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Introduction: Anastomotic leakage is a major concern following total mesorectal excision for rectal cancer, affecting oncological outcomes, morbidity an treatment costs. Body composition has been suggested to influence anastomotic leakage rates. However, literature on how body composition impact anastomotic leakage rates is conflicting. This systematic review aims to evaluate the role of computed tomography derived body composition metrics on anastomotic leakage rates in rectal cancer patients. Methods: Databases PubMed/MEDLINE, Cochrane Library, web of science, and EMBASE, will be systematically searched for papers from January 2010 onwards. Study selection, data collection and quality assessment will be independently performed by three research fellows. Outcomes described in three or more studies will be included in the meta-analysis. The Q-test and I2 statistic will be used to assess statistical heterogeneity between studies. Publication bias will be examined by visual inspection of funnel plots and quantified by Egger's test. Sensitivity analyses will be conducted to examine the robustness of the meta-analysis. Reporting of the findings will be in line with the Preferred Reporting Items for Systematic Review and Meta-Analyses (PRISMA) guidelines. Conclusions: This systematic review will synthesize the current evidence and will identify knowledge gaps. Results of the systematic review will aid health care professional in pre-operative decision making and will be distributed through a peer-reviewed publication and presentation of results at international meetings. Trial registration: PROSPERO protocol number: CRD42023471537. [ABSTRACT FROM AUTHOR]

Introduction: In locally advanced rectal cancer, longer delay to surgery after neoadjuvant radiotherapy increases the likelihood of histopathological tumour response. Chronomodulated radiotherapy in rectal cancer has recently been reported as a factor increasing tumour response to neoadjuvant treatment in patients having earlier surgery, with patients receiving a larger proportion of afternoon treatments showing improved response. This paper aims to replicate this work by exploring the impact of these two temporal factors, independently and in combination, on histopathological tumour response in rectal cancer patients. Methods: A retrospective review of all patients with rectal adenocarcinoma who received long course (≥24 fractions) neoadjuvant radiotherapy with or without chemotherapy at a tertiary referral centre was conducted. Delay to surgery and radiotherapy treatment time were correlated to clinicopathologic characteristics with a particular focus on tumour regression grade. A review of the literature and meta-analysis were also conducted to ascertain the impact of time to surgery from preoperative radiotherapy on tumour regression. Results: From a cohort of 367 patients, 197 patients met the inclusion criteria. Complete pathologic response (AJCC regression grade 0) was seen in 46 (23%) patients with a further 44 patients (22%) having at most small groups of residual cells (AJCC regression grade 1). Median time to surgery was 63 days, and no statistically significant difference was seen in tumour regression between patients having early or late surgery. There was a non-significant trend towards a larger proportion of morning treatments in patients with grade 0 or 1 regression (p = 0.077). There was no difference in tumour regression when composite groups of the two temporal variables were analysed. Visualisation of data from 39 reviewed papers (describing 27379 patients) demonstrated a plateau of response to neoadjuvant radiotherapy after approximately 60 days, and a meta-analysis found improved complete pathologic response in patients having later surgery. Conclusions: There was no observed benefit of chronomodulated radiotherapy in our cohort of rectal cancer patients. Review of the literature and meta-analysis confirms the benefit of delayed surgery, with a plateau in complete response rates at approximately 60-days between completion of radiotherapy and surgery. In our cohort, time to surgery for the majority of our patients lay along this plateau and this may be a more dominant factor in determining response to neoadjuvant therapy, obscuring any effects of chronomodulation on tumour response. We would recommend surgery be performed between 8 and 11 weeks after completion of neoadjuvant radiotherapy in patients with locally advanced rectal cancer. [ABSTRACT FROM AUTHOR]

Colorectal Cancer (CRC) and Obesity constitute two of the most common malignancies in the western world, and previously have been associated with intestinal microbial composition alterations. Our main aim in this study is to provide molecular data on intestinal microbiota patterns in subjects with CRC, as well as to establish possible associations with their Body Mass Index (BMI). A total of 113 samples from 45 subjects were collected and submitted to metagenomics analysis for gut microbiota. This study was performed by 16S ribosomal RNA bacterial gene amplification and sequencing using the Ion Torrent™ technology. The same dominant phyla were observed in feces and colorectal tissues, although a greater proportion of Fusobacteriota was found in tumor samples. Moreover, at the genus level, LEfSe analysis allowed us to detect a significant increase in Fusobacterium and Streptococcus in colorectal tissues with respect to fecal samples, with a significant preponderance of Fusobacterium in tumor tissues. Also, our data revealed relevant associations between gut microbiota composition and tumor location. When comparing bacterial profiles between right and left colon cancers, those from the left-sided colon showed a significant preponderance, among others, of the order Staphylococcales. Moreover, phyla Firmicutes and Spirochaetota were more abundant in the group of right-sided CRCs and phylum Proteobacteria was increased in rectal cancers. In relation to BMI of patients, we detected significant differences in beta diversity between the normal weight and the obese groups of cases. Microbiota from obese patients was significantly enriched, among others, in Bacteroidales. Therefore, our results are useful in the molecular characterization of CRC in obese and non-obese patients, with a clear impact on the establishment of diagnostic and prognosis of CRC. [ABSTRACT FROM AUTHOR]

Background: Pelvic Floor Rehabilitation (PFR) is effective in a selection of patients with low anterior resection syndrome (LARS) after rectal cancer surgery. This study aimed to identify barriers and enablers to prepare for successful implementation into clinical practice. Methods: A qualitative study was performed, guided by the Consolidated Framework for Implementation Research (CFIR). Individual interviews (n = 27) and two focus groups were conducted to synthesize the perspectives of rectal cancer patients, pelvic floor (PF) physiotherapists, and medical experts. Results: Barriers were found to be the absence of guidelines about LARS treatment, underdeveloped network care, suboptimal patient information, and expectation management upfront to PFR. Financial status is frequently a barrier because insurance companies do not always reimburse PFR. Enablers were the current level of evidence for PFR, the positive relationship between patients and PF physiotherapists, and the level of self-motivation by patients. Conclusion: The factors identified in our study play a crucial role in ensuring a successful implementation of PFR after rectal cancer surgery. [ABSTRACT FROM AUTHOR]

Introduction: Lateral pelvic node dissection (LPND) poses significant technical challenges. Despite the advent of robotic surgery, determining the optimal minimally invasive approach remains a topic of debate. This study aimed to compare postoperative outcomes between robotic total mesorectal excision with LPND (R-LPND) and laparoscopic total mesorectal excision with LPND (L-LPND). Methods: This meta-analysis was conducted according to the Preferred Reporting Items for Systematic Review and Meta-analysis (PRISMA) 2020 and AMSTAR 2 (Assessing the Methodological Quality of Systematic Reviews) guidelines. Utilizing the RevMan 5.3.5 statistical package from the Cochrane Collaboration, a random-effects model was employed. Results: Six eligible studies involving 652 patients (316 and 336 in the R-LPND and L-LPND groups, respectively) were retrieved. The robotic approach demonstrated favourable outcomes compared with the laparoscopic approach, manifesting in lower morbidity rates, reduced urinary complications, shorter hospital stays, and a higher number of harvested lateral pelvic lymph nodes. However, longer operative time was associated with the robotic approach. No significant differences were observed between the two groups regarding major complications, anastomotic leak, intra-abdominal infection, neurological complications, LPND time, overall recurrence, and local recurrence. Conclusions: In summary, the robotic approach is a safe and feasible alternative for Total Mesorectal Excision (TME) with LPND in advanced rectal cancer. Notably, it is associated with lower morbidity, particularly a reduction in urinary complications, a shorter hospital stay and increased number of harvested lateral pelvic nodes. The trade-off for these benefits is a longer operative time. [ABSTRACT FROM AUTHOR]

Purpose: To identify the predictive role of sarcopenia in long-term survival among rectal cancer patients who underwent surgery based on available evidence. Methods: The Medline, EMBASE and Web of Science databases were searched up to October 20, 2023, for relevant studies. Overall survival (OS), disease-free survival (DFS) and cancer-specific survival (CSS) were the endpoints. Hazard ratios (HRs) and 95% confidence intervals (CIs) were combined to evaluate the association between sarcopenia and survival. Results: Fifteen studies with 4283 patients were included. The pooled results demonstrated that preoperative sarcopenia significantly predicted poorer OS (HR = 2.07, 95% CI = 1.67–2.57, P<0.001), DFS (HR = 1.85, 95% CI = 1.39–2.48, P<0.001) and CSS (HR = 1.83, 95% CI = 1.31–2.56, P<0.001). Furthermore, subgroup analysis based on neoadjuvant therapy indicated that sarcopenia was a risk factor for worse OS and DFS in patients who received (OS: HR = 2.44, P<0.001; DFS: HR = 2.16, P<0.001) but not in those who did not receive (OS: HR = 2.44, P<0.001; DDFS: HR = 1.86, P = 0.002) neoadjuvant chemoradiotherapy. In addition, subgroup analysis based on sample size and ethnicity showed similar results. Conclusion: Preoperative sarcopenia is significantly related to poor survival in surgical rectal cancer patients and could serve as a novel and valuable predictor of long-term prognosis in these patients. [ABSTRACT FROM AUTHOR]

Objective: The aim of this paper was to compare the efficacy and safety of S-1-based and capecitabine-based preoperative chemoradiotherapy regimens in patients with locally advanced rectal cancer through a retrospective matched-pair analysis. Materials and methods: Between Jan 2010 and Mar 2014, 24 patients with locally advanced rectal cancer who received preoperative radiotherapy concurrently with S-1 were individually matched with 24 contemporary patients with locally advanced rectal cancer who received preoperative radiotherapy concurrently with capecitabine according to clinical stage (as determined by pelvic magnetic resonance imaging and computed tomography) and age (within five years). All these patients performed mesorectal excision 4–8 weeks after the completion of chemoradiotherapy. Results: The tumor volume reduction rates were 55.9±15.1% in the S-1 group and 53.8±16.0% in the capecitabine group (p = 0.619). The overall downstaging, including both T downstaging and N downstaging, occurred in 83.3% of the S-1 group and 70.8% of the capecitabine group (p = 0.508). The significant tumor regression, including regression grade I and II, occurred in 33.3% of S-1 patients and 25.0% of capecitabine patients (p = 0.754). In the two groups, Grade 4 adverse events were not observed and Grade 3 consisted of only two cases of diarrhea, and no patient suffered hematologic adverse event of Grade 2 or higher. However, the incidence of diarrhea (62.5% vs 33.3%, p = 0.014) and hand-foot syndrome (29.2% vs 0%, p = 0.016) were higher in capecitabine group. Other adverse events did not differ significantly between two groups. Conclusions: The two preoperative chemoradiotherapy regimens were effective and safe for patients of locally advanced rectal cancer, but regimen with S-1 exhibited a lower incidence of adverse events. [ABSTRACT FROM AUTHOR]

Purpose: Patients with rectal cancer without distant metastases are typically treated with radical surgery. Post curative resection, several factors can affect tumor recurrence. This study aimed to analyze factors related to rectal cancer recurrence after curative resection using different machine learning techniques. Methods: Consecutive patients who underwent curative surgery for rectal cancer between 2004 and 2018 at Gil Medical Center were included. Patients with stage IV disease, colon cancer, anal cancer, other recurrent cancer, emergency surgery, or hereditary malignancies were excluded from the study. The Synthetic Minority Oversampling Technique with Tomek link (SMOTETomek) technique was used to compensate for data imbalance between recurrent and no-recurrent groups. Four machine learning methods, logistic regression (LR), support vector machine (SVM), random forest (RF), and Extreme gradient boosting (XGBoost), were used to identify significant factors. To overfit and improve the model performance, feature importance was calculated using the permutation importance technique. Results: A total of 3320 patients were included in the study. After exclusion, the total sample size of the study was 961 patients. The median follow-up period was 60.8 months (range:1.2–192.4). The recurrence rate during follow-up was 13.2% (n = 127). After applying the SMOTETomek method, the number of patients in both groups, recurrent and non-recurrent group were equalized to 667 patients. After analyzing for 16 variables, the top eight ranked variables {pathologic Tumor stage (pT), sex, concurrent chemoradiotherapy, pathologic Node stage (pN), age, postoperative chemotherapy, pathologic Tumor-Node-Metastasis stage (pTNM), and perineural invasion} were selected based on the order of permutational importance. The highest area under the curve (AUC) was for the SVM method (0.831). The sensitivity, specificity, and accuracy were found to be 0.692, 0.814, and 0.798, respectively. The lowest AUC was obtained for the XGBoost method (0.804), with a sensitivity, specificity, and accuracy of 0.308, 0.928, and 0.845, respectively. The variable with highest importance was pT as assessed through SVM, RF, and XGBoost (0.06, 0.12, and 0.13, respectively), whereas pTNM had the highest importance when assessed by LR (0.05). Conclusions: In the current study, SVM showed the best AUC, and the most influential factor across all machine learning methods except LR was found to be pT. The rectal cancer patients who have a high pT stage during postoperative follow-up are need to be more close surveillance. [ABSTRACT FROM AUTHOR]

Aim: The purpose of this meta-analysis is to compare the long-term efficacy of transanal local excision (TLE) versus total mesorectal excision (TME) following neoadjuvant therapy for rectal cancer. Method: The Web of Science, Pubmed, Medline, Embase, and the Cochrane Library were systematically searched for correlational research. The Newcastle-Ottawa Scale and the Cochrane risk of bias tool were used to assess the quality of cohort studies (CSs) and randomized controlled trials (RCTs), respectively. Statistically analyzed using RevMan5.4. Result: A total of 13 studies, including 3 randomized controlled trials (RCTs) and 10 cohort studies (CSs), involving 1402 patients, were included in the analysis. Of these, 570 patients (40.66%) underwent TLE, while 832 patients (59.34%) underwent TME. In the meta-analysis of CSs, no significant difference was observed between the TLE group and TME group regarding 5-year overall survival (OS) and 5-year disease-free survival (DFS) (P > 0.05). However, the TLE group had a higher rates of local recurrence (LR) [risk ratio (RR) = 1.93, 95%CI (1.18, 3.14), P = 0.008] and a lower rates of 5-years local recurrence-free survival (LRFS) [hazard ratio (HR) = 2.79, 95%CI (1.04, 7.50), P = 0.04] compared to the TME group. In the meta-analysis of RCTs, there was no significant difference observed between the TLE group and TME group in terms of LR, 5-year OS, 5-year DFS, and 5-year disease-specific survival (P > 0.05). Conclusion: After undergoing neoadjuvant therapy, TLE may provide comparable 5-year OS and DFS to TME for rectal cancer. However, neoadjuvant therapy followed by TLE may has a higher LR and lower 5-year LRFS compared to neoadjuvant therapy followed by TME, so patients should be carefully selected. Neoadjuvant therapy followed by TLE may be a suitable option for patients who prioritize postoperative quality of life. However, the effectiveness of this approach requires further research to draw a definitive conclusion. [ABSTRACT FROM AUTHOR]

Abstract The prevalence of pathological germline mutations in colorectal cancer has been widely studied, as germline mutations in the DNA mismatch repair genes hMLH1 and hMSH2 confer a high risk of colorectal cancer. However, because the sample size and population of previous studies are very different from each other, the conclusions still remain controversial. In this paper, Databases such as PubMed were applied to search for related papers. The data were imported into Comprehensive Meta-Analysis V2, which was used to estimate the weighted prevalence of hMLH1 and hMSH2 pathological mutations and compare the differences of prevalence among different family histories, ethnicities and related factors. This study collected and utilized data from 102 papers. In the Amsterdam-criteria positive group, the prevalence of pathological germline mutations of the hMLH1 and hMSH2 genes was 28.55% (95%CI 26.04%–31.19%) and 19.41% (95%CI 15.88%–23.51%), respectively, and the prevalence of germline mutations in hMLH1/hMSH2 was 15.44%/10.02%, 20.43%/13.26% and 15.43%/11.70% in Asian, American multiethnic and European/Australian populations, respectively. Substitution mutations accounted for the largest proportion of germline mutations (hMLH1: 52.34%, hMSH2: 43.25%). The total prevalence of mutations of hMLH1 and hMSH2 in Amsterdam-criteria positive, Amsterdam-criteria negative and sporadic colorectal cancers was around 45%, 25% and 15%, respectively, and there were no obvious differences in the prevalence of germline mutations among different ethnicities. [ABSTRACT FROM AUTHOR]

Introduction: Colorectal cancer (CRC) care costs the Australian healthcare system more than any other cancer. We estimated costs and days in hospital for CRC cases, stratified by site (colon/rectal cancer) and disease stage, to inform detailed analyses of CRC-related healthcare. Methods: Incident CRC patients were identified using the Australian 45 and Up Study cohort linked with cancer registry records. We analysed linked hospital admission records, emergency department records, and reimbursement records for government-subsidised medical services and prescription medicines. Cases' health system costs (2020 Australian dollars) and hospital days were compared with those for cancer-free controls (matched by age, sex, geography, smoking) to estimate excess resources by phase of care, analysed by sociodemographic, health, and disease characteristics. Results: 1200 colon and 546 rectal cancer cases were diagnosed 2006–2013, and followed up to June 2016. Eighty-nine percent of cases had surgery, chemotherapy or radiotherapy, and excess costs were predominantly for hospitalisations. Initial phase (12 months post-diagnosis) mean excess health system costs were $50,434 for colon and $60,877 for rectal cancer cases, with means of 16 and 18.5 excess hospital days, respectively. The annual continuing mean excess costs were $6,779 (colon) and $8,336 (rectal), with a mean of 2 excess hospital days each. Resources utilised (costs and days) in these phases increased with more advanced disease, comorbidities, and younger age. Mean excess costs in the year before death were $74,952 (colon) and $67,733 (rectal), with means of 34 and 30 excess hospital days, respectively–resources utilised were similar across all characteristics, apart from lower costs for cases aged ≥75 at diagnosis. Conclusions: Health system costs and hospital utilisation for CRC care are greater for people with more advanced disease. These findings provide a benchmark, and will help inform future cost-effectiveness analyses of potential approaches to CRC screening and treatment. [ABSTRACT FROM AUTHOR]

Purpose: The purpose of this study was to evaluate the usefulness of turbo spin-echo (TSE) DWI with fusion images in the T-staging compared with T2-weighted imaging (T2WI) alone and conventional echo-planner imaging (EPI) DWI. Methods: In this prospective study, 4-mm-thick axial EPI-DWI, TSE-DWI, and T2WI were performed with the same slice locations for 20 patients with rectal cancer. Fusion images of DWI and T2WI were created for both EPI-DWI and TSE-DWI. Ten readers independently diagnosed the T-stages and scored the degree of confidence referring to T2WI alone and then to DWI, T2WI, and fusion images (DWI+T2WI) for each EPI-DWI and TSE-DWI. Visual score assessments of image quality were performed for each DWI. Results: Inter-observer agreement of T-staging for 10 readers was slight on T2WI alone but fair on EPI-DWI+T2WI and excellent on TSE-DWI+T2WI images. No readers gave higher confidence scores for T2WI compared to EPI/TSE-DWI+T2WI and for EPI-DWI+T2WI compared to TSE-DWI+T2WI. In seven pathologically-proven cases, poor, poor to slight, and fair to perfect agreements with the pathological T-stage were observed with T2WI alone, EPI-DWI+T2WI, and TSE-DWI+T2WI, respectively. All readers gave higher scores regarding image distortion and lower scores regarding image noise for TSE-DWI compared to EPI-DWI. For DWI utility, higher scores were assigned for TSE-DWI compared to EPI-DWI in 7 readers and there were no significant differences in the other 3 readers. Conclusion: TSE-DWI images might be more appropriate for image fusion with T2WI and rectal cancer T-staging compared with EPI-DWI and T2WI alone. [ABSTRACT FROM AUTHOR]

Introduction: Low anterior resection (LAR) for rectal cancer affects bowel function after the operation, causing a group of symptoms known as LAR Syndrome (LARS). LARS score is a patient-reported questionnaire to assess bowel dysfunction after the LAR operation. This study performed to validate the Persian (Farsi) translation of the LARS score and to investigate the psychometric properties of the score. The impact of LARS on the Quality of Life (QoL) of patients was also assessed. Materials and methods: The LARS score was translated into Persian. Participants with a history of rectal cancer and low anterior resection were asked to complete the LARS score questionnaire. They were also asked a single question evaluating the impact of bowel function on QoL. Discriminative validity, convergent validity, sensitivity, and specificity of the questionnaire were calculated. A group of patients completed the score twice to assess the reliability of the questionnaire. Results: From 358 patients with rectal cancer, 101 participants completed the Persian questionnaire. Answers of a high fraction of participants showed a moderate/perfect fit between their LARS score and their QoL. The Persian score demonstrated good convergent validity. It was able to differentiate between participants in terms of gender and T staging of the primary tumor. The score had high reliability. Conclusion: The Persian translation of the LARS score has excellent psychometric properties compared to previous translations in other languages. Therefore, it is a valid and reliable questionnaire to assess LARS. [ABSTRACT FROM AUTHOR]

Background and purpose: Few tools are available to predict tumor response to treatment. This retrospective study assesses visual and automatic heterogeneity from 18F-FDG PET images as predictors of response in locally advanced rectal cancer. Methods: This study included 37 LARC patients who underwent an 18F-FDG PET before their neoadjuvant therapy. One expert segmented the tumor from the PET images. Blinded to the patient´s outcome, two experts established by consensus a visual score for tumor heterogeneity. Metabolic and texture parameters were extracted from the tumor area. Multivariate binary logistic regression with cross-validation was used to estimate the clinical relevance of these features. Area under the ROC Curve (AUC) of each model was evaluated. Histopathological tumor regression grade was the ground-truth. Results: Standard metabolic parameters could discriminate 50.1% of responders (AUC = 0.685). Visual heterogeneity classification showed correct assessment of the response in 75.4% of the sample (AUC = 0.759). Automatic quantitative evaluation of heterogeneity achieved a similar predictive capacity (73.1%, AUC = 0.815). Conclusion: A response prediction model in LARC based on tumor heterogeneity (assessed either visually or with automatic texture measurement) shows that texture features may complement the information provided by the metabolic parameters and increase prediction accuracy. [ABSTRACT FROM AUTHOR]

Aim: The optimal surgical management strategy for para-aortic lymph node (PALN) metastasis has not attracted as much attention as surgery for liver or lung metastasis. The purpose of this retrospective study was to evaluate the oncologic outcomes after synchronous resection of PALN metastasis in left-sided colon and rectal cancer. Methods: Between January 1986 and August 2016, 29 patients with pathologically positive PALN metastases who underwent curative resection at our hospital were retrospectively reviewed. We examined clinicopathological characteristics, long-term oncologic outcomes, and factors related to favorable prognosis in these patients. Results: The 3-year overall survival and recurrence-free survival (RFS) rates were 50.5% and 17.2%, respectively. In total, 6 (20.7%) patients experienced no recurrence in the 3 years after surgery, while postoperative complications were seen in 9 (31.0%) patients. The 3-year RFS rate was significantly better in the pM1a group than in the pM1b/pM1c group (26.3% and 0.0%, respectively, p = 0.032). Conclusion: PALN dissection for patients without other organ metastases in left-sided colon or rectal cancer is a good indication as it is for liver and lung metastasis. [ABSTRACT FROM AUTHOR]

Purpose: mARC (modulated arc) is the arc therapy technique provided by Siemens. The present study analyses the dose distributions and treatment times corresponding to preoperative rectal cancer mARC treatments. The results are compared to those corresponding to 3D-CRT plans. Methods: The plans of 30 patients, each having one mARC and one 3D-CRT plan, were evaluated. Every plan was calculated on a sequential two-phase treatment scheme with prescription doses of 45 Gy in the initial phase and 5.4 Gy in the boost phase. Dosimetric parameters and mean DVHs corresponding to the PTVs and OARs were assessed for both techniques. Results: All mARC plans were considered valid for treatment and yielded a highly significant improvement in the CI over 3D-CRT plans (p <0.001). They also showed statistically significant advantage on the parameters D98%, D95% and D2% of the high dose PTV. Regarding the OARs, mARC plans showed reductions in the mean dose of 3.5 Gy in the bladder and greater than 4 Gy in the femoral heads. Considering the small bowel, the mARC plans resulted in a 2.7 Gy mean reduction in the mean dose and lower irradiated volumes over the entire dose range. Conclusions: Arc therapy plans with the mARC technique for preoperative rectal cancer treatment in a sequential two-phase treatment scheme provide important advantages in the PTVs and OARs. mARC plans show superior protection of the femoral heads, bladder and small bowel, similar to the results found with other more widespread arc therapy techniques. [ABSTRACT FROM AUTHOR]

Background: Colorectal cancer (CRC) represents a major cause for cancer death and every third patient develops liver metastases (CRLM). Several factors including number and size of metastases and primary tumour lymph-node status have been linked to survival. The primary tumour location along the colo-rectum continuum (sidedness) was analysed in first-line chemotherapy trials, where right-sided CRCs showed decreased survival. This association has not yet been clearly established in patients undergoing resection for CRLM. Methods: Clinicopathological differences in CRLM resections according to sidedness in two Austrian centres (2003–2016) are described and survival is compared through Kaplan-Meier and multivariable analysis. A risk-score is presented with time-dependent receiver operating curve analysis and international validation in two major hepatobiliary centres. Furthermore, a systematic meta-analysis of studies on primary tumour location and survival after CRLM resection was performed. Results: 259 patients underwent hepatectomy. Right-sided CRC patients (n = 59) more often had positive primary tumour lymph-nodes (76.3%/61.3%;p = 0.043) and RAS-mutations (60%/34.9%;p = 0.036). The median overall and disease-free survival was 33.5 and 9.1 months in right-sided versus 55.5 (p = 0.051) and 12.1 months (p = 0.078) in left-sided patients. In multivariable analysis nodal-status (HR 1.52), right-sidedness (HR 1.53), extrahepatic disease (HR 1.71) and bilobar hepatic involvement (HR 1.41) were significantly associated with overall survival. Sidedness was not independently associated with disease-free survival (HR 1.33; p = 0.099). A clinical risk score including right-sidedness, nodal-positivity and extrahepatic involvement significantly predicted overall (p = 0.005) and disease-free survival (p = 0.027), which was confirmed by international validation in 527 patients (p = 0.001 and p = 0.011). Meta-analysis including 10 studies (n = 4312) showed a significant association of right-sidedness with overall survival after resection (HR 1.55;p<0.001). There was no significant association with disease-free survival (HR 1.22;p = 0.077), except when rectal-cancers were excluded (HR 1.39;p = 0.006). Conclusions: Patients with liver metastases from right-sided CRC experience worse survival after hepatic resection. Sidedness is a simple yet effective factor to predict outcome. [ABSTRACT FROM AUTHOR]

Background: Anastomotic leakage can be classified by free and contained leakage according to clinical manifestations. The risk factors and their comparison between these leakage subtypes are uncertain. This study aims to evaluate anastomotic leakage patterns and to compare clinical features between free and contained leakages after low anterior resection for rectal cancer. Materials and methods: Between January 2005 and December 2012, a total of 2035 consecutive patients who underwent low anterior resection for primary rectal cancer were evaluated retrospectively at two-tertiary referral centers. The primary end points of this study were to assess detailed clinical features among leakage subtypes. The secondary end point was to compare risk factors between free and contained leakages. Results: Patients were subdivided into a no leakage group (n = 1890), free leakage group (n = 73), and contained leakage group (n = 72). Free leakage occurred more frequently in laparoscopic and robotic surgeries than open surgery (p = 0.015). On the other hand, contained leakage was developed in a higher rate of patients who received preoperative chemoradiotherapy (p<0.001). The mean development time was 4.6 days in the free leakage group, and 23.6 days in the contained leakage group. Patients with free leakage had a lower rate of a defunctioning stoma than contained leakage (5.5% vs. 29.2%, p<0.001). Risk factors for free leakage were smoking, tumor location, and laparoscopic surgery. However, tumor location and preoperative chemoradiotherapy increased the risk for contained leakage. Conclusions: Contained leakage in rectal cancer surgery showed different clinical manifestations and risk factors compared to free leakage. It is necessary to pay more attention to patients with particular risk factors for anastomotic leakage subtypes. [ABSTRACT FROM AUTHOR]

Background: Recently, it has been questioned if minimally invasive surgery for rectal cancer was surgically successful. We decided to perform a meta-analysis to determine if minimally invasive surgery is adequate to obtain a complete resection for curable rectal cancer. Methods: A systematic search pertaining to evaluation between laparoscopic and open rectal resection for rectal cancer was performed until 30th November 2016 in the electronic databases (PubMed, Web of Science, Scopus, EMBASE), using the following search terms in all possible combinations: rectal cancer, laparoscopy, minimally invasive and open surgery. Outcomes analyzed were number of clear Distal Resection Margins (DRM or DM), complete Circumferential Resection Margins (CRM) and complete, nearly complete and incomplete Total Mesorectal Excision (TME) and of patients who received laparoscopic or open treatment for rectal cancer. Results: 12 articles were included in the final analysis. The prevalence of successful surgical resection was similar between open and laparoscopic surgery. About distance from distal margin of the specimen, clear CRM and complete TME there were no statistically significant difference between the two groups (MD = -0.090 cm, p = 0.364, 95% CI -0.283, 0.104; OR = 1.032, p = 0.821, 95% CI 0.784, 1.360; OR = 0.933, p = 0.720, 95% CI 0.638, 1.364, respectively). The analysis of nearly complete TME showed a significant difference between the two groups (OR = 1.407, p = 0.006, 95% CI 1.103, 1.795), while the analysis of incomplete TME showed a non-significant difference (OR = 1.010, p = 0.964, 95% CI 0.664, 1.534). Conclusions: By pooling together data from 5 RCTs and 7 nRCTs, we are able to provide evidence of safety and efficacy of minimally invasive surgery. Waiting for further randomized clinical trials, our results are encouraging to introduce laparoscopic rectal resection in daily practice. [ABSTRACT FROM AUTHOR]

Background and purpose: The role of preoperative short-course radiotherapy (SCRT) in rectal cancer treatment, when compared to long-course radiochemotherapy (LCRT), is still controversial. Thus the meta-analysis with trial sequential analysis (TSA) was performed to evaluate the long-term survival of SCRT and LCRT as therapeutic regimens for locally advanced rectal cancer. Material and methods: PubMed, Embase, and the Cochrane Central Register of Controlled Trials were searched up to August 2017 for eligible studies. Hazard ratios (HRs) or odds ratios (ORs) of overall survival (OS), disease free survival (DFS) and local recurrence (LR) with the corresponding 95% confidence intervals (CIs) were calculated and TSA was applied. Results: 11 studies with 1984 patients were included. There was no significant difference in OS (HR = 0.92, 95% CI: 0.75–1.13, p = 0.44), DFS (HR = 0.94, 95% CI: 0.79–1.12, p = 0.50) and LR (OR = 0.73, 95% CI: 0.49–1.08, p = 0.11) between SCRT and LCRT groups. TSA suggested firm evidence for lacking on average a -10% relative risk reduction (RRR) in 4-year OS but no statistical significance in 4-year DFS. Conclusions: Preoperative SCRT is as effective as LCRT for locally advanced colorectal cancer in long-term survival. SCRT could be preferential while facing long waiting lists or lacking medical resource. [ABSTRACT FROM AUTHOR]

Background: Neoadjuvant chemotherapy before radical gastrectomy is preferred for locally advanced gastric cancer. To avoid the problematic use of pTNM for patients after neoadjuvant chemotherapy, the Union for International Cancer Control (UICC) and the American Joint Committee on Cancer (AJCC) gastric cancer TNM staging system (8th edition) added ypTNM for the first time. But patients achieving pathological complete response were not covered by the new ypTNM staging system. To investigate whether pathological complete response is associated with better outcome in gastric cancer, as was reported in rectal, breast and bladder cancer. Methods: We systematically searched the databases of PubMed, EMBASE, Web of Science and Cochrane Collaboration’s Central register of controlled trials from January 1988 to April 2015 for publications which reported outcomes of patients with and without pathological complete response (pCR) (pT0N0M0) to investigate whether pCR after neoadjuvant chemotherapy in gastric or gastroesophageal junction (GEJ) treated with radical surgery is associated with better survival. The primary outcome was overall survival (OS). The secondary outcome was disease-free survival (DFS). Both were measured with a relative risk (RR). A meta-analysis was performed using the fixed effects model. Forest plots and the Q test was used to evaluate overall heterogeneity for OS and DFS. Results: A total of seven trials, 1143 patients were included and analyzed after neoadjuvant chemotherapy and radical surgery with no other preoperative treatment. The average rate of pCR was 6.74% (range: 3%-15%). The RR of patients who achieved pCR in the primary tumor and lymph nodes is 0.5 (95% confidence interval [CI], 0.25–0.98; p = 0.04), 0.34 (95% CI, 0.21–0.55; p<0.0001) and 0.44 (95% CI, 0.30–0.63; p<0.0001) for one-year-OS, three-year-OS and five-year-OS, respectively. The summary RR for three-year-DFS was 0.43 (95% CI, 0.25–0.72; p = 0.002). Conclusion: Patients with resectable gastric or GEJ cancer who achieved pCR after neoadjuvant chemotherapy can gain a better outcome than patients without pCR. [ABSTRACT FROM AUTHOR]

Purpose: Neoadjuvant therapy is able to reduce local recurrence in rectal cancer. Immediate surgery after short course radiotherapy allows only for minimal downstaging. We investigated the effect of delayed surgery after short-course radiotherapy at different time intervals before surgery, in patients affected by rectal cancer. Methods: From January 2003 to December 2013 sixty-seven patients with the following characteristics have been selected: clinical (c) stage T3N0 ≤ 12 cm from the anal verge and with circumferential resection margin > 5 mm (by magnetic resonance imaging); cT2, any N, < 5 cm from anal verge; and patients facing tumors with enlarged nodes and/or CRM+ve who resulted unfit for chemo-radiation, were also included. Patients underwent preoperative short-course radiotherapy with different interval to surgery were divided in three groups: A (within 6 weeks), B (between 6 and 8 weeks) and C (after more than 8 weeks). Hystopatolgical response to radiotherapy was measured by Mandard’s modified tumor regression grade (TRG). Results: All patients completed the scheduled treatment. Sixty-six patients underwent surgery. Fifty-three of which (80.3%) received a sphincter saving procedure. Downstaging occurred in 41 cases (62.1%). The analysis of subgroups showed an increasing prevalence of TRG 1–2 prolonging the interval to surgery (group A—16.7%, group B—36.8% and 54.3% in group C; p value 0.023). Conclusions: Preoperative short-course radiotherapy is able to downstage rectal cancer if surgery is delayed. A higher rate of TRG 1–2 can be obtained if interval to surgery is prolonged to more than 8 weeks. [ABSTRACT FROM AUTHOR]

Purpose/Objective(s): Optimal treatment for locally advanced rectal cancer (LARC) with distant metastasis remains elusive. We aimed to evaluate upfront systemic chemotherapy and short-course radiotherapy (RT) followed by delayed surgery for such patients, and to identify favorable prognostic factors. Materials/Methods: We retrospectively reviewed 50 LARC patients (cT4 or cT3, <2 mm from the mesorectal fascia) with synchronous metastatic disease. The primary endpoint was progression-free survival (PFS). The secondary endpoints were overall survival, treatment-related toxicity, and compliance. We considered P values <0.05 significant. Results: At 22 months median follow-up, the median PFS time was 16 months and the 2-year PFS rate was 34.8%. Thirty-five patients who received radical surgery for primary and metastatic tumors were designated the curable group. Six patients with clinical complete response (ypCR) of metastases who underwent radical surgery for only the primary tumor were classified as potentially curable. Nine patients who received no radical surgery (3 received palliative surgery) were deemed the palliative group. The ypCR rate among surgery patients was 13.6%. PFS rates for the curable or potentially curable groups were significantly longer than that of the palliative group (P<0.001). On multivariate analysis, solitary organ metastasis and R0 status were independent prognostic factors for PFS. Conclusions: These findings demonstrated that a strong possibility that upfront chemotherapy and short-course RT with delayed surgery are an effective alternative treatment for LARC with potentially resectable distant metastasis, owing to achievement of pathologic down-staging, R0 resection, and favorable compliance and toxicity, despite the long treatment duration. [ABSTRACT FROM AUTHOR]

Background: Lysosome-associated transmembrane-4 beta (LAPTM4B) is an oncogene that participates tumorgenesis in a variety of human solid tumors, and it has two alleles named as LAPTM4B*1 and *2. The present study aimed to identify the association of LAPTM4B genotype with clinicopathological features and prognosis in colorectal and esophageal cancer patients. Method: Genotypes of LAPTM4B were determined by PCR in 167 colon cancer cases (72 patients in a discovery cohort and 95 patients in a testing cohort), 160 rectal cancer cases and 164 esophageal cancer cases. Association between the LAPTM4B gene polymorphism and clinicopathological variables was calculated by Chi-square test or Fisher’s exact test. Patient survival differences were calculated by the Kaplan-Meier method. Prognostic factors were determined with Log-rank test and Cox regression model. Results: LAPTM4B *1/1 was more frequently detected in colon cancer patients with lymph node metastasis and TNM III+IV stages in total colon cancer (discovery + testing cohorts). LAPTM4B *2/2 decreased in recurrent patients in total colon cancer patients (P = 0.045). Kaplan-Meier survival curves and Log-rank test showed that LAPTM4B*1 was correlated with shorter overall survival (OS) in discovery and testing cohorts of colon cancer (P = 0.0254 and 0.0292, respectively), but not in rectal and esophageal cancer cases (P = 0.7669 and 0.9356, respectively). Multivariate analysis showed that LAPTM4B genotype was an independent prognostic factor for OS in total colon cancer [P = 0.004, hazard ratio (HR) = 0.432; 95% confidence interval (CI) = 0.243–0.768], but not in rectal and esophageal cancers (P = 0.791, HR = 1.073, 95% CI = 0.638–1.804 and 0.998, HR = 1.000, 95% CI = 0.663–1.530, respectively). Conclusion: These findings suggested that LAPTM4B allele *1 was a risk factor associated with poor prognosis in patients with colon cancer, but not in patients with rectal or esophageal cancers. LAPTM4B genotype status might be a useful prognostic indicator for patients that need surgical operation in colon cancer. [ABSTRACT FROM AUTHOR]

Introduction: An increasing number of studies have investigated microRNAs (miRNAs) as potential markers of diagnosis, treatment and prognosis. So far, agreement between studies has been minimal, which may in part be explained by intratumoral heterogeneity of miRNA expression. The aim of the present study was to assess the heterogeneity of a panel of selected miRNAs in rectal cancer, using two different technical approaches. Materials and Methods: The expression of the investigated miRNAs was analysed by real-time quantitative polymerase chain reaction (RT-qPCR) and in situ hybridization (ISH) in tumour specimens from 27 patients with T3-4 rectal cancer. From each tumour, tissue from three different luminal localisations was examined. Inter- and intra-patient variability was assessed by calculating intraclass correlation coefficients (ICCs). Correlations between RT-qPCR and ISH were evaluated using Spearman’s correlation. Results: ICCsingle (one sample from each patient) was higher than 50% for miRNA-21 and miRNA-31. For miRNA-125b, miRNA-145, and miRNA-630, ICCsingle was lower than 50%. The ICCmean (mean of three samples from each patient) was higher than 50% for miRNA-21(RT-qPCR and ISH), miRNA-125b (RT-qPCR and ISH), miRNA-145 (ISH), miRNA-630 (RT-qPCR), and miRNA-31 (RT-qPCR). For miRNA-145 (RT-qPCR) and miRNA-630 (ISH), ICCmean was lower than 50%. Spearman correlation coefficients, comparing results obtained by RT-qPCR and ISH, respectively, ranged from 0.084 to 0.325 for the mean value from each patient, and from -0.085 to 0.515 in the section including the deepest part of the tumour. Conclusion: Intratumoral heterogeneity may influence the measurement of miRNA expression and consequently the number of samples needed for representative estimates. Our findings with two different methods suggest that one sample is sufficient for adequate assessment of miRNA-21 and miRNA-31, whereas more samples would improve the assessment of miRNA-125b, miRNA-145, and miRNA-630. Interestingly, we found a poor correlation between the expression estimates obtained by RT-qPCR and ISH, respectively. [ABSTRACT FROM AUTHOR]

microRNAs (miRNA) repress messenger RNAs post-transcriptionally through binding to the 3’ UTR of the mRNA with the miRNA seed region. It has been purported that longer seed regions have a greater efficacy on mRNA repression. We tested this hypothesis by evaluating differential expression of miRNAs involved in regulating the immune response, an important mechanism in colorectal cancer (CRC), by seed length category. We subsequently evaluated differential expression of these miRNAs’ targets in colonic tissue and the impact of these miRNAs on CRC survival. We determined sequence complementarity between each miRNA seed region and the 3’ UTR of each experimentally verified mRNA target gene. We classified miRNAs into groups based on seed regions matching perfectly to a mRNA UTR with six bases beginning at position two, seven bases beginning at position one, seven bases beginning at position two, or eight bases beginning at position one. We analyzed these groups in terms of miRNA differential expression between carcinoma and normal colorectal mucosa, differential colonic target mRNA expression, and risk of dying from CRC. After correction for multiple comparisons, the proportion of the miRNAs that were associated with differential mRNA expression was 0% for the 6-mer, 13.64% for the 7α-mer group, 12.82% for the 7β-mer group, and 8.70% for the 8-mer group. The proportion of miRNAs associated with survival was 20% for the 6-mer group, 27.27% for the 7α-mer group, 10.23% for the 7β-mer group, and 21.74% for the 8-mer group. We did not see a linear relationship between seed length and miRNA expression dysregulation, mRNA expression, or survival. Our findings do not support the hypothesis the seed region length alone influences mRNA repression. [ABSTRACT FROM AUTHOR]

Objective: To evaluate the predictive value of the apparent diffusion coefficient (ADC) for pathologic complete response (pCR) to neoadjuvant chemoradiotherapy (NCRT) in locally advanced rectal cancer. Methods: A total of 265 patients with rectal adenocarcinoma, whole Diffusion-Weighted MRI (DWI-MRI) images, clinically stage II to III (cT3-4 and/or cN+) and treated with NCRT followed by TME were screened. Fifty patients with pCR and another 50 patients without pCR with similar clinical charcacters and treatment regimens were selected for statistical analysis. All the patients’ pre-CRT and post-CRT average ADC values were calculated from the coefficient maps created by DWI-MRI and recorded independently. The difference in the ADC values between the pCR and non-pCR was analyzed by the Mann-Whitney U test. The cut-off ADC value of the receiver operating characteristic (ROC) curve with pCR was then established. Results: The mean pre- and post-ADC values in all patients, and in pCR patients and non-pCR patients were 0.879±0.06 and 1.383±0.11, 0.859±0.04 and 1.440±0.10, 0.899±0.07 and 1.325±0.09 (×10-3mm2/s), respectively. The difference between the pre- and post-ADC values in all patients, pCR patients, and non-pCR patients were considered to be statistically significant. The pre-ADC value was significantly lower in the pCR patients than in the non-pCR patients (p = 0.003), whereas the post-ADC values were significantly higher in the pCR patients than in the non-pCR patients. The percentage increase of the ADC value (ΔADC%) in the pCR and non-pCR patients were 68% and 48% respectively (p<0.001). The ROC curves of the cut-off value of the pre-CRT patient ADC value was 0.866×10-3mm2/s. The AUC, sensitivity, specificity, PPV, NPV, and accuracy of diagnosing pCR were 0.670 (95% CI 0.563–0.777), 0.600, 0.640, 60%, 60%, and 60%, respectively. The cut-off value of ΔADC% was 58%. The corresponding AUC, sensitivity, specificity, PPV, NPV, and accuracy of diagnosing pCR were 0.856 (95% CI 0.783–0.930), 0.800, 0.760, 76.9%, 79.2%, and 78%, respectively. Conclusions: DWI-MRI technology can be efficient for predicting pCR for LARC after NCRT. Although the mean pre-CRT ADC value and the ΔADC% are moderate predictors for pCR, the latter would be more accurate. [ABSTRACT FROM AUTHOR]

Introduction: Anti-EGFR targeted therapy is of increasing importance in advanced colorectal cancer and prior KRAS mutation testing is mandatory for therapy. However, at which occasions this should be performed is still under debate. We aimed to assess in patients with locally advanced rectal cancer whether there is intra-specimen KRAS heterogeneity prior to and upon preoperative chemoradiotherapy (CRT), and if there are any changes in KRAS mutation status due to this intervention. Materials and Methods: KRAS mutation status analyses were performed in 199 tumor samples from 47 patients with rectal cancer. To evaluate the heterogeneity between different tumor areas within the same tumor prior to preoperative CRT, 114 biopsies from 34 patients (mean 3 biopsies per patient) were analyzed (pre-therapeutic intratumoral heterogeneity). For the assessment of heterogeneity after CRT residual tumor tissue (85 samples) from 12 patients (mean 4.2 tissue samples per patient) were analyzed (post-therapeutic intratumoral heterogeneity) and assessment of heterogeneity before and after CRT was evaluated in corresponding patient samples (interventional heterogeneity). Primer extension method (SNaPshot™) was used for initial KRAS mutation status testing for Codon 12, 13, 61, and 146. Discordant results by this method were reevaluated by using the FDA-approved KRAS Pyro Kit 24, V1 and the RAS Extension Pyro Kit 24, V1 Kit (therascreen® KRAS test). Results: For 20 (43%) out of the 47 patients, a KRAS mutation was detected. With 12 out of 20, the majority of these mutations affected codon 35. We did not obtained evidence that CRT results in changes of the KRAS mutation pattern. In addition, no intratumoral heterogeneity in the KRAS mutational status could be proven. This was true for both the biopsies prior to CRT and the resection specimens thereafter. The discrepancy observed in some samples when using the SNaPshot™ assay was due to insufficient sensitivity of this technique upon massive tumor regression by CRT as application of the therascreen® KRAS test revealed concordant results. Conclusion: Our results indicate that the KRAS mutation status at the primary tumor site of rectal cancer is homogenous. Its assessment for therapeutic decisions is feasible in pre-therapeutic biopsies as well as in post-therapeutic resected specimens. The amount of viable tumor cells seems to be an important determinant for assay sensitivity and should thus be considered for selection of the analytical method. [ABSTRACT FROM AUTHOR]

During a survey of clinical rectal prolapse (RP) cases in the mouse population at MIT animal research facilities, a high incidence of RP in the lamellipodin knock-out strain, C57BL/6-Raph1tm1Fbg (Lpd-/-) was documented. Upon further investigation, the Lpd-/- colony was found to be infected with multiple endemic enterohepatic Helicobacter species (EHS). Lpd-/- mice, a transgenic mouse strain produced at MIT, have not previously shown a distinct immune phenotype and are not highly susceptible to other opportunistic infections. Predominantly male Lpd-/- mice with RP exhibited lesions consistent with invasive rectal carcinoma concomitant to clinically evident RP. Multiple inflammatory cytokines, CD11b+Gr1+ myeloid-derived suppressor cell (MDSC) populations, and epithelial cells positive for a DNA damage biomarker, H2AX, were elevated in affected tissue, supporting their role in the neoplastic process. An evaluation of Lpd-/- mice with RP compared to EHS-infected, but clinically normal (CN) Lpd-/- animals indicated that all of these mice exhibit some degree of lower bowel inflammation; however, mice with prolapses had significantly higher degree of focal lesions at the colo-rectal junction. When Helicobacter spp. infections were eliminated in Lpd-/- mice by embryo transfer rederivation, the disease phenotype was abrogated, implicating EHS as a contributing factor in the development of rectal carcinoma. Here we describe lesions in Lpd-/- male mice consistent with a focal inflammation-induced neoplastic transformation and propose this strain as a mouse model of rectal carcinoma. [ABSTRACT FROM AUTHOR]

Background: Laparoscopic sphincter-preserving low anterior resection for rectal cancer is a surgery demanding great skill. Immense efforts have been devoted to identifying factors that can predict operative difficulty, but the results are inconsistent. Objective: Our study was conducted to screen patients’ factors to build models for predicting the operative difficulty using well controlled data. Method: We retrospectively reviewed records of 199 consecutive patients who had rectal cancers 5–8 cm from the anal verge. All underwent laparoscopic sphincter-preserving low anterior resections with total mesorectal excision (TME) and double stapling technique (DST). Data of 155 patients from one surgeon were utilized to build models to predict standardized endpoints (operative time, blood loss) and postoperative morbidity. Data of 44 patients from other surgeons were used to test the predictability of the built models. Results: Our results showed prior abdominal surgery, preoperative chemoradiotherapy, tumor distance to anal verge, interspinous distance, and BMI were predictors for the standardized operative times. Gender and tumor maximum diameter were related to the standardized blood loss. Temporary diversion and tumor diameter were predictors for postoperative morbidity. The model constructed for the operative time demonstrated excellent predictability for patients from different surgeons. Conclusions: With a well-controlled patient population, we have built a predictable model to estimate operative difficulty. The standardized operative time will make it possible to significantly increase sample size and build more reliable models to predict operative difficulty for clinical use. [ABSTRACT FROM AUTHOR]

Introduction: MicroRNAs (miRNAs) play important roles in regulating biological processes at the post-transcriptional level. Deregulation of miRNAs has been observed in cancer, and miRNAs are being investigated as potential biomarkers regarding diagnosis, prognosis and prediction in cancer management. Real-time quantitative polymerase chain reaction (RT-qPCR) is commonly used, when measuring miRNA expression. Appropriate normalisation of RT-qPCR data is important to ensure reliable results. The aim of the present study was to identify stably expressed miRNAs applicable as normaliser candidates in future studies of miRNA expression in rectal cancer. Materials and Methods: We performed high-throughput miRNA profiling (OpenArray®) on ten pairs of laser micro-dissected rectal cancer tissue and adjacent stroma. A global mean expression normalisation strategy was applied to identify the most stably expressed miRNAs for subsequent validation. In the first validation experiment, a panel of miRNAs were analysed on 25 pairs of micro dissected rectal cancer tissue and adjacent stroma. Subsequently, the same miRNAs were analysed in 28 pairs of rectal cancer tissue and normal rectal mucosa. Results: From the miRNA profiling experiment, miR-645, miR-193a-5p, miR-27a and let-7g were identified as stably expressed, both in malignant and stromal tissue. In addition, NormFinder confirmed high expression stability for the four miRNAs. In the RT-qPCR based validation experiments, no significant difference between tumour and stroma/normal rectal mucosa was detected for the mean of the normaliser candidates miR-27a, miR-193a-5p and let-7g (first validation P = 0.801, second validation P = 0.321). MiR-645 was excluded from the data analysis, because it was undetected in 35 of 50 samples (first validation) and in 24 of 56 samples (second validation), respectively. Significant difference in expression level of RNU6B was observed between tumour and adjacent stromal (first validation), and between tumour and normal rectal mucosa (second validation). Conclusion: We recommend the mean expression of miR-27a, miR-193a-5p and let-7g as normalisation factor, when performing miRNA expression analyses by RT-qPCR on rectal cancer tissue. [ABSTRACT FROM AUTHOR]

The aims of this study were to simultaneously evaluate the expression of Y-box binding protein-1 (YB-1) in non-neoplastic rectal tissue and rectal cancer tissue, and to collect clinical follow-up data for individual patients. Additionally, we aimed to investigate the developmental functions and prognostic value of YB-1 in rectal cancer. We performed immunohistochemical studies to examine YB-1 expression in tissue samples from 80 patients with rectal cancer, 30 patients with rectal tubular adenoma, and 30 patients with rectitis. The mean YB-1 histological scores for rectal cancer, rectal tubular adenoma, and rectitis tissue specimens were 205.5, 164.3, and 137.7, respectively. Shorter disease-free and overall survival times were found in patients with rectal cancer who had higher YB-1 expression than in those with lower expression (38.2 months vs. 52.4 months, P = 0.013; and 44.4 months vs. 57.3 months, P = 0.008, respectively). Our results indicate that YB-1 expression is higher in rectal cancer tissue than in rectal tubular adenoma and rectitis tissue and that it may be an independent prognostic factor for rectal cancer. [ABSTRACT FROM AUTHOR]

Urokinase plasminogen activator receptor (uPAR) has been proposed as a potential prognostic factor for colorectal cancer (CRC) patient survival. However, CRC uPAR expression remains controversial, especially regarding cell types where uPAR is overexpressed (e.g., epithelium (uPARE) or stroma-associated cells (uPARS)) and associated prognostic relevance. In this study, two epitope-specific anti-uPAR monoclonal antibodies (MAbs) could discriminate expression of uPARE from uPARS and were used to examine this association with survival of stages B and C rectal cancer (RC) patients. Using immunohistochemistry, MAbs #3937 and R4 were used to discriminate uPARE from uPARS respectively in the central and invasive frontal regions of 170 stage B and 179 stage C RC specimens. Kaplan-Meier and Cox regression analyses were used to determine association with survival. uPAR expression occurred in both epithelial and stromal compartments with differential expression observed in many cases, indicating uPARE and uPARS have different cellular roles. In the central and invasive frontal regions, uPARE was adversely associated with overall stage B survival (HR = 1.9; p = 0.014 and HR = 1.5; p = 0.031, respectively) reproducing results from previous studies. uPARS at the invasive front was associated with longer stage C survival (HR = 0.6; p = 0.007), reflecting studies demonstrating that macrophage peritumoural accumulation is associated with longer survival. This study demonstrates that different uPAR epitopes should be considered as being expressed on different cell types during tumour progression and at different stages in RC. Understanding how uPARE and uPARS expression affects survival is anticipated to be a useful clinical prognostic marker of stages B and C RC. [ABSTRACT FROM AUTHOR]

Background: The routine application of neoadjuvant chemoradiotherapy for T3N0 rectal cancer remains controversial. The aim of this study was to use clinical, Magnetic resonance imaging, and pathological parameters to identify a subgroup of patients with low risk of local recurrence who might be precluded from neoadjuvant chemoradiotherapy. Methods: We retrospectively reviewed a prospectively maintained database of consecutive rectal cancer patients who underwent curative resection. 166 pathologic confirmed T3N0 rectal cancer patients with tumor located 5–12cm above the anal verge and preoperative circumferential resection margin>1mm were included in analysis. The primary outcomes measured were3- and 5-year local recurrence rates. Results: Local recurrence was demonstrated during follow-up in 5 patients; the actuarial overall 3- and 5-year local recurrence rates were 2.5% and 3.4%, respectively. Inadequate sampling of lymph nodes (≤12) was associated with higher local recurrence (P = 0.03) in this group of patients. Conclusion: For upper and middle T3N0 rectal cancer with preoperative circumferential resection margin>1mm, local recurrence rate after total mesorectal excision is low and surgery alone may be enough for this group of patients. [ABSTRACT FROM AUTHOR]

Purpose: The aim of the study is to identify the risk factors of synchronous ILN metastasis for lower rectal cancer involving the anal canal. Methods: Patients with lower rectal cancer who underwent radical resection at the Fudan University Shanghai Cancer Center were retrospectively analyzed. The synchronous ILN metastasis was defined as the metastasis occurring within 6 months after the diagnosis of rectal cancer. Patients’ gender, age, tumor diameter, dentate line invasion, differentiation level, histological type, depth of invasion, perirectal LN metastasis, lymphovascular invasion or perineural invasion were analyzed in the study. The correlation between synchronous ILN involvement and clinicopathological features were analyzed with Chi-square test/fisher’s exact test. Variables with p<0.05 in univariate analysis were then analyzed in a multivariate logistic model. Odds ratio (OR) along with 95% confidence intervals (95% CI) were calculated. Results: A total of 325 patients (182 men and 143 women) with lower rectal cancer met the criteria and were enrolled in the study. Among them, 20 patients (6.2%) had synchronous ILN metastasis. Both univariate and multivariate analysis showed the invasion of the dentate line had a strong correlation with synchronous ILN metastasis with the odds ratio (OR) of 23.558 [95% confidence interval (CI) 6.380–86.982] (p<0.001). The presence of lymphovascular invasion also showed a significant correlation synchronous ILN metastasis with odds ratio (OR) of 5.260 [95% confidence interval (CI) 1.818–15.212] (p = 0.002). Conclusions: The invasion of dentate line and lymphovascular invasion are two independent risk factors of inguinal lymph node metastasis for lower rectal cancer involving the anal canal. [ABSTRACT FROM AUTHOR]

Background: Obesity is a known risk factor for colorectal cancer (CRC), and emerging data suggest that this association is mediated by visceral fat rather than total body fat. However, there is a lack of studies evaluating the association between visceral fat area and the prevalence of CRC. Methods: To investigate the relationship between visceral adiposity and prevalence of CRC, data of 497 women diagnosed with CRC and 318 apparently healthy women were analysed and data of well-balanced 191 pairs of women with CRC and healthy women matched based on propensity scores were additionally analysed. Diagnosis of CRC was confirmed by colonoscopy and histology. Metabolic parameters were assessed, along with body composition, using computed tomography. Results: The median visceral fat area was significantly higher in the CRC group compared with the control group before and after matching. The prevalence of CRC increased significantly with increasing visceral fat tertiles after matching (p for trend <0.01). A multivariate analysis showed that mean visceral fat area of individuals in the 67th percentile or greater group was associated with an increased prevalence of CRC (adjusted odds ratio: 1.80; 95% confidence interval: 1.12–2.91 before matching and adjusted odds ratio: 2.96; 95% confidence interval: 1.38–6.33) compared with that of individuals in the 33th percentile or lower group. Conclusion: Thus, we conclude that visceral fat area is positively associated with the prevalence of CRC. Although we could not determine the causality, visceral adiposity may be associated with the risk of CRC. Further prospective studies are required to determine the benefits of controlling visceral obesity for reducing CRC risk. [ABSTRACT FROM AUTHOR]

Objective: We elected to analyze the correlation between the pre-treatment apparent diffusion coefficient (ADC) and the clinical, histological, and immunohistochemical status of rectal cancers. Materials and Methods: Forty-nine rectal cancer patients who received surgical resection without neoadjuvant therapy were selected that underwent primary MRI and diffusion-weighted imaging (DWI). Tumor ADC values were determined and analyzed to identify any correlations between these values and pre-treatment CEA or CA19-9 levels, and/or the histological and immunohistochemical properties of the tumor. Results: Inter-observer agreement of confidence levels from two separate observers was suitable for ADC measurement (k  =  0.775). The pre-treatment ADC values of different T stage tumors were not equal (p  =  0.003). The overall trend was that higher T stage values correlated with lower ADC values. ADC values were also significantly lower for the following conditions: tumors with the presence of extranodal tumor deposits (p  =  0.006) and tumors with CA19-9 levels ≥ 35 g/ml (p  =  0.006). There was a negative correlation between Ki-67 LI and the ADC value (r  =  −0.318, p  =  0.026) and between the AgNOR count and the ADC value (r  =  −0.310, p  =  0.030). Conclusion: Significant correlations were found between the pre-treatment ADC values and T stage, extranodal tumor deposits, CA19-9 levels, Ki-67 LI, and AgNOR counts in our study. Lower ADC values were associated with more aggressive tumor behavior. Therefore, the ADC value may represent a useful biomarker for assessing the biological features and possible relationship to the status of identified rectal cancers. [ABSTRACT FROM AUTHOR]

Objective: To assess the impact of oxaliplatin-containing adjuvant chemotherapy on the survival of patients with locally-advanced rectal cancer. Methods: Data on patients with pathologically-confirmed T3/4 or N1/2 rectal cancer who accepted radical surgery at our center from January 2002 to June 2009 were reviewed retrospectively. The patients' 5-year overall survival (OS), disease-specific survival (DSS), and recurrence-free survival (RFS) were analyzed by comparing those who accepted radical surgery only (Group S) with those who accepted radical surgery and oxaliplatin-containing adjuvant chemotherapy (Group SO). Results: A total of 236 patients were analyzed (Group S 135; Group SO 101). Group S patients were older and had a higher proportion with stage II disease and more perioperative complications than those in Group SO (P<0.05). The OS and DSS of patients with stage III disease under 50 years of age or with mucinous adenocarcinoma were higher in Group SO than Group S (P<0.05). In addition, the OS of patients with stage N2b disease was higher in Group SO than Group S (P = 0.016), and the OS of patients with stage N1a or N2b disease who received more than 8 weeks of oxaliplatin-containing chemotherapy was also higher in Group SO than Group S (P<0.05). Although the OS and DSS of patients with stage II disease in Group SO showed a tendency towards improvement, the differences between the groups were not statistically significant. Conclusion: Adjuvant oxaliplatin-containing chemotherapy can improve the survival of patients with locally-advanced low and middle rectal cancers in comparison with observation. Randomized, prospective trials are warranted to confirm this benefit of oxaliplatin for rectal cancer. [ABSTRACT FROM AUTHOR]

Aim: To develop prognostic nomograms for predicting outcomes in patients with locally advanced rectal cancers who do not receive preoperative treatment. Materials and Methods: A total of 883 patients with stage II–III rectal cancers were retrospectively collected from a single institution. Survival analyses were performed to assess each variable for overall survival (OS), local recurrence (LR) and distant metastases (DM). Cox models were performed to develop a predictive model for each endpoint. The performance of model prediction was validated by cross validation and on an independent group of patients. Results: The 5-year LR, DM and OS rates were 22.3%, 32.7% and 63.8%, respectively. Two prognostic nomograms were successfully developed to predict 5-year OS and DM-free survival rates, with c-index of 0.70 (95% CI = [0.66, 0.73]) and 0.68 (95% CI = [0.64, 0.72]) on the original dataset, and 0.76 (95% CI = [0.67, 0.86]) and 0.73 (95% CI = [0.63, 0.83]) on the validation dataset, respectively. Factors in our models included age, gender, carcinoembryonic antigen value, tumor location, T stage, N stage, metastatic lymph nodes ratio, adjuvant chemotherapy and chemoradiotherapy. Predicted by our nomogram, substantial variability in terms of 5-year OS and DM-free survival was observed within each TNM stage category. Conclusions: The prognostic nomograms integrated demographic and clinicopathological factors to account for tumor and patient heterogeneity, and thereby provided a more individualized outcome prognostication. Our individualized prediction nomograms could help patients with preoperatively under-staged rectal cancer about their postoperative treatment strategies and follow-up protocols. [ABSTRACT FROM AUTHOR]

Background: Previous epidemiologic studies have reported that a history of allergy is associated with reduced risk of colorectal cancer and other malignancies. However, no information is available for the association between allergy and the risk of lymph node metastasis. Our study was designed to determine this association in rectal cancer. Methods: Patients who were treated at our hospital in the period from January 2003 to June 2011, and with a pathologically hospital discharge diagnosis of rectal adencarcinoma, were included. The clinical, laboratory, and pathologic parameters were analyzed. A multivariate logistic regression model was used to determine the association. Moreover, for type of allergic drug, sub-group analysis was performed. Results: 469 patients were included, including 231 with pathological lymph node metastasis (pLNM) (49.3%) and 238 without pLNM. Univariate analysis showed, compared with patients without pLNM, patients with pLNM had a younger age (60.6±12.8 yr vs. 63.6±12.2 yr, P = 0.012), a lower percentage of drug allergy (8.7% vs. 16.0%, P = 0.016), an increased CEA (median/interquartile-range 5.40/2.40–13.95 vs. 3.50/2.08–8.67, P = 0.009), and a lower serum sodium (141±3.1 mmol/L vs. 142±2.9 mmol/L, P = 0.028). Multivariate analysis showed that drug allergy was associated with a reduced risk of pLNM (OR = 0.553; 95% CI, 0.308–0.994; P = 0.048). In addition, our results showed that: (1) for tumor classification, patients with drug allergy had a higher percentage of group patients with pT1/pT2; and (2) for type of allergic drug, this inverse association was found for penicillins, not for other allergic drugs. Conclusion: Drug allergy is associated with a reduced risk of pLNM in rectal cancer. [ABSTRACT FROM AUTHOR]

Metastasis is the main cause of mortality in patients with solid tumours. Identifying the exact molecules associated with CRC metastasis may be crucial to understand the process, which might also be translated to the diagnosis and treatment of CRC. In this study, we investigate the association of microRNA expression patterns with the lymph node metastasis of colorectal cancer. Among these candidate miRNAs, the expression of miRNA-145 was significantly related to lymph node metastasis of CRC. Both in vitro and in vivo study demonstrated that up-regulation of miR-145 could improve the ability of migration and invasion of colorectal cancer cell, while no effect on proliferation was observed. The mechanism of this promotion is associated with the stabilization of Hsp-27, a protein which plays an important role in the promotion of metastasis. These results may be crucial to understanding CRC metastasis and may be translated to the diagnosis and treatment of CRC. [ABSTRACT FROM AUTHOR]

Formalin fixed and paraffin-embedded human tissue resected during cancer surgery is indispensable for diagnostic and therapeutic purposes and represents a vast and largely unexploited resource for research. Optical microscopy of such specimen is curtailed by the diffraction-limited resolution of conventional optical microscopy. To overcome this limitation, we used STED super-resolution microscopy enabling optical resolution well below the diffraction barrier. We visualized nanoscale protein distributions in sections of well-annotated paraffin-embedded human rectal cancer tissue stored in a clinical repository. Using antisera against several mitochondrial proteins, STED microscopy revealed distinct sub-mitochondrial protein distributions, suggesting a high level of structural preservation. Analysis of human tissues stored for up to 17 years demonstrated that these samples were still amenable for super-resolution microscopy. STED microscopy of sections of HER2 positive rectal adenocarcinoma revealed details in the surface and intracellular HER2 distribution that were blurred in the corresponding conventional images, demonstrating the potential of super-resolution microscopy to explore the thus far largely untapped nanoscale regime in tissues stored in biorepositories. [ABSTRACT FROM AUTHOR]

Background: Fomitopsis pinicola (Sw. Ex Fr.m) Karst (FPK) which belongs to the Basidiomycota fungal class is one of the most popular medical fungi in China. It has been used for many diseases: cancer, heart diseases, diabetes and so on. However, little study on the pro-apoptotic effect and migration inhibition of FPK chloroform extract (FPKc) has been reported and the possible involved mechanism has not been illuminated. Methodology/Principal Findings: Chemical analysis was performed by HPLC which showed ergosterol (ES) concentration was 105 µg/mg. MTT assay revealed that FPKc could selectively inhibit SW-480 cells viability with the IC50 of 190.28 µg/ml. Wound healing and transwell assay indicated that FPKc could inhibit the migration of SW-480 cells obviously, FPKc could also dramatically decreased the matrix metalloproteinases-2, 9 (MMP-2 and MMP-9) expression. Annexin V–FITC/PI staining, nuclear Hoechst 33342 staining and DNA fragmentation analysis revealed that FPKc and ES could induce SW-480 cells apoptosis. The apoptosis process closely involved in ROS accumulation and depletion of GSH, activation of caspase 3, poly (ADP-ribose) polymerase (PARP) degradation. FPKc could also up-regulate P53 expression and thus lead to G1 phase arrest. When SW-480 cells were pretreated with N-acetylcysteine (NAC), the ROS generation, cell viability and apoptotic ratio were partially declined, which indicated that ROS was vertical in the pro-apoptosis process induced by FPKc. Moreover, in the whole process, ES which has been previously found in FPKc had the similar effect to FPKc. Thus we could conclude that ES, as one of the highest abundant components in FPKc, might also be one of the active constituents. Conclusion/Significance: FPKc could inhibit the migration of SW-480 cells, induce SW-480 cells G1 phase arrest and cause ROS-mediated apoptosis effect. And ES might be one of the effective constituents in the whole process. [ABSTRACT FROM AUTHOR]

Background: The triblock copolymers PEG-P(Asp-DIP)-P(Lys-Ca) (PEALCa) of polyethylene glycol (PEG), poly(N-(N’,N’-diisopropylaminoethyl) aspartamide) (P(Asp-DIP)), and poly (lysine-cholic acid) (P(Lys-Ca)) were synthesized as a pH-sensitive drug delivery system. In neutral aqueous environment such as physiological environment, PEALCa can self-assemble into stable vesicles with a size around 50-60 nm, avoid uptake by the reticuloendothelial system (RES), and encase the drug in the core. However, the PEALCa micelles disassemble and release drug rapidly in acidic environment that resembles lysosomal compartments. Methodology/Principal Findings: The anticancer drug Paclitaxel (PTX) and hydrophilic superparamagnetic iron oxide (SPIO) were encapsulated inside the core of the PEALCa micelles and used for potential cancer therapy. Drug release study revealed that PTX in the micelles was released faster at pH 5.0 than at pH 7.4. Cell culture studies showed that the PTX-SPIO-PEALCa micelle was effectively internalized by human colon carcinoma cell line (LoVo cells), and PTX could be embedded inside lysosomal compartments. Moreover, the human colorectal carcinoma (CRC) LoVo cells delivery effect was verified in vivo by magnetic resonance imaging (MRI) and histology analysis. Consequently effective suppression of CRC LoVo cell growth was evaluated. Conclusions/Significance: These results indicated that the PTX-SPION-loaded pH-sensitive micelles were a promising MRI-visible drug release system for colorectal cancer therapy. [ABSTRACT FROM AUTHOR]

Background: The aberrant regulation of phosphatidylinositide 3-kinases (PI3-K)/Akt, AMP-activated protein kinase (AMPK) and mammalian target of rapamycin (m-TOR) signaling pathways in cancer has prompted significant interest in the suppression of these pathways to treat cancer. Caffeic acid (CA) has been reported to possess important anti-inflammatory actions. However, the molecular mechanisms by which CA derivatives including caffeic acid phenethyl ester (CAPE) and caffeic acid phenylpropyl ester (CAPPE), exert inhibitory effects on the proliferation of human colorectal cancer (CRC) cells have yet to be elucidated. Methodology/Principal Findings: CAPE and CAPPE were evaluated for their ability to modulate these signaling pathways and suppress the proliferation of CRC cells both in vitro and in vivo. Anti-cancer effects of these CA derivatives were measured by using proliferation assays, cell cycle analysis, western blotting assay, reporter gene assay and immunohistochemical (IHC) staining assays both in vitro and in vivo. This study demonstrates that CAPE and CAPPE exhibit a dose-dependent inhibition of proliferation and survival of CRC cells through the induction of G0/G1 cell cycle arrest and augmentation of apoptotic pathways. Consumption of CAPE and CAPPE significantly inhibited the growth of colorectal tumors in a mouse xenograft model. The mechanisms of action included a modulation of PI3-K/Akt, AMPK and m-TOR signaling cascades both in vitro and in vivo. In conclusion, the results demonstrate novel anti-cancer mechanisms of CA derivatives against the growth of human CRC cells. Conclusions: CA derivatives are potent anti-cancer agents that augment AMPK activation and promote apoptosis in human CRC cells. The structure of CA derivatives can be used for the rational design of novel inhibitors that target human CRC cells. [ABSTRACT FROM AUTHOR]

Application of textural features analysis to 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography (PET) images has been used to characterize intra-tumor uptake heterogeneity and has been shown to reflect disease outcome. A current hypothesis is that 18F-FDG uptake heterogeneity may reflect the physiological tracer uptake related to tumor perfusion. The purpose of our study was to investigate the correlations between intra-tumor uptake heterogeneity and vascular parameters derived from dynamic contrast enhanced (DCE) computed tomography (CT) obtained from an integrated 18F-FDG PET/perfusion CT examination. Methods: Thirty patients with proven colorectal cancer prospectively underwent integrated 18F-FDG PET/DCE-CT to assess the metabolic-flow phenotype. Both CT blood flow parametric maps and PET images were analyzed. Correlations between PET heterogeneity and perfusion CT were assessed by Spearman's rank correlation analysis. Results: Blood flow visualization provided by DCE-CT images was significantly correlated with 18F-FDG PET metabolically active tumor volume as well as with uptake heterogeneity for patients with stage III/IV tumors (|ρ|:0.66 to 0.78; p-value<0.02). Conclusion: The positive correlation found with tumor blood flow indicates that intra-tumor heterogeneity of 18F-FDG PET accumulation reflects to some extent tracer distribution and consequently indicates that 18F-FDG PET intra-tumor heterogeneity may be associated with physiological processes such as tumor vascularization. [ABSTRACT FROM AUTHOR]

Background: Tryptase is a serin protease stored and released from mast cells (MCs) that plays a role in tumour angiogenesis. In this study we aimed to evaluate serum tryptase levels in colo-rectal cancer (CRC) patients before (STLBS) and after (STLAS) radical surgical resection. We also evaluated mast cell density positive to tryptase (MCDPT) and microvascular density (MVD) in primary tumour tissue. Methods: A series of 61 patients with stage B and C CRC (according to the Astler and Coller staging system) were selected. Serum blood samples were collected from patients one day before and one day after surgery. Tryptase levels were measured using the UniCAP Tryptase Fluoroenzymeimmunoassay (Pharmacia, Uppsala, Sweden). Tumour sections were immunostained with a primary anti-tryptase antibody (clone AA1; Dako, Glostrup, Denmark) and an anti CD-34 antibody (QB-END 10; Bio-Optica Milan, Italy) by means of immunohistochemistry and then evaluated by image analysis methods. Results: The mean ± s.d. STLBS and STLAS was 5.63±2.61 µg/L, and 3.39±1.47 µg/L respectively and a significant difference between mean levels was found: p = 0.000 by t-test. The mean ± s.d. of MCDPT and MVD was 8.13±3.28 and 29.16±7.39 respectively. A strong correlation between STLBS and MVD (r = 0.83, p = 0.000); STLBS and MCDPT (r = 0.60, p = 0.003); and MCDPT and MVD (r = 0.73; p = 0.001) was found. Conclusion: Results demonstrated higher STLBS in CRC patients, indicating an involvement of MC tryptase in CRC angiogenesis. Data also indicated lower STLAS, suggesting the release of tryptase from tumour-infiltrating MCs. Serum tryptase levels may therefore play a role as a novel bio-marker predictive of response to radical surgery. In this context tryptase inhibitors such as Gabexate and Nafamostat Mesilate might be evaluated in adjuvant clinical trials as a new anti-angiogenic approach. [ABSTRACT FROM AUTHOR]

Background: Mutant p53 protein over-expression has been reported to induce serum antibodies against p53. We assessed the diagnostic precision of serum p53 (s-p53) antibodies for diagnosis of cancer patients and compared the positive rates of the s-p53 antibody in different types of cancers. Methods: We systematically searched PubMed and Embase, through May 31, 2012. Studies were assessed for quality using QUADAS (quality assessment of studies of diagnostic accuracy). The positive likelihood ratio (PLR) and negative likelihood ratio (NLR) were pooled separately and compared with overall accuracy measures using diagnostic odds ratios (DORs) and Area under the curve(AUC). Meta regression and subgroup analyses were done, and heterogeneity and publication bias were assessed. Results: Of 1089 studies initially identified, 100 eligible studies with 23 different types of tumor met the inclusion criteria for the meta-analysis (cases = 15953, controls = 8694). However, we could conduct independent meta analysis on only 13 of 36 types of tumors. Approximately 56% (56/100) of the included studies were of high quality (QUADAS score≥8). The summary estimates for quantitative analysis of serum p53 antibody in the diagnosis of cancers were: PLR 5.75 (95% CI: 4.60–7.19), NLR 0.81 (95%CI: 0.79–0.83) and DOR 7.56 (95% CI: 6.02–9.50). However, for the 13 types of cancers on which meta-analysis was conducted, the ranges for PLR (2.33–11.05), NLR (0.74–0.97), DOR (2.86–13.80), AUC(0.29–0.81), and positive rate (4.47%–28.36%) indicated significant heterogeneity. We found that breast, colorectal, esophageal, gastric, hepatic, lymphoma, lung and ovarian cancer had relatively reasonable diagnostic accuracy. The remaining results of the five types of cancers suggested that s-p53 antibody had limited value. Conclusions: The current evidence suggests that s-p53 antibody has potential diagnostic value for cancer, especially for breast, colorectal, esophageal, gastric, hepatic, lymphoma, lung and ovarian cancer. The results showed that s-p53 antibody had high correlation with cancers. [ABSTRACT FROM AUTHOR]

A hypoxic microenvironment in tumors has been recognized as a cause of malignancy or resistance to various cancer therapies. In contrast to recent progress in understanding the acute response of cancer cells to hypoxia, the characteristics of tumor cells in chronic hypoxia remain elusive. We have identified a pancreatic cancer cell line, AsPC-1, that is exceptionally able to survive for weeks under 1% oxygen conditions while most tested cancer cell lines die after only some days under these conditions. In chronic hypoxia, AsPC-1 cells entered a state of dormancy characterized by no proliferation, no death, and metabolic suppression. They reversibly switched to active status after being placed again in optimal culture conditions. ATP turnover, an indicator of energy demand, was markedly decreased and accompanied by reduced AKT phosphorylation. Forced activation of AKT resulted in increased ATP turnover and massive cell death in vitro and a decreased number of dormant cells in vivo. In contrast to most cancer cell lines, primary-cultured colorectal cancer cells easily entered the dormant status with AKT suppression under hypoxia combined with growth factor–depleted conditions. Primary colorectal cancer cells in dormancy were resistant to chemotherapy. Thus, the ability to survive in a deteriorated microenvironment by entering into dormancy under chronic hypoxia might be a common property among cancer cells. Targeting the regulatory mechanism inducing this dormant status could provide a new strategy for treating cancer. [ABSTRACT FROM AUTHOR]

Chemoresistance in multidrug-resistant (MDR) cells over expressing P-glycoprotein (P-gp) encoded by the MDR1 gene, is a major obstacle to successful chemotherapy for colorectal cancer. Previous studies have indicated that sinomenine can enhance the absorption of various P-gp substrates. In the present study, we investigated the effect of sinomenine on the chemoresistance in colon cancer cells and explored the underlying mechanism. We developed multidrug-resistant Caco-2 (MDR-Caco-2) cells by exposure of Caco-2 cells to increasing concentrations of doxorubicin. We identified overexpression of COX-2 and MDR-1 genes as well as activation of the NF-κB signal pathway in MDR-Caco-2 cells. Importantly, we found that sinomenine enhances the sensitivity of MDR-Caco-2 cells towards doxorubicin by downregulating MDR-1 and COX-2 expression through inhibition of the NF-κB signaling pathway. These findings provide a new potential strategy for the reversal of P-gp-mediated anticancer drug resistance. [ABSTRACT FROM AUTHOR]