Regenerative proliferation of differentiated cells by mTORC1-dependent paligenosis.

In 1900, Adami speculated that a sequence of context-independent energetic and structural changes governed the reversion of differentiated cells to a proliferative, regenerative state. Accordingly, we show here that differentiated cells in diverse organs become proliferative via a shared program. Metaplasia-inducing injury caused both gastric chief and pancreatic acinar cells to decrease mTORC1 activity and massively upregulate lysosomes/autophagosomes; then increase damage associated metaplastic genes such as Sox9; and finally reactivate mTORC1 and re-enter the cell cycle. Blocking mTORC1 permitted autophagy and metaplastic gene induction but blocked cell cycle re-entry at S-phase. In kidney and liver regeneration and in human gastric metaplasia, mTORC1 also correlated with proliferation. In lysosome-defective Gnptab-/- mice, both metaplasia-associated gene expression changes and mTORC1-mediated proliferation were deficient in pancreas and stomach. Our findings indicate differentiated cells become proliferative using a sequential program with intervening checkpoints: (i) differentiated cell structure degradation; (ii) metaplasia- or progenitor-associated gene induction; (iii) cell cycle re-entry. We propose this program, which we term "paligenosis", is a fundamental process, like apoptosis, available to differentiated cells to fuel regeneration following injury.

DDIT4 Licenses Only Healthy Cells to Proliferate During Injury-induced Metaplasia.

BACKGROUND AND AIMS: In stomach, metaplasia can arise from differentiated chief cells that become mitotic via paligenosis, a stepwise program. In paligenosis, mitosis initiation requires reactivation of the cellular energy hub mTORC1 after initial mTORC1 suppression by DNA damage induced transcript 4 (DDIT4 aka REDD1). Here, we use DDIT4-deficient mice and human cells to study how metaplasia increases tumorigenesis risk. METHODS: A tissue microarray of human gastric tissue specimens was analyzed by immunohistochemistry for DDIT4. C57BL/6 mice were administered combinations of intraperitoneal injections of high-dose tamoxifen (TAM) to induce spasmolytic polypeptide-expressing metaplasia (SPEM) and rapamycin to block mTORC1 activity, and N-methyl-N-nitrosourea (MNU) in drinking water to induce spontaneous gastric tumors. Stomachs were analyzed for proliferation, DNA damage, and tumor formation. CRISPR/Cas9-generated DDIT4-/- and control human gastric cells were analyzed for growth in vitro and in xenografts with and without 5-fluorouracil (5-FU) treatment. RESULTS: DDIT4 was expressed in normal gastric chief cells in mice and humans and decreased as chief cells became metaplastic. Paligenotic Ddit4-/- chief cells maintained constitutively high mTORC1, causing increased mitosis of metaplastic cells despite DNA damage. Lower DDIT4 expression correlated with longer survival of patients with gastric cancer. 5-FU-treated DDIT4-/- human gastric epithelial cells had significantly increased cells entering mitosis despite DNA damage and increased proliferation in vitro and in xenografts. MNU-treated Ddit4-/- mice had increased spontaneous tumorigenesis after multiple rounds of paligenosis induced by TAM. CONCLUSIONS: During injury-induced metaplastic proliferation, failure of licensing mTORC1 reactivation correlates with increased proliferation of cells harboring DNA damage, as well as increased tumor formation and growth in mice and humans.

Survival Benefit from Surgical Resection in Lung Cancer Patients with Brain Metastases: a Single-Center, Propensity-Matched Analysis Cohort Study.

BACKGROUND: Brain metastases (BMs) are the most serious complication of lung cancer, affecting the prognosis of lung cancer patients, and pose distinct clinical challenges. This study was designed to explore the prognostic factors related to lung cancer BM and the value of surgical resection in BMs from lung cancer. METHODS: A retrospective analysis was performed on 714 patients with lung cancer BMs screened between January 2010 and January 2018 at the Sun Yat-sen University Cancer Center. A 1:1 propensity score matching analysis was performed to reduce the potential bias between the surgery and the nonsurgery group. In both the raw and the propensity-score matched dataset, univariate and multivariate Cox proportional hazards regression analyses were used to evaluate risk factors for survival. RESULTS: After matching, 258 patients (129 surgery, 129 no surgery) were analyzed. Multivariate analyses after propensity score matching demonstrated that surgical resection was an independent protective factor for overall survival (OS), and older age, lower Karnofsky Performance Scale (KPS) score, and extracranial metastases were independent risk factors for worse OS. Patients without extracranial metastases, without synchronous BM and with a single BM had a better prognosis. CONCLUSIONS: The findings showed that surgical resection, age, KPS score, and extracranial metastases are independent prognostic factors for predicting the OS of patients with lung cancer BMs, and surgical resection for brain metastatic lesions could significantly improve the OS. However, only certain groups of patients with BMs can benefit from intracranial lesion resection, such as no extracranial metastases and metachronous metastases.

Survival landscape of different tumor regression grades and pathologic complete response in rectal cancer after neoadjuvant therapy based on reconstructed individual patient data.

BACKGROUND: Neoadjuvant therapy can lead to different tumor regression grades (TRG) in rectal cancer after neoadjuvant therapy. The purposes of this study are to investigate the relationships among TRG, pathologic complete response (pCR) and long-term survival, on the basis of reconstructed individual patient data (IPD). METHODS: The PubMed, Embase, Ovid and Cochrane CENTRAL databases were searched. The primary endpoint was to evaluate the survival landscape of different TRGs after neoadjuvant therapy and the secondary endpoint was to evaluate the associations between pCR and survival. IPD were reconstructed with Kaplan-Meier curves. RESULTS: The 10-year overall survival (OS) and 5-year disease-free survival (DFS) were clearly higher in the pCR group than in the non-pCR (npCR) group (80.5% vs. 48.3, 90.1% vs. 69.8%). Furthermore, the OS and DFS increased with improvement in tumor regression after neoadjuvant therapy. According to the IPD, the pCR group had longer OS (HR = 0.240, 95% CI = 0.177-0.325, p < 0.001) and DFS (HR = 0.274, 95% CI = 0.205-0.367, p < 0.001) than the npCR group. Better tumor regression was associated with better survival outcomes (p < 0.005). Direct calculation of published HR values yielded similar results. CONCLUSIONS: Our results indicate a positive relationship between better tumor regressions and improved survival benefits among the npCR group and patients with rectal cancer achieving pCR had much longer OS and DFS than patients achieving npCR, presenting a survival landscape of different TRGs and pCR in rectal cancer after neoadjuvant therapy.

Efficacy and safety of modified endoscopic mucosal resection for rectal neuroendocrine tumors: a meta-analysis.

PURPOSE: Rectal neuroendocrine tumors are rare with good prognosis. Several endoscopic methods such as endoscopic polypectomy, endoscopic submucosal dissection (ESD), endoscopic mucosal resection (EMR), and modified endoscopic mucosal resection (m-EMR) are used in the treatment of rectal neuroendocrine tumors. Although m-EMR is derived from traditional EMR, it has not been widely used in clinical practice. In this study, we compared the efficacy and safety of EMR and m-EMR in the treatment of rectal neuroendocrine tumors by performing a meta-analysis. MATERIALS AND METHODS: We searched PubMed, Web of Science, and EMBASE index up to the end of January 2017 for all published literature about EMR and m-EMR in the treatment of rectal neuroendocrine tumors. RESULTS: A total of 11 studies involving 811 patients were included. The pooled data suggested that there was a significantly higher rate of histologic complete resection and endoscopic complete resection among patients treated with m-EMR than those treated with EMR (histologic complete resection: OR = 0.23, 95 % CI = 0.10-0.51, p < 0.01; endoscopic complete resection: OR = 0.13, 95 % CI = 0.02-0.74, p = 0.02). The procedure time of EMR was longer than m-EMR (MD = 2.40, 95 % CI = 0.33-4.46, p = 0.02). There was a significantly higher rate of vertical margin involvement among patients treated with EMR than those treated with m-EMR; whereas, there was no significant difference of lateral margin involvement between the m-EMR and EMR groups (vertical margin involvement: OR = 5.00, 95 % CI = 2.67-9.33, p < 0.01; lateral margin involvement: OR = 1.44, 95 % CI = 0.48-4.37, p = 0.52). There was no significant difference in mean tumor size among patients treated with m-EMR versus those treated with EMR (MD = -0.30, 95 % CI = -0.75-0.14, p = 0.18); further, there was no significant difference in endoscopic mean sizes of the tumor and pathological mean sizes of the tumor between the m-EMR and EMR groups (endoscopic mean sizes of the tumor: MD = 0.20, 95 % CI = -0.44-0.84, p = 0.43; pathological mean sizes of the tumor: MD = 0.62, 95 % CI = -0.68-1.92, p = 0.05). No significant differences were detected among the treatment groups with regard to complications (bleeding: OR = 0.87, 95 % CI = 0.39-1.95, p = 0.73; complications (bleeding and perforation): OR = 0.87, 95 % CI = 0.40-1.88, p = 0.73). CONCLUSION: The efficacy of m-EMR are better than EMR among patients undergoing endoscopic treatment of rectal neuroendocrine tumors, and the safety of m-EMR is equivalent to EMR treatment.

Smoking status and subsequent gastric cancer risk in men compared with women: a meta-analysis of prospective observational studies.

BACKGROUND: Smoking is one of the well-established risk factors for gastric cancer incidence, yet whether men are more or equally susceptible to gastric cancer due to smoking compared with women is a matter of controversy. The aim of this study was to investigate and compare the effect of sex on gastric cancer risk associated with smoking. METHODS: We conducted a systemic literature search in MEDLINE, EMBASE, and the Cochrane CENTRAL databases to identify studies published from inception to December 2018. We included prospective observational studies which reported effect estimates with 95% confidence intervals (CIs) for associations of current or former smokers with the incidence of gastric cancer by sex. We calculated the ratio of relative risk (RRR) with corresponding 95% CI based on sex-specific effect estimates for current or former smokers versus non-smokers on the risk of gastric cancer. RESULTS: We included 10 prospective studies with 3,381,345 participants in our analysis. Overall, the summary RRR (male to female) for gastric cancer risk in current smokers was significantly increased compared with non-smokers (RRR: 1.30; 95% CI: 1.05-1.63; P = 0.019). Furthermore, there was no significant sex difference for the association between former smokers and gastric cancer risk (RRR: 1.20; 95% CI: 0.92-1.55; P = 0.178). However, the result of sensitivity analysis indicated the pooled result was not stable, which was altered by excluding a nested case-control study (RRR: 1.31; 95% CI: 1.10-1.57; P = 0.002). CONCLUSION: This systematic review showed a potential sex difference association between current smokers and the risk of gastric cancer. The sex differential in smokers can give important clues for the etiology of gastric cancers and should be examined in further studies.

The role of EGFR mutation as a prognostic factor in survival after diagnosis of brain metastasis in non-small cell lung cancer: a systematic review and meta-analysis.

BACKGROUND: The brain is a common site for metastasis in non-small-cell lung cancer (NSCLC). This study was designed to evaluate the relationship between the mutational of the epidermal growth factor receptor (EGFR) and overall survival (OS) in NSCLC patients with brain metastases. METHODS: Searches were performed in PubMed, EmBase, and the Cochrane Library to identify studies evaluating the association of EGFR mutation with OS in NSCLC patients through September 2017. RESULTS: 4373 NSCLC patients with brain metastases in 18 studies were involved. Mutated EGFR associated with significantly improved OS compared with wild type. Subgroup analyses suggested that this relationship persisted in studies conducted in Eastern, with retrospective design, with sample size ≥500, mean age of patients ≥65.0 years, percentage male < 50.0%, percentage of patients receiving tyrosine kinase inhibitor ≥30.0%. Finally, although significant publication bias was observed using the Egger test, the results were not changed after adjustment using the trim and fill method. CONCLUSIONS: This meta-analysis suggests that EGFR mutation is an important predictive factor linked to improved OS for NSCLC patients with brain metastases. It can serve as a useful index in the prognostic assessment of NSCLC patients with brain metastases.

Clinical evidence of prevention strategies for capecitabine-induced hand-foot syndrome.

Hand-foot syndrome (HFS) is the most common adverse effect of capecitabine-containing chemotherapy. The purpose of this study was to assess the efficacies of various prevention and treatment strategies for capecitabine-induced HFS. Searches of the PubMed and Embase databases were performed to identify relevant studies. The risk ratio (RR) with the corresponding 95% confidence interval (CI) was used as an effect measure to evaluate the efficacies of these prevention and treatment strategies. Publication bias was evaluated using Begg's and Egger's tests. Overall and subgroup analyses were conducted. All statistical analyses were conducted with Stata software version 12.0. Seventeen eligible studies were included. Our results indicated that celecoxib was significantly associated with a lower incidence of grade ≥2 capecitabine-induced HFS without heterogeneity (RR = 0.43, 95% CI = 0.23-0.81, I2  = 0.0%). However, pyridoxine and topical urea/lactic acid were not effective toward preventing capecitabine-induced grade 1, 2, 3, ≥1 or ≥2 HFS. Moreover, pyridoxine was not effective in treating capecitabine-induced HFS. Similar results were obtained by subgroup analysis. Our results indicate that celecoxib has potential prophylactic efficacy for capecitabine-induced HFS. However, pyridoxine and topical urea/lactic acid are not associated with a decrease in the incidence of capecitabine-induced HFS.

Impact of timing of adjuvant chemotherapy on survival in stage III colon cancer: a population-based study.

BACKGROUND: There is no consensus regarding the optimal time to initiate adjuvant chemotherapy after surgery for stage III colon cancer, and the relevant postoperative complications that cause delays in adjuvant chemotherapy are unknown. METHODS: Eligible patients aged ≥66 years who were diagnosed with stage III colon cancer from 1992 to 2008 were identified using the linked Surveillance, Epidemiology, and End Results-Medicare database. Kaplan-Meier analysis and a Cox proportional hazards model were utilized to evaluate the impact of the timing of adjuvant chemotherapy on overall survival (OS). RESULTS: A total of 18,491 patients were included. Delayed adjuvant chemotherapy was associated with worse OS (9-12 weeks: hazard ratio [HR] = 1.222, 95% confidence interval [CI] = 1.063-1.405; 13-16 weeks: HR = 1.252, 95% CI = 1.041-1.505; ≥ 17 weeks: HR = 1.969, 95% CI = 1.663-2.331). The efficacies of adjuvant chemotherapy within 5-8 weeks and ≤4 weeks were similar (HR = 1.045, 95% CI = 0.921-1.185). Compared with the non-chemotherapy group, chemotherapy initiated at ≥21 weeks did not significantly improve OS (HR = 0.882, 95% CI = 0.763-1.018). Patients with postoperative complications, particularly cardiac arrest, ostomy infection, shock, and septicemia, had a significantly higher risk of a 4- to 11-week delay in adjuvant chemotherapy (p < 0.05). CONCLUSIONS: Adjuvant chemotherapy initiated within 8 weeks was acceptable for patients with stage III colon cancer. Delayed adjuvant chemotherapy after 8 weeks was significantly associated with worse OS. However, adjuvant chemotherapy might still be useful even with a delay of approximately 5 months. Moreover, postoperative complications were significantly associated with delayed adjuvant chemotherapy.

Effect of neoadjuvant chemotherapy in patients with gastric cancer: a PRISMA-compliant systematic review and meta-analysis.

BACKGROUND: Neoadjuvant chemotherapy (NAC) is extensively used in the treatment of patients with gastric cancer (GC), particularly in high risk, advanced gastric cancer. Previous trials testing the efficacy of NAC have reported inconsistent results. METHODS: This study compares the combined use of NAC and surgery with surgery alone for GC by using a meta-analytic approach. We performed an electronic search of PubMed, EmBase, and the Cochrane Library to identify randomized controlled trials (RCTs) on NAC published before Oct 2015. The primary outcome of the studies was data on survival rates for patients with GC. The summary results were pooled using the random-effects model. We included 12 prospective RCTs reporting data on 1538 GC patients. RESULTS: Patients who received NAC were associated with significant improvement of OS (P = 0.001) and PFS (P < 0.001). Furthermore, NAC therapy significantly increased the incidence of 1-year survival rate (SR) (P = 0.020), 3-year SR (P = 0.011), and 4-year SR (P = 0.001). Similarly, NAC therapy was associated with a lower incidence of 1-year (P < 0.001), 2-year (P < 0.001), 3-year (P < 0.001), 4-year (P = 0.001), and 5-year recurrence rate (P = 0.002). Conversely, patients who received NAC also experienced a significantly increased risk of lymphocytopenia (P = 0.003), and hemoglobinopathy (P = 0.021). CONCLUSIONS: The findings of this study suggested that NAC is associated with significant improvement in the outcomes of survival and disease progression for GC patients while also increasing some toxicity.

The efficacy and safety of targeted therapy with or without chemotherapy in advanced gastric cancer treatment: a network meta-analysis of well-designed randomized controlled trials.

BACKGROUND: Advanced gastric cancer (AGC) is a severe malignant tumor associated with high mortality. Targeted therapy is an important approach for improving the therapeutic effects of AGC treatment. This study evaluates the efficacy and safety of targeted agents for AGC patients. METHODS: PubMed, EmBase, and the Cochrane Library were searched for double-blind randomized controlled trials (RCTs) of AGC treatments published prior to July 2017. Progression-free survival (PFS), overall survival (OS), objective response rate (ORR), and severe adverse effects (AEs) were evaluated to determine the efficacy and safety of targeted agents. A network meta-analysis with a frequentist framework was performed to assess the effects of various targeted agents for AGC treatment. RESULTS: Our analysis included 16 articles involving 5371 patients and 11 types of agents. The network meta-analysis showed that apatinib (97.5%) was most likely to improve PFS, followed by regorafenib (86.3%) and rilotumumab (65.4%). Apatinib was similarly best for OS outcome, (95.5%) followed by rilotumumab (74.7%) and regorafenib (70%). Apatinib (89.6%) also had the best improvement on ORR, followed by rilotumumab (75.4%) and everolimus (68.4%). Bevacizumab (85.5%) was likely to get the lowest severe AEs, followed by sunitinib (63%). CONCLUSIONS: Apatinib, regorafenib, and rilotumumab improved patient PFS and OS. When combined with chemotherapy, ramucirumab and rilotumumab had high efficacy but low tolerability, and bevacizumab had moderate efficacy and tolerability for PFS. Without chemotherapy, ramucirumab and regorafenib had relatively high therapeutic efficacy tolerability for PFS.

Increased IFRD1 Expression in Human Colon Cancers Predicts Reduced Patient Survival.

BACKGROUND: Colon cancer (CRC) is the third most common cancer worldwide. CRC develops through combinations of genetic and epigenetic changes. However, there is marked heterogeneity in the "driver gene" mutational profiles within and among colon cancers from individual patients, and these are not sufficient to explain differences in colon cancer behavior and treatment response. Global modulation of the tumor landscape may play a role in cancer behavior. Interferon-related developmental regulator 1 (IFRD1) is a transcriptional co-regulator that modulates expression of large gene cassettes and plays a role in gut epithelial proliferation following massive intestinal resection. AIMS: We address the hypothesis that increased IFRD1 expression in colon cancers is associated with poorer patient survival. METHODS: Tumor and normal tissue from colon cancer patient cohorts from the USA, Spain, and China were used for this study. Cancers were scored for the intensity of IFRD1 immunostaining. The primary clinical outcome was overall survival defined as time from diagnosis to death due to cancer. Kaplan-Meier method and log-rank analysis were used to assess the association between IFRD1 expression and survival. RESULTS: Almost all (98.7%) colon cancers showed readily detectable IFRD1 expression, with immunoreactivity primarily in the tumor cytoplasm. High IFRD1 colon cancer expression was significantly associated with decreased 5-year patient survival. Patients in the American cohort with high IFRD1 expression had a poorer prognosis. CONCLUSIONS: We have demonstrated that high IFRD1 protein expression in colon cancer is associated with poorer patient prognosis, suggesting a potential role for IFRD1 in modulating tumor behavior.

The clinicopathological parameters and prognostic significance of HER2 expression in gastric cancer patients: a meta-analysis of literature.

BACKGROUND: Human epidermal growth factor receptor-2 (HER2) is regarded as an important and promising target in the treatment of HER2-positive breast cancers. However, the correlation of clinicopathological characteristics and prognostic significance of HER2 overexpression in gastric cancer patients remains unclear. Our aim was to clarify this issue. METHODS: Embase, PubMed, and the Cochrane Library were searched for relevant articles published up to May 2016. Outcomes of interest contained sex, age, tumor size, tumor site, tumor node metastasis (TNM) stage, distant metastasis, lymph node metastasis, Lauren's classification, differentiation grade, lymphovascular invasion, neural invasion, and multivariate analysis data for overall survival. RESULTS: A total of 41 studies of 17,494 gastric cancer patients were identified with HER2 test. HER2 positive rate was 19.07% (95% CI = 9.16, 28.98). There existed statistical significance between HER2 overexpression and patients' prognosis (RR = 1.47, 95% CI = 1.09, 1.98). Male patients (OR = 1.48, 95% CI = 1.34, 1.65), proximal tumors (OR = 1.25, 95% CI = 1.07, 1.47), intestinal-type tumors (OR = 3.37, 95% CI = 2.54, 4.47), advanced stage cancers (OR = 1.35, 95% CI = 1.10, 1.66), lymph node metastasis (OR = 1.26, 95% CI = 1.14, 1.41), well-differentiated cancers (OR = 1.79, 95% CI = 1.15, 2.76), and distant metastasis (OR = 1.91, 95% CI = 1.08, 3.38) were correlated with higher HER2 expression rates. However, no statistical differences existed in age, tumor size, lymphovascular invasion, or neural invasion. Subgroup analysis revealed that HER2 expression rates reported in articles from Asian (19.52%) countries were quantitatively higher than those from European (16.91%) areas. Results were consistent with those reports that define HER2 status according to trastuzumab for gastric cancer (ToGA) criteria. CONCLUSION: This study showed that HER2 overexpression was associated with poor prognosis in gastric cancer patients. HER2 positive rates may be associated with sex, tumor site, TNM staging system, distant metastasis, lymph node metastasis, Lauren's classification, and differentiation grade in gastric cancer patients. The HER2 expression rate in Asians may be higher than that in Europeans. This study offers a convenient way for doctors to select patients for relevant HER2 detection and following treatment.

Macroscopic Serosal Classification as a Prognostic Index in Radically Resected Stage pT3-pT4b Gastric Cancer.

BACKGROUND: Macroscopic serosal classification (MSC) is an important clinicopathologic index of gastric cancer (GC). To investigate the prognostic significance of MSC status in patients with radically resected stage pT3-pT4b GC, we examined the relationship between MSC type and pT stage. METHODS: Clinicopathologic and survival data of 1613 patients with stage pT3-pT4b GC were studied retrospectively, in the aftermath of radical surgery. RESULTS: MSC types, including reactive, nodular, tendonoid, and color-diffused type, correlated significantly with overall survival (OS) in this cohort, but prognosis was similar for all stages of color-diffused type GC. We proposed a revised pT stage in which color-diffused type cancers at pT3 or pT4a stage were reclassified into pT4b stage. In two-step multivariate analysis, revised pT stage (stage pT4b for all color-diffused types) proved more suitable for determining prognosis, surpassing both Union for International Cancer Control/American Joint Committee on Cancer pT stage and MSC type as an independent prognostic index. CONCLUSIONS: MSC type is a significant and independent prognostic index of OS in patients with radically resected stage pT3-pT4b GC. For prognostic purposes, tumors of color-diffused type at pT3 or pT4a stage should be considered stage pT4b disease.

Which is better for gastric cancer patients, perioperative or adjuvant chemotherapy: a meta-analysis.

BACKGROUND: The preferred chemotherapy method for gastric cancer continues to be matter of debate. We performed a meta-analysis to comparing prognosis and safety between perioperative chemotherapy and adjuvant chemotherapy to identify the better chemotherapy option for gastric cancer. METHODS: We searched the PubMed, EMBASE, Cochrane Library, and Ovid databases for eligible studies until February 2016. The main endpoints were prognostic value (hazard ratio [HR] for overall survival [OS] and 1-, 2-, 3-, and 5-year survival rate), response rate of chemotherapy, radical resection rate, post-operative complication rate, and adverse effects of chemotherapy. RESULTS: Five randomized controlled trials and six clinical controlled trials involving 1,240 patients were eligible for analysis. Compared with the adjuvant chemotherapy group, the perioperative chemotherapy group had significantly better prognosis (HR, 0.74; 95 % CI, 0.61 to 0.89; P < 0.01). The difference between the two groups remained significant in the studies that used combination chemotherapy as the neoadjuvant chemotherapy regimen (HR, 0.59; 95 % CI, 0.46 to 0.76; P < 0.01) but were not significant in the studies that used fluoropyrimidine monotherapy (HR, 0.93; 95 % CI, 0.56 to 1.55; P = 0.84). Furthermore, the two groups showed no significant differences in the post-operative complication rates (relative risk, 0.98; 95 % CI, 0.63 to 1.51; P = 0.91) or adverse effects of chemotherapy (P > 0.05 for all adverse effects). CONCLUSION: Perioperative chemotherapy showed improved survival compared to adjuvant chemotherapy for gastric cancer. In addition, combination chemotherapy resulted in better survival compared to monotherapy in the neoadjuvant chemotherapy regimens.

Borrmann type IV gastric cancer should be classified as pT4b disease.

BACKGROUND: The impact of macroscopic pathologic features of primary tumor that could be obtained preoperatively on pT classification has not been reported so far. The aim of this study was to investigate the feasibility of incorporation of Borrmann type IV gastric cancer into the pT classification. MATERIALS AND METHODS: Clinicopathologic and prognostic data of 1622 patients with advanced gastric cancer who underwent radical surgery were retrospectively studied. RESULTS: Of 1622 patients, 135 (8.32%) patients were classified as having Borrmann type IV gastric cancer. We first confirmed that Borrmann type IV gastric cancer was one of the independent prognostic factors for patients with advanced gastric cancer who underwent radical surgery. Interestingly, we found that overall survival of patients with Borrmann type IV gastric cancer could be clearly distinguished by pN classification and pathological TNM stage but not by pT classification. Importantly, further analysis demonstrated that the prognosis of Borrmann type IV gastric cancers was homogeneous with that of pT4b cancers but poorer than pT2, pT3, pT4a cancers. Therefore, we proposed a novel pT classification in which pT4b disease was defined as cancers that were Borrmann type IV or those that had invaded adjacent structures. Two-step multivariate analysis demonstrated that the novel pT classification was more suitable for prognostic assessment than the original classification. CONCLUSIONS: Classifying Borrmann type IV gastric cancer as pT4b disease improves pT classification prediction of prognosis in patients with advanced gastric cancer after radical surgery.

Meta-analysis of the laparoscopic versus open colorectal surgery within fast track surgery.

BACKGROUND: Laparoscopic methods and fast-track surgery (FTS) can enhance recovery and reduce postoperative hospital stay. However, whether laparoscopic surgery can provide short-term benefits within FTS is controversial. Thus, we conducted a meta-analysis of published studies to evaluate the effect of laparoscopic colorectal surgery within FTS. METHODS: We searched PubMed, EMBASE, Cochrane Library, and Ovid databases for eligible studies. Endpoints were duration of postoperative hospital stay, time to first bowel movement, total postoperative complication rate, readmission rate, mortality within 30 days after surgery, and conversation rate of laparoscopic surgery. RESULTS: Four randomized controlled trials and six clinical controlled trials (1510 patients) were eligible for analyses. Duration of postoperative hospital stay (weighted mean difference, -1.65 days; p < 0.001), time to first bowel movement (-1.13 days; p < 0.001), total postoperative complication rate (risk ratio [RR], 0.65; p < 0.001), readmission rate (0.46; p < 0.001), and mortality (0.45; p < 0.001) were significantly reduced in the laparoscopic surgery group. Overall conversion rate of laparoscopic surgery was 11.1%. Subgroup analyses based on each FT element demonstrated that studies without the element "prevention of hypothermia," "no bowel preparation," or "no routine use of drains" did not show significant differences between two groups with regard to duration of postoperative hospital stay or total prevalence of postoperative complications. CONCLUSION: Within FTS, laparoscopic methods can significantly shorten postoperative hospital stay, accelerate postoperative recovery, and enhance safety in colorectal surgery. The FT elements "prevention of hypothermia," "no bowel preparation," and "no routine use of drains" may play important parts in the combined effect of these two methods.

A dose-response meta-analysis reveals an association between vitamin B12 and colorectal cancer risk.

OBJECTIVE: The current meta-analysis evaluated the association between vitamin B12 intake and blood vitamin B12 level and colorectal cancer (CRC) risk. DESIGN: The PubMed and EMBASE databases were searched. A dose-response analysis was performed with generalized least squares regression, with the relative risk (RR) and 95 % CI as effect values. SETTING: The meta-analysis included seventeen studies. SUBJECTS: A total of 10 601 patients. RESULTS: The non-linear dose-response relationship between total vitamin B12 intake and CRC risk was insignificant (P=0·690), but the relationship between dietary vitamin B12 intake and CRC risk was significant (P<0·001). Every 4·5 µg/d increment in total and dietary vitamin B12 intake was inversely associated with CRC risk (total intake: RR=0·963; 95 % CI 0·928, 0·999; dietary intake: RR=0·914; 95 % CI 0·856, 0·977). The inverse association between vitamin B12 intake and CRC risk was also significant when vitamin B12 intake was over a dosage threshold, enhancing the non-linear relationship. The non-linear dose-response relationship between blood vitamin B12 level and CRC risk was insignificant (P=0·219). There was an insignificant association between every 150 pmol/l increment in blood vitamin B12 level and CRC risk (RR=1·023; 95 % CI 0·881, 1·187). CONCLUSIONS: Our meta-analysis indicates that evidence supports the use of vitamin B12 for cancer prevention, especially among populations with high-dose vitamin B12 intake, and that the association between CRC risk and total vitamin B12 intake is stronger than between CRC risk and dietary vitamin B12 intake only.

Aspirin and nonsteroidal anti-inflammatory drugs after but not before diagnosis are associated with improved breast cancer survival: a meta-analysis.

PURPOSE: The association between nonsteroidal anti-inflammatory drugs (NSAIDs) and breast cancer survival is still controversial. The aim of our meta-analysis was to assess the survival benefit of NSAIDs. METHODS: A literature search was conducted in PubMed and EMBASE (to September 2014). A meta-analysis was performed with hazard ratios (HRs) and 95% confidence intervals (CIs) as the effect measures. Subgroup analyses were based on time of NSAID use (before and after diagnosis), medication type (aspirin and other nonaspirin NSAIDs), and study design (cohort and case-control studies). RESULTS: There were 16 eligible studies. Use of NSAIDs after diagnosis was significantly inversely associated with relapse/metastasis (HR 0.69, 95% CI 0.59-0.80) and tended toward potentially protective effects on all-cause mortality, although significance was not reached (HR 0.79, 95% CI 0.61-1.02). In cohort studies, the association between post-diagnostic use of NSAIDs and breast cancer survival was stronger with reduced heterogeneity (breast-cancer-specific mortality: HR 0.65, 95% CI 0.48-0.89, I(2) = 65.3%; all-cause mortality: HR 0.73, 95% CI 0.57-0.92, I(2) = 83.2%; relapse/metastasis: HR 0.73, 95% CI 0.61-0.86, I(2) = 48.3%). Aspirin use after diagnosis was significantly associated with breast-cancer-specific mortality (HR 0.69, 95% CI 0.50-0.96) and relapse/metastasis (HR 0.75, 95% CI 0.56-1.00), and tended toward a protective effect on all-cause mortality, although significance was not reached (HR 0.79, 95% CI 0.60-1.03). Including cohort studies only, we obtained similar results and post-diagnostic use of aspirin was significantly associated with all-cause mortality (HR 0.72, 95% CI 0.56-0.93). CONCLUSIONS: NSAIDs and aspirin after but not before diagnosis were associated with improved breast cancer survival, including breast-cancer-specific mortality, all-cause mortality, and relapse/metastasis.

Lung cancer cells induce senescence and apoptosis of pleural mesothelial cells via transforming growth factor-beta1.

Pleural dissemination is commonly associated with metastatic advanced lung cancer. The injury of pleural mesothelial cells (PMCs) by soluble factors, such as transforming growth factor-beta1 (TGF-ß1), is a major driver of lung cancer pleural dissemination (LCPD). In this study, we examine the effects of TGF-ß1 on PMC injury and the ability of TGF-ß1 inhibition to alleviate this effect both in vitro and in vivo. PMCs were co-cultured with the high TGF-ß1-expressing lung cancer cell line A549 and with various TGF-ß1 signaling inhibitors. Expression of cleaved-caspase 3, cleaved-caspase 9, p21, and p16 were evaluated by Western blot and immunofluorescent confocal imaging. Apoptosis was measured by 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltrazoliumbromide assay and AnnexinV-propidium iodide (PI) staining. PMC senescence was assessed by staining for senescence-associated ß-galactosidase (SA-ß-Gal). The ability of lung cancer cells (LCCs) to adhere to injured PMCs was investigated using an LCC-PMC adhesion assay. In our mouse model, PMC injury status was monitored by hematoxylin-eosin (H&E) and Masson's trichrome staining. LCCs expressing high levels of TGF-ß1 induce apoptosis and senescence of PMCs in a co-culture system. Injured PMCs adhere to LCCs, which may further promote LCPD. Importantly, PMC monolayer injury could be reversed with TGF-ß1 inhibitors. This was consistent with our in vivo data showing that the TGF-ß1 inhibitor SB-431542 attenuated PMC barrier injury induced by A549 culture medium in our mouse model. Our study highlights the importance of TGF-ß1 signaling in LCPD and establishes this signaling pathway as a potential therapeutic target in the disease.