External Validation and Update of the Risk Prediction Model for Denosumab-Induced Hypocalcemia Developed From a Hospital-Based Administrative Database.

PURPOSE: Denosumab is used to treat patients with bone metastasis from solid tumors, but sometimes causes severe hypocalcemia, so careful clinical management is important. This study aims to externally validate our previously developed risk prediction model for denosumab-induced hypocalcemia by using data from two facilities with different characteristics in Japan and to develop an updated model with improved performance and generalizability. METHODS: In the external validation, retrospective data of Kameda General Hospital (KGH) and Miyagi Cancer Center (MCC) between June 2013 and June 2022 were used and receiver operating characteristic (ROC)-AUC was mainly evaluated. A scoring-based updated model was developed using the same data set from a hospital-based administrative database as previously employed. Selection of variables related to prediction of hypocalcemia was based on the results of external validation. RESULTS: For the external validation, data from 235 KGH patients and 224 MCC patients were collected. ROC-AUC values in the original model were 0.879 and 0.774, respectively. The updated model consisting of clinical laboratory tests (calcium, albumin, and alkaline phosphatase) afforded similar ROC-AUC values in the two facilities (KGH, 0.837; MCC, 0.856). CONCLUSION: We developed an updated risk prediction model for denosumab-induced hypocalcemia with small interfacility differences. Our results indicate the importance of using data from plural facilities with different characteristics in the external validation of generalized prediction models and may be generally relevant to the clinical application of risk prediction models. Our findings are expected to contribute to improved management of bone metastasis treatment.

Adverse Event Signal Detection Using Patients' Concerns in Pharmaceutical Care Records: Evaluation of Deep Learning Models.

BACKGROUND: Early detection of adverse events and their management are crucial to improving anticancer treatment outcomes, and listening to patients' subjective opinions (patients' voices) can make a major contribution to improving safety management. Recent progress in deep learning technologies has enabled various new approaches for the evaluation of safety-related events based on patient-generated text data, but few studies have focused on the improvement of real-time safety monitoring for individual patients. In addition, no study has yet been performed to validate deep learning models for screening patients' narratives for clinically important adverse event signals that require medical intervention. In our previous work, novel deep learning models have been developed to detect adverse event signals for hand-foot syndrome or adverse events limiting patients' daily lives from the authored narratives of patients with cancer, aiming ultimately to use them as safety monitoring support tools for individual patients. OBJECTIVE: This study was designed to evaluate whether our deep learning models can screen clinically important adverse event signals that require intervention by health care professionals. The applicability of our deep learning models to data on patients' concerns at pharmacies was also assessed. METHODS: Pharmaceutical care records at community pharmacies were used for the evaluation of our deep learning models. The records followed the SOAP format, consisting of subjective (S), objective (O), assessment (A), and plan (P) columns. Because of the unique combination of patients' concerns in the S column and the professional records of the pharmacists, this was considered a suitable data for the present purpose. Our deep learning models were applied to the S records of patients with cancer, and the extracted adverse event signals were assessed in relation to medical actions and prescribed drugs. RESULTS: From 30,784 S records of 2479 patients with at least 1 prescription of anticancer drugs, our deep learning models extracted true adverse event signals with more than 80% accuracy for both hand-foot syndrome (n=152, 91%) and adverse events limiting patients' daily lives (n=157, 80.1%). The deep learning models were also able to screen adverse event signals that require medical intervention by health care providers. The extracted adverse event signals could reflect the side effects of anticancer drugs used by the patients based on analysis of prescribed anticancer drugs. "Pain or numbness" (n=57, 36.3%), "fever" (n=46, 29.3%), and "nausea" (n=40, 25.5%) were common symptoms out of the true adverse event signals identified by the model for adverse events limiting patients' daily lives. CONCLUSIONS: Our deep learning models were able to screen clinically important adverse event signals that require intervention for symptoms. It was also confirmed that these deep learning models could be applied to patients' subjective information recorded in pharmaceutical care records accumulated during pharmacists' daily work.

Platelets Affect the Activity of Amino Acid Transporter SNAT4 in HuH-7 Human Hepatoma Cells.

Platelets have been reported to exert diverse actions besides hemostasis and thrombus formation in the body. However, whether platelets affect transporter activity remains to be determined. In this study, we examined the effects of platelets on the activity of amino acid transporter system A, which is known to be changed by various factors, and we clarified the mechanism by which platelets affect system A activity. Among system A subtypes, we found that sodium-coupled neutral amino acid transporter (SNAT) 4 played a central role in the transport activity of system A in HuH-7 human hepatoma cells. Interestingly, platelets showed a biphasic effect on system A activity: activated platelet supernatants (APS) including the granule contents released from platelets downregulated system A activity at lower concentrations and the downregulation was suppressed at higher concentrations. The downregulation was due to a decrease in the affinity of SNAT4 for its substrate and not a decrease in the SNAT4 abundance on the plasma membrane. In addition, APS did not decrease the expression level of SNAT4 mRNA. On the other hand, platelets did not affect system A activity when the platelet suspension was added to HuH-7 cells. These results indicate that platelets indirectly affect the transport activity of system A by releasing bioactive substances but do not directly affect it by binding to HuH-7 cells.

Serious Bacterial Infections Associated with Eculizumab: A Pharmacovigilance Study.

Objective Molecular-targeted agents, including eculizumab and rituximab, are considered treatment options for refractory myasthenia gravis (MG), but bacterial infections can occur as serious adverse events when using these agents. The present study elucidated the relative risks of bacterial infections associated with eculizumab and rituximab using a pharmacovigilance database. Methods We analyzed eculizumab- and rituximab-associated adverse events reported between 2007 and 2021 in the US Food and Drug Administration Adverse Event Reporting System (FAERS) and herein report a refractory MG patient who developed streptococcal toxic shock syndrome during eculizumab treatment. Patients We evaluated a 74-year-old Japanese woman with refractory MG who developed severe bacteremia after receiving eculizumab. Results A total of 44,215 and 108,485 adverse events were reported with eculizumab and rituximab, respectively, from among 13,742,321 individual case safety reports in the FAERS database after data cleaning. We found a strong association between eculizumab and Neisseria infections. In contrast, we found only one case of meningococcal meningitis treated with rituximab. Both eculizumab and rituximab were weakly associated with streptococcal infections. Two cases of streptococcal toxic shock syndrome were associated with rituximab. Conclusion Careful monitoring of serious bacterial infections associated with eculizumab treatment is warranted.

A Survey of the Status of Methadone Switching in Japan Using a Hospital-Based Administrative Claims Database.

Methadone is generally used for the management of cancer pain in patients who cannot obtain adequate analgesia from other strong opioids; however, it has a complicated and inconsistent conversion ratio from pre-switching opioid dosage to methadone. This issue may be pronounced in Japan because only oral tablets are commercially available. We aimed to elucidate the status of methadone switching in Japan, focusing on its dosage. Using a Japanese hospital-based administrative claims database, we included patients who switched to methadone between April 2008 and January 2021. The proportion of methadone switching completion that required more than the defined conversion ratio in the Japanese package insert (called "high-dose methadone switching") was evaluated as a primary endpoint. Other endpoints included "the duration from initiation to completion of methadone switching" and "factors affecting high-dose methadone switching by using multivariate logistic regression analysis". Of 1585 patients who received methadone, 370 were enrolled. Among those, 130 (35.1%) received high-dose methadone switching. The median duration of methadone switching completion (12 days) was longer in the high-dose methadone switching group than in other patients. Four variables were identified as factors affecting high-dose methadone switching. Younger age and outpatient status increased the risk of requiring high-dose methadone switching, whereas the concomitant use of nonsteroidal anti-inflammatory drugs and fentanyl as a pre-switching opioid decreased the risk. In conclusion, more than 30% of the patients underwent high-dose methadone switching and required long completion periods, suggesting that methadone switching remains challenging in Japan.

Comparison of different sustained-release opioids and acute respiratory conditions in patients with cancer and chronic kidney disease.

STUDY OBJECTIVE: Few data are available on the association between the use of oxycodone in patients with chronic kidney disease (CKD) and acute respiratory conditions. The aim of this study was to investigate whether oxycodone is associated with an increased risk of acute respiratory conditions in patients with cancer and CKD compared with other opioids. DESIGN AND SETTING: The data were obtained from a claims database in Japan. Patients with cancer and CKD who had received sustained-release opioids, including oral oxycodone, oral morphine, or transdermal fentanyl, between April 2014 and May 2021 were selected. The primary outcome was defined as an acute respiratory condition. Data for age and sex, morphine equivalent daily dose, concomitant use of specified medications, comorbidities defined based on the modified Charlson comorbidity index, substance use disorder, and lung cancer or metastatic lung cancer were investigated as covariates. Distribution of acute respiratory conditions was compared among the three sustained-release opioid groups using the log-rank test. Estimates of the incidence of acute respiratory conditions were compared among the groups using a Cox proportional hazards model with time-varying variables. MAIN RESULTS: A significant difference in the distribution of acute respiratory conditions was found among the three groups (p < 0.01). Cox regression analysis showed a significantly higher risk of acute respiratory conditions with morphine (hazard ratio [HR]: 3.04, 95% confidence interval [CI]: 1.07-8.65, p = 0.04) compared with oxycodone but no significant difference in risk with oxycodone (HR 0.67, 95% CI: 0.32-1.38, p = 0.27) compared with fentanyl. CONCLUSIONS: The findings suggest that the risk of acute respiratory conditions may be lower in patients with CKD who use oxycodone for cancer pain than in those who use morphine. Additionally, no difference in the risk of acute respiratory conditions was found between oxycodone and fentanyl use.

Development of a risk prediction model for surgical site infection after lower third molar surgery.

BACKGROUND: There is little evidence regarding risk prediction for surgical site infection (SSI) after lower third molar (L3M) surgery. METHODS: We conducted a nested case-control study to develop a multivariable logistic model for predicting the risk of SSI after L3M surgery. Data were obtained from Hokkaido University Hospital from April 2013 to March 2020. Multiple imputation was applied for the missing values. We conducted decision tree (DT) analysis to evaluate the combinations of factors affecting SSI risk. RESULTS: We identified 648 patients. The final model retained the available distal space (Pell & Gregory II [p = 0.05], Pell & Gregory III [p < 0.01]), depth (Pell & Gregory B [p < 0.01], Pell & Gregory C [p < 0.01]), surgeon's experience (3-10 years [p = 0.25], <3 years [p < 0.01]), and simultaneous extraction of both L3M [p < 0.01]; the concordance-statistic was 0.72. The DT analysis demonstrated that patients with Pell and Gregory B or C and simultaneous extraction of both L3M had the highest risk of SSI. CONCLUSIONS: We developed a model for predicting SSI after L3M surgery with adequate predictive metrics in a single center. This model will make the SSI risk prediction more accessible.

Dysautonomia associated with immune checkpoint inhibitors.

OBJECTIVE: The purpose of this study is to report the clinical characteristics of dysautonomia associated with immune checkpoint inhibitors (ICIs). METHODS: We reported two patients with autoimmune autonomic ganglionopathy (AAG) occurring as immune-related adverse events (irAEs). We also performed a review of previous case reports presenting dysautonomia during ICI therapy. Moreover, we conducted pharmacovigilance analyses using the US Food and Drug Administration Adverse Events Reporting System (FAERS) to investigate dysautonomia associated with ICI. RESULTS: Two patients in our care developed both AAG and autoimmune encephalitis following ICI therapy for lung cancers. We comprehensively reviewed 13 published cases (M:F = 11:2, mean onset age of 53 years) with ICI-associated dysautonomia including AAG (n = 3) and autonomic neuropathy (n = 10). Of these, ICI monotherapy was performed in seven and combination ICI use in six. In 6 of 13 patients, dysautonomia appeared within one month after the start of ICIs. Orthostatic hypotension was observed in 7 and urinary incontinence or retention in five. All patients except three showed gastrointestinal symptoms. Anti-ganglionic acetylcholine receptor antibodies were undetectable. All but two patients received immune-modulating therapy. Immuno-modulating therapy was effective in three patients with AAG and two patients with autonomic neuropathy, but ineffective in the others. Five patients died, of either the neurological irAE (n = 3) or cancer (n = 2). The pharmacovigilance analyses using FAERS showed that ipilimumab monotherapy and the combination of nivolumab and ipilimumab constituted significant risks for developing dysautonomia, consistent with the review of literature. CONCLUSION: ICIs can cause dysautonomia including AAG, and autonomic neuropathy is a neurological irAE.

Usefulness of the Albumin-Bilirubin Score in Determining the Initial Dose of Voriconazole for Patients with Liver Cirrhosis.

The Child-Pugh score is widely used to assess liver function and estimate drug clearance in patients with liver cirrhosis. Recently, the albumin-bilirubin (ALBI) score, which objectively assesses liver function based only on albumin and total bilirubin levels, was developed as a new method. The purpose of this study was to analyze the relationship between the liver function assessment method and the plasma concentration of voriconazole (VRCZ), an antifungal drug for patients with liver cirrhosis. This single-center retrospective study enrolled 159 patients who received VRCZ between 2012 and 2020. In patients administered VRCZ orally, the median concentration to dose (C : D) ratio increased with the progression of Child-Pugh and ALBI grades. Positive correlations between the ALBI score and VRCZ C : D ratio were observed in patients with cirrhosis (r = 0.52 (95% confidence interval, 0.069-0.79); p < 0.05). In addition, a highly negative correlation was observed between the ALBI score and VRCZ daily maintenance dose (r=-0.79 (95% confidence interval, -0.92 to -0.50); p < 0.0001). In contrast, for patients administered VRCZ intravenously, no increase in C : D ratio was observed for both Child-Pugh and ALBI scores compared to the non-liver cirrhosis group. This may be because the injection is often used in severely ill patients, and factors other than impaired liver function may affect the plasma concentrations of VRCZ. In conclusion, the ALBI score was shown to be useful in predicting VRCZ clearance as well as the Child-Pugh score, and the initial dose of VRCZ might be determined according to the ALBI score.

Use of Japanese big data from electronic medical records to investigate risk factors and identify their high-risk combinations for linezolid-induced thrombocytopenia.

PURPOSE: Thrombocytopenia is a major event associated with linezolid (LZD) therapy. Factors affecting LZD-induced thrombocytopenia (LIT) have been reported in previous studies. However, several issues pertaining to LIT have not yet been clarified. In the present study, we used Japanese big data to investigate associated factors and their high-risk combinations that influence LIT. METHODS: Patients administered LZD between May 2006 and October 2020 were included in this study. LIT was defined as either a 30% or more reduction from the baseline platelets or platelet values of < 100,000/µL. We evaluated factors affecting LIT and combinations of factors that alter LIT risk according to a decision tree (DT) analysis, a typical machine learning method. RESULTS: We successfully enrolled 1399 patients and LIT occurred in 44.7% of the patients (n = 626). We classified the laboratory data on renal function, LZD duration, age, and body weight (BW) into smaller categories. The results of multivariate analysis showed that prolonged LZD therapy, BW < 45 kg, estimated glomerular filtration rate (eGFR) < 30 mL/min/1.73 m2, and dialysis were risk factors for LIT. The DT analysis revealed that the highest risk was a combination of LZD duration ≥ 14 days and eGFR < 30 mL/min/1.73 m2. CONCLUSIONS: The present study extracted four risk factors and identified high-risk combinations for LIT. Patients with these risk factors should be closely monitored.

[Efficacy Survey of Naldemedine in the Poor-performance Status Group].

Naldemedine (Nal) is widely used as a therapeutic drug against opioid-induced constipation. However, patients in phase III trials are limited to those with good performance status (PS). Cancer patients may have inferior PS owing to progression of symptoms and adverse events from chemotherapy. Therefore, it is important to survey the efficacy of Nal in patients with poor PS. This study aimed to evaluate Nal efficacy in patients with poor PS. We retrospectively investigated patients from July 2017 to June 2019 and compared Nal efficacy between patients with good and poor PS. The efficacy of Nal was evaluated using changes in the number of spontaneous bowel movements 7 days before and after the introduction of Nal with reference to previous reports. Multivariate analysis was performed to reveal whether poor PS affects Nal efficacy. In total, 141 patients at the Hokkaido University Hospital were analyzed. The effective rate of Nal from day 1 to day 7 of administration was 71.7% and 71.4% in the patients with good and poor PS, respectively, that from day 1 to day 2 of administration was 61.1% and 57.1%, respectively, and that from day 3 to day 7 of administration was 60.2% and 71.4%, respectively, suggesting an absence of significant differences. Furthermore, results of multivariate analysis showed that "best supportive care" and "body weight (55 kg and above)" reduced Nal efficacy. In conclusion, Nal showed similar effectiveness in patients with poor PS as that in those with good PS.

Effects of piperacillin/tazobactam or cefepime on folinate dose in patients receiving high-dose methotrexate: A retrospective cohort study using Japanese administrative claims data.

INTRODUCTION: Delayed methotrexate (MTX) clearance with the co-administration of piperacillin/tazobactam (PIPC/TAZ) has been reported. Penicillins have been associated with reduced MTX clearance but the evidence is limited. There are no cases described with cefepime but penicillins are listed as interacting with MTX. We aimed to reveal whether the co-administration of PIPC/TAZ or CFPM affects MTX clearance using data from an administrative database. METHODS: We used data from the JMDC database, a large insurance claims database constructed in Japan. We included patients who were prescribed PIPC/TAZ or CFPM between days 1 and 3 in high-dose MTX (HD-MTX). We compared one co-administration episode (with PIPC/TAZ or CFPM) to one control episode (without), as a match-control study of two different episodes in the same patient. The primary outcomes were the duration and cumulative dose of leucovorin (LV) as a surrogate indicator of delayed MTX clearance. RESULTS: Three patients who were co-administered PIPC/TAZ and 16 patients who were co-administered CFPM with HD-MTX were included. In the PIPC/TAZ group, the duration and the cumulative doses of LV were similar in co-administration and control episode (median 3.0 vs. 3.0 days and 288.0 vs. 219.0 mg). In the CFPM group, the duration and the cumulative doses of LV were not significantly different in co-administration and control episode (3.0 vs. 4.0 days and 169.5 vs. 258.0 mg). CONCLUSIONS: Our findings revealed that PIPC/TAZ did not necessarily cause a delay in MTX clearance during HD-MTX therapy. Moreover, the co-administration of CFPM with HD-MTX did not affect MTX clearance.

cAMP Signaling Pathway Prevents Dasatinib-Induced Vascular Hyperpermeability.

Dasatinib is a first-line pharmacotherapeutic treatment for chronic myeloid leukemia (CML). It is more effective than traditional treatments but causes adverse effects such as pleural effusion that limits its effective treatment cycle. Since pleural effusion is caused by vascular hyperpermeability and causes discontinuation of treatment with dasatinib, it is important to explore the mechanism of pleural effusion caused by dasatinib and how to prevent it. In this study, we investigated how dasatinib increase vascular permeability, and how it can be prevented. Cytotoxicity was observed in vascular endothelial cells or epithelial cells were exposed to high concentrations of dasatinib. Thus, it was observed in vascular endothelial cells such as human umbilical vascular endothelial cell (HUVEC). Vascular endothelial (VE)-cadherin is one of the important factors that control vascular permeability. When VE-cadherin expression decreases, vascular permeability increases, but it did not change with tyrosine kinase inhibitor exposure. Monolayer permeability significantly increased only with high concentration of dasatinib, but this increase was prevented by cAMP activation. Furthermore, dasatinib affects the cell morphology of HUVEC, with increased inter celluar space compared to control and bosutinib, which were also attenuated by cAMP activation. Dasatinib significantly affected permeability control of vascular endothelial cells compared to bosutinib and imatinib. These results indicated that the cAMP signaling pathway may be involved in the pleural effusion caused by dasatinib in CML patients.

Investigation of the Real-World Situation and Risk Factors Associated with Olanzapine Prescribed to Diabetes Patients by Using a Japanese Claims Database.

Olanzapine is effective for schizophrenia management; however, it is contraindicated in diabetes patients. In addition, olanzapine is useful for treating nausea and vomiting, such as in the case of chemotherapy-induced nausea and vomiting (CINV). Therefore, we hypothesized that the contraindicated prescription of olanzapine likely occurs among cancer patients with diabetes, especially by non-psychiatric physicians. Hence, we conducted a nationwide survey to elucidate the situation of such contraindicated prescriptions and the associated risk factors. We extracted the data of patients who were newly prescribed olanzapine between April 2015 and March 2017 from the health insurance claims database developed by JMDC, Inc., Tokyo. The patients who were prescribed contraindicated olanzapine were defined as those who were prescribed olanzapine after a diagnosis of diabetes and diabetes drug prescription. In all, the data of 7181 patients were analyzed. We evaluated the proportion of diabetes patients who were prescribed contraindicated olanzapine from among those who were prescribed olanzapine. Furthermore, we investigated the background of patients who were prescribed olanzapine for information such as olanzapine prescribers and history of cancer chemotherapy. In all, 100 diabetes patients (1.39%) were prescribed olanzapine. In these patients, the frequency of olanzapine prescription was higher by non-psychiatry/neurology physicians than by psychiatry/neurology physicians (3.25 and 0.85%, respectively). Additionally, all olanzapine prescriptions in cancer chemotherapy-treated diabetes patients were issued by non-psychiatry/neurology physicians. Thus, our study revealed there were diabetes patients who were prescribed olanzapine. Additionally, olanzapine for CINV management was more likely to be a contraindicated prescription.

Construction of a Risk Prediction Model of Extended Release Oxycodone Tablet-Induced Nausea and Clarification of Predictive Factors.

Nausea is a typical adverse event associated with opioids. In this study, we performed logistic regression analysis with the aim of clarifying the risk factors for nausea induced by extended-release oxycodone (ER-OXY). Furthermore, we constructed a decision tree (DT) model, a typical data mining method, to estimate the risk of oxycodone-induced nausea by combining multiple factors. A retrospective study was conducted on patients who newly received ER-OXY for cancer pain during hospitalization at Hokkaido University Hospital in Japan from April 2015 to March 2018. In logistic regression and DT analyses, the dependent variable was the presence or absence of nausea. Independent variables were the potential risk factors. First, univariate analyses were performed to screen potential factors associated with oxycodone-induced nausea. Then, multivariate and DT analyses were performed using factors with p-values <0.1 in the univariate analysis. Of 267 cases included in this study, nausea was observed in 30.3% (81/267). In multivariate logistic regression analysis, only female sex was extracted as an independent factor affecting nausea (odds ratio, 1.98). In the DT analysis, we additionally revealed that an age <50 years was a risk factor for nausea in female patients. Thus, our DT model indicated that the risk of ER-OXY-induced nausea was highest in the subgroup comprising females <50 years of age (66.7%) and lowest in male patients (25.1%). The DT model suggested that the factor of young women may be an increased risk of ER-OXY-induced nausea.

[Verification of Relationship between Administration of Linezolid and Vomiting].

Linezolid (LZD), an antimicrobial agent against methicillin-resistant Staphylococcus aureus, demonstrates good bone and joint penetration, and is used for prosthetic bone and joint infections. Recently, we observed vomiting in several patients administered LZD. However, there are few reports on the incidence rate of, and risk factors for, LZD-induced nausea and vomiting. In this study, we aimed to verify the relationship between LZD administration and vomiting. Patients administered LZD at the Department of Orthopedic Surgery of Hokkaido University Hospital between November 2008 and December 2017 were enrolled in the study. The primary endpoint was the comparison of the vomiting rate between patients administered LZD (LZD group) and those administered other antibiotics (non-LZD group). For the secondary endpoint, to verify the risk factors of vomiting, a univariate logistic regression analysis was performed. In total, 130 patients were included in this study; 77 patients in the LZD group, and 53 in the non-LZD group. Vomiting occurred in 18 patients in the LZD group and 4 patients in the non-LZD group (23.4% and 7.5%, respectively); this was significantly higher in the LZD group. In the univariate logistic regression analysis, LZD administration, gender (female), age ≥65 years, renal impairment (creatinine clearance <60 mL/min) and concomitant use of rifampicin were extracted as potential risk factors of vomiting. The results of this study reveal a possible relationship between LZD administration and vomiting.

Construction of a flow chart-like risk prediction model of ganciclovir-induced neutropaenia including severity grade: A data mining approach using decision tree.

WHAT IS KNOWN AND OBJECTIVE: Haematological toxicities such as neutropaenia are a common side effect of ganciclovir (GCV); however, risk factors for GCV-induced neutropaenia have not been well established. Decision tree (DT) analysis is a typical technique of data mining consisting of a flow chart-like framework that shows various outcomes from a series of decisions. By following the flow chart, users can estimate combinations of risk factors that may increase the probability of certain events. In our previous study, we demonstrated the usefulness of this approach in the evaluation of adverse drug reactions. Therefore, we aimed to construct a risk prediction model of GCV-induced neutropaenia including severity grade. METHODS: We performed a retrospective study at the Hokkaido University Hospital and enrolled patients who received GCV between April 2008 and March 2018. Neutropaenia was defined as an absolute neutrophil count (ANC) <1500 cells/mm3 and a decrease to <75% relative to baseline. We classified the patients who developed neutropaenia in three groups (Grades 2-4) based on the National Cancer Institute-Common Terminology Criteria for Adverse Events. Data collection was achieved through the retrieval of medical records. We employed a chi-squared automatic interaction detection algorithm to construct the DT model and compared the accuracies to the logistic regression model (a conventional statistical method) to evaluate the established model. RESULTS AND DISCUSSION: In total, 396 adult patients were included in the study; 61 (15.4%) developed neutropaenia. Three predictive factors (hematopoietic stem cell transplantation, baseline ANC <3854 cells/mm3 and duration of therapy ≥15 days) were extracted using the DT analysis to produce five subgroups, the incidence of neutropaenia ranged between 1.7% and 52.8%. In each subgroup, patients who developed neutropaenia were categorized based on the severity. The accuracies of each model were the same (84.6%), which indicated precision. WHAT IS NEW AND CONCLUSION: We successfully built a risk prediction model of GCV-induced neutropaenia including severity grade. This model is expected to assist decision-making in the clinical setting.

The use of broad-spectrum antibiotics reduces the incidence of surgical site infection after pancreatoduodenectomy.

PURPOSE: The development of surgical site infection (SSI) after biliary reconstruction is highly influenced by the presence of preoperative bacteria in the bile juice. We selected vancomycin and piperacillin/tazobactam (VCM + PIPC/TAZ) as perioperative prophylactic antibiotics for patients undergoing pancreaticoduodenectomy. This study aimed to retrospectively analyze the effectiveness of VCM + PIPC/TAZ compared to cefmetazole. METHODS: Seventy-two patients who underwent pancreaticoduodenectomy between April 2015 and March 2017 at our department were evaluated. Forty patients were administered cefmetazole as the perioperative prophylactic antibiotic, and 32 were administered VCM + PIPC/TAZ. The intraoperative VCM blood concentration (incision, biliary reconstruction, and wound closure) was measured during surgery to confirm the hemodynamics. RESULTS: The frequency of SSIs was significantly lower in the VCM + PIPC/TAZ group (8/32 patients) than in the cefmetazole group (20/40 patients, P = 0.031). Postoperatively, significantly fewer patients in the VCM + PIPC/TAZ group (4/32 patients) required ≥ 15 days of additional antibiotic administration compared to those in the cefmetazole group (14/40 patients, P = 0.033). Six of 32 patients in the VCM + PIPC/TAZ group showed redneck syndrome symptoms. There was no significant difference in the VCM blood concentration between patients with and without SSIs. CONCLUSIONS: The use of VCM + PIPC/TAZ can reduce the incidence of SSI after pancreaticoduodenectomy and also reduce the need for the additional administration of antibiotics for ≥ 15 days after surgery.

Factors Affecting the Timing of Signal Detection of Adverse Drug Reactions.

We investigated factors affecting the timing of signal detection by comparing variations in reporting time of known and unknown ADRs after initial drug release in the USA. Data on adverse event reactions (AERs) submitted to U.S. FDA was used. Six ADRs associated with 6 drugs (rosuvastatin, aripiprazole, teriparatide, telithromycin, exenatide, varenicline) were investigated: Changes in the proportional reporting ratio, reporting odds ratio, and information component as indexes of signal detection were followed every 3 months after each drugs release, and the time for detection of signals was investigated. The time for the detection of signal to be detected after drug release in the USA was 2-10 months for known ADRs and 19-44 months for unknown ones. The median lag time for known and unknown ADRs was 99.0-122.5 days and 185.5-306.0 days, respectively. When the FDA released advisory information on rare but potentially serious health risks of an unknown ADR, the time lag to report from the onset of ADRs to the FDA was shorter. This study suggested that one factor affecting signal detection time is whether an ADR was known or unknown at release.