Factors Associated With Sacubitril/Valsartan Continuation and the Methods of Combining Heart Failure Medications in Patients With Heart Failure.

BACKGROUND: Sacubitril/valsartan (SV) is recommended for patients with heart failure (HF). In addition, a combination of 4 HF medications, including SV, is recommended in patients with HF with reduced ejection fraction (HFrEF). However, evidence on the characteristics of patients who could continue SV and its initiation methods is limited. OBJECTIVE: To investigate the factors associated with SV continuation and methods of combining HF medications. METHODS: This retrospective cohort study included HF patients who initiated with SV at our institution. The endpoint was SV continuation for 6 months after its initiation. Multivariate analysis was used to extract factors associated with SV continuation. The relationship between the methods of combining HF medications (renin-angiotensin system inhibitors, beta-blockers, mineralocorticoid receptor antagonists, or sodium-glucose cotransporter 2 inhibitors), including the number of HF medications, their combination patterns, and the timing of their initiation, and SV continuation was examined in patients with HFrEF. RESULTS: Of 186 eligible patients, 68.8% had HFrEF, and 79.0% continued SV for 6 months. Significant factors associated with SV continuation were albumin ≥ 3.5 g/dL (odds ratio, 4.81; 95% confidence interval, 2.19-10.59), body mass index (BMI) ≥ 18.5 kg/m2 (4.17; 1.10-15.85), and systolic blood pressure (SBP) ≥ 110 mmHg (2.66; 1.12-6.28). In patients with HFrEF, the proportion of HF medications not initiated simultaneously with SV was significantly higher in the continuation group than in the discontinuation group (67.3% vs 33.3%, P = 0.002). The number of HF medications and their combination patterns were not significantly associated with SV continuation. CONCLUSION AND RELEVANCE: Albumin, BMI, and SBP are useful indicators for selecting patients who are likely to continue SV. In addition, initiating only SV without simultaneously initiating other HF medications in patients with HFrEF may lead to SV continuation.

Anti-vascular endothelial growth factor biosimilars for neovascular age-related macular degeneration.

RATIONALE: Neovascular age-related macular degeneration (AMD) is a progressive eye disease characterized by choroidal neovascularization (CNV) and is a leading cause of vision loss and disability worldwide. Although intravitreal anti-vascular endothelial growth factor (anti-VEGF) therapy is an effective treatment option that helps to prevent vision loss or to improve visual acuity in people with neovascular AMD, treatment imposes a significant financial burden on patients and healthcare systems. A biosimilar is a biological product that has been developed to be nearly identical to a previously approved biological product. The use of biosimilars may help reduce costs and so may increase patient access to effective biologic medicines with similar levels of safety to the drugs on which they are based. OBJECTIVES: To assess the benefits and harms of anti-VEGF biosimilar agents compared with their corresponding anti-VEGF agents (i.e. the reference products) that have obtained regulatory approval for intravitreal injections in people with neovascular AMD. SEARCH METHODS: We searched CENTRAL, MEDLINE, Embase, two other databases, and two trials registries together with reference checking and contact with study authors to identify studies that are included in the review. The latest search date was 2 June 2023. ELIGIBILITY CRITERIA: We included randomized controlled trials (RCTs) that compared approved anti-VEGF biosimilars with their reference products for treating the eyes of adult participants (≥ 50 years) who had an active primary or recurrent choroidal neovascularization lesion secondary to neovascular AMD. OUTCOMES: Our outcomes were: best-corrected visual acuity (BCVA), central subfield thickness (CST), vision-related quality of life, serious ocular and non-ocular adverse events (AE), treatment-emergent adverse events (TEAEs), anti-drug antibodies (ADAs), and serum concentrations of biosimilars and reference drugs. RISK OF BIAS: We assessed the risk of bias (RoB) for seven outcomes reported in a summary of findings table by using the Cochrane RoB 2 tool. SYNTHESIS METHODS: We synthesized results for each outcome using meta-analysis, where possible, by calculating risk ratios (RR) and mean differences (MD) with 95% confidence intervals (CI) for dichotomous outcomes and continuous outcomes, respectively. Where this was not possible due to the nature of the data, we summarized the results narratively. We used GRADE to assess the certainty of evidence for prespecified outcomes. INCLUDED STUDIES: We included nine parallel-group multi-center RCTs that enrolled a total of 3814 participants (3814 participating eyes), with sample sizes that ranged from 160 to 705 participants per study. The mean age of the participants in these studies ranged from 67 to 76 years, and the proportion of women ranged from 26.5% to 58.7%. Ranibizumab (Lucentis) was the reference product in seven studies, and aflibercept (Eyelea) was the reference product in two others. All the included studies had been supported by industry. The follow-up periods ranged from 12 to 52 weeks (median 48 weeks). Five studies (56%) were conducted in multi-country settings across Europe, North America and Asia, two studies in India, and one each in Japan and the Republic of Korea. We judged all the included studies to have met high methodological standards. SYNTHESIS OF RESULTS: With regard to efficacy, our meta-analyses demonstrated that anti-VEGF biosimilars for neovascular AMD resulted in little to no difference compared with the reference products for BCVA change at 8 to 12 weeks (MD -0.55 Early Treatment Diabetic Retinopathy Study (ETDRS) letters, 95% CI -1.17 to 0.07; 8 studies, 3603 participants; high-certainty evidence) and the proportion of participants who lost fewer than 15 letters in BCVA at 24 to 48 weeks (RR 0.99, 95% CI 0.98 to 1.01; 7 studies, 2658 participants; moderate-certainty evidence). Almost all participants (96.6% in the biosimilar group and 97.0% in the reference product group) lost fewer than 15 letters in BCVA. The evidence from two studies suggested that there was no evidence of difference between biosimilars and reference products in vision-related quality of life measured by the 25-item National Eye Institute Visual Function Questionnaire (NEI-VFQ-25) summary scores at 24 to 48 weeks (MD 0.82, 95% CI -0.70 to 2.35; 2 studies, 894 participants; moderate-certainty evidence). With regard to the safety profile, meta-analyses also revealed little to no difference between anti-VEGF biosimilars and the reference products for the proportion of participants who experienced serious ocular AEs (RR 1.24, 95% CI 0.68 to 2.26; 7 studies, 3292 participants; moderate-certainty evidence), and for TEAEs leading to investigational product discontinuation or death (RR 0.96, 95% CI 0.63 to 1.46; 8 studies, 3497 participants; moderate-certainty evidence). Overall, 1.4% of participants in the biosimilar group and 1.2% in the reference product group experienced serious ocular adverse events. The most frequently documented serious ocular AEs were retinal hemorrhage and endophthalmitis. Although the evidence is of low certainty due to imprecision, meta-analysis suggested that anti-VEGF biosimilars led to no difference compared with the reference products for cumulative incidence of ADAs (RR 0.84, 95% CI 0.58 to 1.22; 8 studies, 3066 participants; low-certainty evidence) or mean maximum serum concentrations (MD 0.42 ng/mL, 95% CI -0.22 to 1.05; subgroup of 3 studies, 100 participants; low-certainty evidence). We judged the overall risk of bias to be low for all studies. AUTHORS' CONCLUSIONS: In our review, low to high certainty evidence suggests that there is little to no difference, to date, between the anti-VEGF biosimilars approved for treating neovascular AMD and their reference products in terms of benefits and harms. While anti-VEGF biosimilars may be a viable alternative to reference products, current evidence for their use is based on a limited number of studies - particularly for comparison with aflibercept - with sparse long-term safety data, and infrequent assessment of quality of life outcomes. Our effect estimates and conclusions may be modified once findings have been reported from studies that are currently ongoing, and studies of biosimilar agents that are currently in development. FUNDING: Cochrane Eyes and Vision US Project is supported by grant UG1EY020522, National Eye Institute, National Institutes of Health. Takeshi Hasegawa and Hisashi Noma were supported by Grant-in-Aid for Scientific Research from the Japan Society for the Promotion of Science (Grant numbers: 22H03554, 19K03092, 24K06239). REGISTRATION: Protocol available via doi.org/10.1002/14651858.CD015804.

Efficacy of carbapenems and alternative antimicrobials for treating complicated urinary tract infections caused by third-generation cephalosporin-resistant gram-negative bacteria: A systematic review and meta-analysis of randomised controlled trials.

BACKGROUND: Specific data concerning the efficacy of alternative antibiotics for carbapenems against complicated urinary tract infections (cUTIs) attributed to antimicrobial-resistant (AMR) uropathogens are lacking. OBJECTIVES: This study aimed to assess the efficacy of carbapenems and non-carbapenem antibiotics in the clinical outcomes of cUTIs caused by AMR uropathogens. METHODS: In this systematic review and meta-analysis, databases, including MEDLINE/PubMed, the Cochrane Library, Embase and ClinicalTrials.gov, were searched. The study eligibility criteria were research articles conducted as randomised controlled trials that evaluated the composite outcomes of cUTIs. Participants were adult patients with cUTIs caused by gram-negative uropathogens resistant to third-generation cephalosporins. The intervention involved a non-carbapenem class of antimicrobial agents with in vitro activities against gram-negative uropathogens resistant to third-generation cephalosporins. Two independent researchers assessed the risk-of-bias using the second version of the Cochrane risk-of-bias tool for randomised trials. The treatment effects on each outcome were estimated as a risk ratio (RR) with a 95 % confidence interval (CI) using the random-effects model. Heterogeneity was assessed using the Cochrane Q-test and I2 statistics. RESULTS: Through database searches, 955 articles were retrieved. After screening the titles and abstracts, 52 articles were screened in full text. Finally, 12 studies met the inclusion criteria. No significant differences in efficacy were observed between alternative antibiotics and carbapenems (composite outcome, RR, 0.96; 95 % CI, 0.63-1.49; I2 = 21 %; low certainty of evidence). CONCLUSIONS: Alternative antibiotics had clinical efficacy similar to that of carbapenems for treating patients with cUTI caused by gram-negative uropathogens resistant to third-generation cephalosporins.

Case of nivolumab-induced delayed adrenal insufficiency during the treatment of renal cell carcinoma.

INTRODUCTION: Nivolumab is an immune checkpoint inhibitor used to treat advanced renal cell carcinoma (RCC). Adrenal insufficiency has been reported as an adverse event associated with nivolumab. We report a case of adrenal insufficiency that occurred more than 1 year after the initiation of nivolumab while patient was still receiving treatment. CASE REPORT: The patient was a 90-year-old Japanese woman. Fatigue and decreased cortisol levels were observed after 15 courses of nivolumab. MANAGEMENT & OUTCOME: The symptoms improved with the initiation of oral hydrocortisone 30 mg once a day. Nivolumab was not resumed, and the patient is still under outpatient observation. DISCUSSION: This is the first report of RCC with adrenal insufficiency occurring more than 1 year after the initiation of the nivolumab regimen. Symptoms of adrenal insufficiency are similar to those of cancer progression. When symptoms of fatigue occur in patients receiving nivolumab, adrenal insufficiency should be suspected, regardless of the duration from nivolumab initiation.

Signal of safety due to adverse drug reactions induced by tacrolimus with or without azithromycin.

INTRODUCTION: We identified two reports of drug levels increased and acute kidney injury caused by the drug-drug interaction between azithromycin (AZM) and tacrolimus (TAC). However, it is unclear whether the combination of these two drugs causes additive or synergistic adverse drug reactions. Therefore, we evaluated the disproportionality in reporting drug level increased and acute kidney injury for these two drugs are used alone and in combination with each other. METHOD: Data from the US Food and Drug Administration's Adverse Event Reporting System from 1974 to Q3/2021 were used. Reports based on exposure to macrolide antibiotic alone, TAC alone, and each macrolide antibiotic + TAC were extracted. Proportional reporting ratios (PRRs) and 95% confidence intervals (CIs) were calculated, and a lower limit of the 95% CI (Lower95CI) value of 2.0 or higher was interpreted as a signal of safety. RESULTS: Lower95CIs for macrolide antibiotic alone and TAC showed no potential signals of safety, including drug level increase, acute kidney injury, and control event. The PRRs and 95% CI for drug levels increased were 3.27 (2.69-3.97) for AZM + TAC, and 10.81 (9.59-12.17) for clarithromycin (CAM) + TAC. For CAM + TAC, the PRR and 95% CI were 8.42 (7.51-9.44) in acute kidney injury. However, AZM + TAC was not associated with a signal of safety in acute kidney injury. CONCLUSIONS: This suggests that AZM + TAC has a low risk of causing acute kidney injury but may cause increased drug levels.

Risk Associated with Severe Hematological Toxicity in Patients with Urothelial Cancer Receiving Combination Chemotherapy of Gemcitabine and Cisplatin.

INTRODUCTION: Combination chemotherapy of gemcitabine and cisplatin (GC) is the standard treatment for patients with urothelial cancer (UC). However, hematological toxicity is a major side effect of GC therapy in patients with UC. In particular, discontinuation of the GC therapy is associated to adverse events such as hematological toxicity. Some studies have reported general risk factors of hematological toxicity such as age. However, little is known about risk factors for GC therapy-associated hematological toxicity in patients with UC. OBJECTIVE: We aimed to identify risk factors for hematological toxicity in patients with UC receiving GC therapy. METHODS: We performed a retrospective evaluation of the data of 128 patients with UC who received GC therapy. The study end point was defined as the occurrence of grade 4 neutropenia and grade ≥3 thrombocytopenia. Logistic regression analysis was used to determine risk factors that were significantly associated with neutropenia and thrombocytopenia. RESULTS: In total, 62 (48.4%) patients experienced grade 4 neutropenia, and 27 (21.1%) patients experienced grade ≥3 thrombocytopenia. In the multivariate analysis, performance status (PS) ≥1 (odds ratio [OR] 3.764, 95% confidence interval [CI] 1.410-10.047, p = 0.008) and neutrophil count (OR 0.648, 95% CI 0.468-0.898, p = 0.009) were significantly associated with grade 4 neutropenia. Platelet count (PLT) (OR 0.896, 95% CI 0.832-0.966, p = 0.004) and potassium (K) level (OR 6.966, 95% CI 1.313-36.989, p = 0.023) were also significantly associated with grade ≥3 thrombocytopenia. CONCLUSIONS: PS ≥ 1, neutrophil count, PLT, and K level were important risk factors for GC therapy-induced hematological toxicity in patients with UC. To continue GC therapy, further management systems by hematological toxicity risk factors for patients with UC will be required.

The Association between Fever and Prognosis in Lung Cancer Patients with Bone Metastases Receiving Zoledronic Acid.

Zoledronic acid is an established agent used in the management of metastatic bone disease. The administration of zoledronic acid improves overall survival (OS) of lung cancer patients with bone metastases receiving chemotherapy. However, it is currently unknown whether zoledronic acid-induced fever is associated with OS. The purpose of this study was to examine the association between zoledronic acid-induced fever and prognosis in lung cancer patients with bone metastases. We retrospectively analyzed 98 lung cancer patients with bone metastases who had received zoledronic acid. The end point outcome measure was OS. Multivariate analyses were used to estimate the hazard ratio (HR) for OS due to fever after adjusting for covariates. In multivariate analysis, white blood cell (WBC) count, lactate dehydrogenase (LDH) level, fever, chemotherapy, and hypercalcemia were independent prognostic factors, with HRs of 2.834 for WBC count (<10 × 103/µL vs. ≥10 × 103/µL, p < 0.001), 3.044 for LDH level (<250 vs. ≥250 IU/L, p < 0.001), 0.603 for fever (<37.0 vs. ≥37.0°C, p = 0.039), 0.481 for chemotherapy (chemotherapy not administered vs. administered, p = 0.006), and 2.453 for hypercalcemia (<11.0 vs. ≥11.0 mg/dL, p = 0.001). Zoledronic acid-induced fever was the most important prognostic factor in this cohort of lung cancer patients with bone metastases.

Prognostic Index for Survival in Patients with Advanced Non-Small-Cell Lung Cancer Treated with Third-Generation Agents.

We retrospectively evaluated clinical data from patients with advanced non-small-cell lung cancer (NSCLC) treated with third-generation chemotherapy agents prior to treatment, to determine a reliable method for predicting prognosis in such patients. We analyzed 100 patients who received third-generation agents (paclitaxel, docetaxel, gemcitabine, irinotecan, and vinorelbine) for the treatment of advanced NSCLC. Factors significantly related to prognosis were evaluated using the Cox regression model, and the prognostic index (PI) was determined by combining these factors. The mean follow-up duration was 12.6 months (0.2-67.0 months). Multivariate analysis identified pleural effusion, absolute neutrophil count (ANC), and C-reactive protein (CRP) level as significant factors that independently contribute to prognosis in patients with advanced NSCLC treated with third-generation agents (p < 0.05). The PI was calculated using these 3 factors, according to the following formula: PI = 0.581 × pleural effusion + 0.125 × ANC + 0.105 × CRP. The death rate in the group with the highest PI scores was significantly higher than in the group with the lowest scores (p < 0.001). Pleural effusion, ANC, and CRP level were the most important factors that contributed to prognosis following chemotherapy with third-generation agents in patients with advanced NSCLC. The PI is suggested to be an appropriate index to predict the prognosis of patients with NSCLC.

Scoring system for predicting recurrence after chemoradiotherapy including 5-fluorouracil and platinum for patients with esophageal cancer.

BACKGROUND/AIMS: We have retrospectively evaluated clinical data obtained before therapy to enable reliable prediction of recurrence after chemoradiotherapy (CRT) for esophageal cancer. METHODOLOGY: We analyzed 108 patients who received 5-fluorouracil and platinum combined with 60 Gy radiation. Of the 108 patients, 42 patients with complete response after CRT were selected for this study. The endpoint was recurrence after CRT. Factors significantly related to recurrence were extracted by the multivariate analysis, and a recurrence score was prepared by combining these factors. RESULTS: The median follow-up interval was 18.5 (2-103) months. Recurrent disease was found in 16 (38.1%) patients. In the univariate analysis, recurrence was associated with nutrition status, family history, dysphagia, location, and length of the tumor. In the multivariate analysis, location of the tumor was selected as a significant factor that contributed independently to recurrence after CRT (p < 0.05). The hazard ratios of the five selected factors was approximated and scored. The cumulative probabilities of tumor recurrence were significantly higher in the high score group than in the low score group (47.5% vs. 12.5% at 6 months, p < 0.01). CONCLUSIONS: The recurrence score is suggested to be an appropriate scoring system with which to predict recurrence in patients with esophageal cancer.

A Case of Leg Pain After the Initial Dose of the COVID-19 Vaccine, Followed by Deep Vein Thrombosis and Pulmonary Embolism After the Second Dose.

COVID-19 has been spreading worldwide. Therefore, the COVID-19 vaccine is recommended for prevention. However, adverse events after COVID-19 vaccination remain an issue, and we should monitor patients for adverse events and determine their association with COVID-19 vaccination. Here, we report a case involving a 48-year-old Japanese woman who experienced dull left leg pain that resolved spontaneously after the first vaccine dose, followed by deep vein thrombosis (DVT) and pulmonary embolism (PE) after the second dose. The findings from this case suggest that the COVID-19 vaccine could cause severe adverse events, such as DVT. Therefore, patients should understand their subjective symptoms and report any side effects experienced after the first dose before they take the second dose. Furthermore, medical providers should enquire about all possible symptoms experienced after the initial dose before they administer the second dose.

Factors associated with readmission after long-term administration of tolvaptan in patients with congestive heart failure.

Introduction: We investigated the factors associated with readmission in patients with congestive heart failure (HF) receiving long-term administration of tolvaptan (TLV) to support treatment decisions for HF. Methods: This retrospective cohort study included 181 patients with congestive HF who received long-term administration of TLV. Long-term administration of TLV was defined as the administration of TLV for 60 days or longer. The outcome was a readmission event for worsening HF within 1 year after discharge. Significant factors associated with readmission were selected using multivariate analysis. To compare the time to readmission using significant factors extracted in a multivariate analysis, readmission curves were constructed using the Kaplan-Meier method and analysed using the log-rank test. Results: The median age was 78 years (range, 38-96 years), 117 patients (64.6%) were males, and 77 patients (42.5%) had a hospitalisation history of HF. Readmission for worsening HF within 1 year after long-term TLV treatment occurred in 62 patients (34.3%). In the multivariate analysis, estimated glomerular filtration rate (eGFR) <30 mL/min/1.73 m2 (odds ratio, 3.22; 95% confidence interval, 1.661-6.249; P = 0.001) was an independent significant factor. When eGFR at discharge was divided into two groups (eGFR < 30 vs. eGFR ≥ 30), readmission rates within 1 year were 53.3% vs. 25.4%, respectively (P = 0.001). Conclusion: We revealed that eGFR was strongly associated with readmission in patients with HF who received long-term administration of TLV. Furthermore, we showed that eGFR is an important indicator in guiding treatment of HF in patients receiving TLV.

A case of blood triglyceride increased induced by ABVD therapy for classical Hodgkin lymphoma.

There are no reports of blood triglyceride (TG) levels increasing with the ABVD regimen. Herein, we present a case of Hodgkin's lymphoma that exhibited ABVD-induced blood TG increase. The patient was a 40-year-old Japanese man. Empiric therapy was initiated using the ABVD regimen for Hodgkin lymphoma. On day 58, the fasting blood TG concentration increased to 1,451 mg/dL. Since no adverse events were noted, 0.2 mg/day of pemafibrate was administered, and the ABVD regimen was continued. Blood TG levels should be periodically monitored during ABVD administration for the patients who are at high risk of increased blood TG levels.

Potential Safety Signals for Rhabdomyolysis Associated With High-Potency Statin Use With or Without Sacubitril/Valsartan.

Regarding the drug interactions between sacubitril/valsartan and statins, we identified 3 reports of rhabdomyolysis with high-potency statins. However, it remains unknown whether the combined use of these medications could lead to additive or synergistic effects on rhabdomyolysis. This study aims to assess the disproportionality in reporting rhabdomyolysis for these medications when used alone or in combination. Case reports from the United States Food and Drug Administration's Adverse Event Reporting System from 1991 to Q4/2020 were used. Queries extracted reports based on exposure to statins alone, sacubitril/valsartan alone, and statin+sacubitril/valsartan each. Proportional reporting ratios (PRR) and 95% confidence intervals (CIs) were calculated, where a lower limit of the 95% CI (Lower 95% CI) value of ≥2.0 was interpreted as a safety signal. Lower 95% CIs for statins other than rosuvastatin alone demonstrated no potential safety signals for rhabdomyolysis, death, or the control event. The PRRs and 95% CI for rhabdomyolysis were 2.39 (2.01 to 2.84) with rosuvastatin alone and 2.06 (2.01 to 2.12) for sacubitril/valsartan alone. For atorvastatin+sacubitril/valsartan, the PRR and 95% CI were 0.95 (0.64 to 1.40). Statin+sacubitril/valsartan was not associated with a safety signal. However, rosuvastatin alone and sacubitril/valsartan alone were associated with rhabdomyolysis.

Analysis of the risk factors for myelosuppression after chemoradiotherapy involving 5-fluorouracil and platinum for patients with esophageal cancer.

BACKGROUND/AIMS: Myelosuppression is a serious adverse effect of chemotherapy, but its risk factors remain largely unknown. The present study retrospectively evaluated clinical data obtained before therapy to clarify the risk factors for myelosuppression after chemoradiotherapy in patients with esophageal cancer. METHODOLOGY: One-hundred-and-eight patients who received 5-fluorouracil combined with platinum and 60Gy radiation for esophageal cancer were analyzed. The endpoint of this survey was the occurrence of grade 3 or higher myelosuppression (neutropenia, anemia or thrombocytopenia). Risk factors significantly related to myelosuppression were extracted using logistic regression analysis. RESULTS: Grade 3 or higher neutropenia, anemia or thrombocytopenia occurred in 32.4%, 13.0% and 10.2% of the patients, respectively. According to the multivariate analysis, the risk factors included hoarseness, platelet count and the type of platinum for neutropenia; performance status and hemoglobin for anemia; and performance status, platelet count and serum creatinine concentration for thrombocytopenia (p<0.05). CONCLUSIONS: It was found that performance status, bone marrow function and hoarseness are the most important factors for chemoradiotherapy-induced myelosuppression in esophageal cancer. The prediction of myelosuppression is expected to be useful for the determination of the appropriate therapeutic approach for each patient by a physician.

Comparison of contraceptive failures associated with CYP3A4-inducing drug-drug interactions by route of hormonal contraceptive in an adverse event reporting system.

OBJECTIVE: To estimate associations between contraceptive failures and concomitant CYP3A4-inducing medications by route of administration. STUDY DESIGN: Comparison of unintended pregnancy outcomes within U.S. Food and Drug Administration's Adverse Event Reporting System by couse of CYP3A4-inducing drugs and route of administration for levonorgestrel and etonogestrel/desogestrel. RESULTS: Among 14,504 levonorgestrel case reports, the reporting odds ratio (ROR) was increased for oral (ROR = 4.2 [3.0-5.7]), implants (ROR = 8.0 [5.8-11.0]), but not intrauterine (ROR = 0.9 [0.6-1.3]) levonorgestrel products. For 9348 etonogestrel/desogestrel case reports, oral and vaginal products were not associated with contraceptive failure. Etonogestrel containing implants (ROR = 4.9 [4.1-5.9]) were associated with increased contraceptive failure. CONCLUSION: Levonorgestrel containing combination oral products and implants containing levonorgestrel or etonogestrel were prone to CYP3A4-inducing drug-drug interactions that may increase contraceptive failures. IMPLICATIONS: The progestin components of hormonal contraceptives are susceptible to drug-drug interactions, but this susceptibility is influenced by route of administration. This study provides evidence from an Adverse Event Reporting System that CYP3A4-inducing medications increase the risk of unintended pregnancy for oral and implant contraceptives but not intrauterine or vaginal devices.

The association between cumulative radiation dose and the incidence of severe oral mucositis in head and neck cancers during radiotherapy.

BACKGROUND: Quality of life can be influenced by oral mucositis (OM), and it is necessary to implement OM management strategies before the initiation of radiotherapy (RT) in patients with head and neck cancer (HNC). AIMS: To examine the association between the cumulative radiation dose and the incidence of severe OM in HNC patients receiving RT. METHODS AND RESULTS: A retrospective observational cohort study was conducted in a Showa University Fujigaoka Hospital, in Japan. We retrospectively analyzed 94 patients with HNC who developed OM during RT. We defined OM as a more than grade 2 OM. The cumulative incidence of OM curves of the two categories was estimated using the Kaplan-Meier method and compared using the log-rank test. We estimated the hazard ratio (HR) for OM after the adjustment of factors for covariates using Cox's regression analysis. Patients with smoking history had a significantly later development of OM than those with no smoking history (20 Gy-incidence OM 68.7% vs 39.7%, P = .003). In contrast, patients undergoing concurrent chemotherapy had an earlier development of OM than those undergoing RT alone (20 Gy-incidence OM 24.2% vs 55.7%, P < .001). Multivariate analysis revealed that no smoking history and concurrent chemotherapy were independent predictive factors, with a HR of 0.526 (P = .025) and 2.690 (P < .001), respectively. CONCLUSION: We demonstrated that no smoking history and concurrent chemotherapy may be predictive of OM in HNC patients.

[Risk associated with severe hematological toxicity in patients with advanced or recurrent colonic cancer receiving combination chemotherapy of S-1 and irinotecan hydrochloride].

The aim of this study was to analyze the risk factors for grade 3 to 4 hematological toxicity after primary chemotherapy (Tegafur, gimeracil, oteracil potassium (S-1)/irinotecan hydrochloride (CPT-11)) in 87 (56 male, 31 female; median age 66.1 years) patients with unresectable or recurrent colonic cancer between April 2005 and May 2009, and to prepare a risk classes (low-risk, intermediate-risk or high-risk groups). The rate of grade 3 to 4 hematological toxicity was 16.1%. At multivariate analysis, risk factors for grade 3 to 4 hematological toxicity were baseline WBC, Cr, female (p<0.05). The toxicity index (TI) consisted of risk factors and regression coefficient. We were stratified patients into three groups according to TI that was calculated for each patient. The group with high value was found to include patients with grade 3 to 4 hematological toxicity with a significantly higher frequency than the group with low value (4.2% vs 57.1%, p=0.004). This risk classes could be useful to identify patients at high risk for chemotherapy-induced grade 3 to 4 hematological toxicity.