A comprehensive prognostic analysis of cause-specific mortality in patients with ovarian serous cystadenocarcinoma using a competing-risks model: a case study of the SEER database.

OBJECTIVE: This retrospective study employed a competing-risks analysis utilizing the Surveillance, Epidemiology, and End Results (SEER) database to identify precise prognostic factors associated with ovarian serous cystadenocarcinoma (OSCC) in patients. PATIENTS AND METHODS: Patients with OSCC during 2004-2015 were identified in the SEER database, and their clinicopathological, demographic, and survival data were examined. Univariate analysis using Gray's test and the cumulative incidence function was used to evaluate the prognoses of events of interest. The multivariate analysis involved several models, including the Cox proportional hazards, Fine-Gray, and cause-specific (CS) hazard function models, to estimate the hazard functions of competing risks. Hazard ratios were analyzed to identify the reliability of the prognostic factors. RESULTS: Among the 10,400 individuals diagnosed with OSCC, 5,713 died from the illness, and 1,125 died from other causes. The cumulative incidence rate of events of interest was found to be significant for ethnicity, age at diagnosis, histological grade, American Joint Committee on Cancer (AJCC) stage, chemotherapy and surgery status, tumor size, marital status, and local lymph node metastases (p<0.05). The multivariate analysis revealed that ethnicity, histological grade, surgery and chemotherapy status, age at diagnosis, AJCC stage, marital status, and distant metastases were independent prognostic factors in the Cox model (p<0.05). Finally, the Fine-Gray and CS models demonstrated that ethnicity, histological grade, surgery and chemotherapy status, age at diagnosis, AJCC stage, tumor size, marital status, and combination summary stage were all identified as independent prognostic factors (p<0.05). CONCLUSIONS: This study determined the risk factors for OSCC using a competing risk analysis model established by the SEER database. The findings can help clinicians understand OSCC better and provide more accurate medical support to affected patients.

Acute isolated orchalgia as the initial symptom in thoracic cord disorder: 2 case report and literature review.

INTRODUCTION: Orchalgia is a common andrological disorder and usually results from pathognomonic change of testes and regional structures. However, responsible cause is still unknown in more than one-fourth of patients. METHODS: We report two men who initially suffered an acute, isolated orchalgia and posteriorly complicated with paraparesis. They had previous history of prostate cancer and cervical myelitis. The urological examination was negative in both of them. Finally, prostate cancer metastasis and recurrent myelitis at T2/3 level was identified, respectively. Although their orchalgia progressively subsided, their urological, sexual and neurological dysfunction persisted. CONCLUSIONS: In the literature, the responsible pathology of spinal orchalgia was exclusively found below T10 level, frequently delaying affirmative diagnosis. Therefore, a thorough evaluation of spinal cord above T10 level should be alerted for idiopathic orchalgia with a pre-existing history or risk of spinal cord disorder and a negative urological examination.

Parenchymal hyperdensity on C-arm CT images after endovascular therapy for acute ischaemic stroke predicts a poor prognosis.

AIM: To investigate whether hyperdense areas (HDAs) observed after endovascular treatment on multisection computed tomography (CT) are related to outcome. MATERIALS AND METHODS: Data on 82 patients with acute anterior circulation ischaemic stroke resulting from intracranial large artery occlusion were analysed retrospectively All patients underwent mechanical thrombectomy and/or emergency angioplasty, and partial or complete recanalisation was successfully achieved. C-arm CT was performed immediately after endovascular treatment for all patients. Clinical and radiological data were compared between patients with and those without HDA and between patients with good and those with poor outcomes. RESULTS: Compared with non-HDA patients, HDA patients were more likely to present with severe neurological deficits (admission National Institutes of Health Stroke Scale [NIHSS] score: 18 versus 16, p=0.037) and had a higher number of stent retriever passes performed (2.9±1.3 versus 1.4±1, p<0.001), longer onset-to-presentation times (229±78 versus 171±90 minutes; p=0.002), longer onset-to-recanalisation times (418±94 versus 331±105 minutes; p<0.001), and longer puncture-to-recanalisation times (103±47 versus 69±42 minutes; p=0.001). Fewer HDA patients had a good prognosis (35.7% versus 70%, p<0.001). Multivariate analysis showed the presence of HDAs was an independent negative prognostic factor (OR=0.208; p=0.002). CONCLUSION: HDAs on C-arm CT appear to be common in patients with acute ischaemic stroke who underwent successful endovascular treatment. HDA presence suggests a poor prognosis despite successful reperfusion.

Clinical effectiveness of pemetrexed combined with cisplatin chemotherapy for advanced and maintenance treatment for patients with non-small-cell lung cancer.

OBJECTIVE: To evaluate the clinical effectiveness of pemetrexed combined with cisplatin for the first-line chemotherapy of patients with advanced non-small-cell lung cancer (NSCLC) and maintenance treatment. PATIENTS AND METHODS: 240 advanced NSCLC patients were randomly divided into either a control group (treated with gemcitabine combined with cisplatin) or an observation group (treated with pemetrexed combined with cisplatin). The primary treatment was defined as first-line chemotherapy, and the maintenance treatment was defined as retreatment. The demographic data from both groups were statistically similar. Patients were treated for 21 days for each cycle and underwent between 4 to 6 treatment cycles. RESULTS: The mid-and-long term efficacy between groups was compared using efficacy indexes [objective response rate (ORR), disease control rate (DCR), and chemotherapy toxic reaction rate] and progression-free survival (PFS), median survival time, and one-year survival rates. The observation group showed a statically greater (p<0.05) ORR and DCR than the control group. Comparison of the prevalence of toxic reaction above level III between the two groups revealed no statistical difference (p>0.05). The PFS, median survival time, and one-year survival rate of the observation group were statistically longer (p<0.05) than those of the control group. CONCLUSIONS: Pemetrexed combined with cisplatin was both safe and efficacious for the first-line chemotherapy of NSCLC patients at a progressive stage and for maintenance treatment.

Establishment of a Quantitative Polymerase Chain Reaction Assay for Monitoring Chimeric Antigen Receptor T Cells in Peripheral Blood.

BACKGROUND: The chimeric antigen receptor (CAR) consists of an antigen recognition moiety from a monoclonal antibody fused to an intracellular signalling domain capable of activating T cells. The specific structure of the CAR molecule has been used in various basic research and clinical settings to detect CAR expression, but it is necessary to develop more specific and simpler monitoring methods to observe real-time changes. MATERIALS AND METHODS: To develop a quantitative assay for the universal detection of DNA from anti-CD19 CAR-T cells, a TaqMan real-time quantitative polymerase chain reaction (qPCR) assay was developed using primers based on FMC63-28Z gene sequences. We identified the numbers of copies of CAR gene on T cells transduced with the CAR gene that were obtained from peripheral blood. RESULTS: The assay had a minimum detection limit of 10 copies/µL and a strong linear standard curve (y = -3.3682x + 38.594; R2 = 0.999) within the range of the input CAR gene (10-107 copies/µL). The reproducibility test showed a coefficient of variation ranging from 0.63%-1.65%. Real-time qPCR is a highly sensitive, specific, reproducible, and universal method that can be used to detect anti-CD19 CAR-T cells in peripheral blood.

Polymorphism in dural arteriovenous fistula: matrix metalloproteinase-2-1306 C/T as a potential risk factor for sinus thrombosis.

Essentials Sinus thrombosis may play a crucial role in development of dural arteriovenous fistula (DAVF). Little is known about the association between gene polymorphism and the development of DAVF. MMP-2-1306 C/T showed a higher prevalence rate in DAVF cases with sinus thrombosis. MMP-2-1306C/T polymorphism is likely a potential risk factor for sinus thrombosis in DAVF. SUMMARY: Background Dural arteriovenous fistula (DAVF) is a rare but important cerebrovascular disorder in adults. Little is known about the molecular genetic pathogenesis underlying DAVF development. Objectives To investigate the associations of gene polymorphisms and DAVF. Materials and Methods By the use of real-time PCR genotyping, seven single-nucleotide polymorphisms (SNPs) of angiogenesis-related genes were analyzed in 72 DAVF patients. Pertinent clinical and imaging data were subgrouped on the basis of location (cavernous sinus versus lateral sinus), lesions (single versus multiple), cerebral venous reflux (CVR) grading (Borden I versus Borden II/III), and sinus thrombosis (with versus without). Results We found that individuals carrying the polymorphic allele of matrix metalloproteinase (MMP)-2-1306 C/T (rs243865) had a significantly increased risk of sinus thrombosis in DAVF (odds ratio 6.2; 95% confidence interval 1.7-22.9). There was a weak difference in associations of tissue inhibitor of metalloproteinase (TIMP)-2 (rs2277698) gene polymorphism and DAVF patients subgrouped by CVR grading. Conclusions These preliminary results indicate that MMP-2-1306 C/T, but not MMP-9, TIMP-1, TIMP-2, and vascular endothelial growth factor A SNP variants, is a risk factor for the development of sinus thrombosis in DAVF patients.

Protein kinase Mζ in medial prefrontal cortex mediates depressive-like behavior and antidepressant response.

Neuronal atrophy and alterations of synaptic structure and function in the medial prefrontal cortex (mPFC) have been implicated in the pathogenesis of depression, but the underlying molecular mechanisms are largely unknown. The protein kinase Mζ (PKMζ), a brain-specific atypical protein kinase C isoform, is important for maintaining long-term potentiation and storing memory. In the present study, we explored the role of PKMζ in mPFC in two rat models of depression, chronic unpredictable stress (CUS) and learned helplessness. The involvement of PKMζ in the antidepressant effects of conventional antidepressants and ketamine were also investigated. We found that chronic stress decreased the expression of PKMζ in the mPFC and hippocampus but not in the orbitofrontal cortex. Overexpression of PKMζ in mPFC prevented the depressive-like and anxiety-like behaviors induced by CUS, and reversed helplessness behaviors. Inhibition of PKMζ in mPFC by expressing a PKMζ dominant-negative mutant induced depressive-like behaviors after subthreshold unpredictable stress and increased learned helplessness behavior. Furthermore, stress-induced deficits in synaptic proteins and decreases in dendritic density and the frequency of miniature excitatory postsynaptic currents in the mPFC were prevented by PKMζ overexpression and potentiated by PKMζ inhibition in subthreshold stress rats. The antidepressants fluoxetine, desipramine and ketamine increased PKMζ expression in mPFC and PKMζ mediated the antidepressant effects of ketamine. These findings identify PKMζ in mPFC as a critical mediator of depressive-like behavior and antidepressant response, providing a potential therapeutic target in developing novel antidepressants.

Prognostic value of ZFP36 and SOCS3 expressions in human prostate cancer

Purpose: ZFP36 ring finger protein (ZFP36) and the suppressor of cytokine signaling 3 (SOCS3) have been reported to, respectively, regulate NF-jB and STAT3 signaling pathways. To better understand the correlation of NF-jB and STAT3 negative regulates pathway, we have investigated the involvement of ZFP36 and SOCS3 expressions in human prostate cancer (PCa). Methods: In the present study, paired patient tissue microarrays were analyzed by immunohistochemistry, and the ZFP36 protein expression was quantitated as immunoreactive scores in patients with PCa. Associations between ZFP36/SOCS3 expression and various clinicopathological features and prognosis of PCa patients were statistically analyzed based on the Taylor database. Then, the functions of ZFP36 and SOCS3 in cancerous inflammation were determined using qPCR and immunohistochemistry in vitro and in vivo. Results: ZFP36 protein expression in PCa tissues was significantly lower than those in non-cancerous prostate tissues (P < 0.05). In mRNA level, ZFP36 and SOCS3 had a close correlation with each other (P < 0.01, Pearson r = 0.848), and its upregulation was both significantly associated with low Gleason score (P < 0.001 and P < 0.001, respectively), negative metastasis (P < 0.001 and P < 0.001, respectively), favorable overall survival (P < 0.001 and P < 0.05, respectively), and negative biochemical recurrence (P < 0.001 and P < 0.001, respectively). Functionally, LPS treatment could lead to the overexpression of ZFP36 and SOCS3 in vitro and vivo. Conclusions: Our data offer the convincing evidence for the first time that the aberrant expressions of ZFP36 and SOCS3 may be involved into the progression and patients’ prognosis of PCa, implying their potentials as candidate markers of this cancer

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Overexpression of maelstrom promotes bladder urothelial carcinoma cell aggressiveness by epigenetically downregulating MTSS1 through DNMT3B.

We have recently identified and characterized a novel oncogene, maelstrom (MAEL) from 1q24, in the pathogenesis of hepatocellular carcinoma. In this study, MAEL was investigated for its oncogenic role in urothelial carcinoma of the bladder (UCB) tumorigenesis/aggressiveness and underlying molecular mechanisms. Here, we report that overexpression of MAEL in UCB is important in the acquisition of an aggressive and/or poor prognostic phenotype. In UCB cell lines, knockdown of MAEL by short hairpin RNA is sufficient to inhibit cell growth, invasiveness/metastasis and suppressed epithelial-mesenchymal transition (EMT), whereas ectopic overexpression of MAEL promoted cell growth, invasive and/or metastatic capacity and enhanced EMT both in vitro and in vivo. We further demonstrate that MAEL could induce UCB cell EMT by downregulating a critical downstream target, the metastasis suppressor 1 (MTSS1) gene, ultimately leading to an increased invasiveness of cancer cells. Notably, overexpression of MAEL in UCB cells substantially enhanced the enrichment of DNA methyltrans-ferase (DNMT)3B and histone deacetylase (HDAC)1/2 on the promoter of the MTSS1, and thereby epigenetically suppressing the MTSS1 transcription. Downregulation of MTSS1 by MAEL in UCB cells is partially dependent on DNMT3B. Furthermore, we identify that beside the gene amplification of MAEL, miR-186 is a key negative regulator of MAEL and downregulation of miR-186 is another important mechanism for MAEL overexpression in UCBs. These data suggest that overexpression of MAEL, caused by gene amplification and/or decreased miR-186, has a critical oncogenic role in UCB pathogenesis by downregulation of MTSS1, and MAEL could be used as a novel prognostic marker and/or effective therapeutic target for human UCB.

Association between the thoroughness of the histopathological examination and survival in patients with esophageal squamous cell carcinoma who achieve pathological complete response after chemoradiotherapy.

The College of American Pathologists guidelines recommend examining at least four representative tumor blocks for determining pathological T stage in patients with primarily resected esophageal cancer. Whether the same pathological requirements are adequate in patients undergoing esophagectomy following neoadjuvant chemoradiotherapy (nCRT) remains unclear. We hypothesized that current examination protocols may underestimate the presence of microscopical residual disease after nCRT, potentially leading to under-staging. We retrospectively reviewed the records of patients with esophageal squamous cancer (ESCC) who were diagnosed as having pathological complete response (pCR) following nCRT. The thoroughness of the pathological examination in pCR patients was examined using (i) the number of blocks examined in suspicious tumor area (≤4 vs. >4), and (ii) the block quotient (calculated as the pretreatment tumor length divided by the number of blocks examined in suspicious tumor area). A total of 91 patients were enrolled. The mean number of blocks used to confirm pCR was 4.8 (range: 2-14). The 5-year overall survival (OS) and disease-free survival (DFS) in the entire cohort were 55% and 65%, respectively. Multivariate analyses identified the block quotient as the only independent predictor of OS and DFS. Receiver operating characteristic curve analysis indicated an optimal cutoff value of 1.4 for the block quotient. Among the patients who achieved pCR, the 5-year DFS differed significantly between subjects with a low (≤1.4) or high (>1.4) block quotient (76% vs. 47%, respectively, P = 0.03). The block quotient (calculated by the pretreatment tumor length divided by the number of blocks) - which reflects the meticulousness of the histopathological examination for confirming pCR - is associated with survival in ESCC patients.

Prognostic value of ZFP36 and SOCS3 expressions in human prostate cancer.

PURPOSE: ZFP36 ring finger protein (ZFP36) and the suppressor of cytokine signaling 3 (SOCS3) have been reported to, respectively, regulate NF-κB and STAT3 signaling pathways. To better understand the correlation of NF-κB and STAT3 negative regulates pathway, we have investigated the involvement of ZFP36 and SOCS3 expressions in human prostate cancer (PCa). METHODS: In the present study, paired patient tissue microarrays were analyzed by immunohistochemistry, and the ZFP36 protein expression was quantitated as immunoreactive scores in patients with PCa. Associations between ZFP36/SOCS3 expression and various clinicopathological features and prognosis of PCa patients were statistically analyzed based on the Taylor database. Then, the functions of ZFP36 and SOCS3 in cancerous inflammation were determined using qPCR and immunohistochemistry in vitro and in vivo. RESULTS: ZFP36 protein expression in PCa tissues was significantly lower than those in non-cancerous prostate tissues (P < 0.05). In mRNA level, ZFP36 and SOCS3 had a close correlation with each other (P < 0.01, Pearson r = 0.848), and its upregulation was both significantly associated with low Gleason score (P < 0.001 and P < 0.001, respectively), negative metastasis (P < 0.001 and P < 0.001, respectively), favorable overall survival (P < 0.001 and P < 0.05, respectively), and negative biochemical recurrence (P < 0.001 and P < 0.001, respectively). Functionally, LPS treatment could lead to the overexpression of ZFP36 and SOCS3 in vitro and vivo. CONCLUSIONS: Our data offer the convincing evidence for the first time that the aberrant expressions of ZFP36 and SOCS3 may be involved into the progression and patients' prognosis of PCa, implying their potentials as candidate markers of this cancer.

Transanal total mesorectal excision assisted by single-port laparoscopic surgery for low rectal cancer.

INTRODUCTION: We have combined the minimally invasive single-port laparoscopic surgery and the transanal total mesorectal excision (TaTME) for rectal cancer with the goal to standardize the approach and improve the quality of rectal cancer resection. METHODS: By using two single-port platforms, selected patients were first operated by TaTME, and then a single-port laparoscopic surgery was introduced to assist and complete the abdominal portion. Short-term outcomes including perioperative outcome and pathologic results of these patients were evaluated. RESULTS: Between July 2014 and March 2015, six patients with low rectal cancer (five males and one female) at a median age of 68 years were successfully operated in a median time of 360 min (range 310-420). The median estimated blood loss was 150 ml (range 50-800). In one patient, the spleen was removed because of a lesion identified preoperatively. Their postoperative recovery was uneventful except one acute myocardial infarction on postoperative day 3. Pathologic specimens showed negative margins and a complete excision of the mesorectum in all cases. The median number of harvested lymph nodes was 11.5 (range 4-12). At a median follow-up of 4 months (range 3-9), after ileostomy closure, none of the patients suffered from fecal incontinence. CONCLUSION: TaTME assisted by abdominal single-port may be safely achieved in selected rectal cancer patients.

The impact of plasma Epstein-Barr virus DNA and fibrinogen on nasopharyngeal carcinoma prognosis: an observational study.

BACKGROUND: The impact of combining plasma fibrinogen levels with Epstein-Barr Virus DNA (EBV DNA) levels on the prognosis for patients with nasopharyngeal carcinoma (NPC) was evaluated. METHODS: In this observational study, 2563 patients with non-metastatic NPC were evaluated for the effects of circulating plasma fibrinogen and EBV DNA levels on disease-free survival (DFS), distant metastasis-free survival (DMFS), and overall survival (OS). RESULTS: Compared with the bottom biomarker tertiles, TNM stage-adjusted hazard ratios (HR, 95% confidence intervals (CIs)) for predicting DFS in fibrinogen tertiles 2 to 3 were 1.26 (1.00 to 1.60) and 1.81 (1.45 to 2.26), respectively; HR for EBV DNA tertiles 2 to 3 were 1.49 (1.12 to 1.98) and 4.24 (3.27 to 5.49), respectively. After additional adjustment for established risk factors, both biomarkers were still associated (P for trend <0.001) with reduced DFS (HR: 1.79, 95% CI, 1.43 to 2.25 for top fibrinogen tertiles; HR: 4.04, 95% CI: 3.10 to 5.27 for top EBV DNA tertiles compared with the bottom tertiles). For patients with advanced-stage disease, those with high fibrinogen levels (3.34 g l(-1)) presented with worse DFS, regardless of EBV DNA 4000 or <4000 copies ml(-1) subgroup. Similar findings were observed for DMFS and OS. CONCLUSIONS: Circulating fibrinogen and EBV DNA significantly correlate with NPC patients survival. Combined fibrinogen and EBV DNA data lead to improved prognostic prediction in advanced-stage disease.

Pharmacokinetic of four probe drugs in adriamycin-induced nephropathy rat.

BACKGROUND AND AIM: Probe drugs have been widely used to assess the activities of various CYP450 (cytochromes P450) isoenzymes in many fields of drug metabolism and pharmacogenetics. The nephrotic syndrome characterized by massive proteinuria and hypoproteinemia, whether that would influence the pharmacokinetics of probe drugs or not is still unclear. The purpose of the study was to investigate the pharmacokinetic of four probe drugs in adriamycin (ADR)-induced nephropathy rat. MATERIALS AND METHODS: The rats were randomly divided into Control-group (n = 10) and ADR-group (n = 10). Nephrotic syndrome was established by weekly injections of ADR for 2 weeks. After dynamic monitoring of 24-h total urinary protein for 4 weeks, we confirmed that nephrotic syndrome had developed. The rats were administered intragastrically with phenacetin, tolbutamide, omeprazole and bupropion (15, 5, 15, and 15 mg/kg, respectively). The blood samples were determined by LC-MS (Liquid Chromatography-Mass Spectrometry) method. RESULTS: The pharmacokinetics parameter of tolbutamide in ADR-group and Control-group were AUC(0-t) 15.371 ± 4.107, 6.901 ± 5.738 (mg/L*h), MRT(0-t) 8.751 ± 0.754, 6.032 ± 0.63 (h), t1/2 3.88 ± 0.423, 3.602 ± 0.693 (h), Tmax 6.2 ± 3.768, 1.95 ± 0.798 (h), CL/F 0.038 ± 0.005, 0.107 ± 0.037 (L/h/kg), V/F 0.212 ± 0.043, 0.567 ± 0.258 (L/kg), Cmax 1.853 ± 0.384, 1.422 ± 1.312 (mg/L). There was statistical difference in AUC, MRT, CL, V and Tmax of tolbutamide between two groups (p < 0.05), but no pharmacokinetics difference for phenacetin, bupropion and omeprazole. CONCLUSIONS: The pharmacokinetics of tolbutamide was changed in ADR-induced nephropathy rat. It is not suitable for tolbutamide to evaluate the activity of CYP450 in nephrotic syndrome.

Association between migraine and irritable bowel syndrome: a population-based retrospective cohort study.

BACKGROUND AND PURPOSE: Migraine and irritable bowel syndrome (IBS) share many similarities characterized by their epidemiology, periodic pain, lack of definable organic causes, trigger factors, comorbidities and proposed pathophysiology. In this retrospective case-control study, the association between migraine and IBS was investigated using a nationwide population-based database in Taiwan. METHODS: The data were retrieved from the National Health Insurance Research Database (NHIRD) of Taiwan. In all, 14 117 newly diagnosed migraine cases were identified in a subset of the NHIRD and 56 468 migraine-free individuals were randomly selected as the comparison cohort. The multivariate Cox proportional hazards regression model was used to explore the risk of IBS in migraine sufferers after adjusting for demographic characteristics and comorbidities. RESULTS: After adjusting for the covariates, the incidence of IBS was 1.95-fold higher in the migraine cohort than in the comparison cohort (73.87 vs. 30.14 per 10 000 person-years). The adjusted cumulative incidence of IBS was also higher in the migraine group than in the control group in the follow-up years (log-rank test, P < 0.0001). In addition, the risk was most prominent in the youngest group (<30 years old), exhibiting a 3.36-fold increased risk (95% confidence interval 2.44-4.63) of IBS compared with the migraine-free cohort. Moreover, the incidence of IBS in migraine sufferers tended to increase with the frequency of migraine diagnoses. CONCLUSION: The current population-based study demonstrated that migraine is associated with an increased risk of IBS after adjusting for comorbidities, particularly in the young population.