Characteristics of the medical malpractice cases against orthopedists in China between 2016 and 2017.

BACKGROUND: This study aimed to identify the most frequent reasons for orthopedic medical malpractice, gain insight into the related patient demographics and clinical characteristics, and identify the independent factors associated with it. METHODS: We collected and analyzed the demographic and injury characteristics, hospital levels and treatments, medical errors, and orthopedist's degree of responsibility for the patients who were subject to orthopedic medical malpractice at our institution. Univariate and multivariate analyses were performed to identify the factors associated with the orthopedist's degree of responsibility in the medical malpractice cases. RESULTS: We included 1922 cases of medical malpractice in the final analysis. There were 1195 and 727 men and women, respectively (62.2% and 37.8%, respectively). Of the total patients, 1810, 1038, 1558, 1441, and 414 patients (94.2%, 54.0%, 81.1%, 75.0%, and 21.5%, respectively) were inpatients, had closed injuries, underwent surgery, were trauma cases, and had preoperative comorbidities, respectively. Most medical malpractice cases were in patients with fractures and spinal degenerative disease (1229 and 253 cases; 63.9% and 13.2%, respectively), and occurred in city-level hospitals (1006 cases, 52.3%), which were located in the eastern part of china (1001, 52.1%), including Jiangsu and Zhejiang (279 and 233 cases, 14.52% and 52.1%, respectively). Between 2016 and 2017, the orthopedist's degree of responsibility in medical malpractice claims were deemed as full, primary, equal, secondary, and minor in 135, 654, 77, 716, and 340 orthopedists (7.0%, 34.0%, 4.0%, 37.3%, and 17.7%). Most medical errors made by orthopedists in cases of medical malpractice were related to failure to supervise or monitor cases, improper performance of procedures, and failure to instruct or communicate with the patient (736, 716, and 423 cases; 38.3%, 37.3%, and 22.0%, respectively). The multivariate analysis found that patients with preoperative comorbidities, who sustained humerus injuries, who were aged ≥65 years, who were treated by doctors who failed to supervise or monitor them, and who were treated at the provincial and city level hospitals were more likely to claim that the orthopedist bore a serious degree of responsibility in the medical malpractice case. CONCLUSIONS: Our results provide detailed information on the plaintiff demographics, clinical characteristics, and factors associated with medical malpractice. Medical malpractice is related to poor treatment outcomes. The first preventative measure that is required is a comprehensive improvement in the medical staff quality, mainly through medical ethics cultivation, and professional ability and technique training. Additionally, failure to supervise or monitor cases was the leading cause of medical malpractice and one of the factors that led to orthopedists bearing an equal and higher responsibility for medical malpractice. Orthopedists should improve patient supervision, especially when treating older patients and those with preoperative comorbidities and humerus injuries.

PRMT5 functionally associates with EZH2 to promote colorectal cancer progression through epigenetically repressing CDKN2B expression.

Background: Protein arginine methyltransferase 5 (PRMT5) is a type II arginine methyltransferase that symmetrically di-methylates arginine residues on both histone and non-histone protein substrates. Accumulating evidence suggests that PRMT5 exerts its oncogenic properties in a wide spectrum of human malignancies. However, the underlying mechanisms by which PRMT5 contributes to the progression of colorectal cancer (CRC) remain to be defined. Methods: Western blot and real-time PCR were used to analyze the expression of CDKN2B. Co-immunoprecipitation (Co-IP), immunofluorescence and GST pulldown assays were employed to investigate the interaction between PRMT5 and EZH2. Luciferase reporter and chromatin immunoprecipitation (ChIP) assays were performed to validate CDKN2B as a direct target of PRMT5/EZH2. DNA methylation status at the CpG islands of promoter region of CDKN2B gene was analyzed by bisulfite sequencing. The effect of PRMT5/EZH2 on malignant phenotypes was examined through in vitro and in vivo assays. PRMT5 and EZH2 protein expression levels in CRC tissues were analyzed by immunohistochemistry (IHC) staining. Results: We observed that PRMT5-deficient CRC cells exhibit proliferation defects in vitro. PRMT5 was identified as a major transcriptional repressor of CDKN2B (p15INK4b) for determining CRC progression. Mechanistically, PRMT5-mediated histone marks H4R3me2s and H3R8me2s were predominantly deposited at the promoter region of CDKN2B gene in CRC cells. Knockdown of PRMT5 in CRC cells decreased the accumulation of H4R3me2s and H3R8me2s marks and reduced the CpG methylation level of CDKN2B promoter, then re-activated CDKN2B expression. Strikingly, silencing of CDKN2B partially abrogated the proliferation defects caused by PRMT5 depletion in vitro and in vivo. Furthermore, we proved that PRMT5 interacted with Enhancer of zeste homolog 2 (EZH2), leading to enhanced EZH2 binding and H3K27me3 deposition together with decreased transcriptional output of CDKN2B gene. Importantly, we found that the combined interventions exerted a synergistic inhibitory effect of combined treatment with PRMT5i (GSK591) and EZH2i (GSK126) on the growth of CRC cells/xenografts in vitro and in vivo. Moreover, PRMT5 and EZH2 were found to be significantly elevated and associated with poor prognosis in CRC patients. Conclusion: PRMT5 functionally associates with EZH2 to promote CRC progression through epigenetically repressing CDKN2B expression. Thus, our findings raise the possibility that combinational intervention of PRMT5 and EZH2 may be a promising strategy for CRC therapy.

Low miR-1273a expression predicts poor prognosis of colon cancer and facilitates tumor cell proliferation, migration, and invasion.

MicroRNAs (miRNAs) have been indicated to be frequently dysregulated in various cancers and promising biomarkers for colon cancer. The present study aimed to assess the prognostic significance and biological function of miR-1273a in colon cancer. The expression levels of miR-1273a was estimated using quantitative real-time polymerase chain reaction. Kaplan-Meier survival curves and Cox regression analysis were used to evaluate the prognostic value of miR-1273a in patients of colon cancer. The effects of miR-1273a on cell proliferation, migration, and invasion were investigated by cell experiments. The expression of miR-1273a was downregulated in colon cancer tissues and tumor cell lines compared with the normal controls (all P<0.001). The aberrant expression of miR-1273a was associated with vascular invasion (P=0.005), differentiation (P=0.023), lymph node metastasis (P=0.021), and TNM stage (P=0.004). The patients with low miR-1273a expression had low overall survival compared with the patients with high miR-1273a expression (log-rank P=0.002). miR-1273a was detected to be an independent prognostic biomarker for patients. Furthermore, the results of cell experiments revealed that miR-1273a downregulation promoted, while miR-1273a upregulation suppressed the cell proliferation, migration, and invasion. In conclusion, all data indicated that a downregulated expression of miR-1273a predicted poor prognosis for colon cancer and enhanced tumor cell proliferation, migration, and invasion. Thus, we suggest that methods to promote miR-1273a expression may serve as novel therapeutic strategies in colon cancer.

FBXW7 and Its Downstream NOTCH Pathway Could be Potential Indicators of Organ-Free Metastasis in Colorectal Cancer.

Colorectal cancer (CRC) is one of the leading causes of cancer-related deaths globally. Metastasis is associated with a poor prognosis, yet the underlying molecular mechanism(s) remained largely unknown. In this study, a total of 85 CRC patients were included and the primary tumor lesions were evaluated by next-generation sequencing using a targeted panel for genetic aberrations. Patients were sub-divided according to their metastasis pattern into the non-organ metastases (Non-OM) and organ metastases (OM) groups. By comparing the genetic differences between the two groups, we found that mutations in FBXW7 and alterations in its downstream NOTCH signaling pathway were more common in the Non-OM group. Moreover, correlation analysis suggested that FBXW7 mutations were independent of other somatic alterations. The negative associations of alterations in FBXW7 and its downstream NOTCH signaling pathway with CRC organ metastasis were validated in a cohort of 230 patients in the TCGA CRC dataset. Thus, we speculated that the genomic alterations of FBXW7/NOTCH axis might be an independent negative indicator of CRC organ metastases.

Low miR-1273a expression predicts poor prognosis of colon cancer and facilitates tumor cell proliferation, migration, and invasion

MicroRNAs (miRNAs) have been indicated to be frequently dysregulated in various cancers and promising biomarkers for colon cancer. The present study aimed to assess the prognostic significance and biological function of miR-1273a in colon cancer. The expression levels of miR-1273a was estimated using quantitative real-time polymerase chain reaction. Kaplan-Meier survival curves and Cox regression analysis were used to evaluate the prognostic value of miR-1273a in patients of colon cancer. The effects of miR-1273a on cell proliferation, migration, and invasion were investigated by cell experiments. The expression of miR-1273a was downregulated in colon cancer tissues and tumor cell lines compared with the normal controls (all P<0.001). The aberrant expression of miR-1273a was associated with vascular invasion (P=0.005), differentiation (P=0.023), lymph node metastasis (P=0.021), and TNM stage (P=0.004). The patients with low miR-1273a expression had low overall survival compared with the patients with high miR-1273a expression (log-rank P=0.002). miR-1273a was detected to be an independent prognostic biomarker for patients. Furthermore, the results of cell experiments revealed that miR-1273a downregulation promoted, while miR-1273a upregulation suppressed the cell proliferation, migration, and invasion. In conclusion, all data indicated that a downregulated expression of miR-1273a predicted poor prognosis for colon cancer and enhanced tumor cell proliferation, migration, and invasion. Thus, we suggest that methods to promote miR-1273a expression may serve as novel therapeutic strategies in colon cancer.

TIMP1 mRNA in tumor-educated platelets is diagnostic biomarker for colorectal cancer.

Platelets have been shown to promote the growth of tumors, including colorectal cancer. The RNA profile of tumor-educated platelets has the possibility for cancer diagnosis. We used RNA sequencing to identified the gene expression signature in platelets from colorectal cancer patients and healthy volunteers. We then verified the selected biomarkers from the RNA sequencing in a two-step case-control study using quantitative reverse-transcription polymerase chain reaction. We found that TIMP1 mRNA levels are higher in platelets from colorectal cancer patients than in platelets from healthy volunteers and patients with inflammatory bowel diseases. Additionally, TIMP1 mRNA expressed in platelets from colorectal cancer patients can be carried into colorectal cancer cells, where it promotes tumor growth in vivo and in vitro. These findings show that the TIMP1 mRNA in platelets is a potential independent diagnostic biomarker for colorectal cancer, and that platelets can carry RNAs into colorectal cancer cells to promote colorectal cancer development.

circANKS1B regulates FOXM1 expression and promotes cell migration and invasion by functioning as a sponge of the miR-149 in colorectal cancer.

Background: Circular RNAs (circRNAs) and microRNAs (miRNAs) play key roles in the development of human cancers. CircANKS1B has been reported to be increased in breast cancer. Methods: Real-time polymerase chain reaction (real-time PCR) assay was used to measure expressions of circANKS1B, ANKS1B, and FOXM1. Western blot assay was employed to examine the protein level of FOXM1 and Slug. The abilities of cell migration and invasion were measured by wound-healing and transwell assays. The interaction between circANKS1B and miR-149 was confirmed by site-directed mutagenesis and luciferase assays. Results: The expression of circANKS1B was up-regulated in colorectal cancer tissues and cells. Additionally, circANKS1B increased the expression of FOXM1. Furthermore, the enhancement of CRC cell migration and invasion by circANKS1B was dependent on FOXM1. However, previous studies have shown that miR-149 can directly target FOXM1 and act as tumor suppressor in CRC. Consequently, our results showed that miR-149 could directly bind to circANKS1B and FOXM1. The inhibition of circANKS1B could reduce FOXM1 and Slug protein levels, thus suppressing CRC cell migration and invasion. Conclusion: Taken together, circANKS1B promotes colorectal cancer cell migration and invasion by acting as a molecular sponge of miR-149 to modulate FOXM1 and Slug protein levels.

Effects of neuritin on the differentiation of bone marrow­derived mesenchymal stem cells into neuron­like cells.

While the neurotrophic factor neuritin is known to be involved in neurodevelopment, the effects of this compound on cell differentiation remain unclear. The present study demonstrated that neuritin treatment induced the differentiation of rat bone marrow­derived mesenchymal stem cells (rBM­MSCs) into neuron­like (NL) cells. For these analyses, rBM­MSCs were incubated with 0.5 µg/ml neuritin for 24 h. Following induction, 27% of the rBM­MSCs exhibited typical NL cell morphologies. Subsequently, NL cells were characterized by examining the expression of neuronal markers and by analysis of cell functions. The findings demonstrated that the NL cells produced by neuritin treatment expressed the neuronal markers neuron­specific enolase and microtubule associate protein 2, and secreted the neurotransmitter 5­hydroxytryptamine. Furthermore, the NL cells exhibited certain partial neural­electrophysiological functions. In conclusion, neuritin treatment may be an effective method for inducing the differentiation of BM­MSCs towards NL cells. This may provide an alternative, potentially complementary tool for disease modeling and the development of cell­based therapies.

Carcinoma microsatellite instability status as a predictor of benefit from fluorouracil-based adjuvant chemotherapy for stage II rectal cancer.

PURPOSE: Rectal cancers with high microsatellite-instable have clinical and pathological features that differentiate them from microsatellite-stable or low- frequency carcinomas, which was studied rarely in stage II rectal cancer, promoting the present investigation of the usefulness of microsatellite-instability status as a predictor of the benefit of adjuvant chemotherapy with fluorouracil in stage II rectal cancer. PATIENTS AND METHODS: Data of 460 patients who underwent primary anterior resection with a double stapling technique for rectal carcinoma at a single institution from 2008 to 2012 were retrospectively collected. All patients experienced a total mesorectal excision (TME) operation. Survival analysis were analyzed using the Cox regression method. RESULTS: Five-year rate of disease-free survival (DFS) was noted in 390 (84.8%) of 460 patients with stage II rectal cancer. Of 460 tissue specimens, 97 (21.1%) exhibited high-frequency microsatellite instability. Median age of the patients was 65 (50-71) and 185 (40.2%) were male. After univariate and multivariate analysis, microsatellite instability (p= 0.001), female sex (p< 0.05) and fluorouracil-based adjuvant chemotherapy (p< 0.001), the 3 factors were attributed to a favorable survival status independently. Among 201 patients who did not receive adjuvant chemotherapy, those cancers displaying high-frequency microsatellite instability had a better 5-year rate of DFS than tumors exhibiting microsatellite stability or low-frequency instability (HR, 13.61 [95% CI, 1.88 to 99.28]; p= 0.010), while in 259 patients who received adjuvant chemotherapy, there was no DFS difference between the two groups (p= 0.145). Furthermore, patients exhibiting microsatellite stability or low-frequency instability who received adjuvant chemotherapy had a better 5-year rate of DFS than patients did not (HR, 5.16 [95% CI, 2.90 to 9.18]; p< 0.001), while patients exhibiting high-frequency microsatellite instability were not connected with increased DFS (p= 0.696). It was implied that female patients had better survival than male. CONCLUSION: Survival status after anterior resection of rectal carcinoma is related to the microsatellite instability status, adjuvant chemotherapy and gender. Fluorouracil-based adjuvant chemotherapy benefits patients of stage II rectal cancer with microsatellite-stable or low microsatellite-instable, but not those with high microsatellite- instable. Additionally, free of adjuvant chemotherapy, carcinomas with high microsatellite-instable have a better 5-year rate of DFS than those with microsatellite-stable or low microsatellite-instable, and female patients have a better survival as well.

Outcomes based on risk assessment of anastomotic leakage after rectal cancer surgery.

PURPOSE: Anastomotic leakage (AL) is associated with high morbidity and mortality, high reoperation rates, and increased hospital length of stay. Here we investigated the risk factors for AL after anterior resection for rectal cancer with a double stapling technique. PATIENTS AND METHODS: Data for 460 patients who underwent primary anterior resection with a double stapling technique for rectal carcinoma at a single institution from 2003 to 2007 were prospectively collected. All patients experienced a total mesorectal excision (TME) operation. Clinical AL was defined as the presence of leakage signs and confirmed by diagnostic work-up according to ICD-9 codes 997.4, 567.22 (abdominopelvic abscess), and 569.81 (fistula of the intestine). Univariate and logistic regression analyses of 20 variables were undertaken to determine risk factors for AL. Survival was analysed using the Cox regression method. RESULTS: AL was noted in 35 (7.6%) of 460 patients with rectal cancer. Median age of the patients was 65 (50-74) and 161 (35%) were male. The diagnosis of AL was made between the 6th and 12th postoperative day (POD; mean 8th POD). After univariate and multivariate analysis, age (p=0.004), gender (p=0.007), tumor site (p<0.001), preoperative body mass index (BMI) (p<0.001), the reduction of TSGF on 5th POD less than 10U/ml (p=0.044) and the pH value of pelvic dranage less than or equal to 6.978 on 3rd POD (p<0.001) were selected as 6 independent risk factors for AL. It was shown that significant differences in survival of the patients were AL-related (p<0.001), high ASA score related (p=0.036), high-level BMI related (p=0.007) and advanced TNM stage related (p<0.001). CONCLUSIONS: AL after anterior resection for rectal carcinoma is related to advanced age, low tumor site, male sex, high preoperative BMI, low pH value of pelvic drainage on POD 3 and a significant reduction of TSGF on POD 5. In addition to their high risk of immediate postoperative morbidity and mortality, AL, worse physical status, severe obesity and advanced TNM stage have similarly negative impact on survival.

Acidic pelvic drainage as a predictive factor for anastomotic leakage after surgery for patients with rectal cancer.

PURPOSE: To demonstrate the value of sequential determinations of pelvic drainage in the identification of increased risk of anastomotic leakage (AL) after anterior resection for rectal cancer with a double stapling technique. PATIENTS AND METHODS: Between January 2004 and December 2011, data for the daily postoperative pH of pelvic drainage fluid in 753 consecutive patients with rectal cancer who initially underwent anterior resection with a double stapling technique were reviewed. All patients experienced a total mesorectal excision. Patients with anastomotic leakage (Group AL, n=57) were compared to patients without leakage (Group nAL, n=696). Patients with perioperatively abdominopelvic implants that were likely to affect pH value (determined at 25 °) other than leakage were excluded. Mean postoperative values were compared. RESULTS: Anastomotic leakage was noted in 57 (7.6%) of 753 patients with rectal cancer. The diagnosis of anastomotic leakage was made between the 6th and 12th postoperative day (POD; mean 8th POD). There was no significance of the daily average values of pH on POD1 and 2 in group AL while a significantly sharp declining mean pH value reached its diagnostic point of AL (p<0.001) on POD3. A cut-off value of 6.978 on the 3rd POD maximized the sensitivity (98.7.0%) and specificity (94.7%) in assessing the risk of leakage. CONCLUSION: According to these results, an early and persistent declining of pH value of pelvic drainage fluid after rectal surgery with anastomosis, is a marker of AL. A cut-off value of 6.798 on POD3 maximizes sensitivity and specificity.

Role of MYH polymorphisms in sporadic colorectal cancer in China: a case-control, population-based study.

PURPOSE: Biallelic germline variants of the 8-hydroxyguanine (8-OG) repair gene MYH have been associated with colorectal neoplasms that display somatic G:C?T:A transversions. However, the effect of single germline variants has not been widely studied, prompting the present investigation of monoallelic MYH variants and susceptibility to sporadic colorectal cancer (CRC) in a Chinese population. PATIENTS AND METHODS: Between January 2006 and December 2012, 400 cases of sporadic CRC and 600 age- and sex-matched normal blood donors were screened randomly for 7 potentially pathogenic germline MYH exons using genetic testing technology. Variants of heterozygosity at the MYH locus were assessed in both sporadic cancer patients and healthy controls. Univariate and multivariate analyses were performed to determine risk factors for cancer onset. RESULTS: Five monoallelic single nucleotide polymorphisms (SNPs) were identified in the 7 exon regions of MYH, which were detected in 75 (18.75%) of 400 CRC patients as well as 42 (7%) of 600 normal controls. The region of exon 1 proved to be a linked polymorphic region for the first time, a triple linked variant including exon 1-316 G?A, exon 1-292 G?A and intron 1+11 C?T, being identified in 13 CRC patients and 2 normal blood donors. A variant of base replacement, intron 10-2 A?G, was identified in the exon 10 region in 21 cases and 7 controls, while a similar type of variant in the exon 13 region, intron 13+12 C?T, was identified in 8 cases and 6 controls. Not the only but a newly missense variant in the present study, p. V463E (Exon 14+74 T?A), was identified in exon 14 in 6 patients and 1 normal control. In exon 16, nt. 1678-80 del GTT with loss of heterozygosity (LOH) was identified in 27 CRC cases and 26 controls. There was no Y165C in exon 7 or G382D in exon 14, the hot- spot variants which have been reported most frequently in Caucasian studies. After univariate analysis and multivariate analysis, the linked variant in exon 1 region (p=0.002), intron 10-2 A?G (p=0.004) and p. V463E (p=0.036) in the MYH gene were selected as 3 independent risk factors for CRC. CONCLUSIONS: According to these results, the linked variant in Exon 1 region, Intron 10-2 A?G of base replacement and p. V463E of missense variant, the 3 heterozygosity variants of MYH gene in a Chinese population, may relate to the susceptibility to sporadic CRC. Lack of the hot-spot variants of Caucasians in the present study may due to the ethnic difference in MYH gene.

Cholangiocytes of cirrhotic rats are more tolerant to ischemia than normal rats: a role for abnormal hepatic arteriovenous communications?

BACKGROUND: To assess whether cholangiocytes of rats with liver cirrhosis are more tolerant to ischemic changes than normal rats, and whether this is due to arteriovenous fistulas. METHODS: Ninety-eight Sprague-Dawley rats were divided into the normal group (n = 30) and the cirrhosis group (n = 68), and then each group was divided into controls and those with bile duct ischemia. At 0 h, 6 h, 3 d, and 14 d after the induction of bile duct ischemia, the liver of each rat was removed and stained with toluidine blue to compare cholangiocyte morphology. Cholangiocyte apoptosis was evaluated by a deoxynucleotidyl transferase-mediated dUTP-biotin nick-end labeling (TUNEL) assay. Expression of VEGF, HIF1, NF-kB(p65) was assessed by quantitative analysis of the products of reverse-transcriptase polymerase chain reaction. Resin casts were used to reproduce the intrahepatic vasculature of cirrhotic rats, and the presence of communications between the portal vein and hepatic artery was assessed with stereomicroscopy. RESULTS: Rats with liver cirrhosis were more tolerant than normal rats 6 h after bile duct ischemia (P < 0.05); at 3 and 14 d after the ischemic insult, there was no significant difference between the cirrhotic rats and normal rats. Levels of expression of VEGF, HIF1, and NF-kB(p65) genes, either in normal rats or cirrhotic rats, were significantly elevated compared with those in the control group (∗, ∗∗P < 0.05), but a lower extent changes appeared in the cirrhotic rats (∗∗∗P < 0.05). Several communications could be observed between the portal vein and hepatic artery. CONCLUSION: Cholangiocytes of cirrhotic rats appear to be more tolerant to ischemia of bile duct than non-cirrhotic rats. This may be due to the protective role of arterioportal fistulas.