Alex H. Mirnezami

Increased local recurrence and reduced survival from colorectal cancer following anastomotic leak: systematic review and meta-analysis.

Objective: To examine the long-term oncological impact of anastomotic leakage (AL) after restorative surgery for colorectal cancer using meta-analytical methods. Outcomes evaluated were local recurrence, distant recurrence, and survival. Background: Recurrence after potentially curative surgery for colorectal cancer remains a significant clinical problem and has a poor prognosis. AL may be a risk factor for disease recurrence, however available studies have been conflicting. A meta-analysis was conducted to investigate the impact of AL on disease recurrence and long-term survival. Methods: Studies published between 1965 and 2009 evaluating the long-term oncological impact of AL were identified by an electronic literature search. Outcomes evaluated included local recurrence, distant recurrence, and cancer specific survival. Meta-analysis was performed using the DerSimonian-Laird random-effects model to compute odds ratio and 95% confidence intervals. Study heterogeneity was evaluated using Q statistics and I 2 and publication bias assessed with funnel plots and Eggers test. Results: Twenty-one studies comprising 13 prospective nonrandomized studies, 1 prospective randomized, and 7 retrospective studies met the inclusion criteria, yielding a total of 21,902 patients. For rectal anastomoses, the odd ratios (OR) of developing a local recurrence when there was AL was 2.05 (95% CI = 1.51–2.8; P = 0.0001). For studies describing both colon and rectal anastomoses, the OR of local recurrence when there was an AL was 2.9 (95% CI = 1.78–4.71; P < 0.001). The OR of developing a distant recurrence after AL was 1.38 (95% CI = 0.96–1.99; P = 0.083). Long term cancer specific mortality was significantly higher after AL with an OR of 1.75 (95% CI = 1.47–2.1; P = 0.0001). Conclusions: AL has a negative prognostic impact on local recurrence after restorative resection of rectal cancer. A significant association between colorectal AL and reduced long-term cancer specific survival was also noted. No association between AL and distant recurrence was found.

Short- and long-term outcomes after laparoscopic and open hepatic resection: systematic review and meta-analysis

BACKGROUND Laparoscopic liver resection (LLR) is now considered a feasible alternative to open liver resection (OLR) in selected patients. Nevertheless studies comparing LLR and OLR are few and concerns remain about long-term oncological equivalence. The present study compares outcomes with LLR vs. OLR using meta-analytical methods. METHODS Electronic literature searches were conducted to identify studies comparing LLR and OLR. Short-term outcomes evaluated included operating time, blood loss, length of hospital stay, peri-operative morbidity and resection margin status. Longer-term outcomes included local and distant recurrence, and overall (OS) and disease-free survival (DFS). Meta-analyses were performed using the Mantel-Haenszel method and Cohens d method, with results expressed as odds ratio (OR) or standardized mean difference (SMD), respectively, with 95% confidence intervals (CI). RESULTS Twenty-six studies met the inclusion criteria with a population of 1678 patients. LLR resulted in longer operating time, but reduced blood loss, portal clamp time, overall and liver-specific complications, ileus and length of stay. No difference was found between LLR and OLR for oncological outcomes. DISCUSSION LLR has short-term advantages and seemingly equivalent long-term outcomes and can be considered a feasible alternative to open surgery in experienced hands.

MicroRNAs : Key players in carcinogenesis and novel therapeutic targets

MicroRNAs (miRNAs) represent a recently uncovered class of small and endogenous non-coding RNAs. MiRNA function is critical to normal cellular processes such as differentiation and apoptosis, and recent studies have demonstrated that deregulated miRNA expression contributes to the malignant phenotype. The purpose of this review is to summarise these findings in relation to the most common human malignancies, and to analyse the clinical and therapeutic opportunities they provide.

MicroRNAs: critical regulators of epithelial to mesenchymal (EMT) and mesenchymal to epithelial transition (MET) in cancer progression

MicroRNAs (miRNAs) are a class of small highly conserved RNAs that provide widespread expressional control through the translational repression of mRNA. MiRNAs have fundamental roles in the regulation of intracellular processes, and their importance during malignant transformation and metastasis is becoming increasingly well recognized. An important event in the metastatic cascade is epithelial to mesenchymal transition (EMT), a reversible phenotypic switch over, which endows malignant epithelial cells with the capacity to break free from one another and invade the surrounding stroma. Our understanding of EMT has been significantly improved by the characterization of miRNAs that influence the signalling pathways and downstream events that define EMT on a molecular level.

Robotic colorectal surgery: hype or new hope? A systematic review of robotics in colorectal surgery

Aim  Robotic colorectal surgery is an emerging field and may offer a solution to some of the difficulties inherent to conventional laparoscopic surgery. The aim of this review is to provide a comprehensive and critical analysis of the available literature on the use of robotic technology in colorectal surgery.

Hdm2 Recruits a Hypoxia-Sensitive Corepressor to Negatively Regulate p53-Dependent Transcription

The transcription factor p53 lies at the center of a protein network that controls cell cycle progression and commitment to apoptosis. p53 is inactive in proliferating cells, largely because of negative regulation by the Hdm2/Mdm2 oncoprotein, with which it physically associates. Release from this negative regulation is sufficient to activate p53 and can be triggered in cells by multiple stimuli through diverse pathways. This diversity is achieved in part because Hdm2 uses multiple mechanisms to inactivate p53; it targets p53 for ubiquitination and degradation by the proteosome, shuttles it out of the nucleus and into the cytoplasm, prevents its interaction with transcriptional coactivators, and contains an intrinsic transcriptional repressor activity. Here we show that Hdm2 can also repress p53 activity through the recruitment of a known transcriptional corepressor, hCtBP2. This interaction, and consequent repression of p53-dependent transcription, is relieved under hypoxia or hypoxia-mimicking conditions that are known to increase levels of intracellular NADH. CtBP proteins can undergo an NADH-induced conformational change, which we show here results in a loss of their Hdm2 binding ability. This pathway represents a novel mechanism whereby p53 activity can be induced by cellular stress.

Pathology and prognosis in pseudomyxoma peritonei: a review of 274 cases.

Aims The classification of abdominal mucinous neoplasia is a controversial area. In 2010, WHO published a classification which divides pseudomyxoma peritonei (PMP) into low and high grades. The aim of the authors was to correlate this classification with the prognosis and site of primary neoplasm. Methods The authors reviewed 274 patients with PMP who had undergone surgery at a single institution and classified them according to WHO criteria. The findings were correlated with clinical information and survival data. Results PMP was low grade in 78% of patients and high grade in 22%. The appendix accounted for 94% of lesions, and the most common primary tumour was a low grade appendiceal mucinous neoplasm. Colorectal primaries were more likely to be associated with high grade PMP. There was an excellent correlation between the grade of the PMP and the primary neoplasm; only two cases showed discordant morphology: both were high grade appendiceal adenocarcinomas that were associated with low grade PMP. Nodal metastases were more likely in high grade lesions, but there was no significant difference in the rate of parenchymal organ invasion between low grade and high grade. Low grade morphology was associated with significantly longer survival than high grade (overall 5-year survival of 63% for low grade and 23% for high grade). Conclusions Categorisation as either low grade or high grade by WHO criteria correlates with prognosis. The grade of the PMP is generally consistent with the grade of the primary neoplasm. Colorectal primaries are more likely to be associated with high grade PMP.

miR-153 Supports Colorectal Cancer Progression via Pleiotropic Effects That Enhance 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.

Clinical algorithms for the surgical management of locally recurrent rectal cancer.

PURPOSE: Advances in surgical practice have helped expand the options for patients with locally recurrent rectal cancer through improvements in reconstructive options, management of operative complications, addition of intraoperative adjuvant therapies, and postoperative care. This review outlines the presentation and management of patients with locally recurrent rectal cancer, and it describes easy-to-apply clinical algorithms to aid management. METHODS: The electronic literature was searched for studies reporting outcomes for locally recurrent rectal cancer limited to the English language. RESULTS: Prospective and retrospective case series and single-center experiences were identified. A total of 106 articles were selected for full-text review of which 82 fulfilled the inclusion criteria. No randomized studies were identified. We found that multimodality treatment of locally recurrent rectal cancer can improve 5-year survival from 0% to over 40%, and selected patients may survive up to 10 years. A mixture of imaging modalities is used in patient selection for surgery. An R0 resection is consistently a favorable prognostic factor. R1 resection and surgery in the setting of oligometastases compare favorably with nonoperative palliation. Although mortality figures remain low, morbidity is significant and mostly wound related. CONCLUSIONS: Improvements in radiological imaging modalities and technical improvements in surgical and reconstructive options have facilitated more accurate staging, better selection of patients for surgery, reduced morbidity and mortality, and higher R0 resections. Optimal management is in specialist units with a multidisciplinary approach with the use of multimodal therapy.

MicroRNA control of invasion and metastasis pathways

Despite recent advances, cancer remains a leading cause of death worldwide. In developed countries, the incidence of colorectal and breast cancer has been stable, but no improvement in prognosis has been observed if the patient presents with metastases at diagnosis. This fact highlights the importance of therapeutic approaches targeting cellular invasion and metastasis programs as the next step in cancer treatment. During carcinoma progression a process called epithelial–mesenchymal transition (EMT) results in enhanced invasion and motility which is directly linked with loss of epithelial polarity and epithelial junctions, migration permissive cytoskeleton alterations, and the acquisition of mesenchymal properties. The recent discovery of microRNAs (miRNAs) controlling key cellular pathways has opened a new era in understanding how EMT pathways are modulated. In this review, we classify EMT regulating proteins according to their cellular localization (membrane, cytoplasmic, and nuclear), and summarize the current knowledge on how they are controlled by miRNAs and propose potential miRNAs for the transcripts that may control their expression.