Dispensing patterns of antidepressant and antianxiety medications for psychiatric disorders after benign hysterectomy in reproductive-age women: Results from group-based trajectory modeling.

BACKGROUND: Women with gynecologic disorders requiring a hysterectomy often have co-existing psychiatric diagnoses. A change in the dispensing pattern of antidepressant (AD) and antianxiety (AA) medications around the time of hysterectomy may be due to improvement in gynecologic symptoms, such as pelvic pain and abnormal bleeding, or the emotional impact of the hysterectomy. Unfortunately, these dispensing patterns before and after hysterectomy are currently undescribed. OBJECTIVES: To model the dispensing patterns of AD and AA medications over time among women with psychiatric disorders before and after benign hysterectomy for endometriosis and uterine fibroids; and to characterize clusters of patients with various dispensing behaviors based on these patterns. DESIGN: Retrospective cohort study. METHODS: This is a study of women who underwent a benign hysterectomy using data from the Merative MarkertScan® Research Databases (Ann Arbor, MI, USA). Inclusion criteria were reproductive-aged women (18-50 years), diagnosis of at least one mood or anxiety disorder, and at least one dispensing of AD or AA medications. We measured monthly adherence and persistence of AD/AA medication use over 12 months after hysterectomy. Group-based-trajectory modeling (GBTM) was used to identify trajectory groups of monthly AD/AA medication dispensing over the study period. Multinomial logistic regression was used to identify factors independently associated with individual dispensing trajectory patterns. RESULTS: For a total of 11,607 patients, 6 dispensing trajectory groups were identified during the study period: continuously high (27.0%), continuously moderate (21.9%), continuously low (17.9%), low-to-high (10.0%), moderate-to-low (9.8%), and low-to-moderate (13.4%). Compared with the continuously high group, younger age, no history of a mood disorder, and uterine fibroids were clinical predictors of low dispensing. The discontinuation rate at 3 months after hysterectomy was higher at 88.6% in the continuously low group and at 66.5% in the continuously low-to-moderate group. CONCLUSIONS: This study demonstrates that GBTM identified six distinct trajectories of AD/AA medication dispensing in the perioperative period. Trajectory models could be used to identify specific dispensing patterns for targeting interventions.

Dispensing patterns of antidepressant and antianxiety medications for psychiatric disorders after benign hysterectomy in reproductive-aged women: Results from the group-based trajectory modelingWomen with gynecologic disorders often have coexisting psychiatric diagnoses. A change in the dispensing pattern of antidepressant and antianxiety medications may be due to improvement in gynecologic symptoms or the emotional impact of the hysterectomy. However, static measures, such as the proportion of days covered or medication possession ratio, may not adequately predict meaningful dispensing patterns. Using the group-based trajectory modeling, 6 distinct patterns of medication dispensing over the perioperative periods of women with benign hysterectomy are identified and therefore used to assess how certain clinical characteristics influence these dispensing patterns. This study concludes that trajectory modeling may be a more appropriate approach to investigating dispensing patterns among women with preexisting psychiatric conditions.

Predictors of new persistent opioid use after benign hysterectomy in the United States.

BACKGROUND: Despite substantial reductions in the past decade, prescription opioids continue to cause widespread morbidity and mortality in the United States. Little is known regarding patterns and predictors of opioid use among women undergoing benign hysterectomy. OBJECTIVE: This study aimed to identify the incidence and predictors of new persistent opioid use after benign hysterectomy among opioid-naïve women from a set of demographic, operative, and opioid prescription characteristics of patients. STUDY DESIGN: In this retrospective cohort study, we identified women undergoing benign hysterectomy from 2011 to 2016 using a validated national insurance claims database (IBM MarketScan Commercial Database). After excluding women with prevalent opioid use (from 365 to 31 days preoperatively), we identified patients who received a perioperative opioid prescription (30 days before to 14 days after hysterectomy) and evaluated them for new persistent opioid use, defined as at least 1 prescription from 15 to 90 days and at least 1 prescription from 91 to 365 days postoperatively. Multivariate logistic regression was used to examine demographic, clinical, operative, and opioid prescription-related factors associated with new persistent use. International Classification of Diseases, Ninth and Tenth Revisions, and Clinical Classification Software codes were used to identify hysterectomies, preoperative pain and psychiatric diagnoses, surgical indications, and surgical complications included as covariates. RESULTS: We identified 114,260 women who underwent benign hysterectomy and were not prevalent opioid users, of which 93,906 (82.2%) received at least 1 perioperative opioid prescription. Of 93,906 women, 4334 (4.6%) developed new persistent opioid use. Logistic regression demonstrated that new persistent use odds is significantly increased by younger age (18-34 years; adjusted odds ratio, 1.97; 95% confidence interval, 1.69-2.30), southern geographic location (adjusted odds ratio, 2.03; 95% confidence interval, 1.79-2.27), preoperative psychiatric and pain disorders (anxiety: adjusted odds ratio, 1.20 [95% confidence interval, 1.09-1.33]; arthritis: adjusted odds ratio, 1.30 [95% confidence interval, 1.21-1.40]), >1 perioperative prescription (adjusted odds ratio, 1.53; 95% confidence interval, 1.24-1.88), mood disorder medication use (adjusted odds ratio, 1.51; 95% confidence interval, 1.40-1.64), tobacco smoking (adjusted odds ratio, 1.65; 95% confidence interval, 1.45-1.89), and surgical complications (adjusted odds ratio, 1.84; 95% confidence interval, 1.69-2.00). Although statistically nonsignificant, total morphine milligram equivalent of ≥300 in the first perioperative prescription increased persistent use likelihood by 9% (95% confidence interval, 1.01-1.17). Dispensing of a first perioperative prescription before the surgery, as opposed to after, increased new persistent use odds by 61% (95% confidence interval, 1.50-1.72). Each additional perioperative day covered by a prescription increased the likelihood of persistent use by 2% (95% confidence interval, 1.02-1.03). In contrast, minimally invasive hysterectomy (laparoscopic: adjusted odds ratio, 0.89 [95% confidence interval, 0.71-0.88]; vaginal: adjusted odds ratio, 0.82 [95% confidence interval, 0.72-0.93]) and a more recent surgery year (2016 vs reference 2011: adjusted odds ratio 0.58; 95% confidence interval, 0.51-0.65) significantly decreased its likelihood. CONCLUSION: New persistent opioid use after hysterectomy was associated with several patient, operative, and opioid prescription-related factors. Considering these factors may be beneficial in counseling patients and shared decision-making about perioperative prescription to decrease the risk of persistent opioid use.

Phase II study of capecitabine and trastuzumab combination chemotherapy in patients with HER2 overexpressing metastatic breast cancers resistant to both anthracyclines and taxanes.

PURPOSE: The purpose of this study was to investigate the activity of capecitabine and trastuzumab in patients with HER2-overexpressing metastatic breast cancer resistant to both anthracyclines and taxanes. METHOD: From June 2003 and May 2006, 40 female patients with measurable or assessable metastatic breast cancer were enrolled and data from 38 patients were reviewed extramurally and analyzed. Patients were treated with weekly trastuzumab given at a dose of 2 mg/kg/day over 90 min (4 mg/kg/day on the first infusion) and capecitabine given at a dose 1,657 mg/m(2)/day during 21 days with a subsequent pause of 7 days. This cycle was repeated every 28 days. The primary endpoint was overall survival and secondary endpoints were progression-free survival and response rate. RESULT: A median of 4.5 cycles (range 1-9 cycles) were delivered. The median age was 53 (range 30-69 years). Median overall survival and progression-free survival was 22.3 and 4.1 months, respectively. Survival rate at 1 and 2 year was 81.6 and 47.4%, respectively. Response rate was 18.4% (95% CI, 7.7-34.3%). All evaluable patients have responded with two CR (5.3%), 5 PR (13.2%), 20 SD (52.6%), 8 PD (21.1%) and 3 NE (7.9%). Regarding the hematological toxicities, grade 1/2/3 neutropenia, grade 1/2 anemia, grade 1 thrombocytopenia and grade 1/2 liver dysfunction were also common. No treatment-related death was reported. CONCLUSION: The combination of capecitabine and trastuzumab is active and well-tolerated in patients with HER2-overexpressing breast caner resistant to both anthracyclines and taxanes.

Safety evaluation of oral fluoropyrimidine S-1 for short- and long-term delivery in advanced gastric cancer: analysis of 3,758 patients.

PURPOSE: To evaluate the comprehensive safety profile of S-1, a promising novel oral fluoropyrimidine derivative, based on large cohort data. PATIENTS AND METHODS: Study subjects were identified from a prospective registry of 3,758 advanced gastric cancer patients in Japan. Each patient was treated with an identical regimen of S-1 monotherapy (40 mg b.i.d. on days 1-28, every 6 weeks) and assessed for all adverse events. RESULTS: The median duration of treatment was 88 days; 1,605 (43%) patients underwent three or more treatment cycles. The relative dose intensity was 0.87 in the first two cycles (short-term treatment period) and 0.89 thereafter (long-term treatment period). Neutropenia was the most common severe (grade 3-4) hematological event (6.3% in the short-term period and 5.3% in the long-term period). Other hematological or key gastrointestinal events (diarrhea, nausea/vomiting, and stomatitis) had a low incidence of severe cases throughout the whole administration period (0.3-3.8%). The time to onset of severe events did not differ between patients with mild renal impairment (creatinine clearance, 50-79 ml/min) and those with normal renal function (>or=80 ml/min) (hazard ratio, 1.04; 95% CI, 0.87-1.23; P = 0.691). CONCLUSIONS: S-1 had manageable severe toxicity and allowed good compliance regardless of treatment duration. Prolonged administration of the drug was sustainable.

Analysis of risk factors for severe adverse effects of oral 5-fluorouracil S-1 in patients with advanced gastric cancer.

BACKGROUND: S-1 is an oral fluoropyrimidine that promises better and accessible treatment. This article identifies the risk factors for severe adverse events of S-1 from nationwide survey data. METHODS: Advanced gastric cancer patients scheduled to receive S-1 monotherapy (80 mg/day for days 1-28, every 6 weeks) were registered throughout Japan between 1999 and 2000 (n = 3758). Univariate and multivariate analyses were performed to explore the risk factors for severe adverse events. RESULTS: A multivariate analysis revealed that grade 3 or 4 neutropenia was significantly associated with baseline renal function [odds ratios (ORs) corresponding to creatinine clearance (ml/min) ranges of 50-79, 30-49, and <30 in reference to >80 increased to 1.21, 1.79, and 2.43, respectively], and the estimated incidence probability of grade 3 or 4 neutropenia ranged from 5.0% to 33.7% depending on the initial status of renal function and baseline neutrophil count. Some prior chemotherapeutic drug use may be implicated in the experience of adverse events; decreases in hemoglobin, nausea/vomiting, and hyperbilirubinemia were observed to be influenced by the previous use of irinotecan (OR = 3.07, P = 0.003), mitomycin (OR = 2.28, P = 0.004), and cisplatin (OR = 1.60, P = 0.007), respectively. CONCLUSION: These findings identified possible risk factors for severe adverse events of S-1 and the patient subgroups at potentially higher risk from its administration. The results will facilitate safer administration of S-1 and thus promote enhanced tolerability and efficacy.

The baseline ratio of neutrophils to lymphocytes is associated with patient prognosis in advanced gastric cancer.

OBJECTIVE: In cancer patients, the balance between neutrophil (N) and lymphocyte (L) cell counts fluctuates with advancing disease. The objective of our study was to determine the prognostic implications of the N/L ratio in the peripheral blood of gastric cancer patients. METHODS: Study participants were identified from a prospective cohort of patients with advanced gastric cancer in Japan (n = 1,220). RESULTS: The median baseline N/L was 2.58 (range, 0.63-12.7). Univariate analysis revealed that patients with an N/L > pr =2.5 (n = 644) had a significantly poorer prognosis than those with an N/L <2.5 (n = 576; log rank test, p = 0.019 x 10(-12)). The median survival times for these two groups were 239 (95% confidence interval, CI, 217-251 days) and 363 days (95% CI, 334-406 days), respectively, while the 1-year survival rates were 30 (95% CI, 26-34%) and 50% (95% CI, 45-54%), respectively. A multivariate Cox model established a significant relationship between the N/L ratio and survival (adjusted hazard ratio = 1.52; 95% CI, 1.32-1.75; p = 0.077 x 10(-8)). CONCLUSIONS: These results suggest that the N/L ratio is an independent prognostic factor in advanced gastric cancer. Measurement of this ratio may serve as a clinically accessible and useful biomarker for patient survival.

Evidence for a p27 tumor suppressive function independent of its role regulating cell proliferation in the prostate.

Reduced p27 levels correlate with poor prognosis in a wide spectrum of human tumors and can accelerate tumorigenesis in mouse tissues. To determine whether p27 deficiency can accelerate tumorigenesis in tissues with inactive Rb and p53 pathways, we examined the effect of p27 status on prostate tumorigenesis in mice expressing simian virus 40 large T antigen (LT). In p27-deficient mice expressing LT, tumors progressed from high-grade prostatic intraepithelial neoplasia to poorly differentiated carcinoma at a greatly accelerated rate. p27 deficiency could not collaborate with a mutant of LT that fails to inactivate the Rb pathway alone. Furthermore, p27 deficiency does not increase the proliferation index, reduce the apoptotic index, or affect the expression of E2F-dependent genes in cells expressing LT at any stage of the disease. Expression of LT alone leads to maximal proliferation, but p27 deficiency still increases the amount of cyclin A and cyclin-dependent kinase 2-associated kinase activity in tissues. Interestingly, this model recapitulates an important feature of the human disease, specifically a high frequency of allelic loss of chromosome 16q, which is syntenic to mouse chromosome 8. Loss of heterozygosity may accelerate the inactivation of other tumor suppressors, such as E-cadherin, which are located in this interval. These experiments provide direct physiological and causal evidence that p27 has tumor suppressive functions independent of its role regulating cell proliferation.