Significance of UGT1A6, UGT1A9, and UGT2B7 genetic variants and their mRNA expression in the clinical outcome of renal cell carcinoma.

UDP-glucuronosyltransferase (UGT) metabolizes a number of endogenous and exogenous substrates. Renal cells express high amounts of UGT; however, the significance of UGT in patients with renal cell carcinoma (RCC) remains unknown. In this study, we profile the mRNA expression of UGT subtypes (UGT1A6, UGT1A9, and UGT2B7) and their genetic variants in the kidney tissue of 125 Japanese patients with RCC (Okayama University Hospital, Japan). In addition, we elucidate the association between the UGT variants and UGT mRNA expression levels and clinical outcomes in these patients. The three representative genetic variants, namely, UGT1A6 541A > G, UGT1A9 i399C > T, and UGT2B7-161C > T, were genotyped, and their mRNA expression levels in each tissue were determined. We found that the mRNA expression of the three UGTs (UGT1A6, UGT1A9, and UGT2B7) are significantly downregulated in RCC tissues. Moreover, in patients with RCC, the UGT2B7-161C > T variant and high UGT2B7 mRNA expression are significantly correlated with preferable cancer-specific survival (CSS) and overall survival (OS), respectively. As such, the UGT2B7-161C > T variant and UGT2B7 mRNA expression level were identified as significant independent prognostic factors of CSS and CSS/OS, respectively. Taken together, these findings indicate that UGT2B7 has a role in RCC progression and may, therefore, represent a potential prognostic biomarker for patients with RCC.

Proton Pump Inhibitors and Rhabdomyolysis: Analysis of Two Different Cross-Sectional Databases.

BACKGROUND: It is unclear whether use of a proton pump inhibitors (PPIs) increases the risk of rhabdomyolysis. OBJECTIVE: To clarify whether use of PPIs increases the risk of rhabdomyolysis. METHODS: This cross-sectional study analyzed data entered into the Medical Data Vision (MDV) database in Japan and into the U.S. Food and Drug Administration Adverse Event Reporting System (FAERS). The MDV data were analyzed to evaluate the association between use of PPIs and rhabdomyolysis. Then, the FAERS data were analyzed to evaluate whether the risk of rhabdomyolysis was increased further when a statin or fibrate was used concomitantly with a PPI. In both analyses, histamine-2 receptor antagonist was set as a comparator because it is used to treat gastric disease. In the MDV analysis, Fisher's exact test and multiple logistic regression analysis were performed. In the FAERS analysis, a disproportionality analysis using Fisher's exact test and multiple logistic regression analysis were performed. RESULTS: Multiple logistic regression analysis of both databases showed a significant association between use of PPIs and an increased risk of rhabdomyolysis (odds ratio [OR] = 1.74-1.95, P ≤ 0.01). However, use of a histamine-2 receptor antagonist was not significantly associated with increased risk of rhabdomyolysis. In the sub-analysis of the FAERS data, use of a PPI did not increase the risk of rhabdomyolysis in patients receiving a statin. CONCLUSION AND RELEVANCE: The data in 2 separate databases consistently suggest that PPIs may increase the risk of rhabdomyolysis. The evidence for this association should be assessed in further drug safety studies.

The Efficacy and Safety of Lubiprostone for Constipation in Cancer Patients Compared with Non-cancer Patients: A Retrospective Cohort Study.

Lubiprostone is an effective drug for various types of constipation in patients without cancer; however, there is no report on its efficacy and safety in patients with cancer. Our purpose was to evaluate the efficacy and safety of lubiprostone for constipation in cancer patients. We retrospectively studied 124 patients (cancer, N = 67) who were treated with lubiprostone for constipation in our hospital between June 2013 and May 2016. The number of bowel movements (BMs) increased in the both the cancer and non-cancer groups. The mean change in BM frequency did not differ between the two groups. Approximately 70% of patients in both groups had an initial BM within 24 h after administration of lubiprostone. The most common lubiprostone-related adverse events in both groups were diarrhea (38.8 vs. 14%), and nausea (22.4 vs. 8.8%). No lubiprostone-related serious adverse events occurred. Discontinuation due to the side effects of lubiprostone was more frequent in cancer patients (p = 0.023). Logistic regression analysis showed that the risk of discontinuation of lubiprostone in cancer patients was high in patients with a body-mass index (BMI) <22, and low in patients using opioids and magnesium oxide dosage ≥1000 mg/d. Our study showed that while lubiprostone was as effective in cancer patients as in non-cancer patients, in cancer patients it was associated with a high incidence of diarrhea and nausea side effects and warranted caution, especially in patients with a low BMI.

Incidence and Risk Factors of Osteonecrosis of the Jaw in Advanced Cancer Patients after Treatment with Zoledronic Acid or Denosumab: A Retrospective Cohort Study.

Zoledronic acid and denosumab are two antiresorptive drugs currently in use for treating osteoporosis. They have different mechanisms of action, but both have been shown to delay the onset of skeletal-related events in patients with advanced cancer. However, medication-related osteonecrosis of the jaw (MRONJ) has been reported in cancer patients treated with zoledronic acid or denosumab. We studied 155 patients with several types of advanced cancer who were treated with zoledronic acid or denosumab in our hospital during the period from April 2010 through March 2013. Thirteen of these 155 patients (8.4%) developed MRONJ. MRONJ development was significantly associated with the number of zoledronic acid or denosumab infusions (p<0.001) and the duration of zoledronic acid or denosumab therapy (p<0.001). Logistic regression analysis showed that diabetes [odds ratio (OR)=6.699, 95% confidence interval (CI), 1.435-31.277, p=0.016], anemia [OR=14.559, 95% CI, 2.161-98.069, p=0.006], and pus discharge [OR=6.491, 95% CI, 1.514-27.835, p=0.012] significantly increased the risk of developing MRONJ. However, the risk of MRONJ was significantly lower [OR=0.137, 95% CI, 0.020-0.944, p=0.043] when patients received periodical dentistry maintenance. Diabetes, anemia, and pus discharge may also play roles in its development. These findings suggest that the active inclusion of dentistry maintenance in bisphosphonate or denosumab treatment of cancer patients can reduce MRONJ development.

Cetuximab-induced skin reactions are suppressed by cigarette smoking in patients with advanced colorectal cancer.

BACKGROUND: Smoking is widely accepted as the most important risk factor for cancer in the modern world. Several constituents of cigarette smoke are known to interact with drug-metabolizing enzymes, potentially affecting the outcomes of drug treatment. Cetuximab (Erbitux(®); Merck Serono) is indicated for the treatment of colorectal cancer with respect to restoring chemosensitivity to irinotecan in irinotecan-resistant patients. The purpose of this study was to determine whether cigarette smoking adversely affects the actions of cetuximab in the treatment of colorectal cancer. METHODS: We studied 56 patients with colorectal cancer who were treated with cetuximab in our hospital during the time period from 2009 through 2010. We compared the adverse reaction rates of 16 patients who smoked (smokers) with those of 38 patients who did not smoke (non-smokers, including 16 patients who never smoked and 22 patients who were former smokers). RESULTS: The incidence of skin reactions after cetuximab treatment was lower in the smokers than in the non-smokers. In addition, the incidence of anorexia was higher in the smokers than in the non-smokers. Within the group of non-smokers, no statistically significant differences were observed between the never smokers and the former smokers with regard to adverse reactions. CONCLUSION: Our findings suggest that cigarette smoking during anticancer treatment with cetuximab-based regimens reduces the skin reaction, which leads to a reduction in the benefit of the treatment; therefore, patients should quit smoking, at least while receiving cetuximab-based treatment.

Adverse Events of Axitinib plus Pembrolizumab Versus Lenvatinib plus Pembrolizumab: A Pharmacovigilance Study in Food and Drug Administration Adverse Event Reporting System.

No head-to-head postmarket surveillance study has compared the differences in adverse events (AEs) between two combination therapies, axitinib (AXI) + pembrolizumab (PEMBRO) and lenvatinib (LEN) + PEMBRO, against metastatic renal cell carcinoma. This study aims to highlight the comprehensive differences in AEs between these two therapies based on the real-world big data from the Food and Drug Administration Adverse Event Reporting System (FAERS) database. In total, 28 937 records were extracted from the FAERS database, and 139 AEs grouped into the System Organ Class according to the Medical Dictionary for Regulatory Activities were analysed. Logistic regression analyses were performed, and the reporting odds ratio with a 95% confidence interval was determined. We found that the incidences of cardiac and hepatobiliary disorders for AXI + PEMBRO, and blood and lymphatic system, metabolism and nutrition, and vascular disorders for LEN + PEMBRO, all of which were associated with serious AEs, were higher than those for LEN + PEMBRO and AXI + PEMBRO, respectively. The differences in the AEs between AXI + PEMBRO and LEN + PEMBRO were not derived merely from those between AXI and LEN monotherapies. Furthermore, remarkable AE potentiation was observed for AXI + PEMBRO. As FAERS is a spontaneous reporting system comprising partially limited information, analysing more detailed relationships between AEs and patient or treatment characteristics was challenging in this study. The present study is the first to show the overall real-world postmarketing differences in AEs between AXI + PEMBRO and LEN + PEMBRO. Our novel findings will substantially improve clinical practice; we recommend comparing patients' conditions associated with the above AEs when selecting between these two therapies. PATIENT SUMMARY: Herein, we highlight the differences in adverse events (AEs) between axitinib + pembrolizumab and lenvatinib + pembrolizumab therapies using data from the real-world Food and Drug Administration Adverse Event Reporting System database aimed at patients with metastatic renal cell carcinoma. We identified AEs that needed attention in each combination. We recommend the differences in AEs to be considered when selecting these two therapies.

Trends in Head and Neck Cancer Mortality from 1999 to 2019 in Japan: An Observational Analysis.

Globally, the numbers of head and neck cancer (HNC) cases and related deaths have recently increased. In Japan, few studies have examined crude or age-adjusted HNC mortality rates. Therefore, this study aimed to determine the trends in crude and age-adjusted mortality rates for HNC per million individuals in Japan from 1999 to 2019. Data on HNC-associated deaths were extracted from the national death certificate database using the International Classification of Diseases, Tenth Revision (n = 156,742). HNC mortality trends were analysed using joinpoint regression models to estimate annual percentage change (APC) and average APC (AAPC). Among men, no significant change was observed in the age-adjusted death rate trend from 1999 to 2014; however, a marked decrease was observed from 2014 to 2019. No changing point was observed in women. Age-adjusted mortality rates continuously decreased over the 21-year period, with an AAPC of -0.7% in men and -0.6% in women. In conclusion, the overall trend in age-adjusted rates of HNC-associated deaths decreased, particularly among men, in the past 5 years. These results will contribute to the formulation of medical policies to develop targeted screening and prevention programmes for HNC in Japan and determine the direction of treatment strategies.

Effects of vonoprazan and proton pump inhibitors on the efficacy of bevacizumab: a multicentre retrospective study.

Gastric acid secretion inhibitors such as proton pump inhibitors (PPIs) and vonoprazan may change the duration of treatment with bevacizumab, a vascular endothelial growth factor (VEGF) inhibitor, for cancer. However, there are no data on this prolongation effect. Here, we aimed to determine whether the use of PPIs or vonoprazan in patients with cancer receiving bevacizumab affected the duration of bevacizumab treatment. This observational study was conducted at two national university hospitals in Japan and involved 222 patients using oral PPIs (N = 190) or vonoprazan (N = 32) at the start of bevacizumab treatment between January 2015 and December 2018. Patients who received only one course of bevacizumab were excluded. The primary endpoint was the duration of bevacizumab treatment. The duration of bevacizumab treatment varied significantly between the PPI and vonoprazan groups. For cancer types other than colorectal cancer (breast, lung, brain, and ovarian cancers), the median duration of treatment was 217 days (p < 0.05) and was longer in the vonoprazan group than in the PPI group. However, for colorectal cancer, the median duration of bevacizumab treatment was 147 days longer in the PPI group than in the vonoprazan group. Selection of appropriate gastric acid secretion inhibitors may improve the therapeutic efficacy of anti-VEGF drugs, including bevacizumab. Oestrogen is a key regulator of this effect and may be responsible for the varying association between PPI or vonoprazan administration and the difference in bevacizumab treatment duration between colon cancer and other cancer types.

Anxiolytic-like effects of hochuekkito in lipopolysaccharide-treated mice involve interleukin-6 inhibition.

Hochuekkito (HET) is a Kampo medicine used to treat postoperative and post-illness general malaise and decreased motivation. HET is known to regulate immunity and modulate inflammation. However, the precise mechanism and effects of HET on inflammation-induced central nervous system disorders remain unclear. This study aimed to assess the effect of HET on inflammation-induced anxiety-like behavior and the mechanism underlying anxiety-like behavior induced by lipopolysaccharide (LPS). Institute of Cancer Research mice were treated with LPS (300 µg/kg, intraperitoneally), a bacterial endotoxin, to induce systemic inflammation. The mice were administered HET (1.0 g/kg, orally) once a day for 2 weeks before LPS treatment. The light-dark box test and the hole-board test were performed 24 h after the LPS injection to evaluate the effects of HET on anxiety-like behaviors. Serum samples were obtained at 2, 5, and 24 h after LPS injection, and interleukin-6 (IL-6) levels in serum were measured. Human and mouse macrophage cells (THP-1 and RAW264.7 cells, respectively) were used to investigate the effect of HET on LPS-induced IL-6 secretion. The repeated administration of HET prevented anxiety-like behavior and decreased serum IL-6 levels in LPS-treated mice. HET significantly suppressed LPS-induced IL-6 secretion in RAW264.7 and THP-1 cells. Similarly, glycyrrhizin, one of the chemical constituents of HET, suppressed LPS-induced anxiety-like behaviors. Our study revealed that HET ameliorated LPS-induced anxiety-like behavior and inhibited IL-6 release in vivo and in vitro. Therefore, we postulate that HET may be useful against inflammation-induced anxiety-like behavior.

IL-4-induced selective clearance of oligomeric beta-amyloid peptide(1-42) by rat primary type 2 microglia.

A hallmark of immunopathology associated with Alzheimer's disease is the presence of activated microglia (MG) surrounding senile plaque deposition of beta-amyloid (Abeta) peptides. Abeta peptides are believed to be potent activators of MG, which leads to Alzheimer's disease pathology, but the role of MG subtypes in Abeta clearance still remains unclear. In this study, we found that IL-4 treatment of rat primary-type 2 MG enhanced uptake and degradation of oligomeric Abeta(1-42) (o-Abeta(1-42)). IL-4 treatment induced significant expression of the scavenger receptor CD36 and the Abeta-degrading enzymes neprilysin (NEP) and insulin-degrading enzyme (IDE) but reduced expression of certain other scavenger receptors. Of cytokines and stimulants tested, the anti-inflammatory cytokines IL-4 and IL-13 effectively enhanced CD36, NEP, and IDE. We demonstrated the CD36 contribution to IL-4-induced Abeta clearance: Chinese hamster ovary cells overexpressing CD36 exhibited marked, dose-dependent degradation of (125)I-labeled o-Abeta(1-42) compared with controls, the degradation being blocked by anti-CD36 Ab. Also, we found IL-4-induced clearance of o-Abeta(1-42) in type 2 MG from CD36-expressing WKY/NCrj rats but not in cells from SHR/NCrj rats with dysfunctional CD36 expression. NEP and IDE also contributed to IL-4-induced degradation of Abeta(1-42), because their inhibitors, thiorphan and insulin, respectively, significantly suppressed this activity. IL-4-stimulated uptake and degradation of o-Abeta(1-42) were selectively enhanced in type 2, but not type 1 MG that express CD40, which suggests that the two MG types may play different neuroimmunomodulating roles in the Abeta-overproducing brain. Thus, selective o-Abeta(1-42) clearance, which is induced by IL-4, may provide an additional focus for developing strategies to prevent and treat Alzheimer's disease.

Replacing zoledronic acid with denosumab is a risk factor for developing osteonecrosis of the jaw.

OBJECTIVE: Intravenous zoledronic acid (ZA) is often replaced with subcutaneous denosumab in patients with bone metastatic cancer. Despite their different pharmacologic mechanisms of action, both denosumab and ZA are effective in bone metastasis but cause osteonecrosis of the jaw (ONJ) as a side effect. ZA persists in the body almost indefinitely, whereas denosumab does not persist for long periods. This study evaluated the risks of developing ONJ when replacing ZA with denosumab. STUDY DESIGN: In total, 161 Japanese patients administered ZA for bone metastatic cancer were enrolled in this single-center, retrospective, observational study. The risk of developing ONJ was evaluated by logistic regression analysis using the following factors: age, gender, cancer type, angiogenesis inhibitors, steroids, and replacement of ZA with denosumab. RESULTS: Seventeen patients (10.6%) developed ONJ. Multiple regression analysis indicated a significant difference in rate of ONJ associated with replacement of ZA with denosumab (odds ratio = 3.81; 95% confidence interval 1.04-13.97; P = .043). CONCLUSIONS: Replacing ZA with denosumab is a risk factor for the development of ONJ. Both binding of bisphosphonate to bone and receptor activator of nuclear factor-κ B ligand inhibition could additively increase the risk of ONJ. We bring the replacement of ZA with denosumab to the attention of clinical oncologists.

Investigation of Mental Disorders in Lung Cancer Outpatients: A Retrospective Analysis.

Cancer patients often develop mental conditions, including anxiety and depressive disorder. And, patients with chemotherapy often exhibit mental changes including anxiety and depressive disorder. Furthermore, it is well known that the frequency of delirium is increased in cancer patients receiving terminal care. Thus, the psychiatric and cognitive functions of cancer survivors are significantly influenced by their quality of life. In this study, we performed a retrospective analysis to identify the risk factors for psychiatric disorders in lung cancer survivors. Most lung cancer survivors that were diagnosed with psychiatric disorders had stage 4 disease. In addition, it was found that an increase in disease stage and high doses of opioids are associated with an increased risk of psychiatric disorders in lung cancer survivors. These findings suggest that it is necessary to consider the mental changes experienced by lung cancer patients during disease progression.

Effectiveness of medical supportive team for outpatients treated with sorafenib: a retrospective study.

BACKGROUND: It is well known that molecular-targeted drugs, of which sorafenib (Nexavar®) is one, differ from previous anticancer drugs and cause various unusual adverse drug reactions. Treatment with sorafenib causes adverse drug reactions such as hand-foot skin reactions, hypertension, and diarrhea. Physicians spend a lot of time monitoring adverse drug reactions to sorafenib in outpatients. As such, at Okayama University Hospital, pharmacists and nurses have organized a medical supportive team to help physicians in this regard. However, the effectiveness of interventions for sorafenib-treated outpatients by this medical supportive team remains unclear. The purpose of this study was thus to clarify the effectiveness of interventions for sorafenib-treated outpatients by this medical supportive team. METHODS: We retrospectively studied 70 outpatients treated with sorafenib between May 2009 and December 2012 at Okayama University Hospital. These outpatients were classified into two groups, an intervention group (31 outpatients) and a non-intervention group (39 outpatients). We compared the duration of sorafenib treatment between these groups. RESULTS: The duration of treatment with sorafenib was significantly longer in the intervention group than in the non-intervention group. No outpatients in the intervention group discontinued sorafenib due to adverse drug reactions such as hand-foot skin reactions or diarrhea. CONCLUSION: The duration of sorafenib treatment was significantly longer in the intervention group than in the non-intervention group. Our findings suggest that interventions by the medical supportive team consisting of health care professionals were effective in preventing the discontinuation of sorafenib.

Refractory cachexia is associated with increased plasma concentrations of fentanyl in cancer patients.

BACKGROUND: An appropriate plasma concentration of fentanyl is the key to achieving good pain control in cancer patients. Cachexia, a multifactorial syndrome, is known to affect drug-metabolizing enzymes. However, the fentanyl concentrations in the blood of patients with cachexia have not been analyzed. The aim of this study was to evaluate the influence of cancer cachexia on dose-adjusted plasma fentanyl concentrations in cancer patients. METHODS: Blood was collected from 21 Japanese cancer patients treated with a 24-hour trans-dermal fentanyl patch during the steady state of fentanyl plasma concentration. Plasma fentanyl concentrations were analyzed using liquid chromatography with tandem mass spectrometry (LC-MS/MS), and the levels were adjusted with the dose of fentanyl. Laboratory data were collected, and the cachexia stage was determined, based on study by Fearon et al. Multiple regression analysis was performed to identify the factors that affected fentanyl plasma concentrations. RESULTS: Eight patients were classified as precachexia, nine as cachexia, and four as refractory cachexia, and the median dose-adjusted fentanyl concentrations (ng/mL per mg/kg/day) were 27.5, 34.4, and 44.5, respectively. The dose-adjusted fentanyl concentration in patients with refractory cachexia was higher than that in patients with precachexia (Kruskal-Wallis test and post hoc Mann-Whitney U-test, P<0.01). The factors that were found to possibly affect the dose-adjusted concentration of fentanyl included aspartate aminotransferase, C-reactive protein, and estimated glomerular filtration rate, when analyzed as six independent variables (multiple regression analysis, P<0.05). CONCLUSION: The dose-adjusted plasma concentrations of fentanyl increased with progression of cancer cachexia. Such an increase is associated with a multifactorial and systemic syndrome in cancer cachexia patients, including lower albumin, higher C-reactive protein, and impaired kidney function. In patients with cancer cachexia, we suggest that evaluation of cancer cachexia might help pain management when using a transdermal fentanyl patch in palliative care.