Preoperative chemoradiotherapy in older patients with rectal cancer guided by comprehensive geriatric assessment within a multidisciplinary team-a multicenter phase II trial.

BACKGROUND: The purpose of this study was to evaluate the safety and efficacy of preoperative concurrent chemoradiotherapy (preCRT) for locally advanced rectal cancer in older people who were classified as "fit" by comprehensive geriatric assessment (CGA). METHODS: A single-arm, multicenter, phase II trial was designed. Patients were eligible for this study if they were aged 70 years or above and met the standards of "fit" (SIOG1) as evaluated by CGA and of the locally advanced risk category. The primary endpoint was 2-year disease-free survival (DFS). Patients were scheduled to receive preCRT (50 Gy) with raltitrexed (3 mg/m2 on days 1 and 22). RESULTS: One hundred and nine patients were evaluated by CGA, of whom eighty-six, eleven and twelve were classified into the fit, intermediate and frail category. Sixty-eight fit patients with a median age of 74 years were enrolled. Sixty-four patients (94.1%) finished radiotherapy without dose reduction. Fifty-four (79.3%) patients finished the prescribed raltitrexed therapy as planned. Serious toxicity (grade 3 or above) was observed in twenty-four patients (35.3%), and fourteen patients (20.6%) experienced non-hematological side effects. Within a median follow-up time of 36.0 months (range: 5.9-63.1 months), the 2-year overall survival (OS), cancer-specific survival (CSS) and disease-free survival (DFS) rates were 89.6% (95% CI: 82.3-96.9), 92.4% (95% CI: 85.9-98.9) and 75.6% (95% CI: 65.2-86.0), respectively. Forty-eight patients (70.6%) underwent surgery (R0 resection 95.8%, R1 resection 4.2%), the corresponding R0 resection rate among the patients with positive mesorectal fascia status was 76.6% (36/47). CONCLUSION: This phase II trial suggests that preCRT is efficient with tolerable toxicities in older rectal cancer patients who were evaluated as fit based on CGA. TRIAL REGISTRATION: The registration number on ClinicalTrials.gov was NCT02992886 (14/12/2016).

ID1 expressing macrophages support cancer cell stemness and limit CD8+ T cell infiltration in colorectal cancer.

Elimination of cancer stem cells (CSCs) and reinvigoration of antitumor immunity remain unmet challenges for cancer therapy. Tumor-associated macrophages (TAMs) constitute the prominant population of immune cells in tumor tissues, contributing to the formation of CSC niches and a suppressive immune microenvironment. Here, we report that high expression of inhibitor of differentiation 1 (ID1) in TAMs correlates with poor outcome in patients with colorectal cancer (CRC). ID1 expressing macrophages maintain cancer stemness and impede CD8+ T cell infiltration. Mechanistically, ID1 interacts with STAT1 to induce its cytoplasmic distribution and inhibits STAT1-mediated SerpinB2 and CCL4 transcription, two secretory factors responsible for cancer stemness inhibition and CD8+ T cell recruitment. Reducing ID1 expression ameliorates CRC progression and enhances tumor sensitivity to immunotherapy and chemotherapy. Collectively, our study highlights the pivotal role of ID1 in controlling the protumor phenotype of TAMs and paves the way for therapeutic targeting of ID1 in CRC.

Efficacy of acupuncture on repair of glial scars in rats with traumatic brain injury.

OBJECTIVE: To explore the underlying mechanism of acupuncture on nerve repair by investigating its effect on the differentiation of glial cells and the repair of glial scars. METHODS: Sprague-Dawley rats were randomly allocated to three groups: normal group, model group, and acupuncture group. Acupuncture was applied at Renzhong (GV26), Baihui (GV20), Fengfu (GV16), Yamen (GV15) and Hegu (LI4) within 12 h after TBI modeling with a frequency of one session per day for 4 weeks. Neurobehavioral assessment, hematoxylin and eosin staining, immunofluorescence detection, and magnetic resonance imaging scanning were performed on days 3, 7, 14, and 28 after modeling of traumatic brain injury (TBI). RESULTS: Acupuncture promoted the proliferation of glial cells and glial scars at an early stage but inhibited the proliferation of glial cells and glial scars at a late stage. Morphological observations and immunofluorescence histochemistry showed that the morphology of the perilesional cortex in the acupuncture group was improved and the number of neurons was increased when compared with the model group. The lesion size of ipsilateral brain parenchyma in the acupuncture group was smaller than in the model group on days 7, 14, and 28 ( < 0.05) after TBI modeling. CONCLUSIONS: Acupuncture might have a bidirectional regulatory effect on glial scar repair after TBI by promoting the proliferation of glial cells and glial scars to limit the injured area and relieve nerve injury during the early stages, and by inhibiting glial scar hyperplasia to benefit the regeneration and repair of neurons and axons and promote neurological function recovery during the later stages.

The research progress of high altitude environment-associated chronic obstructive pulmonary disease and therapeutic drugs / 生理学报

The plateau environment is characterized by low oxygen, low air pressure, low temperature, and strong ultraviolet rays, etc. Chronic obstructive pulmonary disease (COPD) is a preventable and treatable chronic lung disease. High altitude environment increases COPD prevalence, clinical manifestation and mortality. The therapeutic window of theophylline drugs for COPD is narrow, and the high altitude environment has an influence on the pharmacokinetics of the drugs. This review summarizes the differences in the prevalence, mortality, clinical manifestation and clinical symptoms of COPD in the plateau and plain, providing a basis for identifying the risk factors of COPD in the plateau areas. The effects of plateau hypoxic environment on the pharmacokinetics of COPD drugs were also discussed. It can provide a rationale for more effective prevention and treatment of COPD at high altitude.

The safety of an MRI simulation-guided boost after short-course preoperative radiotherapy for unresectable rectal cancer (SUNRISE): interim analysis of a randomized phase II trial.

PURPOSE: The safety of an MRI simulation-guided boost after short-course preoperative radiotherapy (SCPRT) for unresectable rectal cancer is assessed with a planned interim analysis. METHODS AND MATERIALS: Patients diagnosed with clinical stage T3-4 or regional lymph node-positive disease with positive mesorectal fascia or T4b disease evaluated by pelvic MRI were randomly assigned to the SCPRT-boost group (25 Gy in 5 fractions plus 4 Gy delivered to the gross tumor volume, followed by four cycles of chemotherapy) or preoperative chemoradiotherapy group (50 Gy in 25 fractions with concurrent chemotherapy). Then, patients received total mesorectal excision surgery after preoperative treatment. The primary endpoint was the R0 resection rate. The interim analysis was performed when 42 patients completed their assigned treatments. RESULTS: From October 2018 to November 2019, a total of 43 patients were enrolled, and 42 patients were included in the interim analysis. During preoperative therapy, grade 3 or above toxicities were observed in 10/21 (47.6%) patients in the experimental group, and 4/21 (19.0%) patients in the control group. A total of 17 (81.0%) and 13 (61.9%) patients in the experimental group and control group underwent surgery, respectively. Overall, 65.1% of the patients achieved R0 resection in the intention-to-treat analysis. Surgery-related adverse complications were observed in 2 patients (11.8%) in the experimental group and 1 patient (7.7%) in the control group. CONCLUSION: Our results show that the toxicity of an MRI simulation-guided boost after SCPRT for unresectable rectal cancer is acceptable. Thus, this clinical trial will be continued as planned.

Multicenter, Randomized, Phase III Trial of Short-Term Radiotherapy Plus Chemotherapy Versus Long-Term Chemoradiotherapy in Locally Advanced Rectal Cancer (STELLAR).

PURPOSE: To ascertain if preoperative short-term radiotherapy followed by chemotherapy is not inferior to a standard schedule of long-term chemoradiotherapy in patients with locally advanced rectal cancer. MATERIALS AND METHODS: Patients with distal or middle-third, clinical primary tumor stage 3-4 and/or regional lymph node-positive rectal cancer were randomly assigned (1:1) to short-term radiotherapy (25 Gy in five fractions over 1 week) followed by four cycles of chemotherapy (total neoadjuvant therapy [TNT]) or chemoradiotherapy (50 Gy in 25 fractions over 5 weeks, concurrently with capecitabine [chemoradiotherapy; CRT]). Total mesorectal excision was undertaken 6-8 weeks after preoperative treatment, with two additional cycles of CAPOX (intravenous oxaliplatin [130 mg/m2, once a day] on day 1 and capecitabine [1,000 mg/m2, twice a day] from days 1 to 14) in the TNT group and six cycles of CAPOX in the CRT group. The primary end point was 3-year disease-free survival (DFS). RESULTS: Between August 2015 and August 2018, a total of 599 patients were randomly assigned to receive TNT (n = 302) or CRT (n = 297). At a median follow-up of 35.0 months, 3-year DFS was 64.5% and 62.3% in TNT and CRT groups, respectively (hazard ratio, 0.883; one-sided 95% CI, not applicable to 1.11; P < .001 for noninferiority). There was no significant difference in metastasis-free survival or locoregional recurrence, but the TNT group had better 3-year overall survival than the CRT group (86.5% v 75.1%; P = .033). Treatment effects on DFS and overall survival were similar regardless of prognostic factors. The prevalence of acute grade III-V toxicities during preoperative treatment was 26.5% in the TNT group versus 12.6% in the CRT group (P < .001). CONCLUSION: Short-term radiotherapy with preoperative chemotherapy followed by surgery was efficacious with acceptable toxicity and could be used as an alternative to CRT for locally advanced rectal cancer.

TRIB3 reduces CD8+ T cell infiltration and induces immune evasion by repressing the STAT1-CXCL10 axis in colorectal cancer.

High CD8+ T cell infiltration in colorectal cancer (CRC) should suggest a favorable prognosis and a satisfactory response to immunotherapy; however, the vast majority of patients with CRC do not benefit from immunotherapy due to poor T cell infiltration. Therefore, a better understanding of the mechanisms for T cell exclusion from CRC tumors is needed. Tribbles homolog 3 (TRIB3) has been implicated as an oncoprotein, but its role in regulating antitumor immune responses has not been defined. Here, we demonstrated that TRIB3 inhibits CD8+ T cell infiltration in various CRC mouse models. We showed that TRIB3 was acetylated by acetyltransferase P300, which inhibited ubiquitination and subsequent proteasomal degradation of TRIB3. Ectopically expressed TRIB3 inhibited signal transducer and activator of transcription 1 (STAT1) activation and STAT1-mediated CXCL10 transcription by enhancing the epidermal growth factor receptor signaling pathway, causing a reduction in tumor-infiltrating T cells. Genetic ablation of Trib3 or pharmacological acceleration of TRIB3 degradation with a P300 inhibitor increased T cell recruitment and sensitized CRCs to immune checkpoint blockade therapy. These findings identified TRIB3 as a negative modulator of CD8+ T cell infiltration in CRCs, highlighting a potential therapeutic target for treating immunologically "cold" CRCs.

Exploration of the preponderant population for primary tumor resection of asymptomatic metastatic colorectal cancer / 国际肿瘤学杂志

Objective:To explore the population who benefit from primary tumor resection (PTR) of asymptomatic metastatic colorectal cancer (mCRC) .Methods:The clinicopathological data of 121 patients with asymptomatic mCRC with unresectable liver metastases treated in the First Affiliated Hospital of Yangtze University from January 2014 to January 2019 were retrospectively analyzed. Kaplan-Meier method was used to draw the survival curve accompanied with log-rank test. Cox regression model was used to analyze the prognostic factors.Results:The median overall survival (OS) of 121 mCRC patients was 20 months, and the 3- and 5-year survival rates were 34.71% and 10.74%. The median OS of PTR and non-PTR patients were 21 months and 18 months respectively, with no statistically significant difference ( χ2=0.79, P=0.375) . In 65 mCRC patients received targeted therapy, the median OS of PTR and non-PTR patients were 25 months and 28 months respectively, with no statistically significant difference ( χ2=1.65, P=0.199) . In 84 patients with mCRC of the left colon and rectum, the median OS of PTR and non-PTR patients were 24 months and 18 months respectively, with a statistically significant difference ( χ2=4.25, P=0.039) . In 37 patients with mCRC of the right colon, the median OS of PTR and non-PTR patients were 19 months and 17 months respectively, with no statistically significant difference ( χ2=0.18, P=0.675) . In 64 mCRC patients who received liver local treatment, the median OS of PTR and non-PTR patients were 36 months and 17 months respectively, with a statistically significant difference ( χ2=12.60, P<0.001) . In 57 mCRC patients who did not receive liver local treatment, the median OS of PTR and non-PTR patients were 15 months and 17 months respectively, with no significant difference ( χ2=0.58, P=0.445) . Univariate analysis showed that the location of the primary tumor ( HR=0.51, 95% CI: 0.25-0.76, P=0.025) , the degree of differentiation ( HR=1.46, 95% CI: 1.13-9.45, P=0.004) , the maximum diameter of the liver metastases ( HR=1.86, 95% CI: 1.35-4.60, P=0.012) , the level of serum carcinoembryonic antigen ( HR=3.55, 95% CI: 2.55-8.45, P<0.001) , local treatment of liver metastases ( HR=0.35, 95% CI: 0.19-0.93, P<0.001) were influencing factors for OS of asymptomatic mCRC patients with unresectable liver metastases. Multivariate analysis showed that the primary sites of the left colon and rectum ( HR=0.43, 95% CI: 0.25-0.93, P=0.039) , local treatment of liver metastases ( HR=0.78, 95% CI: 0.27-0.86, P<0.001) were independent influencing factors for OS of asymptomatic mCRC patients with unresectable liver metastases. Conclusion:Asymptomatic mCRC patients with unresectable liver metastases with primary sites of the left colon and rectum and local treatment of liver metastases can benefit from PTR.

Analysis of therapeutic effects on endovascular recanalization of symptomatic non-acute middle cerebral artery occlusion / 中国综合临床

Objective:To investigate the preoperative evaluation, safety and clinical efficacy of intravascular recanalization for patients with symptomatic non-acute middle cerebral artery occlusion .Methods:Twenty-six patients with symptomatic non-acute middle cerebral artery occlusion admitted between January 2018 to June 2021 were retrospectively analyzed. The clinical symptoms, cerebral perfusion, occlusive site, occlusive length, collateral circulation and distal capillary were evaluated. There were 17 cases accorded with intravascular recanalization. The cerebral blood flow , cerebral blood volume, MTT, peak time and scores of 17 patients before and after revascularization were compared by paired t test.Results:Endovascular recanalization was performed in 17 patients and extracranial-intracranial artery bypass grafting was performed in 9 patients. Among the 17 cases, there were 7 cases of hemiplegia of contralateral limbs, 6 cases of recurrent cerebral infarction, 4 cases of paroxysmal contralateral limb numbness or weakness, 3 cases of cognitive dysfunction and 3 cases of headache. The cerebral perfusion of the occluded side of the middle cerebral artery in 17 cases was significantly lower than that of the healthy side. One patient failed to pass through the occlusion with micro guide wire, and gave up the operation after repeated attempts. The occluded vessels were successfully recanalized in 16 cases (thrombolytic grade of cerebral infarction=2b-3), and recanalized in 16 cases, including 9 cases of simple balloon dilatation and 7 cases of stent implantation. Three months after the operation, the National Institute of Health Stroke Scale (NIHSS) score of 17 patients decreased from (9.57±2.32) to (3.75±1.42). The cerebral blood flow, cerebral blood volume, mean transit time and peak time were also significantly improved compared with those before the operation（ t value was 9.08，5.54，4.26，8.56，6.00，respectively，all P<0.001）. The Montreal Cognitive Assessment (MoCA) score of cognitive function was (22.70±1.70) before the operation, and there months after operation (26.30±2.30) points ( t=6.66, P<0.001) were statistically significant. After operation, CT cerebral angiography or whole cerebral angiography showed that 1 case was occluded, 15 cases had good recanalization, no intracranial hemorrhage occurred during the perioperative period, and no new stroke occurred during the 6-month follow-up period. Conclusion:For patients with symptomatic non acute middle cerebral artery occlusion, the patients who may benefit from multi-dimensional evaluation are selected for intravascular recanalization treatment. There are few complications and high recanalization rate. The short-term follow-up clinical effect is good, but the long-term effect needs to be further observed.

Impact of neoadjuvant chemoradiotherapy on the local recurrence and distant metastasis pattern of locally advanced rectal cancer: a propensity score-matched analysis.

BACKGROUND: Previous studies have demonstrated different predominant sites of distant metastasis between patients with and without neoadjuvant chemoradiotherapy (NCRT). This study aimed to explore whether NCRT could influence the metastasis pattern of rectal cancer through a propensity score-matched analysis. METHODS: In total, 1296 patients with NCRT or post-operative chemoradiotherapy (PCRT) were enrolled in this study between January 2008 and December 2015. Propensity score matching was used to correct for differences in baseline characteristics between the two groups. After propensity score matching, the metastasis pattern, including metastasis sites and timing, was compared and analyzed. RESULTS: After propensity score matching, there were 408 patients in the PCRT group and 245 patients in the NCRT group. NCRT significantly reduced local recurrence (4.1% vs. 10.3%, P = 0.004), but not distant metastases (28.2% vs. 27.9%, P = 0.924) compared with PCRT. In both the NCRT and PCRT groups, the most common metastasis site was the lung, followed by the liver. The NCRT group developed local recurrence and distant metastases later than the PCRT group (median time: 29.2 [18.8, 52.0] months vs. 18.7 [13.3, 30.0] months, Z = -2.342, P = 0.019; and 21.2 [12.2, 33.8] vs. 16.4 [9.3, 27.9] months, Z = -1.765, P = 0.035, respectively). The distant metastases occurred mainly in the 2nd year after surgery in both the PCRT group (39/114, 34.2%) and NCRT group (21/69, 30.4%). However, 20.3% (14/69) of the distant metastases appeared in the 3rd year in the NCRT group, while this number was only 13.2% (15/114) in the PCRT group. CONCLUSIONS: The predominant site of distant metastases was the lung, followed by the liver, for both the NCRT group and PCRT group. NCRT did not influence the predominant site of distant metastases, but the NCRT group developed local recurrence and distant metastases later than the PCRT group. The follow-up strategy for patients with NCRT should be adjusted and a longer intensive follow-up is needed.

Clinical characteristics, medical service utilization, and expenditure for colorectal cancer in China, 2005 to 2014: Overall design and results from a multicenter retrospective epidemiologic survey.

BACKGROUND: Colorectal cancer (CRC) is the third most common cancer in China, however, publicly available, descriptive information on the clinical epidemiology of CRC is limited. METHODS: Patients diagnosed with primary CRC during 2005 through 2014 were sampled from 13 tertiary hospitals in 9 provinces across China. Data related to sociodemographic characteristics, the use of diagnostic technology, treatment adoption, and expenditure were extracted from individual medical records. RESULTS: In the full cohort of 8465 patients, the mean ± SD age at diagnosis was 59.3 ± 12.8 years, 57.2% were men, and 58.7% had rectal cancer. On average, 14.4% of patients were diagnosed with stage IV disease, and this proportion increased from 13.5% in 2005 to 20.5% in 2014 (P value for trend < .05). For diagnostic techniques, along with less use of x-rays (average, 81.6%; decreased from 90.0% to 65.7%), there were increases in the use of computed tomography (average, 70.4%; increased from 4.5% to 90.5%) and magnetic resonance imaging (average, 8.8%; increased from 0.1% to 20.4%) over the study period from 2005 to 2014. With regard to treatment, surgery alone was the most common (average, 50.1%), but its use decreased from 51.3% to 39.8% during 2005 through 2014; and the use of other treatments increased simultaneously, such as chemotherapy alone (average, 4.1%; increased from 4.1% to 11.9%). The average medical expenditure per patient was 66,291 Chinese Yuan (2014 value) and increased from 47,259 to 86,709 Chinese Yuan. CONCLUSIONS: The increasing proportion of late-stage diagnoses presents a challenge for CRC control in China. Changes in diagnostic and treatment options and increased expenditures are clearly illustrated in this study. Coupled with the recent introduction of screening initiatives, these data provide an understanding of changes over time and may form a benchmark for future related evaluations of CRC interventions in China.

Safety and efficacy of preoperative chemoradiotherapy in fit older patients with intermediate or locally advanced rectal cancer evaluated by comprehensive geriatric assessment: A planned interim analysis of a multicenter, phase II trial.

BACKGROUND AND PURPOSE: Comprehensive geriatric assessment (CGA) is a diagnostic method to assess the physical and mental health status of older patients. The purpose of this study was to assess the safety and efficacy of preoperative concurrent chemoradiotherapy (preCRT) for intermediate or locally advanced rectal cancer in older people who were classified as "fit" by CGA. The interim analysis focusing on safety was reported here as the first part of this trial. METHODS AND MATERIALS: This is a single arm, multicenter, phase II trial. The eligible patients for this study were aged 70 years or above that fulfilled the standard of intermediate or locally advanced risk category, and met the standard of fit (SIOG1) evaluated by CGA. All patients received preCRT (50 Gy) with Raltitrexed (3 mg/m2 on d1 and d22). Qualitative and quantitative variables were described using descriptive statistics. The surgery adherence predicting was analyzed by multivariate logistic regression. RESULTS: Thirty-nine fit patients were enrolled. All patients except one finished radiotherapy without dose reduction. Thirty-two patients finished the prescribed Raltitrexed therapy as scheduled. A serious toxicity was observed in 12 patients (30.8%), and only six patients (15.4%) experienced non-hematological side effects. CONCLUSION: Overall, our results showed that preCRT was feasible and safe in older patients with rectal cancer who were evaluated as fit based on CGA, supporting the use of CGA to tailor oncological treatment and predict the tolerance of a specific therapy. Completing this trial as planned would provide further valuable insights.

Impact of neoadjuvant chemoradiotherapy on the local recurrence and distant metastasis pattern of locally advanced rectal cancer: a propensity score-matched analysis / 中华医学杂志(英文版)

BACKGROUND@#Previous studies have demonstrated different predominant sites of distant metastasis between patients with and without neoadjuvant chemoradiotherapy (NCRT). This study aimed to explore whether NCRT could influence the metastasis pattern of rectal cancer through a propensity score-matched analysis.@*METHODS@#In total, 1296 patients with NCRT or post-operative chemoradiotherapy (PCRT) were enrolled in this study between January 2008 and December 2015. Propensity score matching was used to correct for differences in baseline characteristics between the two groups. After propensity score matching, the metastasis pattern, including metastasis sites and timing, was compared and analyzed.@*RESULTS@#After propensity score matching, there were 408 patients in the PCRT group and 245 patients in the NCRT group. NCRT significantly reduced local recurrence (4.1% vs. 10.3%, P = 0.004), but not distant metastases (28.2% vs. 27.9%, P = 0.924) compared with PCRT. In both the NCRT and PCRT groups, the most common metastasis site was the lung, followed by the liver. The NCRT group developed local recurrence and distant metastases later than the PCRT group (median time: 29.2 [18.8, 52.0] months vs. 18.7 [13.3, 30.0] months, Z = -2.342, P = 0.019; and 21.2 [12.2, 33.8] vs. 16.4 [9.3, 27.9] months, Z = -1.765, P = 0.035, respectively). The distant metastases occurred mainly in the 2nd year after surgery in both the PCRT group (39/114, 34.2%) and NCRT group (21/69, 30.4%). However, 20.3% (14/69) of the distant metastases appeared in the 3rd year in the NCRT group, while this number was only 13.2% (15/114) in the PCRT group.@*CONCLUSIONS@#The predominant site of distant metastases was the lung, followed by the liver, for both the NCRT group and PCRT group. NCRT did not influence the predominant site of distant metastases, but the NCRT group developed local recurrence and distant metastases later than the PCRT group. The follow-up strategy for patients with NCRT should be adjusted and a longer intensive follow-up is needed.

Study on the laboratory historical control values of biological indicators in SD rats with 28-day repeated dose oral toxicity tests / 中国职业医学

OBJECTIVE: To establish the laboratory historical control values for biological indicators in SD rats with 28-day repeated dose oral toxicity tests. METHODS: The body mass, blood routine indexes, serum biochemical indexes, organ mass and organ coefficient of 10 batches of specific pathogen free SD rats in the control group and the control additional group were collected for 28-day repeated dose oral toxicity tests, and the historical control values was established. RESULTS: The body mass of both male and female SD rats increased with the increasing age(all P<0.01). The body mass of male rats was higher than that of female rats each week(all P<0.01). The body mass, blood routine and serum biochemical indexes, organ mass and organ coefficient of SD rats were affected by the age and gender of rats to varying degrees. The effects of age and gender on organ mass and organ coefficient were not consistent. The laboratory historical control values of body mass, blood routine indexes, serum biochemical indexes, organ mass and organ coefficient of SD rats were established according to the age measured in weeks and the gender of rats. CONCLUSION: The laboratory control values of biological indicators of SD rats should be established according to different weekly age and the gender of rats. Organ coefficient is more suitable as an observation index for toxicological safety evaluation compared with organ mass.

The prognostic significance of the treatment response of regional lymph nodes and the refinement of the current TNM staging system in locally advanced rectal cancer after neoadjuvant chemoradiotherapy.

The current TNM staging system uses the same category definitions for both rectal cancer patients with and without neoadjuvant chemoradiotherapy (NCRT). However, ypTNM stage, especially ypN stage does not predict patient survival after NCRT well. Whether tumor regression in lymph nodes (LRG) may improve the prediction has not been well studied. In total, 358 patients with rectal cancer who received NCRT followed by radical resection were recruited from 2004 to 2015, and the median follow-up time was 57.5 months. The main outcome measure was disease-free survival (DFS). In univariate analysis, factors associated with DFS were ypT stage, ypN stage, number of negative lymph nodes (NLN), lymph node ratio (LNR), tumor regression grade (TRG), M-TTRG (modified ypT stage by combining ypT stage and TRG), maximum LRG (LRGmax), sum score of LRG (LRGsum), LRG ratio (average value of LRGsum), and M-NLRG (modified ypN stage by combining LRGmax and LNR). In the multivariate Cox regression analysis, M-TTRG and M-NLRG (p < 0.001 and p = 0.030, respectively) were significantly associated with DFS. The estimated 5-year DFS rates were 86.6%, 60.3%, and 36.4% for patients with M-NLRG-0, M-NLRG-1, and M-NLRG-2, respectively (p < 0.001). A significant difference in survival was observed among patients with NCRT after incorporating TRG and LRG simultaneously into the current ypTNM staging system (p < 0.001). LRG was an important prognostic factor in rectal cancer patients treated with NCRT and could refine the ypTNM staging system. The modified ypTNM staging system in combination with LRGmax, LNR, and TRG could improve the DFS prediction in each subset of patients.

Risk factors for nonclosure of defunctioning stoma and stoma-related complications among low rectal cancer patients after sphincter-preserving surgery.

BACKGROUND: Defunctioning stoma is widely used to reduce anastomotic complications in rectal cancer surgery. However, the complications of stoma and stoma reversal surgery should not be underestimated. Furthermore, in some patients, stoma reversal failed. Here, we investigated the complications of defunctioning stoma surgery and subsequent reversal surgery and identify risk factors associated with the failure of getting stoma reversed. METHODS: In total, 154 patients who simultaneously underwent low anterior resection and defunctioning stoma were reviewed. Patients were divided into two groups according to whether their stoma got reversed or not. The reasons that patients received defunctioning stoma and experienced stoma-related complications and the risk factors for failing to get stoma reversed were analysed. RESULTS: The mean follow-up time was 47.54 (range 4.0-164.0) months. During follow-up, 19.5% of the patients suffered stoma-related long-term complications. Only 79 (51.3%) patients had their stomas reversed. The morbidity of complications after reversal surgery was 45.6%, and these mainly consisted of incision-related complications. Multivariate analyses showed that pre-treatment comorbidity (HR = 3.17, 95% CI 1.27-7.96, P = 0.014), postoperative TNM stage (HR = 2.55, 95% CI 1.05-6.18, P = 0.038), neoadjuvant therapy (HR = 2.75, 95% CI 1.07-7.05, P = 0.036), anastomosis-related complications (HR = 4.52, 95% CI 1.81-11.29, P = 0.001), and disease recurrence (HR = 24.83, 95% CI 2.90-213.06, P = 0.003) were significant independent risk factors for a defunctioning stoma to be permanent. CONCLUSIONS: Defunctioning stoma is an effective method to reduce symptomatic anastomotic leakage, but the stoma itself and its reversal procedure are associated with high morbidity of complications, and many defunctioning stomas eventually become permanent. Therefore, surgeons should carefully assess preoperatively and perform defunctioning stomas in very high risk patients. In addition, doctors should perform stoma reversal surgery more actively to prevent temporary stomas from becoming permanent.

TRIB3 Interacts With ß-Catenin and TCF4 to Increase Stem Cell Features of Colorectal Cancer Stem Cells and Tumorigenesis.

BACKGROUND & AIMS: Activation of Wnt signaling to ß-catenin contributes to the development of colorectal cancer (CRC). Expression of tribbles pseudo-kinase 3 (TRIB3) is increased in some colorectal tumors and associated with poor outcome. We investigated whether increased TRIB3 expression promotes stem cell features of CRC cells and tumor progression by interacting with the Wnt signaling pathway. METHODS: We performed studies with C57BL/6J-ApcMin/J mice injected with an adeno-associated virus vector that expresses a small hairpin RNA against Trib3 mRNA (ApcMin/J-Trib3KD) or a control vector (ApcMin/J-Ctrl). We created BALB/c mice that overexpress TRIB3 from an adeno-associated virus vector and mice with small hairpin RNA-mediated knockdown of ß-catenin. The mice were given azoxymethane followed by dextran sodium sulfate to induce colitis-associated cancer. Intestinal tissues were collected and analyzed by histology, gene expression profiling, immunohistochemistry, and immunofluorescence. Leucine-rich repeat-containing G-protein-coupled receptor 5 (LGR5)-positive (LGR5Pos) and LGR5-negative (LGR5Neg) HCT-8 CRC cells, with or without knockdown or transgenic expression of TRIB3, were sorted and analyzed in sphere-formation assays. We derived organoids from human and mouse colorectal tumors to analyze the function of TRIB3 and test the effect of a peptide inhibitor. Wnt signaling to ß-catenin was analyzed in dual luciferase reporter, chromatin precipitation, immunofluorescence, and immunoblot assays. Proteins that interact with TRIB3 were identified by immunoprecipitation. CRC cell lines were grown in nude mice as xenograft tumors. RESULTS: At 10 weeks of age, more than half the ApcMin/J-Ctrl mice developed intestinal high-grade epithelial neoplasia, whereas ApcMin/J-Trib3KD mice had no intestinal polyps and normal histology. Colon tissues from ApcMin/J-Trib3KD mice expressed lower levels of genes regulated by ß-catenin and genes associated with cancer stem cells. Mice with overexpression of Trib3 developed more tumors after administration of azoxymethane and dextran sodium sulfate than BALB/c mice. Mice with knockdown of ß-catenin had a lower tumor burden after administration of azoxymethane and dextran sodium sulfate, regardless of Trib3 overexpression. Intestinal tissues from mice with overexpression of Trib3 and knockdown of ß-catenin did not have activation of Wnt signaling or expression of genes regulated by ß-catenin. LGR5Pos cells sorted from HCT-8 cells expressed higher levels of TRIB3 than LGR5Neg cells. CRC cells that overexpressed TRIB3 had higher levels of transcription by ß-catenin and formed larger spheroids than control CRC cells; knockdown of ß-catenin prevented the larger organoid size caused by TRIB3 overexpression. TRIB3 interacted physically with ß-catenin and transcription factor 4 (TCF4). TRIB3 overexpression increased, and TRIB3 knockdown decreased, recruitment of TCF4 and ß-catenin to the promoter region of genes regulated by Wnt. Activated ß-catenin increased expression of TRIB3, indicating a positive-feedback loop. A peptide (P2-T3A6) that bound ß-catenin disrupted its interaction with TRIB3 and TCF4. In primary CRC cells and HCT-8 cells, P2-T3A6 decreased expression of genes regulated by ß-catenin and genes associated with cancer stem cells and decreased cell viability and migration. Injection of C57BL/6J-ApcMin/J mice with P2-T3A6 decreased the number and size of tumor nodules and colon expression of genes regulated by ß-catenin. P2-T3A6 increased 5-fluorouracil-induced death of CRC cells and survival times of mice with xenograft tumors. CONCLUSION: TRIB3 interacts with ß-catenin and TCF4 in intestine cells to increase expression of genes associated with cancer stem cells. Knockdown of TRIB3 decreases colon neoplasia in mice, migration of CRC cells, and their growth as xenograft tumors in mice. Strategies to block TRIB3 activity might be developed for treatment of CRC.

Article Effect and Mechanism of Ganoderma lucidum Polysaccharides on Human Fibroblasts and Skin Wound Healing in Mice / 中国结合医学杂志

OBJECTIVE@#To investigate the effects of Ganoderma lucidum polysaccharides (GL-PS) on human fibroblasts and skin wound healing in Kunming male mice and to explore the putative molecular mechanism.@*METHODS@#Primary human skin fibroblasts were cultured. The viability of fibroblasts treated with 0, 10, 20, 40, 80, and 160 μg/mL of GL-PS, respectively were detected by 3-4,5-dimethyl-2-thiazolyl-2,5-diphenyl-2-Htetrazolium bromide (MTT). The migration ability of fibroblasts treated with 0, 10, 20, and 40 μg/mL of GL-PS were measured by transwell assay. The secretion of the C-terminal peptide of procollagen type I (CICP) and transforming growth factor-β1 (TGF-β1) in the cell supernatant was tested by enzyme-linked immunosorbent assay. The expression of β-catenin was detected by Western blot. Furthermore, the Kunming mouse model with full-layer skin resection trauma was established, and was treated with 10, 20, and 40 mg/mL of GL-PS, respectively as external use. The size of the wound was measured daily, complete healing time in each group was recorded and the percentage of wound contraction was calculated.@*RESULTS@#Compared with the control group, 10, 20, and 40 μg/mL of GL-PS significantly increased the viability of fibroblasts, promoted the migration ability of fibroblasts, and up-regulated the expressions of CICP and TGF-β1 in fibroblasts (Plt;0.05 or Plt;0.01). The expression of β-catenin in fibroblasts treated with 20 and 40 μg/mL of GL-PS was significantly higher than that of the control group (Plt;0.01). Furthermore, after external use of 10, 20, and 40 mg/mL of GL-PS, the rates of wound healing in mice were significantly higher and the wound healing time was significantly less than the control group (Plt;0.05 or Plt;0.01).@*CONCLUSION@#A certain concentration of GL-PS may promote wound healing via activation of the Wnt/β-catenin signaling pathway and up-regulation of TGF-β1, which might serve as a promising source of skin wound healing.

Renal rhabdoid synovial sarcoma: report of a case with literature review / 临床与实验病理学杂志

Purpose To report a rare case of renal rhabdoid synovial sarcoma and review the literature,in order to improve the realization for this disease and reduce misdiagnosis.Method The clinicopathological data of 1 case rhabdoid renal synovial sarcoma were retrospectively analyzed.The tumors were examined by immunohistochemical of EnVision two-step staining and FISH,the related literatures were reviewed.Result A 31-year-old male patient accepted the right kidney radical operation in November 2014 after imaging examination of right kidney tumor.Microscopically,the tumor cells showed short spindle cells with rich cytoplasm and eosinophilic bodies in the cytoplasm.The pathological diagnosis is the renal rhabdoid tumor for this time.The patient was found a tumor between the liver and the diaphragm by imaging examination in October 2015.The second operation was carried out successfully.Microscopically,the tumor cells were spindle with little cytoplasm and without eosinophilic bodies in the cytoplasm.It was a typical synovial sarcoma in morphology for this time.Immunohistochemical staining showed positive for vimentin,EMA,CD56,and TLE1,SS18SSX fusion gene was disclosed in the primary and recurrent tumor cells,it was therefore corrected as rhabdoid synovial sarcoma for the primary tumor.Conclusion Renal rhabdoid synovial sarcoma is rare.Renal primary rhabdoid synovial sarcoma is easily misdiagnosed as renal rhabdoid tumor.The renal rhabdoid synovial sarcoma has broadened the differential diagnosis of renal rhabdoid tumors spectrum.Even for a tumor with typical rhabdoid morphology,molecular biology method for differential diagnosis is needed.SS18-SSX fusion gene is the basis for diagnosis of synovial sarcoma.

Increased 5-hydroxymethylcytosine and Ten-eleven Translocation Protein Expression in Ultraviolet B-irradiated HaCaT Cells / 中华医学杂志(英文版)

<p><b>BACKGROUND</b>DNA hydroxymethylation refers to a chemical modification process in which 5-methylcytosine (5mC) is catalyzed to 5- hydroxymethylcytosine (5hmC) by ten-eleven translocation (TET) family proteins. Recent studies have revealed that aberrant TETs expression or 5hmC level may play important roles in the occurrence and development of various pathological and physiological processes including cancer and aging. This study aimed to explore the relation between aberrant DNA hydroxymethylation with skin photoaging and to investigate the levels of TETs, 5mC, and 5hmC expression 24 h after 40 mJ/cm2 and 80 mJ/cm2 doses of ultraviolet B (UVB) irradiation to HaCaT cells.</p><p><b>METHODS</b>To explore whether aberrant DNA hydroxymethylation is also related to skin photoaging, 40 mJ/cm2 and 80 mJ/cm2 doses of UVB were chosen to treat keratinocytes (HaCaT cells). After 24 h of UVB irradiation, 5mC and 5hmC levels were determined by immunohistochemistry (IHC) and immunofluorescence (IF), and at the same time, the expression levels of matrix metalloproteinase 1 (MMP-1) and TETs were assessed by reverse transcription-polymerase chain reaction or Western blot analysis.</p><p><b>RESULTS</b>After 40 mJ/cm2 and 80 mJ/cm2 doses of UVB exposure, both IHC and IF results showed that 5hmC levels increased significantly, while the 5mC levels did not exhibit significant changes in HaCaT cells, compared with HaCat cells without UVB exposure. Moreover, compared with HaCat cells without UVB exposure, the levels of TET1, TET2, and TET3 mRNA and protein expression were significantly upregulated (mRNA: P = 0.0022 and 0.0043 for TET1; all P < 0.0001 for TET2; all P = 0.0006 for TET3; protein: P = 0.0012 and 0.0006 for TET1; all P = 0.0022 for TET2; and all P = 0.0002 for TET3), and the levels of MMP-1 mRNA expression increased dose dependently in 40 mJ/cm2 and 80 mJ/cm2 UVB-irradiated groups.</p><p><b>CONCLUSION</b>UVB radiation could cause increased 5hmC and TET expression, which might become a novel biomarker in UVB-related skin aging.</p>