Human Poisoning with Chlorpyrifos and Cypermethrin Pesticide Mixture: Assessment of Clinical Outcome of Cases Admitted in a Tertiary Care Hospital in Taiwan.

Background and Purpose: There is an overall paucity of data regarding the human toxicity of chlorpyrifos and cypermethrin pesticide mixture. Both organophosphate and pyrethroid insecticides are metabolized by carboxylesterases. Thus, its pesticide combination, organophosphates may boost the toxicity of pyrethroids via inhibited its detoxification by carboxylesterases. This study examined the clinical course, laboratory tests, and outcomes of patients with chlorpyrifos, cypermethrin or their pesticide mixture poisoning, and to determine what association, if any, might exist between these findings. Patients and Methods: Between 2000 and 2021, 121 patients poisoned with chlorpyrifos, cypermethrin, or their pesticide mixture were treated at Chang Gung Memorial Hospital. Patients were categorized as chlorpyrifos (n=82), cypermethrin (n=27) or chlorpyrifos and cypermethrin (n=12) groups. Demographic, clinical, laboratory and mortality data were collected for analysis. Results: The patients experienced a broad range of clinical symptoms, including aspiration pneumonia (44.6%), salivation (42.5%), acute respiratory failure (41.3%), acute kidney injury (13.9%), seizures (7.5%), hypotension (2.6%), etc. Leukocytosis (12,700±6600 /uL) and elevated serum C-reactive protein level (36.8±50.4 mg/L) were common. The acute respiratory failure rate was 41.3%, comprising 48.8% in chlorpyrifos, 11.1% in cypermethrin as well as 58.3% in chlorpyrifos and cypermethrin poisoning. Patients with chlorpyrifos and cypermethrin pesticide mixture poisoning suffered higher rates of acute respiratory failure (P=0.001) and salivation (P=0.001), but lower Glasgow Coma Scale score (P=0.011) and serum cholinesterase level (P<0.001) than other groups. A total of 17 (14.0%) patients expired. The mortality rate was 14.0%, including 17.1% in chlorpyrifos, 3.7% in cypermethrin as well as 16.7% in chlorpyrifos and cypermethrin poisoning. No significant differences in mortality rate were noted (P=0.214). Conclusion: Chlorpyrifos pesticide accounted for the major toxicity of the pesticide mixture. While the data show a higher rate of respiratory failure in the chlorpyrifos and cypermethrin pesticide mixture group than others, other measures of toxicity such as mortality and length of stay were not increased.

Daily Aspirin Reduced the Incidence of Hepatocellular Carcinoma and Overall Mortality in Patients with Cirrhosis.

BACKGROUND: Cirrhosis is the primary risk factor for hepatocellular carcinoma (HCC) and gastrointestinal bleeding (GI). We aimed to assess the efficacy and safety of daily aspirin on HCC occurrence, overall survival, and GI bleeding in cirrhotic patients. METHODS: A total of 35,898 eligible cases were enrolled for analyses from an initial 40,603 cirrhotic patients without tumor history. Patients continuously treated with aspirin for at least 84 days were in the therapy group, whereas those without treatment were controls. A 1:2 propensity score matching by age, sex, comorbidities, drugs, and significant clinical laboratory tests with covariate assessment was used. RESULTS: Multivariable regression analyses revealed that daily aspirin use was independently associated with a reduced risk of HCC (three-year HR 0.57; 95% CI 0.37-0.87; p = 0.0091; five-year HR 0.63, 95% CI 0.45-0.88; p = 0.0072) inversely correlated with the treatment duration [3-12 months: HR 0.88 (95% CI 0.58-1.34); 12-36 months: HR 0.56 (0.31-0.99); and ≥ 36 months: HR 0.37 (0.18-0.76)]. Overall mortality rates were significantly lower among aspirin users compared with untreated controls [three-year HR 0.43 (0.33-0.57); five-year HR 0.51 (0.42-0.63)]. Consistent results were obtained when the laboratory data were included in the propensity score for matching. CONCLUSIONS: Long-term aspirin use significantly reduced the incidence of HCC and overall mortality without increasing gastrointestinal bleeding in cirrhotic patients.

Discontinuing Hepatitis Activity Reduced Hepatocellular Carcinoma Recurrence after Primary Curative Therapy.

BACKGROUND: Hepatocellular carcinoma (HCC) tends to recur after curative treatment. This study aimed to identify the clinical factors associated with HCC recurrence after initial curative therapy. METHODS: We retrospectively included patients with early stage HCC Barcelona Clinic Liver Cancer (BCLC) stages 0 and A who received curative surgical resection or local ablation at three different Chang Gung Memorial Hospitals in Taiwan (527 patients from Linkou, 150 patients from Keelung, and 127 patients from Chiayi) from 2000 to 2009. Pretreatment clinical data were subjected to univariate and multivariate logistic analyses to identify the risk factors for HCC recurrence within five years after the primary curative treatment. Recurrence and survival rates were assessed using Kaplan-Meier curves and log-rank tests. RESULTS: Patients with a history of nucleoside analog or peg-interferon treatment for hepatitis B or hepatitis C infection had lower HCC recurrence rates than did those without such treatment. By contrast, alcohol drinking habits (p = 0.0049, hazard ratio (HR): 1.508, 95%CI: 1.133-2.009), a platelet count of < 14 × 104/µL (p = 0.003, HR: 1.533, 95%CI: 1.155-2.035), and a serum alanine aminotransferase level > 40 U/L (p = 0.0450, HR: 1.305, 95%CI: 1.006-1.694) were independent risk factors for HCC recurrence. The five-year HCC recurrence rates did not differ between patients who received either local radiofrequency ablation or surgical resection at BCLC stages 0 and A. CONCLUSIONS: Factors contributing to persistent hepatitis activity and advanced fibrosis precipitate tumor recurrence. Active intervention to discontinue liver injury or hepatitis could reduce HCC recurrence.

Outcomes of Geriatric Patients with Hepatocellular Carcinoma.

Background: The treatment modalities and outcomes of geriatric patients with hepatocellular carcinoma (HCC) remain controversial. This retrospective observational cohort study compared the outcomes of HCC between geriatric and younger patients. Methods: The medical records of patients with HCC managed between January 2001 and December 2017 were retrieved from the Chang Gung Memorial Hospital Research Database. Patients were stratified by age into two groups: a geriatric group (65−75 years) and a younger group (<65 years). The two groups were matched through 1:2 propensity score matching (PSM) according to sex, cardiovascular disease, cerebrovascular attack, diabetes mellitus, cirrhosis, hepatitis, and hypertension. Results: Of the 11,033 patients with HCC, 2147 patients aged 65−75 years and 4294 patients aged <65 years were identified after 1:2 PSM. The Kaplan−Meier model revealed that the HCC outcomes in patients older than 65 years were not significantly different after 3 years (p = 0.060). Consistent results were also obtained when the laboratory data associated with HCC incidence were included in the Fine−Gray competing risk model after 1:2 PSM (p = 0.1695). The major risk factors for HCC survival were systemic immune-inflammation index (SII) ≥ 610 × 109 cells/L, advanced tumor stage, and model for end-stage liver disease (MELD) score, etc. Conclusion: Age was not an independent factor for mortality in patients with HCC in the first 3 years. Geriatric patients with HCC should be as aggressively managed as younger patients.

Functional Genomics Identifies Hepatitis-Induced STAT3-TYRO3-STAT3 Signaling as a Potential Therapeutic Target of Hepatoma.

PURPOSE: Hepatitis promotes the development and recurrence of hepatocellular carcinoma (HCC). Receptor tyrosine kinases (RTK) play critical roles in the development of many cancers. We explored the potential roles of RTKs in hepatitis-related liver cancers. EXPERIMENTAL DESIGN: We conducted loss-of-function screening to elucidate the roles of RTKs in the development of HCC in vitro and in vivo. RESULTS: Many RTKs were coexpressed in HCC and were involved in tumor development and growth. Of these, TYRO3 promoted tumor growth and was clinically associated with hepatitis activity and poor prognosis. In mice, chemical-induced hepatitis transcriptionally activated Tyro3 expression via IL-6/IL6R-STAT3 signaling. Moreover, hepatitis-associated apoptotic cells facilitated the presentation of GAS6, a TYRO3 ligand, to further activate TYRO3-mediated signaling. Furthermore, TYRO3 activation elicited intracellular SRC- and STAT3 signaling. In mice, hepatitis and Tyro3 synergistically promoted HCC development. Silencing TYRO3 expression or inhibiting its kinase activity suppressed xenograft HCC growth in nude mice. CONCLUSIONS: Many RTKs are simultaneously involved in HCC development. Hepatitis exerts dual effects on the activation of TYRO3-mediated signaling in HCC cells, which further elicits the "TYRO3-STAT3-TYRO3" signaling loop to facilitate tumor growth. Our findings unveil a previously unrecognized link between RTKs and hepatitis-associated HCC and suggest TYRO3 as a marker and therapeutic target for the HCCs with higher hepatitis activity.

Association between Ambient Particulate Matter 2.5 Exposure and Mortality in Patients with Hepatocellular Carcinoma.

Air pollution is a severe public health problem in Taiwan. Moreover, Taiwan is an endemic area for hepatocellular carcinoma (HCC). This study examined the effect of particulate matter 2.5 (PM2.5) exposure on mortality in this population. A total of 1003 patients with HCC treated at Chang Gung Memorial Hospital between 2000 and 2009 were included in this study. At the end of the analysis, 288 (28.7%) patients had died. Patients with HCC living in environments with PM2.5 concentrations of ≥36 µg/m3 had a higher mortality rate than patients living in environments with PM2.5 concentrations of <36 µg/m3 (36.8% versus 27.5%, p = 0.034). The multivariate Cox regression analysis confirmed that PM2.5 ≥ 36 µg/m3 was a significant risk factor for mortality (1.584 (1.162-2.160), p = 0.004). A nonlinear relationship was observed between the odds ratio and PM2.5. The odds ratio was 1.137 (1.015-1.264) for each increment of 5 µg/m3 in PM2.5 or 1.292 (1.030-1.598) for each increment of 10 µg/m3 in PM2.5. Therefore, patients with HCC exposed to ambient PM2.5 concentrations of ≥36 µg/m3 had a 1.584-fold higher risk of death than those exposed to PM2.5 concentrations of <36 µg/m3. Further studies are warranted.

Nomogram predicting extrahepatic metastasis of hepatocellular carcinoma based on commonly available clinical data.

BACKGROUND AND AIM: Extrahepatic metastasis (EHM) of hepatocellular carcinoma (HCC) leads to a worse prognosis. We aimed to develop a nomogram based on noninvasive pretreatment clinical data to predict EHM of HCC sooner. METHODS: Three cohorts containing 1820, 479, and 988 HCC patients were enrolled from three hospitals in different regions in Taiwan and served as the training and validation cohorts. Pretreatment clinical data were analyzed by Cox regression modeling for independent risk factors of EHM. RESULTS: Platelet count ≥ 200 × 103/µL, serum alfa-fetoprotein ≥ 100 ng/dL, tumor size ≥ 3 cm, tumor number > 1, and macrovascular invasion were independent risk factors for EHM and were used to develop a nomogram. This nomogram had concordance indices of 0.733 (95% confidence interval [CI]: 0.688-0.778) and 0.739 (95% CI: 0.692-0.787) for the prediction of EHM during a 5-year follow-up duration in the training and validation cohorts, respectively. A nomogram score > 61 implied a high risk of EHM (hazard ratio [HR] = 3.83; 95% CI: 2.77-5.31, P < 0.001). CONCLUSION: We have developed a nomogram that could accurately predict EHM of HCC and be readily available for formulating individualized treatment for all individual HCC patients to improve therapeutic efficacy.

Hepatocellular carcinoma in hemodialysis patients.

We investigated the rates and predictors of mortality in hepatocellular carcinoma (HCC) patients who were or were not undergoing long-term hemodialysis. The participants in this retrospective observational study were 1298 HCC patients (60.0 ± 12.1 years old, 72% male), of whom 172 were undergoing hemodialysis and 1126 were not. HCC patients on hemodialysis exhibited a higher hepatitis C virus carrier rate (49.4% versus 39.3%, P = 0.012), lower hepatitis B virus carrier rate (37.2% versus 58.3%, P < 0.001) and lower hepatitis B or C virus carrier rate (77.9% versus 89.3%, P < 0.001) than those not on hemodialysis. Serum alkaline phosphatase levels were higher in the hemodialysis than non-hemodialysis group (162.8 ± 141.1 u/l versus 124.6 ± 102.5 u/l, P < 0.001). By the end of the analysis, 32.0% of HCC patients on hemodialysis and 28.0% of those not on hemodialysis had died. Kaplan-Meier analysis confirmed that cumulative survival was poorer in HCC patients on hemodialysis (P = 0.004). In a multivariate Cox regression model, hemodialysis (P < 0.001), older age (P < 0.001) and advanced tumor stages (P < 0.001) were found to be risk factors for mortality. HCC patients on hemodialysis had a 2.036-fold greater chance of death than HCC patients not on hemodialysis. Prospective studies with longer follow-ups and larger samples are warranted.

Pretreatment platelet count early predicts extrahepatic metastasis of human hepatoma.

BACKGROUND & AIMS: Thrombocytosis is associated with metastasis in many human cancers. Most hepatocellular carcinomas (HCC) develop in cirrhotic livers, which are characterized by thrombocytopenia. We aimed to elucidate the pretreatment platelet count in prediction of extrahepatic metastasis of HCC during the follow-up. METHODS: Three cohorts containing 1660, 480 and 965 HCC patients enrolled from three hospitals were used for discovery and validation respectively. Pretreatment clinical factors associated with extrahepatic metastasis during follow-up up to 5 years were identified using multivariate Cox regression model. RESULTS: In early-stage HCC (BCLC stage 0-A), pretreatment platelet count (hazard ratio [HR], 1.04 per 10,000/µl; 95% CI, 1.01-1.07; P = 0.010) and serum alpha-foetoprotein (AFP) >100 ng/ml (HR, 1.70; 95% CI, 1.04-2.78; P = 0.033) were the only two independent factors associated with extrahepatic metastasis. Receiver operating characteristic evidenced that pretreatment platelet count predicted metastasis better than AFP did. Survival tree analysis identified platelet counts <118,000/µl (HR, 0.49; 95% CI, 0.38-0.63; P < 0.001) or >212,000/µl (HR, 2.12; 95% CI, 1.67-2.70; P < 0.001) to categorize patients into low and high risk of metastasis subgroups, which were verified using both validation cohorts. CONCLUSIONS: Pretreatment platelet count is a reliable marker to predict extrahepatic metastasis of early-stage HCC following curative treatment. Cirrhotic thrombocytopenia contributes to relatively low metastasis incidence of HCC than many other cancers. High platelet count identifies a subgroup of HCC patients at high risk of metastasis, who might benefit from adjuvant therapies following initial curative treatment.

Hepatocellular carcinoma in patients with chronic kidney disease.

AIM: To investigate outcomes of hepatocellular carcinomas (HCCs) in patients with chronic kidney disease (CKD). METHODS: Four hundred and forty patients referred between 2000 and 2002 for management of HCCs were categorized according to their CKD stage, i.e., estimated glomerular filtration rate (eGFR) > 90 (stage 1), 60-90 (stage 2), 30-60 (stage 3), 15-30 (stage 4), and < 15 (stage 5) mL/min per 1.73 m², respectively. Demographic, clinical and laboratory data were collected and mortality rates and cause of mortality were analyzed. The mortality data were examined with Kaplan-meier method and the significance was tested using a log-rank test. An initial univariate Cox regression analysis was performed to compare the frequency of possible risk factors associated with mortality. To control for possible confounding factors, a multivariate Cox regression analysis (stepwise backward approach) was performed to analyze those factors that were significant in univariate models (P < 0.05) and met the assumptions of a proportional hazard model. RESULTS: Most HCC patients with CKD were elderly, with mean age of diagnosis of 60.6 ± 11.9 years, and mostly male (74.8%). Hepatitis B, C and B and C co-infection virus were positive in 61.6%, 45.7% and 14.1% of the patients, respectively. It was found that patients with stages 4 and 5 CKD were not only older (P = 0.001), but also had higher hepatitis C virus carrier rate (P = 0.001), lower serum albumin level (P = 0.001), lower platelet count (P = 0.037), longer prothrombin time (P = 0.001) as well as higher proportions of advanced cirrhosis (P = 0.002) and HCCs (P = 0.001) than patients with stages 1 and 2 CKD. At the end of analysis, 162 (36.9%) patients had died. Kaplan-Meier analysis revealed that patients with stages 4 and 5 CKD suffered lower cumulative survival than stages 1 and 2 CKD (log-rank test, χ² = 11.764, P = 0.003). In a multivariate Cox-regression model, it was confirmed that CKD stage [odds ratio (OR) = 1.988, 95%CI: 1.012-3.906, P = 0.046)], liver cirrhosis stage (OR = 3.571, 95%CI: 1.590-8.000, P = 0.002) and serum albumin level (OR = 0.657, 95%CI: 0.491-0.878, P = 0.005) were significant predictors for mortality in this population. CONCLUSION: HCC patients with stages 4 and 5 CKD had inferior survival than stages 1 and 2 CKD. This warrants further studies.

Comparison of clinical characteristics of combined hepatocellular-cholangiocarcinoma and other primary liver cancers.

BACKGROUND AND AIM: Combined hepatocellular-cholangiocarcinoma (CHC) is a rare liver malignancy. In this study, we compared patient characteristics and outcomes for primary CHC, intrahepatic cholangiocarcinoma (ICC), and hepatocellular carcinoma (HCC). METHODS: Medical records of patients with tissue-proven CHC (65 cases) treated at the Chang Gung Memorial Hospital between 1991 and 2005 were retrospectively reviewed. These records were compared to records of patients diagnosed with tissue-proven HCC (1985 cases) and ICC (127 cases) during the same period. RESULTS: Hepatitis B and C are major causes of CHC. CHC patients exhibited greater similarity to HCC than to ICC patients with respect to cirrhotic changes, age, and positive serology for hepatitis B surface antigen and anti-hepatitis C antibody. Survival was related to tumor characteristics and intervention therapies, but not to etiologies. CONCLUSIONS: The clinical characteristics of CHC are similar to those of HCC, but overall survival is more similar to that of ICC; survival may be related to tumor biology rather than the cause. Multimodal treatment with an initial aggressive therapeutic approach can improve survival.

Aeromonas hydrophila bacteremia presenting as non-traumatic acute osteomyelitis in a cirrhotic patient.

Aeromonas hydrophila is a low-virulence gram-negative bacillus. It has never been reported as a pathogen of non-traumatic acute osteomyelitis in a cirrhotic patient. Herein, we reported on a case of decompensated liver cirrhosis with Aeromonas hydrophila infection presenting as acute gastroenteritis and non-traumatic acute osteomyelitis. It has been shown that Aeromonas bacteremia usually affects immunocompromised subjects, such as those with liver cirrhosis. Non-traumatic acute osteomyelitis should be highly suggested when a cirrhotic patient with Aeromonas bacteremia presents with severe low back pain and no associated trauma.