Changes in liver-related mortality by etiology and sequelae: underlying versus multiple causes of death.

BACKGROUND: The expanded definition of liver-related deaths includes a wide range of etiologies and sequelae. We compared the changes in liver-related mortality by etiology and sequelae for different age groups between 2008 and 2018 in the USA using both underlying and multiple cause of death (UCOD and MCOD) data. METHODS: We extracted mortality data from the CDC WONDER. Both the absolute (rate difference) and relative (rate ratio and 95% confidence intervals) changes were calculated to quantify the magnitude of change using the expanded definition of liver-related mortality. RESULT: Using the expanded definition including secondary liver cancer and according to UCOD data, we identified 68,037 liver-related deaths among people aged 20 years and above in 2008 (29 per 100,000) and this increased to 90,635 in 2018 (33 per 100,000), a 13% increase from 2008 to 2018. However, according to MCOD data, the number of deaths was 113,219 (48 per 100,000) in 2008 and increased to 161,312 (58 per 100,000) in 2018, indicating a 20% increase. The increase according to MCOD was mainly due to increase in alcoholic liver disease and secondary liver cancer (liver metastasis) for each age group and hepatitis C virus (HCV) and primary liver cancer among decedents aged 65-74 years. CONCLUSION: The direction of mortality change (increasing or decreasing) was similar in UCOD and MCOD data in most etiologies and sequelae, except secondary liver cancer. However, the extent of change differed between UCOD and MCOD data.

Long-term Effects of Hepatitis B Immunization of Infants in Preventing Liver Cancer.

BACKGROUND & AIMS: The incidence of hepatocellular carcinoma (HCC) increases with age, but protective antibody responses decrease with time after infants are immunized against hepatitis B virus (HBV). We investigated whether immunization of infants against HBV prevents their developing HCC as adults. We also searched for strategies to maximize the cancer-preventive effects. METHODS: We collected data from 2 Taiwan HCC registry systems on 1509 patients (6-26 years old) diagnosed with HCC from 1983 through 2011. Data on history of HBV immunization and prenatal maternal levels of HBV antigens of all HCC patients born after July 1984 were retrieved from the HBV immunization data bank of the Taiwan Center for Disease Control. We collected data on birth cohort-specific populations (6-26 years old) of Taiwan using the National Household Registry System. Rates of HCC incidence per 10(5) person-years were derived by dividing the number of patients with HCC by the person-years of the general population. Relative risks (RR) for HCC were estimated by Poisson regression analysis in vaccinated vs unvaccinated birth cohorts. We stratified patients by age group to evaluate the association of birth cohorts and HCC risks. RESULTS: Of the 1509 patients with HCC, 1343 were born before, and 166 were born after, the HBV vaccination program began. HCC incidence per 10(5) person-years was 0.92 in the unvaccinated cohort and 0.23 in the vaccinated birth cohorts. The RRs for HCC in patients 6-9 years old, 10-14 years old, 15-19 years old, and 20-26 years old who were vaccinated vs unvaccinated were 0.26 (95% confidence interval [CI], 0.17-0.40), 0.34 (95% CI, 0.25-0.48), 0.37 (95% CI, 0.25-0.51), and 0.42 (95% CI, 0.32-0.56), respectively. The RR for HCC in 6- to 26-year-olds was lower in the later vs the earlier cohorts (born in 1992-2005 vs 1986-1992; P < .001 and 1986-1992 vs 1984-1986; P < .002). Transmission of HBV from highly infectious mothers and incomplete immunization were associated with development of HCC. CONCLUSIONS: Based on an analysis of 1509 patients with HCC in Taiwan, immunization of infants against HBV reduces their risk of developing HCC as children and young adults. Improving HBV vaccination strategies and overcoming risk factors could reduce the incidence of liver cancer.

Prognostic significance of DSG3 in rectal adenocarcinoma treated with preoperative chemoradiotherapy.

AIM: This study aimed to investigate the prognostic significance of DSG3 and its association with response to neoadjuvant concurrent chemoradiotherapy (CCRT) in rectal cancer. MATERIALS & METHODS: Data mining of a publicly available dataset was performed to find genes associated with CCRT response. Immunohistochemistry was applied to evaluate DSG3 expression. The relationships between DSG3 expression and various clinicopathological parameters and survival were analyzed. RESULTS: The DSG3 gene was significantly associated with CCRT response. The expression of DSG3 negatively correlated with poorer tumor regression (p < 0.001) and had an independent negative impact on disease-specific survival (p = 0.011), local recurrence-free survival (p = 0.031) and metastasis-free survival (p = 0.029). CONCLUSION: DSG3 was a key prognostic factor and predictor for CCRT response in rectal cancer patients.

Unintentional drowning mortality, by age and body of water: an analysis of 60 countries.

BACKGROUND: To examine unintentional drowning mortality by age and body of water across 60 countries, to provide a starting point for further in-depth investigations within individual countries. METHODS: The latest available three years of mortality data for each country were extracted from WHO Health Statistics and Information Services (updated at 13 November 2013). We calculated mortality rate of unintentional drowning by age group for each country. For countries using International Classification of Disease 10 (ICD-10) detailed 3 or 4 Character List, we further examined the body of water involved. RESULTS: A huge variation in age-standardised mortality rate (deaths per 100 000 population) was noted, from 0.12 in Turkey to 9.19 in Guyana. Of the ten countries with the highest age-standardised mortality rate, six (Belarus, Lithuania, Latvia, Russia, Ukraine and Moldova) were in Eastern Europe and two (Kazakhstan and Kyrgyzstan) were in Central Asia. Some countries (Japan, Finland and Greece) had a relatively low rank in mortality rate among children aged 0-4 years, but had a high rank in mortality rate among older adults. On the contrary, South Africa and Colombia had a relatively high rank among children aged 0-4 years, but had a relatively low rank in mortality rate among older adults. With regard to body of water involved, the proportion involving a bathtub was extremely high in Japan (65%) followed by Canada (11%) and the USA (11%). Of the 13 634 drowning deaths involving bathtubs in Japan between 2009 and 2011, 12 038 (88%) were older adults aged 65 years or above. The percentage involving a swimming pool was high in the USA (18%), Australia (13%), and New Zealand (7%). The proportion involving natural water was high in Finland (93%), Panama (87%), and Lithuania (85%). CONCLUSIONS: After considering the completeness of reporting and quality of classifying drowning deaths across countries, we conclude that drowning is a high-priority public health problem in Eastern Europe, Central Asia, Japan (older adults involving bathtubs), and the USA (involving swimming pools).

BCL6 overexpression is associated with decreased p19 ARF expression and confers an independent prognosticator in gallbladder carcinoma.

B cell lymphoma 6 (BCL6) is a protein that is vital for lymphogenesis. Its expression has been well established in lymphoma, especially in diffuse large B-cell lymphoma. Its role in carcinogenesis is less well understood. Previous study shows that BCL6 expression may regulate p19 functions, an important regulator for the p53 pathway. No prior study has attempted to evaluate the significance of BCL6 and p19(ARF) expression in a large cohort of patients with gallbladder carcinomas (GBCs). We selected 164 patients with GBC and performed immunostains for BCL6 and p19(ARF). BCL6 expression and p19(ARF) expression were evaluated using a histochemical score (H-score). We then correlated the results with various clinicopathological factors, disease-specific survival (DSS), and disease-free survival (DFS). BCL6 overexpression was significantly associated with high pT status, high TNM stage, higher histological grade (p = 0.029), vascular invasion, perineurial invasion, high Ki-67 labeling index, and low p19 expression. Importantly, BCL6 overexpression in GBC was strongly associated with worse DSS (p < 0.0001) and DFS (p < 0.0001) in the univariate analysis, and remained independently predictive of adverse outcomes (p = 0.001, hazard ratio (H.R.) = 3.098 for DSS; p = 0.002, H.R. = 2.255 for DFS). Low p19(ARF) expression was correlated with a poor DSS (p = 0.0144) and DFS (p = 0.0032) in the univariate analysis but was not prognosticatory in the multivariate analysis. In GBC, BCL6 overexpression correlated with adverse phenotypes and decreased p19(ARF) expression. BCL6 overexpression also independently predicts worse DSS and DFS, suggesting it has a role in tumorigenesis or carcinogenesis and could be a potential prognostic indicator in GBC.

Cyclin-dependent kinase 4 overexpression is mostly independent of gene amplification and constitutes an independent prognosticator for nasopharyngeal carcinoma.

Data mining in the public domain demonstrates that cyclin-dependent kinase 4 (CDK4) is highly expressed in nasopharyngeal carcinomas (NPC). Associated with cyclin-D, CDK4 phosphorylates and inactivates retinoblastoma (Rb) protein family members and mediates progression through the G1- to the S-phase of the cell cycle. Amplification and overexpression of CDK4 has been identified in various human malignancies. However, its expression and amplification has never been systemically evaluated in NPC. This study aimed to evaluate the amplification and expression status, correlation with clinicopathological features, and prognostic implications of CDK4 based on public domain dataset and in our well-defined cohort of NPC patients. The association between CDK4 transcript level and gene dosage was explored by analysis of an independent public domain dataset. We retrospectively assessed CDK4 immunoexpression in biopsies of 124 consecutive NPC patients devoid of initial distant metastasis and treated according to consistent guidelines. The results were correlated with clinicopathological features, local recurrence-free survival (LRFS), distant metastasis-free survival (DMeFS), and disease-specific survival (DSS). High levels of CDK4 protein were positively correlated with the T 3, 4 status (p = 0.024); N 2, 3 status (p < 0.001); and the American Joint Committee on Cancer stage 3, 4 (p < 0.001). Multivariate analysis suggested high CDK4 expression was an independent prognostic indicator of worse DMeFS (p = 0.001, hazard ratio (HR) = 3.226) and DSS (p = 0.037, HR = 1.838). Although CDK4 is frequently upregulated, its gene locus is very uncommonly amplified in NPC. CDK4 overexpression is mostly independent with gene amplification and represents a potential prognostic biomarker in NPC and may indicate tumor aggressiveness through cell cycle dysregulation.

Overexpression of ANXA1 confers independent negative prognostic impact in rectal cancers receiving concurrent chemoradiotherapy.

Neoadjuvant concurrent chemoradiation therapy (CCRT) is an increasingly common therapeutic strategy for rectal cancer. Clinically, it remains a major challenge to predict therapeutic response and patient outcomes after CCRT. Annexin I (ANXA1), encoded by ANXA1, is a Ca(2+)/phospholipid-binding protein that mediates actin dynamics and cellular proliferation, as well as suggesting tumor aggressiveness and predicting therapeutic response in certain malignancies. However, expression of ANXA1 has never been reported in rectal cancer receiving CCRT. This study examined the predictive and prognostic impact of ANXA1 expression in patients with rectal cancer following neoadjuvant CCRT. We identified ANXA1 as associated with resistance to CCRT through data mining from a published transcriptomic dataset. Its immunoexpression was retrospectively assessed using H scores on pre-treatment biopsies from 172 rectal cancer patients treated with neoadjuvant CCRT followed by curative surgery. Results were correlated with clinicopathological features, therapeutic response, tumor regression grade (TRG), and metastasis-free survival (MeFS), as well as local recurrent-free survival (LRFS) and disease-specific survival (DSS). High expression of ANXA1 was associated with advanced pre-treatment tumor status (T3, T4, p = 0.022), advanced pre-treatment nodal status (N1, N2, p = 0.004), advanced post-treatment tumor status (T3, T4, p < 0.001), advanced post-treatment nodal status (N1, N2, p = 0.001) and inferior TRG (p = 0.009). In addition, high expression of ANXA1 emerged as an adverse prognosticator for DSS (p < 0.0001), LRFS (p = 0.0001) and MeFS (p = 0.0004). Moreover, high expression of ANXA1 also remained independently prognostic of worse DSS (hazard ratio [HR] = 3.998; p = 0.007), LRFS (HR = 3.206; p = 0.028) and MeFS (HR = 3.075; p = 0.017). This study concludes that high expression of ANXA1 is associated with poor therapeutic response and adverse outcomes in rectal cancer patients treated with neoadjuvant CCRT.

Deficiency in asparagine synthetase expression in rectal cancers receiving concurrent chemoradiotherapy: negative prognostic impact and therapeutic relevance.

Locally advanced rectal cancers are currently treated with neoadjuvant concurrent chemoradiotherapy (CCRT) followed by surgery, but risk stratification and final outcomes remain suboptimal. In this study, we identify and validate targetable metabolic drivers relevant to the prognosis of patients with rectal cancer treated with CCRT. Using a published transcriptome of rectal cancers, we found that asparagine synthetase (ASNS) gene significantly predicted the response to CCRT. From 172 patients with rectal cancer, the expression levels of ASNS, using immunohistochemistry assays, were further evaluated in tumor specimens initially obtained by using colonoscopy. Expression levels of ASNS were further correlated with major clinicopathological features and clinical survivals in this valid cohort. ASNS deficiency was significantly related to advanced posttreatment tumor (T3, T4; P = .015) and nodal status (N1, N2; P = .004) and inferior tumor regression grade (P < .001). In survival analyses, ASNS deficiency was significantly associated with shorter local recurrence-free survival (LRFS; P = .0039), metastasis-free survival (MeFS; P = .0001), and disease-specific survival (DSS; P = .0006). Furthermore, ASNS deficiency was independently predictive of worse outcomes for MeFS (P = .012, hazard ratio = 3.691) and DSS (P = .022, hazard ratio = 2.845), using multivariate analysis. ASNS deficiency is correlated with poor therapeutic response and worse survivals in patients with rectal cancer receiving neoadjuvant CCRT. These findings indicate that ASNS is a prognostic factor with therapeutic potential for treating rectal cancer.

Overexpression of CPS1 is an independent negative prognosticator in rectal cancers receiving concurrent chemoradiotherapy.

Locally advanced rectal cancers are currently treated with neoadjuvant concurrent chemoradiotherapy (CCRT) followed by surgery, but stratification of risk and final outcomes remain suboptimal. In view of the fact that glutamine metabolism is usually altered in cancer, we profiled and validated the significance of genes involved in this pathway in rectal cancers treated with CCRT. From a published transcriptome of rectal cancers (GSE35452), we focused on glutamine metabolic process-related genes (GO:0006541) and found upregulation of carbamoyl phosphate synthetase 1 (CPS1) gene most significantly predicted poor response to CCRT. We evaluated the expression levels of CPS1 using immunohistochemistry to analyze tumor specimens obtained during colonoscopy from 172 rectal cancer patients. Expression levels of CPS1 were further correlated with major clinicopathological features and survivals in this validation cohort. To further confirm CPS1 expression levels, Western blotting was performed for human colon epithelial primary cell (HCoEpiC) and four human colon cancer cells, including HT29, SW480, LoVo, and SW620. CPS1 overexpression was significantly related to advanced posttreatment tumor (T3, T4; P = 0.006) and nodal status (N1, N2; P < 0.001), and inferior tumor regression grade (P = 0.004). In survival analyses, CPS1 overexpression was significantly associated with shorter disease-specific survival (DSS) and metastasis-free survival (MeFS). Furthermore, using multivariate analysis, it was also independently predictive of worse DSS (P = 0.021, hazard ratio = 2.762) and MeFS (P = 0.004, hazard ratio = 3.897). CPS1 protein expression, as detected by Western blotting, is more abundant in colon cancer cells than nonneoplastic HCoEpiC. Overexpression of CPS1 is associated with poor therapeutic response and adverse outcomes among rectal cancer patients receiving CCRT, justifying the potential theranostic value of CPS1 for such patients.

Reporting of aspiration pneumonia or choking as a cause of death in patients who died with stroke.

BACKGROUND AND PURPOSE: It is not known how many stroke patients die from fatal pulmonary complications such as aspiration pneumonia (AP) and choking each year in the United States. This study aimed to determine the frequency of reporting of AP or choking as a cause of death on death certificates with mention of stroke in the United States as a proxy measure of the incidence of dying from AP or choking among patients with stroke. METHODS: We used multiple-cause mortality data for the years 2001 to 2010 to identify death certificates with mention of stroke (International Classification of Diseases, Tenth Revision code I60-I69), AP (International Classification of Diseases, Tenth Revision code J69), and choking (International Classification of Diseases, Tenth Revision code W78-W80) for analysis. RESULTS: Of 2 424 379 death certificates with mention of stroke in the United States between 2001 and 2010, 5.1% (n=124 503) reported AP as a cause of death, and 1.5% (n=36 997) reported choking as a cause of death. However, if we confined the analysis to autopsy-confirmed cases, the frequency decreased to 1.3% (555/42 732) and 1.3% (541/42 732), respectively. The adjusted odds ratios of reporting AP or choking as a cause of death were higher among men, increased with age, and were higher among decedents who died in a nursing home/long-term care. CONCLUSIONS: The estimated incidence of dying from AP and choking among patients who died with stroke was 5% (~12 000 deaths per year) and 1% (~3700 deaths per year) according to information reported on death certificates. Efforts are needed to reduce the number of deaths from these 2 preventable complications.

Nicotinamide N-methyltransferase overexpression is associated with Akt phosphorylation and indicates worse prognosis in patients with nasopharyngeal carcinoma.

Nicotinamide N-methyltransferase (NNMT) is overexpressed in many human cancers and is associated with poor prognosis. Akt (also known as protein kinase B) is an evolutionarily conserved serine/threonine kinase, serving as a downstream effector of the phosphatidylinositol 3-kinase signaling pathway. NNMT was first identified as a differentially upregulated gene in nasopharyngeal cancer tissues through data mining from published transcriptomic databases. Since no prior study has attempted to evaluate the clinical significance of NNMT or phosphorylated Akt (pAkt) expression in nasopharyngeal cancer, this study explores their expression in a large cohort of patients with nasopharyngeal cancer. The study included 124 nasopharyngeal cancer patients who were free of distant metastasis at initial diagnosis. Pathological slides were reviewed and clinical findings collected. We evaluated the expression of NNMT and pAkt immunohistochemically, stratified them into two groups (high and low expression) and examined the correlation with disease-specific survival (DSS), metastasis-free survival (MeFS), local recurrence-free survival (LRFS), and various clinicopathological factors. NNMT expression was significantly positively associated with pAkt expression. The high expression of both markers was significantly associated with an increment of tumor stage (p = 0.006 and p = 0.006, respectively). High expression of NNMT correlated significantly with a more aggressive clinical course and a significantly shorter DSS. Furthermore, NNMT expression and pAkt expression were strongly predictive of MeFS (p = 0.008; p = 0.0063) and LRFS (p = 0.005; p = 0.0125). In multivariate analysis, high expression of NNMT remained as a robust prognosticator for both end points evaluated. It independently portended inferior DSS (p = 0.02, HR = 1.976) and worse MeFS (p = 0.029, HR = 2.022) after tumor stage (p = 0.033, HR = 2.150; p = 0.028, HR = 2.942, for DSS and LRFS, respectively). We found NNMT positively correlated with pAkt expression and was independent adverse prognosticators of patient survival. NNMT therefore has potential utility as an indicator for prognosis, predicting treatment response to chemotherapy or radiation therapy, and even as a therapeutic target in the future.

Clinicopathological significance of HuR expression in gallbladder carcinoma: with special emphasis on the implications of its nuclear and cytoplasmic expression.

Gallbladder carcinoma (GBC) is a relatively rare disease which pathogenesis is less clarified. Human antigen R (HuR), a RNA-binding protein, modulates the expressions of various cancer-related proteins by stabilizing or regulating the transcription of the corresponding messenger RNA. The significance of HuR expression in a large cohort with GBCs is yet to be evaluated. In total, 164 cases of GBC were selected, and immunostaining for HuR was performed. HuR nuclear (HuR-N) expression and HuR cytoplasmic (HuR-C) expression were evaluated by using a histochemical score. The results of HuR expression were correlated with various clinicopathological factors, disease-specific survival (DSS), and disease-free survival (DFS) in 161 patients with follow-up data. HuR-N overexpression was strongly associated with high histological grade (p = 0.001), vascular invasion (p < 0.001), and high Ki-67 labeling index (p < 0.001). HuR-C overexpression was significantly related to higher primary tumor status (p < 0.001), advanced tumor stage (p < 0.001), histological type (p = 0.006), high histological grade (p < 0.001), vascular and perineurial invasion (p < 0.001 and p = 0.002, respectively), tumor necrosis (p = 0.042), and high Ki-67 labeling index (p = 0.002). Besides, HuR-C overexpression also correlates with HuR-N overexpression (p < 0.001) and cyclin A overexpression (p = 0.026). HuR-N overexpression correlated with poor DFS (p = 0.0348) in univariate analysis, but HuR-C overexpression strongly correlated with a worse DSS and DFS in both univariate (both p < 0.0001) and multivariate (DSS, p = 0.006; DFS, p = 0.001) analyses. Subcellular localization of HuR expression correlates with different adverse phenotypes of GBC. Besides, HuR-C overexpression is an independent prognostic factor for dismal DSS and DFS, suggesting its roles in tumorigenesis or carcinogenesis and as a potential prognostic marker of GBC.

SKP2 overexpression is associated with a poor prognosis of rectal cancer treated with chemoradiotherapy and represents a therapeutic target with high potential.

The S-phase kinase-associated protein 2 (SKP2) oncoprotein is an E3 ubiquitin ligase. Overexpression of SKP2 was found in various human cancers, including colorectal cancers, but its potential role as a prognostic marker after neoadjuvant chemoradiotherapy (CRT) and for therapeutic intervention in rectal cancers is unknown. This study examined the correlation of SKP2 expression in the prognosis of rectal cancer patients and the viability of colorectal cancer cells treated with CRT. SKP2 immunoexpression was retrospectively assessed in pretreatment biopsies of 172 rectal cancer patients treated with neoadjuvant CRT followed by surgery. Results were correlated with clinicopathological features, therapeutic responses, and patient survival. Pharmacologic assays were used to evaluate the therapeutic relevance of Bortezomib in two colorectal cancer cell lines (HT-29 and SW480). High expression of SKP2 was correlated with the advanced Post-Tx nodal status (p = 0.002), Post-Tx International Union for Cancer Control stage (p = 0.002), and a lower-degree tumor regression grade (p < 0.001). Moreover, high expression of SKP2 (p = 0.027, hazard ratio 3.21) was an independent prognostic factor for local recurrence-free survival. In vitro, Bortezomib downregulated SKP2 expression, induced caspase activation, and decreased the viability of colorectal cancer cells with or without a combination with fluorouracil. Bortezomib also promoted caspase activation and gamma-H2AX formation in colorectal cancer cells concurrently treated with CRT. High expression of SKP2 was associated with a poor therapeutic response and adverse outcomes in rectal cancer patients treated with neoadjuvant CRT. In the presence of chemotherapy with or without radiotherapy, the promoted sensitivity of colorectal cancer cells to Bortezomib with an SKP2-repressing effect indicated that it is a potential therapeutic target.

State differences in the reporting of 'unspecified stroke' on death certificates: implications for improvement.

BACKGROUND AND PURPOSE: Little is known about the comparability of stroke subtype mortality across states. We conducted a cross-sectional descriptive study to examine state differences in the reporting of "unspecified stroke" on death certificates in the United States. METHODS: The number of deaths from different subtypes of stroke in each state for the years 2007 to 2009 were obtained from the CDC WONDER online databases. We calculated the percentage of stroke deaths classified as unspecified stroke (International Classification of Diseases, 10th Revision [ICD-10] code I64) among all stroke deaths (ICD-10 codes I60-I69) for each state. RESULTS: Of 398 942 people who died from stoke in the United States between 2007 and 2009, in 209 933 (53%) cases, the medical certifier did not specify whether the stroke was hemorrhage or infarction on the death certificate. There were 44 states in which the percentage of unspecified stroke among all strokes was ≥50 and 20 states in which the percentage was ≥55%. The percentage was lowest in the District of Columbia (46%) and highest in Oklahoma (64%). The state variation in the proportion of unspecified stroke decreased with age of the deceased. The state percentage of unspecified stroke correlated most with the state percentage of cerebral infarction and other and sequelae of cerebrovascular disease. CONCLUSIONS: Owing to the high percentage and state variation in the reporting of unspecified stroke on death certificates, the comparability of stroke subtype mortality is threatened. Querying of medical certifiers for more specific information for better coding is needed.

HuR cytoplasmic expression is associated with increased cyclin A expression and poor outcome with upper urinary tract urothelial carcinoma.

BACKGROUND: HuR is an RNA-binding protein that post-transcriptionally modulates the expressions of various target genes implicated in carcinogenesis, such as CCNA2 encoding cyclin A. No prior study attempted to evaluate the significance of HuR expression in a large cohort with upper urinary tract urothelial carcinomas (UTUCs). METHODS: In total, 340 cases of primary localized UTUC without previous or concordant bladder carcinoma were selected. All of these patients received ureterectomy or radical nephroureterectomy with curative intents. Pathological slides were reviewed, and clinical findings were collected. Immunostaining for HuR and cyclin A was performed and evaluated by using H-score. The results of cytoplasmic HuR and nuclear cyclin A expressions were correlated with disease-specific survival (DSS), metastasis-free survival (MeFS), urinary bladder recurrence-free survival (UBRFS), and various clinicopathological factors. RESULTS: HuR cytoplasmic expression was significantly related to the pT status, lymph node metastasis, a higher histological grade, the pattern of invasion, vascular and perineurial invasion, and cyclin A expression (p = 0.005). Importantly, HuR cytoplasmic expression was strongly associated with a worse DSS (p < 0.0001), MeFS (p < 0.0001), and UBRFS (p = 0.0370) in the univariate analysis, and the first two results remained independently predictive of adverse outcomes (p = 0.038, relative risk [RR] = 1.996 for DSS; p = 0.027, RR = 1.880 for MeFS). Cyclin A nuclear expression was associated with a poor DSS (p = 0.0035) and MeFS (p = 0.0015) in the univariate analysis but was not prognosticatory in the multivariate analyses. High-risk patients (pT3 or pT4 with/without nodal metastasis) with high HuR cytoplasmic expression had better DSS if adjuvant chemotherapy was performed (p = 0.015). CONCLUSIONS: HuR cytoplasmic expression was correlated with adverse phenotypes and cyclin A overexpression and also independently predictive of worse DSS and MeFS, suggesting its roles in tumorigenesis or carcinogenesis and potentiality as a prognostic marker of UTUC. High HuR cytoplasmic expression might identify patients more likely to be beneficial for adjuvant chemotherapy.

Intermediate bioelectrolyte changes after phospho-soda or polyethylene glycol precolonoscopic laxatives in a population undergoing health examinations.

BACKGROUND: Colonoscopy is a common procedure for diagnosing and screening colon cancer and other bowel-related diseases. Many studies have pointed out that using phospho-soda as a bowel preparation can cause obvious electrolyte abnormalities or acute kidney injury. Nonetheless, there are few studies related to its prevalence and risk factors in the population undergoing health examinations. Our aim was to compare the biochemical and electrolyte changes after using two commonly used bowel preparation regimens in this population. METHODS: In this retrospective study, we collected data about participants who, before a screening colonoscopy, used oral phospho-soda laxatives in 2006, and those who used polyethylene glycol-based laxatives in 2005. Several serum biochemical and electrolyte profiles were compared between the two groups. Additional risk factors of hyperphosphatemia, a well-known side effect of phospho-soda, were also derived. RESULTS: We enrolled a total of 2270 participants (1321 in 2005; 1449 in 2006). The basic demographic data of the two groups were not statistically different. Nonetheless, between the two groups, some serum biochemical and electrolytic data differed significantly: in those using oral phospho-soda laxatives, we found a higher prevalence of hyperuricemia, hypocalcemia, hypokalemia, hypernatremia and hyperphosphatemia. Further analyses showed that using oral phospho-soda laxatives was a risk factor for hyperphosphatemia; conversely, being male was a protective factor. CONCLUSION: Oral phospho-soda laxatives indeed influence the biochemical and electrolyte profiles of persons undergoing health examinations. One should be careful when interpreting bioelectrolytic data while using phospho-soda as a bowel preparation.

Reporting of incorrect cause-of-death causal sequence on death certificates in the USA: using hypertension and diabetes as an educational illustration.

BACKGROUND: Little is known about the extent of reporting an incorrect cause-of-death (COD) causal sequence on death certificates. OBJECTIVE: To determine the frequency of incorrect reporting of hypertension as cause of diabetes on death certificates in the USA. METHODS: Multiple-cause mortality files were used to identify death certificates which mentioned both hypertension and diabetes in the USA from 1985 to 2005. The frequency of reporting hypertension on the line below diabetes in part I of the death certificate was calculated. RESULTS: The percentage of cases in which both hypertension and diabetes were included in part I of the death certificate, in which hypertension was reported on the line below diabetes on the death certificate-that is, suggesting that hypertension was a cause of diabetes-increased from 15.5% in 1985 to 36.1% in 2000 and 38.2% in 2005. CONCLUSIONS: The frequency of reporting of an incorrect COD causal sequence on death certificates in the USA has increased. Education, training and questioning the opinions of certifying physicians are needed to improve the quality of reporting of COD statements.

Risk of acute kidney injury after exposure to gadolinium-based contrast in patients with renal impairment.

OBJECTIVES: Gadolinium-based contrast media (Gd-CM) are reported to induce acute kidney injury (AKI) in a high-risk population group at the usual dose for magnetic resonance imaging (MRI) and magnetic resonance angiography (MRA) examinations. We assessed gadolinium-induced nephropathy in patients with renal impairment who underwent MRI or MRA examinations, and evaluated the risk factors. MATERIALS AND METHODS: In this retrospective study, 238 patients with baseline renal impairment, who received MRI or MRA examinations with Gd-CM, were recruited. After all other AKI causes-liver decompensation, severe heart failure, all kinds of shock, and severe sepsis-and patients on dialysis were excluded, 158 patients were enrolled. AKI was defined as a decrease in glomerular filtration rate (GFR) >10% of baseline data within 3 days after administration of Gd-CM. Regression analysis was used to find independent risk factors for gadolinium-induced AKI (Gd-AKI). RESULTS: Twenty-six of the 158 patients (16.5%) developed Gd-AKI. There were no significant differences in gender, age, or baseline GFR between those who did and who did not develop AKI. Comorbid coronary artery disease, liver cirrhosis, diabetes mellitus, and hypertension were not significantly associated with the development of Gd-AKI. However, sepsis was an independent risk factor for Gd-AKI after multivariate regression analysis (adjusted odds ratio: 4.417; 95% confidence interval: 1.671-11.676, p = 0.03). CONCLUSIONS: It is potential AKI after administration of Gd-CM under sepsis condition at the dose for MRI and MRA examinations in patients with renal impairment. It is important to identify high-risk patients and closely monitor renal function after administration of Gd-CM.

CKS1B overexpression implicates clinical aggressiveness of hepatocellular carcinomas but not p27(Kip1) protein turnover: an independent prognosticator with potential p27 (Kip1)-independent oncogenic attributes?

BACKGROUND: Through data mining the Stanford Microarray Database, the CKS1B transcript was found to be frequently upregulated in hepatocellular carcinomas (HCCs) with low alpha-fetal protein (AFP) expression. Together with SKP2, CKS1B is known to implicate p27(Kip1) protein turnover promoting cell-cycle progression. METHODS: CKS1B, p27(Kip1), and SKP2 were immunostained in 75 HCCs and correlated with clinicopathological features, local recurrence-free survival (LRFS), and overall survival (OS). Silencing of CKS1B and SKP2 with interference short-hairpin RNA (shRNA) was performed in SK-Hep1 and Hep-3B cell lines. RESULTS: Immunohistochemically, increased CKS1B and SKP2, and attenuated p27(Kip1) were all associated with tumor multiplicity (P < 0.05) and increasing American Joint Committee on Cancer (AJCC) stage (P < 0.05). Overexpression of CKS1B significantly correlated with advanced Okuda stages (P = 0.048) and SKP2 overexpression (P = 0.047). Neither CKS1B nor SKP2 was inversely related to p27(Kip1), which was reinforced by no alteration in p27(Kip1) abundance in HCC-derived cells with CKS1B or SKP2 silencing. Both CKS1B overexpression (P = 0.0011 and P = 0.0017) and p27(Kip1) attenuation (P = 0.0079 and P = 0.0085) were predictive of OS and LRFS, respectively, while SKP2 overexpression was associated with worse OS alone (P = 0.0043). Combined assessment of CKS1B and p27(Kip1) was able to robustly distinguish three prognostically different groups (P < 0.0001). In multivariate comparison, CKS1B overexpression represented the strongest independent adverse prognosticator [OS, P = 0.0235, hazard ratio (HR): 4.193; LRFS, P = 0.0204, HR: 4.262], followed by p27(Kip1) attenuation (OS, P = 0.0320, HR: 2.553; LRFS, P = 0.0262, HR: 2.533). CONCLUSIONS: CKS1B protein overexpression in HCCs is implicated in clinical aggressiveness but not in p27(Kip1) turnover, implying presence of p27(Kip1)-independent oncogenic attributes. The combined assessment of CKS1B and p27(Kip1) immunoexpressions effectively risk-stratifies HCCs with different prognoses, which may aid in the management of this deadly malignancy.

Elevated serum vitamin B(12) levels in association with tumor markers as the prognostic factors predictive for poor survival in patients with hepatocellular carcinoma.

Elevated blood vitamin B(12) (VitB(12)) level has recently been identified as a prognostic indicator for advanced cancer patients. The predictive value of blood VitB(12) for survival of patients with hepatocellular carcinoma (HCC) remains unclear. Our objective was to examine the determinants of elevated serum VitB(12) levels and their associations with prognosis of patients with HCC. The cohort study included 90 HCC patients who were consecutively admitted to the Chi-Mei Hospital, Taiwan, from April 2005 to December 2006. Nutrition and clinical pathological data were collected. Serum VitB(12) levels were determined by radioimmunoassay. Survival curves were calculated by the Kaplan-Meier method. Multivariate analysis of outcome predictors was assessed by Cox regression. Elevated serum VitB(12) levels of HCC patients were associated with reduced levels of albumin, hemoglobin, red blood cells count, and glutamate-pyruvate transaminase (GPT) (P < 0.05). Serum VitB(12) levels were positively correlated with alpha-fetal protein (AFP) levels (r = 0.623, P = 0.001) and tumor size (r = 0.630, P = 0.001; Table 3). By univariate analysis, survival was significantly worse in patients with elevated serum AFP (> 200 mu g/l) and VitB(12) levels (> 1,500 ng/l; P < 0.05). In multivariate analysis, both elevated AFP (> 200 vs. < 20; HR 4.4; CI = 1.9-10.3, P = 0.001) and VitB(12) levels (> 699 vs. < or = 699; HR = 2.88; CI = 1.26-6.6, P = 0.012) were found to be favorable predictive factors for HCC survival. This study shows that the determinants of elevated serum VitB(12) levels in HCC patients were in association with malnourishment, liver injuries, and tumor progression. Elevated VitB(12) levels in concurrence with AFP levels serve as the prognostic factors predictive for poor survival of HCC patients.