Landscape of driver mutations and their clinical effects on Down syndrome-related myeloid neoplasms.

ABSTRACT: Transient abnormal myelopoiesis (TAM) is a common complication in newborns with Down syndrome (DS). It commonly progresses to myeloid leukemia (ML-DS) after spontaneous regression. In contrast to the favorable prognosis of primary ML-DS, patients with refractory/relapsed ML-DS have poor outcomes. However, the molecular basis for refractoriness and relapse and the full spectrum of driver mutations in ML-DS remain largely unknown. We conducted a genomic profiling study of 143 TAM, 204 ML-DS, and 34 non-DS acute megakaryoblastic leukemia cases, including 39 ML-DS cases analyzed by exome sequencing. Sixteen novel mutational targets were identified in ML-DS samples. Of these, inactivations of IRX1 (16.2%) and ZBTB7A (13.2%) were commonly implicated in the upregulation of the MYC pathway and were potential targets for ML-DS treatment with bromodomain-containing protein 4 inhibitors. Partial tandem duplications of RUNX1 on chromosome 21 were also found, specifically in ML-DS samples (13.7%), presenting its essential role in DS leukemia progression. Finally, in 177 patients with ML-DS treated following the same ML-DS protocol (the Japanese Pediatric Leukemia and Lymphoma Study Group acute myeloid leukemia -D05/D11), CDKN2A, TP53, ZBTB7A, and JAK2 alterations were associated with a poor prognosis. Patients with CDKN2A deletions (n = 7) or TP53 mutations (n = 4) had substantially lower 3-year event-free survival (28.6% vs 90.5%; P < .001; 25.0% vs 89.5%; P < .001) than those without these mutations. These findings considerably change the mutational landscape of ML-DS, provide new insights into the mechanisms of progression from TAM to ML-DS, and help identify new therapeutic targets and strategies for ML-DS.

Achieving osteoporosis treat-to-target goals with teriparatide or alendronate: sub-analysis of Japanese Osteoporosis Intervention Trial-05 (JOINT-05).

INTRODUCTION: The purpose of this study was to evaluate whether bone mineral density (BMD) ≥ -2.5 SD could be used as the treat-to-target (T2T) goal when treating osteoporosis with teriparatide (TPTD) and alendronate (ALN), and to investigate the relationship with incident vertebral fracture by re-analyzing data from a randomized, controlled trial (JOINT-05) involving postmenopausal Japanese women at high fracture risk. MATERIALS AND METHODS: Participants received sequential therapy with once-weekly TPTD for 72 weeks, followed by ALN for 48 weeks (TPTD-ALN group) or ALN monotherapy for 120 weeks (ALN group). BMDs were measured at the lumbar spine (L2-4), total hip, and femoral neck at 0, 24, 48, 72, and 120 weeks by dual-energy X-ray absorptiometry. The T2T goal was BMD ≥ -2.5 SD, and the endpoint was the proportion of participants with baseline BMD < -2.5 SD in three measurement sites achieving BMD ≥ -2.5 SD. RESULTS: A total of 559 participants were selected. BMD ≥ -2.5 SD at 120 weeks in the L2-4, total hip, and femoral neck sites was achieved in 20.5%, 23.1%, and 5.9%, respectively, in the TPTD-ALN group and 22.2%, 11.7%, and 7.3%, respectively, in the ALN group. Incident vertebral fractures occurred in areas of both lower and high BMD. CONCLUSION: During the 1.5-year treatment period, more than 20% of participants achieved BMD ≥ -2.5 SD as a T2T goal at L2-4. Since the achievement level differed depending on the BMD measurement site, the appropriate site should be selected according to the baseline BMD level.

A crossover comparison of patient satisfaction with two teriparatide regimens: primary results of the Japanese Osteoporosis Intervention Trial 06 (JOINT-06).

INTRODUCTION: This study aimed to compare treatment satisfaction with two dosing regimens (two teriparatide [TPTD] self-injection systems) in osteoporosis patients at high risk of fracture. MATERIALS AND METHODS: In this open-label crossover randomized trial comparing self-injected once-daily (1/D)-TPTD with self-injected twice-weekly (2/W)-TPTD, three satisfaction variables were evaluated by questionnaire for 2 years. The primary endpoint was overall satisfaction and secondary endpoints were satisfaction with treatment effectiveness and with utility of the self-injection device. Changes in quality of life (QOL) assessed by EuroQol-5 Dimension, pain assessed by visual analogue scale (VAS), and anthropometric parameters were also analyzed. Safety was evaluated based on the incidence and severity of adverse events (AEs). RESULTS: The 1/D-TPTD and 2/W-TPTD groups consisted of 180 (75.9 ± 7.3 years) and 179 (age: 75.5 ± 6.9 years) patients, respectively. After 26 weeks of treatment, no significant between-group difference in the persistence rate (79.4% vs 72.6% in the 1/D-TPTD and 2/W-TPTD groups, respectively), distributions of overall satisfaction scores, and satisfaction with treatment (p > 0.05) were observed. However, several items of satisfaction with the utility of the injection device were significantly higher in the 2/W-TPTD group (p < 0.05). Statistical improvements from baseline values were observed in QOL and pain VAS in both groups (p < 0.05). No serious AEs were reported. CONCLUSION: The between-group similarity of overall treatment satisfaction and effectiveness scores and between-group difference in satisfaction with the utility of the self-injection device was useful information for real-world treatment of osteoporosis. Both medication regimens were well tolerated.

A targeted review of worldwide indirect treatment comparison (ITC) guidelines and best practices.

OBJECTIVES: Controls and governance over the methodology and reporting of indirect treatment comparisons (ITCs) have been introduced to minimize bias and ensure scientific credibility and transparency in healthcare decision-making. The objective of this study was to highlight ITC techniques that are key to conducting objective and analytically-sound analyses, and to ascertain circumstantial suitability of ITCs as a source of comparative evidence for healthcare interventions. METHODS: Ovid MEDLINE® was searched from January 2010 through August 2023 to identify publicly available ITC-related documents (i.e., guidelines and best practices) in the English language. This was supplemented with hand-searches of websites of various international organizations, regulatory agencies, and reimbursement agencies of Europe, North America, and Asia-Pacific. The jurisdiction-specific ITC methodology and reporting recommendations were reviewed. RESULTS: Sixty-eight guidelines from 10 authorities worldwide were included for synthesis. Many of the included guidelines were updated within the last five years and commonly cited the absence of direct comparative studies as primary justification for employing ITCs. Most jurisdictions favored population-adjusted or anchored ITC techniques opposed to naïve comparisons. Recommendations on the reporting and presentation of these ITCs varied across authorities; however, there was some overlap among the key elements. CONCLUSIONS: Given the challenges of conducting head-to-head randomized controlled trials, comparative data from ITCs offer valuable insights into clinical effectiveness. As such, multiple ITC guidelines have emerged worldwide. According to the most recent versions of the guidelines, the suitability and subsequent acceptability of the ITC technique employed depends on the data sources, available evidence, and magnitude of benefit/uncertainty.

Rare event approximation between subdistribution hazard ratio and cause-specific hazard ratio in survival analysis with competing risks.

BackgroundDespite the fact that competing risks are inevitable in epidemiological and clinical studies, distinctions between the hazard ratio estimated by handling competing risks as censoring and the subditribution hazard ratio are often overlooked.MethodsWe derive quantitative relationships between subdistribution hazard ratio and cause-specific hazard ratio, and derive an approximate calculation method to transform the two into each other. Numerical examinations of hypothetical six scenarios and published information of a randomized clinical trial of cholesterol-lowering therapy and a registry of acute myeloid leukemia were provided.ResultsGeneral and approximate relationships under rare event assumptions between the two types of hazard ratio were given. The approximation formula is based on a survival ratio and has two possible applications. First, one can calculate a subdistribution hazard ratio from published information. Second, this formula allows sample size estimation that takes the presence of competing risks into account.ConclusionsThe distinction between the two types of hazard ratio can be addressed by focusing on two quantities. One is how the event of interest and competing risk is rare, and the other is the survival ratio.

Correction: Electronic Health Record-Nested Reminders for Serum Lithium Level Monitoring in Patients With Mood Disorder: Randomized Controlled Trial.

[This corrects the article DOI: 10.2196/40595.].

Decoupling power and type I error rate considerations when incorporating historical control data using a test-then-pool approach.

To accelerate a randomized controlled trial, historical control data may be used after ensuring little heterogeneity between the historical and current trials. The test-then-pool approach is a simple frequentist borrowing method that assesses the similarity between historical and current control data using a two-sided test. A limitation of the conventional test-then-pool method is the inability to control the type I error rate and power for the primary hypothesis separately and flexibly for heterogeneity between trials. This is because the two-sided test focuses on the absolute value of the mean difference between the historical and current controls. In this paper, we propose a new test-then-pool method that splits the two-sided hypothesis of the conventional method into two one-sided hypotheses. Testing each one-sided hypothesis with different significance levels allows for the separate control of the type I error rate and power for heterogeneity between trials. We also propose a significance-level selection approach based on the maximum type I error rate and the minimum power. The proposed method prevented a decrease in power even when there was heterogeneity between trials while controlling type I error at a maximum tolerable type I error rate larger than the targeted type I error rate. The application of depression trial data and hypothetical trial data further supported the usefulness of the proposed method.

The association between intraoperative anesthesia methods used during gastric cancer surgery and long-term mortality: A retrospective observational study using a Japanese claims database.

PURPOSE: Various basic and clinical studies have investigated the association between the types of anesthetic agents and prognosis. However, the results have varied among studies and remain controversial. In the present study, we aimed to investigate whether the risk of all-cause mortality differs between inhaled or intravenous anesthetics in patients with gastric cancer undergoing gastrectomy. METHODS: Using a Japanese nationwide insurance claims database, we analyzed patients who underwent gastrectomy under general anesthesia for gastric cancer between January 2005 and September 2019. Postoperative outcomes were compared between two groups: those who received inhaled anesthetics (Sevoflurane, Isoflurane, or Desflurane) and those who received intravenous anesthetics (propofol), using a multivariable Cox proportional hazards model. The primary outcome was overall survival. RESULTS: Among 2671 eligible patients, 2105 were in the inhaled anesthetic group, and 566 were in the intravenous anesthetic group. The median (interquartile range) age was 58 (51-63) years, and 1979 (74.1%) were men. The median follow-up period was 795 days. We identified 56 (2.7%) and 16 (2.8%) deaths during the follow-up period in the inhaled and intravenous anesthetic use groups, respectively. There was no difference in postoperative overall survival between the two groups (hazard ratio, 0.97; 95% confidence interval, 0.56-1.70; P = 0.93). CONCLUSIONS: We found no significant difference in the postoperative risks of overall survival between inhaled and intravenous anesthesia in patients with gastric cancer undergoing gastrectomy.

Sequential therapy with once-weekly teriparatide injection followed by alendronate versus monotherapy with alendronate alone in patients at high risk of osteoporotic fracture: final results of the Japanese Osteoporosis Intervention Trial-05.

In this randomized, controlled trial, sequential therapy with once-weekly subcutaneous injection of teriparatide for 72 weeks, followed by alendronate for 48 weeks resulted in a significantly lower incidence of morphometric vertebral fracture than monotherapy with alendronate for 120 weeks in women with osteoporosis at high risk of fracture. PURPOSE: To determine whether the anti-fracture efficacy of sequential therapy with teriparatide, followed by alendronate is superior to that of monotherapy with alendronate, a prospective, randomized, open-label, blinded-endpoint trial was performed. METHODS: Japanese women aged at least 75 years were eligible for the study, if they had primary osteoporosis and if they were at high risk of fracture. Patients were randomly assigned (1:1) to receive the sequential therapy (once-weekly subcutaneous injection of teriparatide 56.5 µg for 72 weeks, followed by alendronate for 48 weeks) or monotherapy with alendronate for 120 weeks. The primary endpoint in the final analysis was the incidence of morphometric vertebral fracture during the 120-week follow-up period. RESULTS: Between October 2014 and June 2020, 505 patients in the sequential therapy group and 506 in the monotherapy group were enrolled. Of these, 489 and 496, respectively, were included in the main analysis. The incidence of morphometric vertebral fracture during the 120-week follow-up period in the sequential therapy group (64 per 627.5 person-years, annual incidence rate 0.1020) was significantly lower than that in the monotherapy group (126 per 844.2 person-years, annual incidence rate 0.1492), with a rate ratio of 0.69 (95% confidence interval 0.54 to 0.88, P < 0.01). After 72 weeks, no patient had a severe adverse event that was considered related to the study drug. CONCLUSION: Once-weekly injection of teriparatide, followed by alendronate resulted in a significantly lower incidence of morphometric vertebral fracture than alendronate monotherapy in women with osteoporosis who were at high risk of fracture. TRIAL REGISTRATION NUMBER, DATE OF REGISTRATION: jRCTs031180235 and UMIN000015573, March 12, 2019.

Effect of Bone Resorption Inhibitors on Serum Cholesterol Level and Fracture Risk in Osteoporosis: Randomized Comparative Study Between Minodronic Acid and Raloxifene.

The positive link between osteoporosis and hypercholesterolemia has been documented, and bone resorption inhibitors, such as nitrogen-containing bisphosphonates (N-BP) and selective estrogen receptor modulators (SERMs), are known to reduce serum cholesterol levels. However, the relationship between the baseline cholesterol level and incident fracture rate under the treatment using the bone resorption inhibitors has not been documented. We investigated the relation between vertebral fracture incident and the baseline cholesterol levels and cholesterol-lowering effect of N-BP and SERM in osteoporosis through a prospective randomized open-label study design. Patients with osteoporosis (n = 3986) were allocated into two groups based on the drug used for treatment: minodronic acid (MIN) (n = 1624) as an N-BP and raloxifene (RLX) as an SERM (n = 1623). Serum levels of cholesterol and incidence of vertebral fracture were monitored for 2 years. The vertebral fracture rates between the two groups were compared using the pre-specified stratification factors. The patients receiving MIN with baseline low-density lipoprotein (LDL)-cholesterol level of ≥ 140 mg/dL, high-density lipoprotein cholesterol level < 40 mg/dL, age group of ≥ 75 years, and T score of BMD ≥ -3 SD had significantly lower vertebral fracture rates than those receiving RLX (incidence rate ratios (IRR) 0.45 [95% confidence interval (CI) 0.30 0.75, p = 0.001], 0.25 [95% CI 0.09 0.65, p = 0.005], 0.71 [95% CI 0.56 0.91, p = 0.006], 0.47 [95% CI 0.30 0.75, p = 0.0012], respectively). The cholesterol-lowering effect was stronger in the RLX group than in the MIN group, regardless of prior statin use. These results indicated that MIN treatment was more effective in reducing fracture risk in patients with higher LDL cholesterol levels, although its cholesterol-lowering ability was lesser than the RLX treatment.Trial registration University Hospital Medical Information Network-Clinical Trials Registry (UMIN-CTR), No. UMIN000005433; date: April 13, 2011.

Relationship between the magnitude of body mass index reductions and remission in patients with type 2 diabetes in real world settings: Analysis of nationwide patient registry in Japan (JDDM74).

AIMS: To determine the association between the magnitude of weight loss and incidence of remission according to baseline characteristics in patients with diabetes in clinical settings. METHODS: In total, 39 676 Japanese patients with type 2 diabetes aged ≥18 years with glycated haemoglobin (HbA1c) ≥6.5% and/or glucose-lowering drug prescription were identified from databases of specialists' clinics from 1989 and followed until September 2022. Remission was diagnosed as maintaining HbA1c <6.5% at least 3 months after cessation of a glucose-lowering drug. Factors associated with remission were evaluated by logistic regression analysis according to weight change in 1 year (i.e. ≥10%, 7.0-9.9%, 3.0-6.9% reduction, <3% change and ≥3.0% increase). RESULTS: During the study period, 3454 remissions occurred. The rates of remission were higher in the group with the greatest reduction of body mass index (BMI) in any category examined (i.e. baseline BMI, HbA1c, duration of diabetes and treatment). The incidences of remission per 1000 person-years were about 25 and 50, respectively, for those with BMI ≥22.5 and reductions in BMI of 7.0-9.9% and ≥10% in 1 year. Remissions per 1000 person-years were 99.2 and 91.8, respectively, for those with baseline HbA1c of 6.5-6.9 and a 10% BMI reduction and those not taking glucose-lowering drugs accompanied by a 10% BMI reduction. CONCLUSIONS: Modest weight losses of 3.0-7.9% were significantly associated with remission, but a minimum of 10% weight loss would be required in addition to an early diagnosis to achieve a 10% remission rate in clinical settings. Our results implied that remission may be expected with a relatively lower BMI in an Asian population compared with that was reported in Western populations if accompanied by weight loss.

Incidence and predictors of remission and relapse of type 2 diabetes mellitus in Japan: Analysis of a nationwide patient registry (JDDM73).

AIMS: To determine the incidence of remission and 1-year relapse from remission and associated factors in patients with type 2 diabetes. MATERIALS AND METHODS: A total of 48 320 Japanese patients with type 2 diabetes aged ≥18 years, with glycated haemoglobin (HbA1c) levels ≥48 mmol/mol (6.5%) and/or glucose-lowering drug prescription, were identified from databases of specialist clinics from 1989 and followed until September 2022. Remission was defined as HbA1c <48 mmol/mol at least 3 months after cessation of a glucose-lowering drug. Relapse was defined as failure to maintain remission for 1 year. Factors associated with remission and relapse were evaluated by logistic regression analysis. RESULTS: The overall incidence of remissions per 1000 person-years was 10.5, and for those with HbA1c levels of 48 to 53 mmol/mol (6.5% to 6.9%), those taking no glucose-lowering drugs at baseline, and those with a ≥10% body mass index (BMI) reduction in 1 year, it was 27.8, 21.7 and 48.2, respectively. Shorter duration, lower baseline HbA1c, higher baseline BMI, higher BMI reduction at 1 year, and no glucose-lowering drugs at baseline were significantly associated with remission. Among 3677 persons with remission, approximately two-thirds (2490) relapsed within 1 year. Longer duration, lower BMI at baseline, and lower BMI reduction at 1 year were significantly associated with relapse. CONCLUSIONS: The results showed that the incidence of remission and predictors of relapse, especially baseline BMI, might differ greatly between East Asian and Western populations. Furthermore, the relationships of BMI reduction with remission and relapse may be greater in East Asian than in Western populations, implying ethnic differences in returning from overt hyperglycaemia to nearly normal glucose levels.

G-estimation of structural nested mean models for interval-censored data using pseudo-observations.

Two large-scale randomized clinical trials compared fenofibrate and placebo in diabetic patients with pre-existing retinopathy (FIELD study) or risk factors (ACCORD trial) on an intention-to-treat basis and reported a significant reduction in the progression of diabetic retinopathy in the fenofibrate arms. However, their analyses involved complications due to intercurrent events, that is, treatment-switching and interval-censoring. This article addresses these problems involved in estimation of causal effects of long-term use of fibrates in a cohort study that followed patients with type 2 diabetes for 8 years. We propose structural nested mean models (SNMMs) of time-varying treatment effects and pseudo-observation estimators for interval-censored data. The first estimator for SNMMs uses a nonparametric maximum likelihood estimator (MLE) as a pseudo-observation, while the second estimator is based on MLE under a parametric piecewise exponential distribution. Through numerical studies with real and simulated datasets, the pseudo-observations estimators of causal effects using the nonparametric Wellner-Zhan estimator perform well even under dependent interval-censoring. Its application to the diabetes study revealed that the use of fibrates in the first 4 years reduced the risk of diabetic retinopathy but did not support its efficacy beyond 4 years.

Employment Status of Patients With Colorectal Cancer After Surgery: A Multicenter Prospective Cohort Study in Japan.

BACKGROUND: Because of improved survival rates, patients with colorectal cancer may try to return to work. Many countries, however, have limited knowledge of the employment status of these patients. OBJECTIVE: To explore the employment status of patients with colorectal cancer after surgery in Japan and the risk factors affecting the same. DESIGN: This is a prospective multicenter cohort study that used self-administered questionnaires. Patients were recruited from June 2019 to August 2020 and were followed up for 12 months after surgery. SETTING: Six community hospitals and 1 university hospital in Japan. PATIENTS: Patients with clinical stages I to III colorectal cancer, employed at the time of diagnosis. INTERVENTIONS: Patients who underwent surgical resection between June 2019 and August 2020. MAIN OUTCOME MEASUREMENTS: The time it takes patients to return to work after surgery and the proportion of working patients 12 months after surgery were collected using self-administered questionnaires. RESULTS: A total of 129 patients were included in the analyses. The median time to return-to-work was 1.1 months, and the proportion of working patients at 12 months after surgery was 79%. Risk factors for delayed return-to-work after surgery were an advanced tumor stage, stoma, severe postoperative complications, shorter years of service at the workplace, and lower willingness to return-to-work. Risk factors for not working 12 months after surgery were stoma, lower willingness to return-to-work, nonregular employee status, lower income, national health insurance, and no private medical insurance. LIMITATIONS: This study is limited by its short-term follow-up and small sample size. CONCLUSIONS: This study revealed that Japanese patients with stages I to III colorectal cancer found favorable employment outcomes in the 12 months after surgery. These results may help health care providers better understand the employment status of patients with colorectal cancer and encourage them to consider returning to work after surgery. SITUACIN LABORAL DE LOS PACIENTES CON CNCER COLORRECTAL DESPUS DE LA CIRUGA UN ESTUDIO DE COHORTE PROSPECTIVO MULTICNTRICO EN JAPN: ANTECEDENTES:Debido a las mejores tasas de supervivencia, los pacientes con cáncer colorrectal pueden intentar volver al trabajo. Muchos países, sin embargo, tienen un conocimiento limitado de su situación laboral.OBJETIVO:Explorar la situación laboral de los pacientes con cáncer colorrectal después de la cirugía en Japón y los factores de riesgo que afectan a la misma.DISEÑO:Este es un estudio prospectivo de cohortes multicéntrico que utiliza cuestionarios autoadministrados. Los pacientes fueron reclutados desde junio de 2019 hasta agosto de 2020 y fueron seguidos durante 12 meses después de la cirugía.ENTORNO CLINICO:Seis hospitales comunitarios y un hospital universitario en Japón.PACIENTES:Pacientes con estadios clínicos I-III de cáncer colorrectal, trabajando en el momento del diagnóstico.INTERVENCIONES:Pacientes que recibieron resección quirúrgica desde junio de 2019 hasta agosto de 2020.PRINCIPALES MEDIDAS DE RESULTADO:El tiempo que tardan los pacientes en volver al trabajo después de la cirugía y la proporción de pacientes que trabajan 12 meses después de la cirugía se recogieron mediante cuestionarios autoadministrados.RESULTADOS:Un total de 129 pacientes fueron incluidos en los análisis. La mediana de tiempo de reincorporación al trabajo fue de 1,1 meses y la proporción de pacientes que trabajaban a los 12 meses de la cirugía fue del 79%. Los factores de riesgo para el retraso en el regreso al trabajo después de la cirugía fueron un estadio avanzado del tumor, estoma, complicaciones postoperatorias graves, menos años de servicio en el lugar de trabajo y menor disposición para volver al trabajo. Los factores de riesgo para no trabajar 12 meses después de la cirugía fueron estoma, menor voluntad de volver al trabajo, condición de empleado no regular, ingresos más bajos, seguro nacional de salud y la falta de seguro médico privado.LIMITACIONES:Este estudio está limitado por su seguimiento a corto plazo y tamaño de muestra pequeño.CONCLUSIONES:Este estudio reveló que los pacientes japoneses con cáncer colorrectal en estadios I-III obtuvieron resultados laborales favorables en los 12 meses posteriores a la cirugía. Estos resultados pueden ayudar a los proveedores de atención médica a comprender mejor la situación laboral de los pacientes con cáncer colorrectal y alentarlos a considerar regresar al trabajo después de la cirugía. (Traducción- Dr. Francisco M. Abarca-Rendon ).

Frequency and determinants of serum calcium monitoring during eldecalcitol therapy in patients with osteoporosis.

INTRODUCTION: Eldecalcitol (ELD) is an active vitamin D3 analog (AVD) commonly used to treat osteoporosis in Japan. Although routine monitoring of serum calcium levels during ELD therapy is recommended, little is known about the actual frequency and determinants of monitoring. MATERIALS AND METHODS: This was a descriptive cohort study using a Japanese electronic medical records database. We identified osteoporosis patients who initiated treatment with ELD or other AVDs (alfacalcidol and calcitriol) between April 1, 2011 and September 10, 2021. The index date for cohort entry was the first prescription date of ELD or other AVDs. The frequency of serum calcium monitoring was evaluated every 6 months. Determinants of serum calcium monitoring were identified using multivariable logistic regression models. We also calculated the incidence of hypercalcemia and the frequency of serum calcium monitoring within 6 months before hypercalcemia. RESULTS: We identified 12,671 ELD users and 7867 other AVD users. Within 6 months after cohort entry, 45.9% of ELD users and 58.7% of other AVD users underwent serum calcium monitoring. Female sex, no use of systemic corticosteroids, moderate-to-good renal function, treatment in smaller hospitals, and treatment in orthopedic surgery departments were associated with a lower likelihood of receiving serum calcium monitoring during ELD therapy. The incidence of hypercalcemia among ELD users was 6.36 per 100 person-years, with 20.6% of cases not receiving serum calcium monitoring before hypercalcemia. CONCLUSION: Our findings suggest that serum calcium monitoring is not given adequate attention during ELD therapy in routine clinical practice.

Reliability of early stage symptoms/clinical findings of osteonecrosis of the jaw: Japanese Osteoporosis Intervention Trial-05 (JOINT-05).

INTRODUCTION: To investigate the differences in the incidence rates of suspected stage 0/1 osteonecrosis of the jaw (ONJ) and incidence risk of relevant clinical findings of suspected stage 0 ONJ between patients treated with sequential therapy comprising weekly teriparatide for 72 weeks followed by alendronate for 48 weeks vs. those who received monotherapy with alendronate for 120 weeks. MATERIALS AND METHODS: Suspected stage 0/1 ONJ was defined by non-specific symptoms. Tooth mobility and periodontal symptoms (gingival bleeding, swelling, and/or pain) were selected as clinical findings of suspected stage 0 ONJ. Poisson regression models were applied to calculate the incidence rate ratios of suspected stage 0/1 between the teriparatide group (TG) and alendronate group (AG). Generalized linear models were used to calculate the risk ratios of clinical findings between groups. RESULTS: Two hundred and sixty-one participants in the TG and 344 in the AG answered a structured questionnaire on oral health and were included in this study. There were no significant differences between the groups in the incidence rate of suspected stage 0/1 ONJ at both 72 and 120 weeks. The risk ratio of the TG to AG for tooth mobility was 0.34 (95% confidence interval [CI] 0.13-0.88, p = 0.02) at 72 weeks and 0.90 (95% CI 0.40-2.03, p = 0.83) at 120 weeks. The incidence rate of tooth mobility related to periodontal symptoms decreased in the TG and increased in the AG during the study. CONCLUSION: Tooth mobility accompanied by clinical periodontal symptoms may be a useful early sign of stage 0 ONJ.

Risk Ratio and Risk Difference Estimation in Case-cohort Studies.

BACKGROUND: In case-cohort studies with binary outcomes, ordinary logistic regression analyses have been widely used because of their computational simplicity. However, the resultant odds ratio estimates cannot be interpreted as relative risk measures unless the event rate is low. The risk ratio and risk difference are more favorable outcome measures that are directly interpreted as effect measures without the rare disease assumption. METHODS: We provide pseudo-Poisson and pseudo-normal linear regression methods for estimating risk ratios and risk differences in analyses of case-cohort studies. These multivariate regression models are fitted by weighting the inverses of sampling probabilities. Also, the precisions of the risk ratio and risk difference estimators can be improved using auxiliary variable information, specifically by adapting the calibrated or estimated weights, which are readily measured on all samples from the whole cohort. Finally, we provide computational code in R (R Foundation for Statistical Computing, Vienna, Austria) that can easily perform these methods. RESULTS: Through numerical analyses of artificially simulated data and the National Wilms Tumor Study data, accurate risk ratio and risk difference estimates were obtained using the pseudo-Poisson and pseudo-normal linear regression methods. Also, using the auxiliary variable information from the whole cohort, precisions of these estimators were markedly improved. CONCLUSION: The ordinary logistic regression analyses may provide uninterpretable effect measure estimates, and the risk ratio and risk difference estimation methods are effective alternative approaches for case-cohort studies. These methods are especially recommended under situations in which the event rate is not low.

Antiresorptive Drugs and the Risk of Femoral Shaft Fracture in Men and Women With Osteoporosis: A Cohort Study Using the National Database of Health Insurance Claims of Japan.

BACKGROUND: This cohort study aimed to estimate incidence rates of femoral shaft fracture in patients who were treated with antiresorptive drugs. METHODS: We used data from the National Database of Health Insurance Claims of Japan from April 2009 and October 2016. All patients with new use of an antiresorptive drug, prescription-free period of ≥3 months, and no prior femoral fractures were included. Femoral shaft fractures were identified using a validated definition based on International Classification of Diseases, 10th revision (ICD-10) codes. Incidence rate ratios were estimated using Poisson regression, with adjustment for sex, age, and the Charlson Comorbidity Index. RESULTS: We identified 7,958,655 patients (women: 88.4%; age ≥75 years: 51.2%). Femoral shaft fractures were identified in 22,604 patients. Incidence rates per 100,000 person-years were 74.8 for women, 30.1 for men, 30.1 for patients aged ≤64 years, 47.7 for patients aged 65-74 years, and 99.0 for patients aged ≥75 years. Adjusted incidence rate ratios in patients taking versus not taking each type of antiresorptive drug were 1.00 (95% confidence interval [CI], 0.98-1.03) for bisphosphonates, 0.46 (95% CI, 0.44-0.48) for selective estrogen receptor modulators, 0.24 (95% CI, 0.18-0.32) for estrogens, 0.75 (95% CI, 0.71-0.79) for calcitonins, and 0.93 (95% CI, 0.84-1.03) for denosumab. The adjusted incidence rate ratio for alendronate was 1.18 (95% CI, 1.14-1.22). CONCLUSION: The incidence rates of femoral shaft fracture varied across patients treated with different antiresorptive drugs. Further research on a specific antiresorptive drug can increase understanding of the risk of femoral shaft fracture.

Electronic Health Record-Nested Reminders for Serum Lithium Level Monitoring in Patients With Mood Disorder: Randomized Controlled Trial.

BACKGROUND: Clinical guidelines recommend regular serum lithium monitoring every 3 to 6 months. However, in the real world, only a minority of patients receive adequate monitoring. OBJECTIVE: This study aims to examine whether the use of the electronic health record (EHR)-nested reminder system for serum lithium monitoring can help achieve serum lithium concentrations within the therapeutic range for patients on lithium maintenance therapy. METHODS: We conducted an unblinded, single-center, EHR-nested, parallel-group, superiority randomized controlled trial comparing EHR-nested reminders with usual care in adult patients receiving lithium maintenance therapy for mood disorders. The primary outcome was the achievement of therapeutically appropriate serum lithium levels between 0.4 and 1.0 mEq/L at 18 months after enrollment. The key secondary outcomes are included as follows: the number of serum lithium level monitoring except for the first and final monitoring; exacerbation of the mood disorder during the study period, defined by hospitalization, increase in lithium dose, addition of antipsychotic drugs or mood stabilizers, or addition or increase of antidepressants; adherence defined by the proportion of days covered by lithium carbonate prescription during the study period. RESULTS: A total of 111 patients were enrolled in this study. A total of 56 patients were assigned to the reminder group, and 55 patients were assigned to the usual care group. At the follow-up, 38 (69.1%) patients in the reminder group and 33 (60.0%) patients in the usual care group achieved the primary outcome (odds ratio 2.14, 95% CI 0.82-5.58, P=.12). The median number of serum lithium monitoring was 2 in the reminder group and 0 in the usual care group (rate ratio 3.62; 95% CI 2.47-5.29, P<.001). The exacerbation of mood disorders occurred in 17 (31.5%) patients in the reminder group and in 16 (34.8%) patients in the usual care group (odds ratio 0.97, 95% CI 0.42-2.28, P=.95). CONCLUSIONS: We found insufficient evidence for an EHR-nested reminder to increase the achievement of therapeutic serum lithium concentrations. However, the number of monitoring increased with relatively simple and inexpensive intervention. The EHR-based reminders may be useful to improve quality of care for patients on lithium maintenance therapy, and they have potentials to be applied to other problems. TRIAL REGISTRATION: University Hospital Medical Information Network Clinical Trials Registry UMIN000033633; https://tinyurl.com/5n7wtyav.

Machine-learning model derived gene signature predictive of paclitaxel survival benefit in gastric cancer: results from the randomised phase III SAMIT trial.

OBJECTIVE: To date, there are no predictive biomarkers to guide selection of patients with gastric cancer (GC) who benefit from paclitaxel. Stomach cancer Adjuvant Multi-Institutional group Trial (SAMIT) was a 2×2 factorial randomised phase III study in which patients with GC were randomised to Pac-S-1 (paclitaxel +S-1), Pac-UFT (paclitaxel +UFT), S-1 alone or UFT alone after curative surgery. DESIGN: The primary objective of this study was to identify a gene signature that predicts survival benefit from paclitaxel chemotherapy in GC patients. SAMIT GC samples were profiled using a customised 476 gene NanoString panel. A random forest machine-learning model was applied on the NanoString profiles to develop a gene signature. An independent cohort of metastatic patients with GC treated with paclitaxel and ramucirumab (Pac-Ram) served as an external validation cohort. RESULTS: From the SAMIT trial 499 samples were analysed in this study. From the Pac-S-1 training cohort, the random forest model generated a 19-gene signature assigning patients to two groups: Pac-Sensitive and Pac-Resistant. In the Pac-UFT validation cohort, Pac-Sensitive patients exhibited a significant improvement in disease free survival (DFS): 3-year DFS 66% vs 40% (HR 0.44, p=0.0029). There was no survival difference between Pac-Sensitive and Pac-Resistant in the UFT or S-1 alone arms, test of interaction p<0.001. In the external Pac-Ram validation cohort, the signature predicted benefit for Pac-Sensitive (median PFS 147 days vs 112 days, HR 0.48, p=0.022). CONCLUSION: Using machine-learning techniques on one of the largest GC trials (SAMIT), we identify a gene signature representing the first predictive biomarker for paclitaxel benefit. TRIAL REGISTRATION NUMBER: UMIN Clinical Trials Registry: C000000082 (SAMIT); ClinicalTrials.gov identifier, 02628951 (South Korean trial).