conclusions: The results of this study suggest that ELAPE is not associated with deterioration in short-term outcomes or QOL when compared with LAPE or OAPE

A minimum core outcome dataset for the reporting of preclinical chemotherapeutic drug studies: Lessons learned from multiple discordant methodologies in the setting of colorectal cancer

In vivo studies in animal models are critical tools necessary to study the fundamental complexity of carcinogenesis. A constant strive to improve animal models in cancer exists, especially those investigating the use of chemotherapeutic effectiveness. In the present systematic review, colorectal cancer (CRC) is used as an example to highlight and critically evaluate the range of reporting strategies used when investigating chemotherapeutic agents in the preclinical setting. A systematic review examining the methodology and reporting of preclinical chemotherapeutic drug studies using CRC murine models was conducted. A total of 45 studies were included in this systematic review. The literature was found to be highly heterogeneous with various cell lines, animal strains, animal ages and chemotherapeutic compounds/regimens tested, proving difficult to compare outcomes between similar studies or indeed gain any significant insight into which chemotherapeutic regimen caused adverse events. From this analysis we propose a minimum core outcome dataset that could be regarded as a standardised way of reporting results from in vivo experimentation