Primary Surgery Followed by Selective Chemoradiotherapy Versus Preoperative Chemoradiotherapy Followed by Surgery for Locally Advanced Rectal Cancer: A Randomized Clinical Trial.

PURPOSE: The aim of this work was to determine whether locally advanced rectal cancer (LARC) with negative mesorectal fascia (MRF) predicted by magnetic resonance imaging (MRI) can be excluded from preoperative radiation therapy treatment. METHODS AND MATERIALS: This multicenter, open-label, non-inferiority, randomized clinical trial enrolled patients with LARC within 6 to 12 cm from the anal verge and with negative MRI-predicted MRF. Participants were randomized to the intervention group (primary surgery, in which the patients with positive pathologic [CRM] circumferential margins were subjected to chemoradiotherapy [CRT] and those with negative CRM underwent adjuvant chemotherapy according to pathologic staging) or the control group (preoperative CRT, in which all patients underwent subsequent surgery and adjuvant chemotherapy). The primary endpoint was 3-year disease-free survival (DFS). RESULTS: A total of 275 patients were randomly assigned to the intervention (n = 140) and control (n = 135) groups, in which 33.57% and 28.15% patients were at clinical T4 stage and 85.92% and 80.45% patients were at "bad" or "ugly" risk in the intervention and control groups, respectively. There were 2 patients (1.52%) and 1 patient (0.77%) with positive CRM in the intervention and control groups, respectively (P > .05). The non-adherence rates for the intervention and control groups were 3.6% and 23.7%, respectively. After a median follow-up of 34.6 months (IQR, 18.2-45.7), 43 patients had positive events (28 patients and 15 patients in the intervention and control groups, respectively). There were 6 patients (4.4%) with local recurrence in the intervention group and none in the control group, which led to the termination of the trial. The 3-year DFS rate was 81.82% in the intervention group (95% CI, 78.18%-85.46%) and 85.37% in the control group (95% CI, 81.75%-88.99%), with a difference of -3.55% (95% CI, -3.71% to -3.39%; hazard ratio, 1.76; 95% CI, 0.94-3.30). In the per-protocol data set, the difference between 3-year DFS rates was -5.44% (95% CI, -5.63% to -5.25%; hazard ratio, 2.02; 95% CI, 1.01-4.06). CONCLUSIONS: Based on the outcomes of this trial, in patients with LARC and MRI-negative MRF, primary surgery could negatively influence their DFS rates. Therefore, primary surgery was an inferior strategy compared with preoperative CRT followed by surgery and cannot be recommended for patients with LARC.

Influence of hypoxia on retinal progenitor and ganglion cells in human induced pluripotent stem cell-derived retinal organoids.

AIM: To observe the effect of low oxygen concentration on the neural retina in human induced pluripotent stem cell (hiPSC)-derived retinal organoids (ROs). METHODS: The hiPSC and a three-dimensional culture method were used for the experiments. Generated embryoid bodies (EBs) were randomly and equally divided into hypoxic and normoxic groups. Photographs of the EBs were taken on days 38, 45, and 52, and the corresponding volume of EBs was calculated. Simultaneously, samples were collected at these three timepoints, followed by fixation, sectioning, and immunofluorescence. RESULTS: The proportion of Ki67-positive proliferating cells increased steadily on day 38; this proliferation-promoting effect tended to increase tissue density rather than tissue volume. On days 45 and 52, the two groups had relatively similar ratios of Ki67-positive cells. Further immunofluorescence analysis showed that the ratio of SOX2-positive cells significantly increased within the neural retina on day 52 (P<0.05). In contrast, the percentage of PAX6- and CHX10-positive cells significantly decreased following hypoxia treatment at all three timepoints (P<0.01), except for CHX10 at day 45 (P>0.05). Moreover, the proportion of PAX6-/TUJ1+ cells within the neural retinas increased considerably (P<0.01, <0.05, <0.05 respectively). CONCLUSION: Low oxygen promotes stemness and proliferation of neural retinas, suggesting that hypoxic conditions can enlarge the retinal progenitor cell pool in hiPSC-derived ROs.

Specific metabolic response of patient-derived organoids to curcumin of colorectal cancer.

Organoid is a burgeoning model that have emerged in the past decade. Tumor organoids can simulate specific aspects of the 3D structure, cell type composition and function of real tumors to make up for the deficiencies of cell models and animal models. Curcumin has been found to be effective in suppressing various phases of colorectal cancer development. Nevertheless, there is no clear evidence that the results obtained on cultured cells or animal models can be translated in humans. Therefore, we constructed patient-derived organoids of colorectal cancer to show the curcumin responses of these organoids. Then, a MS-based non-targeted metabolomic strategy was to gain a system-level understanding of the mechanism of curcumin on colorectal cancer patient-derived organoids. Then non-targeted metabonomic analysis found that curcumin mainly regulated the phenylalanine, tyrosine and tryptophan biosynthesis, nicotinate and nicotinamide metabolism, purine metabolism in the organoids of colorectal cancer. Our research provided a reference for further revealing the role of curcumin in human-derived colorectal cancer-like solid tumors.

Development of humanized mouse with patient-derived xenografts for cancer immunotherapy studies: A comprehensive review.

Immunotherapy has revolutionized cancer treatment, however, not all tumor types and patients are completely responsive to this approach. Establishing predictive pre-clinical models would allow for more accurate and practical immunotherapeutic drug development. Mouse models are extensively used as in vivo system for biomedical research. However, due to the significant differences between rodents and human, it is impossible to translate most of the findings from mouse models to human. Pharmacological development and advancing personalized medicine using patient-derived xenografts relies on producing mouse models in which murine cells and genes are substituted with their human equivalent. Humanized mice (HM) provide a suitable platform to evaluate xenograft growth in the context of a human immune system. In this review, we discussed recent advances in the generation and application of HM models. We also reviewed new insights into the basic mechanisms, pre-clinical evaluation of onco-immunotherapies, current limitations in the application of these models as well as available improvement strategies. Finally, we pointed out some issues for future studies.

Association between potentially functional polymorphisms of chemokine family members and the survival of esophageal cancer patients in a Chinese population.

Background: The chemokine family plays an important role in the growth, invasion, and metastasis of tumors. However, most studies have only focused on a few genes or a few gene loci, and thus could not reveal the associations between functional polymorphisms of chemokine family members and tumor progression. This study aimed to determine the associations between single nucleotide polymorphisms (SNPs) of chemokine family members and the prognosis of esophageal cancer (EC). Methods: The Cox risk proportional model and log-rank test were used to analyze the associations of 16 potentially functional SNPs in 13 genes from the chemokine family with the survival of 729 Chinese patients with EC. Results: Prognostic analysis on the 16 SNPs showed that different genotypes of 5 SNPs were associated with patients' survival and the risk of death. Multivariate Cox regression analysis showed that the risk of death was higher in CCL26rs2302009 genotype A/C carriers than in A/A carriers and it was also higher in CX3CL1rs2239352 genotype T/T carriers than in C/C carriers. Stepwise Cox regression analysis showed that CCL26rs2302009 genotype A/C was an independent prognostic factor of EC, and its association with increased risk of death was stronger in patients who were ≤60 years old, female, with tumors located in the middle part of esophagus, with undifferentiated or poorly differentiated tumors, with early-stage pathologic type disease, with the longest diameter of tumor ≤5cm than in their counterparts. Conclusion: These findings suggest that CCL26rs2302009 may be a candidate biomarker for EC and its effect on death risk are associated with the histological grade, pathologic type, and the longest diameter of tumor.

Role of interleukin-17 in the pathogenesis of perianal abscess and anal fistula: a clinical study on 50 patients with perianal abscess.

BACKGROUND: To investigate the role of interleukin (IL)-17 in tissue and peripheral blood of perianal abscess and anal fistula. METHODS: Patients with primary perianal abscess (n = 50) admitted to Jinhua Municipal Central Hospital between March 2003 and August 2004 were enrolled. Fifty patients with mixed haemorrhoids, who showed no perianal abscess or anal fistula, were also recruited as the control. After surgery, patients were followed up for 6 months. Protein and gene expression of IL-17 was determined in surgically harvested anal tissues and peripheral blood, respectively. The relationship between IL-17 and clinical pathological features were analysed. RESULTS: As shown by immunohistochemistry of anorectal tissues, the positive rate of IL-17 protein was higher in the perianal abscess group than in the control group. In patients with perianal abscess, the expression of IL-17 significantly correlated with the diameter of the abscess (P = 0.013), the wound surface healing time (P = 0.010) and the progression into anal fistula (P = 0.003). For the gene expression of IL-17 in peripheral blood cells, the level was significantly higher in patients with perianal abscess comparing to the control group (0.4350 ± 0.1190 versus 0.1785 ± 0.1230, P ≤ 0.001). Comparing to the recovery group, patients with their perianal abscess progressed to anal fistula showed higher levels of IL-17 gene expression (P = 0.014). CONCLUSIONS: Expression of IL-17 was increased in the anorectal tissues and peripheral blood of patients with perianal abscess and anal fistula. IL-17 may play an important role in the pathogenesis of perianal abscess and anal fistula.

Evaluation of seven recombinant VCA-IgA ELISA kits for the diagnosis of nasopharyngeal carcinoma in China: a case-control trial.

OBJECTIVE: Seven recombinant viral capsid antigen-IgA (VCA-IgA) ELISA kits are widely used in China, but their diagnostic effects have not been evaluated. In this study, we evaluated whether the diagnostic effects of these kits are similar to those of the standard kit (EUROIMMUN, Lübeck, Germany). METHODS: A diagnostic case-control trial was conducted with 200 cases of nasopharyngeal carcinoma (NPC) and 200 controls from NPC-endemic areas in southern China. The areas under the curve (AUCs), the sensitivities and the specificities of testing kits were compared with those of the standard kit. The test-retest reliability of each kit was determined by intraclass correlation coefficient (ICC). Their diagnostic accuracy in combination with Epstein-Barr virus nuclear antigen 1-IgA (EBNA1-IgA) was also evaluated in logistic models. RESULTS: Three testing kits-BB, HA and KSB-showed diagnostic accuracy equal to that of the standard kit, with good performance in the AUCs (0.926-0.945), and no significant differences in sensitivity were found between early-stage and advanced-stage NPCs. ICCs exceeded 0.8. Three logistic regression models were built, and the AUCs of these models (0.961-0.977) were better than those of the individual VCA-IgA kits. All new models had diagnostic accuracy equal to that of the standard kit. New cut-off values of these three kits and their corresponding combinations for researchers to replicate and use in NPC early detection and screening in the future were provided. CONCLUSIONS: Three recombinant VCA-IgA kits-BB,HA and KSB-had diagnostic effects equal to those of the standard kit, and, in combination with EBNA1-IgA in logistic regression models, can be used in future screening for NPC.

Subtype distribution and long-term titer fluctuation patterns of serum anti-Epstein-Barr virus antibodies in a non-nasopharyngeal carcinoma population from an endemic area in South China: a cohort study.

BACKGROUND: Serum immunoglobulin A antibodies against Epstein-Barr virus (EBV), viral capsid antigen (VCA-IgA) and early antigen (EA-IgA), are used to screen for nasopharyngeal carcinoma (NPC) in endemic areas. However, their routine use has been questioned because of a lack of specificity. This study aimed to determine the distributions of different subtypes of antibody and to illustrate how the natural variation patterns affect the specificity of screening in non-NPC participants. METHODS: The distribution of baseline VCA-IgA was analyzed between sexes and across 10-year age groups in 18,286 non-NPC participants using Chi square tests. Fluctuations in the VCA-IgA level were assessed in 1056 non-NPC participants with at least two retests in the first 5-year period (1987-1992) after the initial screening using the Kaplan-Meier method. RESULTS: The titers of VCA-IgA increased with age (P < 0.001). Using a previous serological definition of high NPC risk, nasopharyngeal endoscopy and/or nasopharyngeal biopsy would be recommended in 55.5% of the non-NPC participants with an initial VCA-IgA-positive status and in 20.6% with an initial negative status during the 5-year follow-up. However, seroconversions were common; 85.2% of the participants with a VCA-IgA-positive status at baseline converted to negative, and all VCA-IgA-negative participants changed to positive at least once during the 5-year follow-up. The EA-IgA status had a high seroconversion probability (100%) from positive to negative; however, it had a low probability (19.6%) from negative to positive. CONCLUSIONS: Age- and sex-specific cutoff titer values for serum anti-EBV antibodies as well as their specific titer fluctuation patterns should be considered when defining high NPC risk criteria for follow-up diagnostics and monitoring.

Robot-assisted intersphincteric resection for rectal submucosal tumour.

BACKGROUND: Rectal submucosal tumours are rare. The purpose of this study was to evaluate the safety and feasibility of robot-assisted rectal surgery. METHODS: Patients who received robot-assisted intersphincteric resection (ISR) were included in the present study. Clinical outcomes, operating time, length of hospital stay and pathological status were analysed. RESULTS: There were three patients with gastrointestinal tumours and three patients diagnosed with neuroendocrine tumours. The mean operating time was 369.2 min and the estimated blood loss was 66.7 ml. There were neither intraoperative complications nor conversions. On pathological examination, the mean number of lymph nodes harvested was 10.3 (range 3-16), the mean distal resection margin was 1.1 (range 0.1-3) cm and all six patients had the circumferential resection margins clear. CONCLUSIONS: Our data show that robotic surgery is feasible and safe, with no morbidity or mortality, and that ISR provides bowel continuity and eliminates the need for colostomy. Copyright © 2015 John Wiley & Sons, Ltd.

Hepatitis B virus infection and risk of nasopharyngeal carcinoma in southern China.

BACKGROUND: Whether or not hepatitis B virus (HBV) infection plays a role in the development of nasopharyngeal carcinoma (NPC) is largely unknown. Our study aimed to assess the association between HBV infection and the risk of NPC in Southern China. METHODS: We conducted a case-control study including 711 NPC cases and two groups of controls. The first control group consisted of 656 individuals with other benign tumors unrelated to HBV infection and the second group consisted of 680 healthy population controls. Multivariable ORs and corresponding 95% confidence intervals (CI) for NPC were estimated by logistic regression. RESULTS: Patients with NPC had higher prevalence of antibodies against hepatitis B core antigen-positive [anti-HBc-(+); 47.26%] compared with either benign tumor controls (39.33%; P < 0.01) or healthy controls (41.18%; P = 0.04). In multivariable models adjusting for a set of risk factors for NPC, anti-HBc-(+) was significantly associated with a higher risk of NPC [adjusted OR (AOR), 1.40; 95% CI, 1.12-1.74 compared with the benign tumor controls and AOR, 1.48; 95% CI, 1.05-2.08 compared with the healthy controls]. The association was not modified by hepatitis B surface antigen (HBsAg) status. Finally, compared with the healthy controls, individuals with both anti-HBc-(+) and EBV antibodies had largely increased risk of NPC (AOR, 141.82; 95% CI, 68.73-292.62). CONCLUSION: Our study suggests that HBV infection is associated with NPC risk in Southern China. IMPACT: Prevention for HBV infection may play a role in the development of NPC.

Secular trend analysis of lung cancer incidence in Sihui city, China between 1987 and 2011.

BACKGROUND: With industrial and econom ic development in recent decades in South China, cancer incidence may have changed due to the changing lifestyle and environment. However, the trends of lung cancer and the roles of smoking and other environmental risk factors in the development of lung cancer in rural areas of South China remain unclear. The purpose of this study was to explore the lung cancer incidence trends and the possible causes of these trends. METHODS: Joinpoint regression analysis and the age-period-cohort (APC) model were used to analyze the lung cancer incidence trends in Sihui, Guangdong province, China between 1987 and 2011, and explore the possible causes of these trends. RESULTS: A total of 2,397 lung cancer patients were involved in this study. A 3-fold increase in the incidence of lung cancer in both sexes was observed over the 25-year period. Joinpoint regression analysis showed that while the incidence continued to increase steadily in females during the entire period, a sharp acceleration was observed in males starting in 2005. The full APC model was selected to describe age, period, and birth cohort effects on lung cancer incidence trends in Sihui. The age cohorts in both sexes showed a continuously significant increase in the relative risk (RR) of lung cancer, with a peak in the eldest age group (80-84 years). The RR of lung cancer showed a fluctuating curve in both sexes. The birth cohorts identified an increased trend in both males and females; however, males had a plateau in the youngest cohorts who were born during 1955-1969. CONCLUSIONS: Increasing trends of the incidence of lung cancer in Sihui were dominated by the effects of age and birth cohorts. Social aging, smoking, and environmental changes may play important roles in such trends.

Association between glutathione S-transferases M1 and T1 gene polymorphisms and esophageal cancer prognosi.

OBJECTIVE: To investigate the independent factors affecting the prognosis of patients after resection of esophageal cancer, and to inquire into the relationship between GSTM1, GSTT1 gene polymorphisms and esophageal cancer prognosis. METHODS: The clinical data of 273 patients with esophageal cancer were retrospectively analyzed. The patients were followed-up after their surgery, and the gene polymorphisms of GSTM1 and GSTT1 in each individual were detected by polymerase chain reaction (PCR). The clinical features along with the gene polymorphisms of GSTM1 and GSTT1 associated with the prognosis of patients were analyzed by using the method of univariate analysis and Cox proportional hazard model. The cumulative survival rate was estimated by Kaplan-Meier methods, and the survival curves were compared by using the log-rank test. RESULTS: The overall cumulative survival rate of first year, third year and fifth year is 94.6%, 58.5% and 17.8%, respectively. The median survival time (MST) is 38.7 months. The results of univariate analysis showed that: infiltration depth, length of tumor, the number of lymph node metastasis, the region of lymph node metastasis and the genetic polymorphism of GSTM1 and GSTT1 gene loci were associated with the survival of postoperative patients. Cox multivariate analysis further indicated that the length of tumor, the number of lymph node metastasis and the combined genotype (1) [GSTM1 (+/+) or (+/-) & GSTT1 (-/-)] were the independent prognostic factors. The length of tumor, the number of lymph node metastasis were the risk factors for the prognosis, and the combined genotype (1) had protective effect on survival when compared with reference [GSTM1 (+/+) or (+/-) & GSTT1 (+/+) or (+/-)]. CONCLUSION: The length of tumor, the number of lymph node metastasis were confirmed as the independent prognostic factors of esophageal carcinoma, and the null genotypes for GSTT1 (-/-) might be a protective factor for survival and GSTM1 (-/-) might be a potential negative prognostic factor in patients with esophageal cancer.

Effects of α-enolase (ENO1) over-expression on malignant biological behaviors of AGS cells.

OBJECTIVE: To investigate the effects of α-Enolase (ENO1) over-expression on the proliferative and migratory abilities of AGS cells. METHODS: The target gene was cloned and mounted to the eukaryotic expression vector pcDNA3.1(+), then was transfected into gastric cancer cell lines AGS. mRNA and protein level of ENO1 in AGS cells were verified by real-time quantitative RT-PCR and Western Blot, respectively. The effects of over-expression of ENO1 on proliferative and migratory abilities of AGS cells were detected by the experiments of CCK-8, colony formation and wound healing assays. RESULTS: The eukaryotic expression vector pcDNA3.1(+)/eno1 was successfully constructed, and verified by sequencing. It was shown from the cell proliferation curves that the proliferative ability of AGS-ENO1 transfected group was higher than that of the control group after 72 hours (t = 3.44, P = 0.04), meanwhile, the number of the cell-colonies of the AGS-ENO1 group were significantly greater than that of the control group (t = 5.26, P = 0.01). For the ability of migration, it was significantly enhanced in the over-expression ENO1 cells than in the negative cells (t = 7.35, P < 0.001). CONCLUSION: The over-expression of ENO1 protein can enhance the abilities of proliferation and migration in gastric cancer cells of AGS, which indicates that ENO1 may be an important potential tumor-marker associated with the development of gastric cancer.