Protocol of the optimal study: Optimization of polypharmacy in geriatric oncology - A randomized controlled trial.

BACKGROUND: Polypharmacy is very common in older cancer patients and these patients are particularly vulnerable to drug-drug interactions and adverse drug reactions because they often receive chemotherapy and symptom-relieving agents. METHODS: The primary aim of the randomized, controlled Optimization of Polypharmacy in Geriatric Oncology (OPTIMAL) trial is to test whether an advisory letter with the results of a comprehensive medication review conducted with the Fit fOR The Aged (FORTA) list to the caring physician in rehabilitation clinics improves the quality of life (QoL) of older cancer patients exposed to polypharmacy more than usual care. The FORTA list detects medication overuse, underuse, and potentially inappropriate drug use among older adults. In the oncology departments of approximately 10 German rehabilitation clinics, we aim to recruit 514 cancer patients (22 common cancers; diagnosis or recurrence requiring treatment in the last 5 years; all stages) who are ≥ 65 years old, regularly take ≥ 5 drugs, and have ≥ 1 medication-related problem. All necessary information about the patients will be provided to a pharmacist at the coordinating center (German Cancer Research Center, Heidelberg), who will perform randomization (1:1) and conduct the medication review with the FORTA list. For the intervention group only, the results are sent by letter to the treating physician in the rehabilitation clinics, who shall discuss medication changes with the patient at the discharge visit, as well as implement them afterwards and disclose them in the discharge letter to the general practitioner. The control group gets the usual care provided in German rehabilitation clinics, which usually does not include a comprehensive medication review but can include medication changes. Patients will be blinded, as they cannot know whether proposed medication changes were part of the study or part of usual care. Study physicians cannot be blinded. The primary endpoint will be the EORTC-QLQ-C30 global health status/QoL score, assessed via self-administered questionnaires 8 months after baseline. DISCUSSION: If the planned study shows that a medication review with the FORTA list improves the QoL of older cancer patients in oncological rehabilitation more than usual care, it would provide the necessary evidence to translate the trial's findings into routine care. TRIAL REGISTRATION: German Clinical Trials Register (DRKS): DRKS00031024.

About the associations of vitamin D deficiency and biomarkers of systemic inflammatory response with all-cause and cause-specific mortality in a general population sample of almost 400,000 UK Biobank participants.

It is unknown whether the well-known association between vitamin D deficiency and mortality could be explained by the immune system modulating effects of vitamin D, which may protect from a systemic inflammatory response (SIR) to adverse health conditions. This study aims to investigate the interrelationships of vitamin D deficiency, biomarkers of SIR, and mortality. We used multivariate logistic regression with adjustment for 51 covariates to assess the associations of vitamin D deficiency with disadvantageous levels of nine biomarkers of SIR in the UK Biobank cohort. Furthermore, we tested with Cox regression and mediation analysis whether biomarkers of SIR and vitamin D deficiency were independently associated with mortality. We included 397,737 participants aged 37-73 years. Vitamin D deficiency was associated with disadvantageous levels of all blood cell count-based biomarkers, but not with C-reactive protein (CRP)-based biomarkers after adjustment for body weight. Vitamin D deficiency and all biomarkers of SIR were significantly associated with all-cause mortality and mortality from cancer, cardiovascular and respiratory disease. The strength of these associations was unaltered if vitamin D deficiency and biomarkers of SIR were put in the same model. This finding was further supported by the mediation analyses. This study showed that vitamin D deficiency is associated with disadvantageous levels of blood cell count-based but not CRP-based biomarkers of SIR. Vitamin D deficiency and systemic inflammation were independently and strongly associated with mortality. The potential of clinical interventions against both vitamin D deficiency and underlying causes of systemic inflammation should be explored.

Incorporation of functional status, frailty, comorbidities and comedication in prediction models for colorectal cancer survival.

Limitations in functional status, frailty, multiple comorbidities and comedications are common among older colorectal cancer (CRC) patients. We investigated whether adding these factors could improve the predictive value of a reference model containing age, sex, tumor stage and location for prediction of 5-year overall survival (OS), disease-free survival (DFS), disease-specific survival (DSS), recurrence-free survival (RFS) and nondisease-specific survival (nDSS) for all CRC patients as well as for younger (<65 years) and older patients (≥65 years). Overall, 3410 CRC patients from the DACHS study were analyzed and area under receiver operating characteristic curves (AUC) and net reclassification improvements (NRI) were assessed. In prediction of OS, the reference model plus functional status was identified as the best model among all CRC patients (AUC: 0.762) and younger CRC patients (AUC: 0.820). In older CRC patients, comorbidity should additionally be added (AUC: 0.747). For nDSS, the reference model plus comorbidity and frailty had the best predictive performance in all CRC patients (AUC: 0.776). For the outcomes DFS (AUC: 0.727), DSS (AUC: 0.838) and RFS (AUC: 0.784), the reference model was already the best model in all CRC patients because no significant NRIs were observed. The pattern "The less CRC-specific the survival outcome and the older the CRC patients, the more relevant the inclusion of functional status, comorbidity, and frailty in CRC prognostic scores is" was observed. Thus, different nomograms for younger and older CRC patients for 1-, 3- and 5-year OS prognosis estimation are being suggested.

SHP-1/STAT3-Signaling-Axis-Regulated Coupling between BECN1 and SLC7A11 Contributes to Sorafenib-Induced Ferroptosis in Hepatocellular Carcinoma.

Ferroptosis is a type of iron-dependent cell death pertaining to an excess of lipid peroxidation. It has been suggested that sorafenib-an anti-angiogenic medication for hepatocellular carcinoma (HCC)-induces ferroptosis, but the underlying mechanism for this remains largely unknown. We employed siRNA-mediated gene silencing to investigate the role of Src homology region 2 domain-containing phosphatase-1 (SHP-1), following sorafenib treatment, in cystine/glutamate-antiporter-system-Xc--regulated cystine uptake. Co-immunoprecipitation was also performed to examine the interactions between MCL1, beclin 1 (BECN1), and solute carrier family 7 member 11 (SLC7A11), which functions as the catalytic subunit of system Xc-. The results of this study showed that sorafenib enhanced the activity of SHP-1, dephosphorylated STAT3, downregulated the expression of MCL1 and, consequently, reduced the association between MCL1 and BECN1. In contrast, increased binding between BECN1 and SLC7A11 was observed following sorafenib treatment. The elevated interaction between BECN1 and SLC7A11 inhibited the activity of system Xc-, whereas BECN1 silencing restored cystine intake and protected cells from ferroptosis. Notably, ectopic expression of MCL1 uncoupled BECN1 from SLC7A11 and rescued cell viability by attenuating lipid peroxidation. The results revealed that ferroptosis could be induced in HCC via SHP-1/STAT3-mediated downregulation of MCL1 and subsequent inhibition of SLC7A11 by increased BECN1 binding.

Long-Term Survival of Combined Hepatocellular-Cholangiocarcinoma: A Nationwide Study.

BACKGROUND: Combined hepatocellular-cholangiocarcinoma (HCC-CC) is an aggressive primary liver cancer. However, the clinical features are not clearly understood because of limited literature and the complex nature of both hepatocellular carcinoma (HCC) and cholangiocarcinoma (CC). METHODS: The records of 100,754 patients with newly diagnosed liver cancer between 2004 and 2013 were obtained from the Taiwan Cancer Registry. The primary outcome measures were overall survival and local recurrence-free survival. The median follow-up time was 60 months (29-120 months). RESULTS: HCC-CC tended to share some characteristics with HCC, including increased frequency of stage I cases, high individual tumor rates, and similar patterns of viral hepatitis B and hepatitis C infections. In contrast, HCC-CC showed malignant behavior similar to that of CC, as high-grade tumor cell differentiation and presentation of jaundice were predominant in HCC-CC and CC compared with HCC. Overall survival and local recurrence-free survival rates of HCC-CC were between HCC and CC rates. The mortality rate of HCC-CC was 79.2% (HCC, 77.5%; CC, 93.5%) and the local recurrence rate of HCC-CC was 65.3% (HCC, 74.6%; CC, 88.4%). Surgical treatment was an independent factor for the long-term prognosis of HCC-CC, whereas transarterial chemoembolization (TAcE) promoted survival in both surgical and nonsurgical groups. CONCLUSION: Our data confirmed that, although it reflects the malignant behavior of CC, HCC-CC should mainly be characterized as a subtype of HCC. With careful selection of patients, curative resection and TAcE might benefit the survival of patients with HCC-CC. IMPLICATIONS FOR PRACTICE: Combined hepatocellular-cholangiocarcinoma (HCC-CC) is a rare cancer that shares demographic characteristics, as well as survival probabilities, with both hepatocellular carcinoma and cholangiocarcinoma. It occurs frequently in patients with hepatitis B virus infection, cirrhotic liver background, and early-stage disease. Compared with 20% of initial resection rates of its counterparts, HCC-CC has higher initial resection rate (55%). Although short-term overall survival is inferior to HCC, its long-term overall survival is similar with HCC.

Survival Predictability Between the American Joint Committee on Cancer 8th Edition Staging System and the Barcelona Clinic Liver Cancer Classification in Patients with Hepatocellular Carcinoma.

This study compared the prognostic significance of staging between the American Joint Committee on Cancer 8th edition Tumor, Node, Metastasis (TNM) staging system and the Barcelona Clinic Liver Cancer (BCLC) classification in patients with hepatocellular carcinoma (HCC). The study population comprised patients with liver cancer registered in the Taiwan Cancer Database from 2007 to 2013 and was followed up until December 31, 2016. The study included patients with HCC, with known staging in both TNM and BCLC systems, and with follow-up >1 month. Primary endpoint was overall survival. Univariate and multivariate Cox proportional hazards model were constructed to investigate the significance of staging by two systems. Goodness-of-fit of model was evaluated via Akaike's information criterion (AIC), the lower the better. Among 73,136 patients with newly diagnosed liver cancer, a total of 37,062 patients with HCC (25.6% underwent surgery) were eligible. The mean age and overall survival of this cohort were 63.9 years and 27.2%, respectively. Overall survivals for stages I, II, III, and IV (the TNM system) were 54.5%, 34.9%, 10.3%, and 6.4%, respectively. Overall survivals for stages A, B, C, and D (the BCLC classification) were 54.5%, 29.2%, 9.8%, and 4.0%, respectively. The median follow-up time was 59.4 months. Multivariate Cox proportional hazards model revealed that both systems predicted overall survival, cancer-specific survival, disease-free survival, and local recurrence-free rate well. Values of ΔAIC of the BCLC classification and the TNM system were lower for the surgery group and nonsurgery group, respectively. The TNM system (8th edition) predicted long-term outcome better than the BCLC classification in patients with HCC. But in patients treated initially with surgery, the BCLC classification outperformed the 8th edition of the TNM system. IMPLICATIONS FOR PRACTICE: This work demonstrates that the Tumor, Node, Metastasis (TNM) system (8th edition) and the Barcelona Clinic Liver Cancer (BCLC) classification both predict long-term outcome significantly in patients with hepatocellular carcinoma but that the TNM system (8th edition) predicts long-term outcome better than the BCLC classification. For patients treated initially with surgery, BCLC classification outperforms in 8th edition TNM system in predicting long-term outcome.

Association of Polypharmacy with Colorectal Cancer Survival Among Older Patients.

BACKGROUND: In geriatric oncology, polypharmacy is often assessed during a comprehensive geriatric assessment. Previous studies about its association with survival among patients with colorectal cancer (CRC) were inconclusive and had high risk for indication bias. PATIENTS AND METHODS: A cohort study was conducted with 3,239 patients with CRC, aged ≥65 years, who were recruited in Germany between 2003 and 2016, while being hospitalized for CRC surgery. We defined polypharmacy as the concurrent use of five or more drugs, and excessive polypharmacy (EPP) as concurrent use of eight or more drugs. Cox proportional hazards regression models were performed to assess the associations of polypharmacy with 5-year overall (OS), CRC-specific (CSS), and non-cancer-specific survival (NCS) with rigorous adjustment for morbidity to minimize indication bias (e.g., for cancer stage, functional status, and 13 common diseases/conditions). RESULTS: The prevalence of polypharmacy was 54.7% and that of EPP was 24.2%. During up to 5 years of follow-up, 1,070 participants died, among whom 615 died of CRC and 296 died of other causes than cancer. EPP was statistically significantly associated with poorer up-to-5-year OS (hazard ratio [HR], 1.23; 95% confidence interval [CI], 1.02-1.47) and CSS (HR, 1.31; 95% CI, 1.03-1.68). HR point estimate for NCS was higher than 1 (1.22) but not statistically significant. CONCLUSION: Polypharmacy was very common and EPP was a weak risk factor for mortality in this large cohort of older patients with CRC. Clinical trials are needed to address the causality of this relationship because older patients with CRC might benefit from deprescribing drugs without an indication. IMPLICATIONS FOR PRACTICE: The results of this study support the hypothesis that excessive polypharmacy, defined as use of eight or more concurrently used active substances, has a negative impact on the prognosis of older patients with colorectal cancer (CRC). This study suggests to oncologists that performing a medication review for older patients with CRC with eight drugs or more is indicated (especially when a broader comprehensive geriatric assessment is being performed). Such a medication review should not only focus on reducing the number of medications (by deprescribing drugs without an indication) but also check the appropriateness of indicated drugs for older patients with cancer.

Comparison of Five Lists to Identify Potentially Inappropriate Use of Non-Steroidal Anti-Inflammatory Drugs in Older Adults.

OBJECTIVE: To compare the prevalence of potentially inappropriate non-steroidal anti-inflammatory drugs (NSAIDs) among NSAIDs users defined with frequently used potentially inappropriate medication (PIM) lists and to identify the determinants of their use. DESIGN AND SETTING: Cross-sectional survey among community-dwelling older adults from Germany. SUBJECTS: N = 284 NSAIDs users aged 65-89 years. METHODS: All currently regularly or as-needed used drugs were recorded during a home visit. Multivariate logistic regression models were applied to assess the potential determinants of potentially inappropriate NSAIDs use. RESULTS: Prevalence of potentially inappropriate NSAIDs use was 54.2%, 45.4%, 29.9%, 20.4%, and 3.5% when applying the STOPP, 2019 Beers, EU(7)-PIM, FORTA, and PRISCUS list, respectively. No study participant was identified as a potentially inappropriate NSAIDs user by all five lists simultaneously. The majority (68%) were identified only by one or two lists. Merely the STOPP and Beers criteria had a moderate inter-instrument agreement. Lower pain severity, gout, peptic ulcer (PU), cardiovascular disease (CVD), and chronic kidney disease (CKD) were statistically significantly associated with potentially inappropriate NSAIDs use defined by the STOPP criteria and the latter three conditions also with the 2019 Beers criteria. CONCLUSIONS: The STOPP and Beers criteria may be superior to the other lists because they more frequently identify potentially inappropriate NSAIDs use in conditions implying a high risk for NSAIDs' adverse events (i.e., PUD, CKD and CVD). We developed a harmonized, country-independent PIM list for NSAIDs with the same advantages as observed for the STOOP and 2019 Beers criteria and recommended its use.

Epidemiology, treatment patterns and survival of chronic lymphocytic leukaemia/small lymphocytic lymphoma (CLL/SLL) in Taiwan, 2006-2015.

AIM/OBJECTIVE: Chronic lymphocytic leukaemia/small lymphocytic lymphoma (CLL/SLL) is one of the most frequent types of leukaemia/lymphoma in adults in Western countries. However, there are few studies regarding its epidemiology and treatment patterns in Asian countries. METHODS: To investigate CLL/SLL in Asian populations, we identified CLL/SLL patients diagnosed during 2006 to 2015 from the Taiwan Cancer Registry Database and estimated the incidence. Further, patients diagnosed during 2008 to 2015 were included for the analysis of treatment patterns and survivals. Treatments for CLL/SLL were retrieved from the Taiwan's National Health Insurance Research Database and survival data from the National Death Registry. RESULTS: In total, 1497 patients who were older than 20 years and had newly diagnosed CLL/SLL during 2006-2015 were identified. The age-standardized incidence rates of CLL/SLL (0.36 per 100 000 persons in 2006, and 0.54 in 2015) increased during the 10-year period. The sex ratio was ranged from 1.21 to 2.63 with male predominant during 2006 and 2015. For the analysis of treatment patterns (n = 1236), 72.8% patients received chemotherapies. The median duration between the diagnosis and start of treatments was 27 days, and monotherapy of chlorambucil, bendamustine or cyclophosphamide was the most common regimen in initial treatments. The median follow-up duration for the patients receiving therapies was 29.6 months, and 45.0% patients experienced relapse or refractory. In patients with relapse/refractory CLL/SLL, 34.1% received rituximab-containing chemotherapies. Three hundred and ninety-nine (32.3%) patients received intensive treatments, and 175 (43.9%) of them received rituximab-containing chemotherapies. The 5-year overall survival (OS) rate was 61%, and age was an important prognostic factor for CLL/SLL patients. CONCLUSIONS: This study is the first population-based study in Asia and provides comprehensive evidence of epidemiology, treatment patterns and survivals of CLL/SLL in an Asian population.

Pain severity and analgesics use in the community-dwelling older population: a drug utilization study from Germany.

PURPOSE: Chronic pain is common in the older population and a significant public health concern. However, comprehensive studies on analgesics use in this age group from Germany are scarce. This study aims to give a comprehensive overview on the use of the most common therapeutic groups of analgesics in community-dwelling older adults from Germany. METHODS: A cross-sectional study was carried out using data from a German cohort of 2038 community-dwelling adults aged 63-89 years. Descriptive statistics and logistic regression models were applied to assess the utilization of analgesics by age, sex, pain severity, pain duration, and locations. RESULTS: One out of four study participants was suffering from high-intensity or disabling pain. Approximately half of those taking analgesics still reported to suffer from high-intensity or disabling pain. Among analgesics users, occasional non-steroidal anti-inflammatory drugs (NSAIDs) use was the most frequent pain therapy (in 43.6% of users), followed by metamizole (dipyrone) use (16.1%), regular NSAIDs use (12.9%), strong opioids use (12.7%), and weak opioids use (12.0%). In multivariate logistic regression models, higher age, higher pain severity, longer pain duration, abdominal pain, and back pain were statistically significantly associated with opioids use. Metamizole use was also statistically significantly associated with higher pain severity but inversely associated with pain duration. CONCLUSIONS: A significant number of older German adults are affected by high-intensity and disabling chronic pain despite receiving analgesics. Long-term studies are needed to compare the effectiveness and safety of different treatments for chronic pain in older adults.

Frontline treatments in extremely elderly patients with diffuse large B-cell lymphoma: a population-based study in Taiwan, 2010-2015.

BACKGROUND: The standard frontline therapy for patients with diffuse large B cell lymphoma (DLBCL) is R-CHOP. However, patients older than 80 years are excluded from clinical trials. The importance of rituximab and anthracycline remains unknown in extremely elderly DLBCL patients. Here, we incorporated data from the Taiwan Cancer Registry Database (TCRD), National Health Insurance Research Database (NHIRD), and National Death Registry to evaluate the clinical benefits of rituximab and anthracycline in elderly patients. From the TCRD and NHIRD, we included DLBCL patients aged older than 60 years who received R-CHOP, R-CVP, CHOP, or CVP between 2010 and 2015. RESULTS: Of the 3228 eligible patients, 2559 were between 60 and 79 years (the 60-79 group), and 669 were older than 80 years (the 80+ group). The proportions of patients in the different Ann Arbor stages and the practice settings were similar in both groups. The male-to-female ratio and the Charlson comorbidity index (CCI) scores in the 80+ group were higher than those in the 60-79 group. Patients in the 60-79 group received R-CHOP more frequently than those in the 80+ group. In the 60-79 group, the median age of the patients receiving R-CVP or CVP was older than those receiving R-CHOP or CHOP. In the analysis of overall survival (OS) and time to treatment failure (TTF), R-CHOP, female sex, younger age, lower Ann Arbor stage, lower CCI score, and care at a medical center predicted a favorable prognosis in the 60-79 group. However, only R-CHOP, younger age, and lower Ann Arbor stage remained independent favorable prognostic factors in the 80+ group. CONCLUSIONS: Our population-based study demonstrated the clinical benefits of rituximab and anthracycline in extremely elderly Asian patients with DLBCL.

Antagonizing SET Augments the Effects of Radiation Therapy in Hepatocellular Carcinoma through Reactivation of PP2A-Mediated Akt Downregulation.

Increasing evidence suggests that SET functions as an oncoprotein and promotes cancer survival and therapeutic resistance. However, whether SET affects radiation therapy (RT)-mediated anticancer effects has not yet been explored. We investigated the impact of SET on RT sensitivity in hepatocellular carcinoma (HCC). Using colony and hepatosphere formation assays, we found that RT-induced proliferative inhibition was critically associated with SET expression. We next tested a novel SET antagonist, N4-(3-ethynylphenyl)-6,7-dimethoxy-N2-(4-phenoxyphenyl) quinazoline-2,4-diamine (EMQA), in combination with RT. We showed that additive use of EMQA significantly enhanced the effects of RT against HCC in vitro and in vivo. Notably, compared with mice receiving either RT or EMQA alone, the growth of PLC5 xenografted tumor in mice receiving RT plus EMQA was significantly reduced without compromising treatment tolerability. Furthermore, we proved that antagonizing SET to restore protein phosphatase 2A-mediated phospho-Akt (p-AKT) downregulation was responsible for the synergism between EMQA and RT. Our data demonstrate a new oncogenic property of SET and provide preclinical evidence that combining a SET antagonist and RT may be effective for treatment of HCC. Further investigation is warranted to validate the clinical relevance of this approach.

Serine/threonine protein phosphatase 5 is a potential therapeutic target in cholangiocarcinoma.

BACKGROUND & AIMS: Few molecules are currently verified to be actionable drug targets in cholangiocarcinoma (CCA). Serine/threonine protein phosphatase 5 (PP5) dysregulation is related to several malignancies. However, the role of PP5 in CCA is poorly defined. METHODS: Colony and tumorsphere formation assays were conducted to establish the role of PP5 in CCA tumorigenesis. Cantharidin (CTD) and norcantharidin (NCTD), both potent PP5 inhibitors, were used in in vitro and in vivo experiments to validate the potential therapeutic role of PP5. RESULTS: Increased cell growth, colony formation and tumorsphere formation were observed in PP5-overexpressing CCA cells, whereas PP5 knockdown by shRNA decreased cell growth and colony formation. Tumours from HuCCT1 xenograft-bearing mice treated with PP5-shRNA showed decreased growth and increased AMP-activated protein kinase (AMPK) phosphorylation. Furthermore, CTD treatment decreased cell viability, reduced PP5 activity and enhanced AMPK phosphorylation in CCA cell lines. Overexpressing PP5 or enhancing PP5 activity suppressed AMPK phosphorylation and decreased CTD-induced cell death. Suppressing p-AMPK with siRNA or inhibitors also decreased CTD-induced cell death, suggesting a pivotal role for PP5-AMPK cascades in CCA. Immunoprecipitation revealed that PP5 interacted with AMPK. Importantly, treatment of HuCCT1 xenograft-bearing mice with NCTD, a CTD analogue with a lower systemic toxicity in vivo, suppressed PP5 activity, increased p-AMPK and reduced tumour volume. CONCLUSIONS: Protein phosphatase 5 negatively regulates AMPK phosphorylation and contributes to CCA aggressiveness; thus, PP5 may be a potential therapeutic target in CCA.

Protein tyrosine phosphatase 1B dephosphorylates PITX1 and regulates p120RasGAP in hepatocellular carcinoma.

UNLABELLED: The effective therapeutic targets for hepatocellular carcinoma remain limited. Pituitary homeobox 1 (PITX1) functions as a tumor suppressor in hepatocarcinogenesis by regulating the expression level of Ras guanosine triphosphatase-activating protein. Here, we report that protein tyrosine phosphatases 1B (PTP1B) directly dephosphorylated PITX1 at Y160, Y175, and Y179 to further weaken the protein stability of PITX. The PTP1B-dependent decline of PITX1 reduced its transcriptional activity for p120RasGAP (RASA1), a Ras guanosine triphosphatase-activating protein. Both silencing of PTP1B and PTP1B inhibitor up-regulated the PITX1-p120RasGAP axis through hyperphosphorylation of PITX1. Sorafenib, the first and only targeted drug approved for hepatocellular carcinoma, directly decreased PTP1B activity and promoted the expression of PITX1 and p120RasGAP by PITX1 hyperphosphorylation. Molecular docking also supported the potential interaction between PTP1B and sorafenib. PTP1B overexpression impaired the sensitivity of sorafenib in vitro and in vivo, implying that PTP1B has a significant effect on sorafenib-induced apoptosis. In sorafenib-treated tumor samples, we further found inhibition of PTP1B activity and up-regulation of the PITX1-p120RasGAP axis, suggesting that PTP1B inhibitor may be effective for the treatment of hepatocellular carcinoma. By immunohistochemical staining of hepatic tumor tissue from 155 patients, the expression of PTP1B was significantly in tumor parts higher than nontumor parts (P = 0.02). Furthermore, high expression of PTP1B was significantly associated with poor tumor differentiation (P = 0.031). CONCLUSION: PTP1B dephosphorylates PITX1 to weaken its protein stability and the transcriptional activity for p120RasGAP gene expression and acts as a determinant of the sorafenib-mediated drug effect; targeting the PITX1-p120RasGAP axis with a PTP1B inhibitor may provide a new therapy for patients with hepatocellular carcinoma.

Is vegetarian diet associated with a lower risk of breast cancer in Taiwanese women?

BACKGROUND: Studies on the relationship between vegetarian diet and breast cancer in Asian populations are limited. This study aimed to investigate the relationship between vegetarian diet, dietary patterns, and breast cancer in Taiwanese women. METHODS: This case-control study compared the dietary patterns of 233 breast cancer patients and 236 age-matched controls. A questionnaire about vegetarian diets and 28 frequently-consumed food items was administered to these 469 patients in the surgical department of Taipei Tzu Chi Hospital. Serum biochemical status was also examined. RESULTS: There were no significant differences between the two groups for age, education, family history, oral contraceptive usage, or regular exercise. However, the cancer group presented with both a higher body mass index and an older age of primiparity (P < 0.05). Two food items (shellfish and seafood) were highly correlated (correlation coefficient = 0.77), so shellfish was excluded to avoid multicollinearity. A factor analysis of 27 food items produced five dietary patterns: meat, processed meat, fruit/vegetable/soybean, dessert/sugar, and fermented food. Multivariate logistic regression showed that meat/fat and processed meat dietary patterns were associated with breast cancer risk (odds ratio (OR): 2.22, 95% CI 1.67-2.94, P < 0.001; OR: 1.49, 95% CI 1.09-2.04, P = 0.013, respectively). Vegetarian diet, high isoflavone intake, and high albumin levels were inversely associated with breast cancer risk (P < 0.05). Vegetarians had a higher daily soy isoflavone intake than non-vegetarians (25.9 ± 25.6 mg vs. 18.1 ± 15.6 mg, P < 0.001). CONCLUSIONS: Vegetarian diets show as protective role against breast cancer risk, while meat and processed meat dietary patterns are associated with a higher breast cancer risk.

Accessibility of ophthalmic healthcare for residents of an offshore island-an example of integrated delivery system.

BACKGROUND: To assess the utilization of and satisfaction with ophthalmic healthcare provided by integrated delivery system (IDS) since 2000 and vision-related quality of life (VRQoL) for residents of an offshore island of Taiwan. METHODS: Facilitators interviewed residents (age ≥ 50 years) with the 25-item National Eye Institute Visual Function Questionnaire (NEI-VFQ-25) for VRQoL and a questionnaire on clinical information, ophthalmic care utilization and satisfaction. RESULTS: A total of 841 participants (response rate 93.4 %, 841/900) completed the questionnaire survey. Mean age was 63.7 (±10. 7) years. The common eye diseases were cataract (44.7 %), dry eye (15.5 %), and glaucoma (8.7 %). Among the participants, 61.0 % sought ophthalmic care under the IDS in the past year and 17.6 % experienced unmet ophthalmic needs in the past 6 months. Satisfaction with ophthalmic care under the IDS was 88.1 %. Determinants of dissatisfaction under the IDS were distance to healthcare facility and VRQoL. Predictors of VRQoL included age, residential area, marital status, occupation, comorbid condition, commercial insurance, household income, cataracts and glaucoma. CONCLUSIONS: The implementation of IDS improves accessibility of ophthalmic care for residents of an offshore island. Geographic proximity to avail healthcare facility and VRQoL affect satisfaction with the IDS.

Thyroid surgery without antibiotic prophylaxis: experiences with 1,030 patients from a teaching hospital in China.

OBJECTIVE: Our objective was to evaluate the outcome of thyroidectomy without the use of prophylactic antibiotics. This study was held from January 2005 to May 2012 in a teaching hospital in Dongguan, China. METHODS: A total of 1,030 thyroidectomy patients were retrospectively reviewed and basic data were recorded, including age, sex, peri-operative antibiotic use, type of thyroid surgery done, and post-operative complications. Either an open approach or an endoscopic approach was performed according to the doctor's or patient's preference following a strict aseptic technique. The drain was routinely placed. Any complications were analyzed. RESULTS: A total of 834 (81 %) females and 196 (19 %) males were included, giving a ratio of 4.2:1. The average age was 38.3 years. The mean operation time was 85.3 min. Pathological type included 818 (79.4 %) nodular goiter, 34 (3.3 %) Graves' disease, 102 (9.9 %) nodular papillary hyperplasia, 12 (1.2 %) Hashimoto's disease, 62 (6 %) papillary carcinoma, and 2 (0.2 %) medullary carcinoma. Four patients had postoperative bleeding, four had temporally recurrent nerve paralysis. Only one had wound infection (0.09 %). CONCLUSION: Antibiotic prophylaxis in elective thyroidectomy is not an essential pre-operation preparation for all patients, if guidelines for antibiotic prophylaxis in clean surgery are adhered to and surgeons have sophisticated skills in the procedure.

Longitudinal associations of polypharmacy and frailty with major cardiovascular events and mortality among more than half a million middle-aged participants of the UK Biobank.

BACKGROUND: Studies of the associations of polypharmacy and frailty with adverse health outcomes in middle-aged adults are limited. Furthermore, a potentially stronger association of polypharmacy with adverse health outcomes in frail than in non-frail adults is of interest. OBJECTIVE: To evaluate associations of frailty (assessed using a frailty index) and polypharmacy (defined as taking five or more drugs) with major cardiovascular events, cancer incidence, all-cause, cardiovascular disease-specific, and cancer-specific mortality. METHODS: Cox proportional hazards regression models were used to analyze 501,548 participants of the UK Biobank cohort study aged 40-69 years who were followed up for an average of 12 years. RESULTS: The prevalence of pre-frailty and frailty were 43.2 % and 2.3 %, respectively, and that of polypharmacy was 18.3 %. Although strongly associated with each other, frailty and polypharmacy were independently, statistically significantly associated with major cardiovascular events, cardiovascular disease-specific, and all-cause mortality. In addition, the hazard ratios of polypharmacy were stronger among (pre-)frail than non-frail study participants. No profound associations with cancer incidence and cancer mortality were observed. No sex and age differences were observed. CONCLUSIONS: This large cohort study showed that polypharmacy and frailty are independent risk factors for major cardiovascular events, cardiovascular disease-specific and all-cause mortality in both middle-aged (40-64 years) and older people (≥ 65 years). In addition, the hazard ratios of polypharmacy were stronger among (pre-)frail than non-frail study participants. This underlines the need to avoid polypharmacy as far as possible not only in older but also in middle-aged subjects (40-64 years), especially if they are pre-frail or frail.

Serum 25-Hydroxyvitamin D Status and Vitamin D Supplements Use Are Not Associated with Low Back Pain in the Large UK Biobank Cohort.

Longitudinal studies assessing the association of vitamin D deficiency, defined by serum 25-hydroxyvitamin D levels < 30 nmol/L, and vitamin D supplement (VDS) use with low back pain (LBP) are sparse. This investigation assessed the cross-sectional and longitudinal association of vitamin D status and VDS use with LBP among 135,934 participants from the UK Biobank cohort. Approximately 21.6% of the participants had vitamin D deficiency, while only 4% regularly took VDS. In the month before study enrollment, 3.8% of the population reported experiencing LBP. An additional 3.3% of the population were diagnosed with LBP by their general practitioners for the first time during a median follow-up of 8.5 years. Vitamin D deficiency and VDS use were cross-sectionally associated with LBP in age- and sex-adjusted models, but these associations were not evident in comprehensively adjusted models. In longitudinal analyses, both vitamin D deficiency and VDS use were not associated with LBP in any model after correction for multiple testing. In conclusion, not unexpectedly due to the fact that LBP is multifactorial, our findings provide no evidence for the role of the vitamin D status in the etiology of LBP.

The associations of serum vitamin D status and vitamin D supplements use with all-cause dementia, Alzheimer's disease, and vascular dementia: a UK Biobank based prospective cohort study.

BACKGROUND: Prior studies on vitamin D and dementia outcomes yielded mixed results and had several important limitations. OBJECTIVES: We aimed to assess the associations of both serum vitamin D status and supplementation with all-cause dementia, Alzheimer's disease (AD), and vascular dementia (VD) incidence. METHODS: With a prospective cohort study design, we comprehensively assessed the associations of vitamin D and multivitamin supplementation, as well as vitamin D deficiency {25-hydroxyvitamin D [25(OH)D] <30 nmol/L}, and insufficiency [25(OH)D 30 to <50 nmol/L], with the 14-year incidence of all-cause dementia, AD, and VD in 269,229 participants, aged 55 to 69, from the UK Biobank. RESULTS: Although 5.0% reported regular vitamin D use and 19.8% reported multivitamin use, the majority of participants exhibited either vitamin D deficiency (18.3%) or insufficiency (34.0%). However, vitamin D deficiency was less prevalent among users of vitamin D (6.9%) or multivitamin preparations (9.5%) than among nonusers (21.5%). Adjusted Cox regression models demonstrated 19% to 25% increased risk of all 3 dementia outcomes for those with vitamin D deficiency [hazard ratio (HR) 95% confidence interval (CI)]: 1.25 (1.16, 1.34) for all-cause dementia; 1.19 (1.07-1.31) for AD; 1.24 (1.08-1.43) for VD] and 10% to 15% increased risk of those with vitamin D insufficiency [HR (95% CI): 1.11 (1.05, 1.18) for all-cause dementia; 1.10 (1.02-1.19) for AD; 1.15 (1.03-1.29) for VD]. Regular users of vitamin D and multivitamins had 17% and 14% lower risk of AD [HR (95% CI): 0.83 (0.71, 0.98)] and VD [HR (95% CI): 0.86 (0.75, 0.98)] incidence, respectively. CONCLUSIONS: Although our findings indicate the potential benefits of vitamin D supplementation for dementia prevention, randomized controlled trials are essential for definitive evidence.