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The Cochrane Database of Systematic... May 2024Endometrial cancer is one of the most common gynaecological cancers in the world. Rates of endometrial cancer are rising, in part because of rising obesity rates.... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Endometrial cancer is one of the most common gynaecological cancers in the world. Rates of endometrial cancer are rising, in part because of rising obesity rates. Endometrial hyperplasia is a precancerous condition in women that can lead to endometrial cancer if left untreated. Endometrial hyperplasia occurs more commonly than endometrial cancer. Progesterone tablets that are currently used to treat women with endometrial hyperplasia are associated with adverse effects in up to 84% of women. A levonorgestrel intrauterine device may improve compliance, but it is invasive, is not acceptable to all women, and is associated with irregular vaginal bleeding in 82% of cases. Therefore, an alternative treatment for women with endometrial hyperplasia is needed. Metformin, a drug that is often used to treat people with diabetes, has been shown, in some human studies, to reverse endometrial hyperplasia. However, the effectiveness and safety of metformin for treatment of endometrial hyperplasia remain uncertain. This is an update of a review first published in 2017.
OBJECTIVES
To determine the effectiveness and safety of metformin in treating women with endometrial hyperplasia.
SEARCH METHODS
We searched the Cochrane Gynaecology and Fertility Specialised Register, CENTRAL, MEDLINE, PubMed, Embase, Google Scholar, OpenGrey, LILACS, and two trials registers from inception to 5 September 2022. We searched the bibliographies of all relevant studies, and contacted experts in the field for any additional trials.
SELECTION CRITERIA
We included randomised controlled trials (RCTs) and cross-over trials comparing metformin (used alone or in combination with other medical therapies) versus placebo, no treatment, any conventional medical treatment, or any other active intervention for women with histologically confirmed endometrial hyperplasia of any type.
DATA COLLECTION AND ANALYSIS
Two review authors independently assessed studies for eligibility, extracted data from included studies, assessed the risk of bias in the included studies, and assessed the certainty of the evidence for each outcome. We resolved disagreements by discussion or by deferring to a third review author. When study details were missing, review authors contacted the study authors. The primary outcome of this review was regression of endometrial hyperplasia histology (with or without atypia) towards normal histology.
MAIN RESULTS
We included seven RCTs, in which a total of 387 women took part. In the comparison, Metformin plus megestrol versus megestrol alone, we rated the certainty of the evidence as low for the outcome, regression of endometrial hyperplasia. We rated the quality of the evidence as very low for the rest of the outcomes, in all three comparisons. Although there was a low risk of selection bias, there was a high risk of bias in the blinding of personnel and outcome assessment (performance bias and detection bias) in many studies. This update identified four new RCTs and six ongoing RCTs. Metformin versus megestrol We are uncertain whether metformin increases the regression of endometrial hyperplasia towards normal histology over megestrol (odds ratio (OR) 4.89, 95% confidence interval (CI) 1.56 to 15.32; P = 0.006; 2 RCTs, 83 participants; I² = 7%; very low-certainty evidence). This evidence suggests that if the rate of regression with megestrol is 61%, the rate of regression with metformin would be between 71% and 96%. It is unresolved whether metformin results in different rates of abnormal uterine bleeding or hysterectomy compared to megestrol. No study in this comparison reported progression of hyperplasia to endometrial cancer, recurrence of endometrial hyperplasia, health-related quality of life, or adverse effects during treatment. Metformin plus megestrol versus megestrol monotherapy The combination of metformin and megestrol may enhance the regression of endometrial hyperplasia towards normal histology more than megestrol alone (OR 3.27, 95% CI 1.65 to 6.51; P = 0.0007; 4 RCTs, 258 participants; I² = 0%, low-certainty evidence). This suggests that if the rate of regression with megestrol monotherapy is 54%, the rate of regression with the addition of metformin would be between 66% and 84%. In one study, 3/8 (37.5%) of participants who took metformin had nausea that settled without further treatment. It is unresolved whether the combination of metformin and megestrol results in different rates of recurrence of endometrial hyperplasia, progression of endometrial hyperplasia to endometrial cancer, or hysterectomy compared to megestrol monotherapy. No study in this comparison reported abnormal uterine bleeding, or health-related quality of life. Metformin plus levonorgestrel (intrauterine system) versus levonorgestrel (intrauterine system) monotherapy We are uncertain whether there is a difference between groups in the regression of endometrial hyperplasia towards normal histology (OR 0.29, 95% CI 0.01 to 7.56; 1 RCT, 46 participants; very low-certainty evidence). This evidence suggests that if the rate of regression with levonorgestrel monotherapy is 96%, the rate of regression with the addition of metformin would be between 73% and 100%. It is unresolved whether the combination of metformin and levonorgestrel results in different rates of abnormal uterine bleeding, hysterectomy, or the development of adverse effects during treatment compared to levonorgestrel monotherapy. No study in this comparison reported recurrence of endometrial hyperplasia, progression of hyperplasia to endometrial cancer, or health-related quality of life.
AUTHORS' CONCLUSIONS
Review authors found insufficient evidence to either support or refute the use of metformin, specifically megestrol acetate, given alone or in combination with standard therapy, for the treatment of women with endometrial hyperplasia. Robustly designed and adequately powered randomised controlled trials, yielding long-term outcome data are still needed to address this clinical question.
Topics: Female; Humans; Endometrial Hyperplasia; Hypoglycemic Agents; Metformin; Randomized Controlled Trials as Topic
PubMed: 38695827
DOI: 10.1002/14651858.CD012214.pub3 -
Frontiers in Endocrinology 2023Due to its high heterogenicity and unclear etiology, there is currently no specific treatment for polycystic ovary syndrome (PCOS). Metformin, as an insulin sensitizer,... (Meta-Analysis)
Meta-Analysis
AIMS
Due to its high heterogenicity and unclear etiology, there is currently no specific treatment for polycystic ovary syndrome (PCOS). Metformin, as an insulin sensitizer, combined with spironolactone, an antiandrogen medication, may exert complementary effects on PCOS. We therefore performed a meta-analysis of trials in which metformin combined with spironolactone was applied to treat PCOS to evaluate the efficacy and safety of the combination therapy.
METHODS
We retrieved the PubMed, Embase, Scopus, Cochrane Library, CNKI, CBM, Wangfang, and VIP databases for literatures published from their inception to December 16, 2022 on the effects of metformin combined with spironolactone in the treatment of PCOS. Inclusion criteria according to P.I.C.O.S criteria were: PCOS patients, metformin combined with spironolactone interventions, metformin alone control group, and randomized controlled trials with the following outcome data: body mass index (BMI), hirsutism score, luteinizing hormone (LH), follicle-stimulating hormone (FSH), total testosterone (TT), fasting blood glucose (FBG), Homeostatic Model Assessment for Insulin Resistance (HOMA-IR), and side effects including nausea, vomiting, diarrhea and drug withdrawal.
RESULTS
Our results revealed that metformin combined with spironolactone significantly reduced BMI and TT, but that it exerted no significant effects on hirsutism score, or on FSH or LH concentrations. Combined treatment also resulted in a significant diminution in FBG and insulin resistance using the HOMA-IR when the interventional time was greater than 6 months. In addition, the combination did not have a higher occurrence of adverse reactions than metformin alone.
CONCLUSION
Compared with metformin alone, metformin combined with spironolactone therapy may be more effective in reducing BMI and serum androgen levels, but the combination showed no significant effect on the hirsutism score or gonadotropin hormone levels, and was not associated with an elevation in side-effects. Moreover, when the treatment course was greater than 6 months, combination therapy reduced FBG and improved insulin resistance more effectively than metformin alone. However, more research is needed to determine the most effective course of treatment.
SYSTEMATIC REVIEW REGISTRATION
https://www.crd.york.ac.uk/PROSPERO/, identifier CRD42022355515.
Topics: Female; Humans; Hirsutism; Insulin Resistance; Polycystic Ovary Syndrome; Spironolactone; Drug-Related Side Effects and Adverse Reactions; Follicle Stimulating Hormone, Human; Luteinizing Hormone
PubMed: 37635987
DOI: 10.3389/fendo.2023.1223768 -
Pediatrics Mar 2021The efficacy and safety of metformin for obesity in children and adolescents remains unclear.
CONTEXT
The efficacy and safety of metformin for obesity in children and adolescents remains unclear.
OBJECTIVE
To assess the efficacy and safety of metformin via systematic review.
DATA SOURCES
Data sources included PubMed, Embase, the Cochrane Library, Scopus, and ClincalTrials.gov (inception to November 2019).
STUDY SELECTION
We selected randomized controlled trials (RCTs) in which researchers assessed the efficacy and safety of metformin with lifestyle interventions, compared with a placebo with lifestyle interventions, in children and adolescents with obesity.
DATA EXTRACTION
Two researchers independently extracted data and assessed quality. The primary outcomes were mean changes from baseline in BMI, BMI score, homeostatic model assessment of insulin resistance, and gastrointestinal adverse effects.
RESULTS
Twenty-four RCTs (1623 patients; range: 16 to 151) were included. Ages ranged from 4 to 19 years, and follow-up ranged from 2 months to 2 years. Metformin resulted in a modest decrease in BMI (range of mean values: -2.70 to 1.30 vs -1.12 to 1.90), BMI score (range of mean values: -0.37 to -0.03 vs -0.22 to 0.15), and homeostatic model assessment of insulin resistance (range of mean values: -3.74 to 1.00 vs -1.40 to 2.66). Metformin resulted in a higher frequency of gastrointestinal adverse effects (range: 2% to 74% vs 0% to 42%).
LIMITATIONS
The available evidence is of varying quality, with high heterogeneity between trials, suggesting some uncertainty in the benefits of metformin in this population.
CONCLUSIONS
With this systematic review of RCTs, we suggest that metformin has modest but favorable effects on weight and insulin resistance and a tolerable safety profile among children and adolescents with obesity.
Topics: Adolescent; Anti-Obesity Agents; Body Mass Index; Child; Child, Preschool; Humans; Hypoglycemic Agents; Insulin Resistance; Life Style; Metformin; Pediatric Obesity; Placebos; Randomized Controlled Trials as Topic; Young Adult
PubMed: 33608415
DOI: 10.1542/peds.2020-1610 -
PloS One 2022Metformin has been suggested to reduce thyroid cancer incidence and to improve thyroid cancer prognosis. We aimed to evaluate the associations between metformin and... (Meta-Analysis)
Meta-Analysis
Metformin has been suggested to reduce thyroid cancer incidence and to improve thyroid cancer prognosis. We aimed to evaluate the associations between metformin and thyroid cancer incidence and prognosis (metastasis/recurrence/progression-free survival). Cochrane Library, PubMed, ClinicalTrials.gov, and U.S. National Library of Medicine Clinical Trials were searched through the end of December 2021. Data were collected from original observational studies or clinical trials on the incidence or prognosis of thyroid carcinoma outcomes in type 2 diabetes mellitus (T2DM) patients with and without metformin use. Risk of bias in non-randomized studies of interventions (ROBINS-I) tool and Grading of Recommendations, and Assessment, Development and Evaluations (GRADE) approach were used to evaluate the risk of bias and quality of the body of evidence, respectively. In general, 4 studies were related to the thyroid cancer incidence, including 1,705,123 participants metformin users and non-users and yielding a total of 3,238 thyroid cancer events; 3 studies reported the prognosis of thyroid carcinoma based on a total of 4,972 individuals with primary thyroid carcinoma and comorbid type 2 diabetes, and the number of thyroid cancer prognosis cases ranged from 3 to 79. The overall risk of bias of the included studies ranged from moderate to serious. In the random-effects model, the summary relative risk (SRR) for thyroid cancer incidence was 0.743 (95% CI: 0.453-1.220; I2 = 88.7%, low certainty) comparing metformin users to non-users; and SRR for the prognosis of thyroid cancer was 0.504 (95% CI: 0.178-1.430; I2 = 57.5%, low certainty). Non-statistically significant negative associations between metformin use and incidence and prognosis of thyroid cancer were found in the current analysis, although the quantity and quality of the evidence were limited. Futher investigation is needed to evaluate the clinical benefits of metformin on thyroid cancer prevention and treatments.
Topics: Diabetes Mellitus, Type 2; Humans; Hypoglycemic Agents; Incidence; Metformin; Thyroid Neoplasms
PubMed: 35901016
DOI: 10.1371/journal.pone.0271038 -
Journal of Drugs in Dermatology : JDD Aug 2023Hidradenitis suppurativa (HS) is an inflammatory skin condition characterized by recurrent abscesses, nodules, and sinus tracts. Hormones are thought to play an...
Hidradenitis suppurativa (HS) is an inflammatory skin condition characterized by recurrent abscesses, nodules, and sinus tracts. Hormones are thought to play an important role in HS pathophysiology, but there is a lack of an updated review on hormonal treatments in HS. Objective: Perform a systematic review of the literature on hormonal treatments in patients with HS. Methods: In April 2022, MEDLINE and EMBASE databases were searched for articles on hormonal treatments in HS. Non-English, duplicate, and irrelevant results were excluded. Data extraction was performed by two reviewers. Results: From 1952 to 2022, 30 articles (634 patients) met the inclusion criteria. Anti-androgen treatments discussed include finasteride (n=8), spironolactone (n=7), cyproterone acetate (CPA) (n=5), flutamide (n=1), leuprolide (n=1), and buserelin acetate (n=1). Metabolic treatments reported include metformin (n=8) and liraglutide (n=2). Three articles on hormonal contraceptives and 2 articles on testosterone were included. Of the articles which reported response rates, 62.8% (27/43) of patients improved with finasteride, 53.3% (32/60) with CPA mono/combination therapy, 50.5% (51/101) with spironolactone, and 46.0% (74/161) with metformin. Improvement in HS was also noted in case reports of patients treated with buserelin acetate, leuprolide, flutamide, and liraglutide. Conclusions: Hormonal treatments for HS, especially finasteride, spironolactone, and metformin, are efficacious and safe; but large-scale randomized controlled trials are needed to determine the patient populations which would benefit from these therapies. Masson R, Shih T, Jeong C, et al. Hormonal treatments in hidradenitis suppurativa: a systematic review. J Drugs Dermatol. 2023;22(8):785-794. doi:10.36849/JDD.7325.
Topics: Humans; Finasteride; Hidradenitis Suppurativa; Flutamide; Spironolactone; Liraglutide; Metformin
PubMed: 37556513
DOI: 10.36849/jdd.7325 -
Journal of Gastroenterology and... May 2017Although it is known that metformin can reduce risk of colorectal cancer, it is unclear whether it protects against colorectal adenoma. (Meta-Analysis)
Meta-Analysis Review
BACKGROUND AND AIM
Although it is known that metformin can reduce risk of colorectal cancer, it is unclear whether it protects against colorectal adenoma.
METHODS
This study conducted a systematic literature search on MEDLINE, EMBASE, and the Cochrane Library using the primary keywords "colorectal," "colon," "rectal," "rectum," "adenoma," "polyp," "neoplasia," "neoplasm," "metformin," and "diabetes." Studies were included if they evaluated the association between metformin use and colorectal adenoma and reported odds ratios (ORs) or provided data from which these could be estimated.
RESULTS
Ten studies and a total of 8726 patients were evaluated. Across all studies, a median of 32.1% (range: 15.2-53.0%) of patients taking metformin also had adenoma; a median of 43.5% (range: 20.5-59.6%) of those not taking metformin had adenoma. In our meta-analysis, metformin use reduced the risk of adenoma (pooled OR = 0.76, 95% confidence interval [CI] = 0.63-0.92, I = 60%). Upon subgroup analyses, metformin use tended to reduce risk of adenoma in a high-risk population consisting of patients with a history of colorectal neoplasia (CRN) (pooled OR = 0.61, 95% CI = 0.34-1.10, I = 79%). In addition, metformin reduced the risk of adenoma in a high-risk population consisting of patients with diabetes mellitus (pooled OR = 0.75, 95% CI = 0.62-0.91, I = 57%).
CONCLUSION
Metformin use seemed to be associated with a reduced risk of colorectal adenoma, especially in high-risk populations consisting of patients with diabetes mellitus or a history of CRN, although statistical power was not achieved in patients with a history of CRN.
Topics: Adenoma; Colorectal Neoplasms; Databases, Bibliographic; Diabetes Complications; Diabetes Mellitus; Humans; Metformin; Odds Ratio; Risk
PubMed: 28449338
DOI: 10.1111/jgh.13639 -
Nutrients Dec 2016The aim of this systematic review is to assess whether metformin could change the concentration of serum homocysteine (Hcy) with and without simultaneous supplementation... (Meta-Analysis)
Meta-Analysis Review
The aim of this systematic review is to assess whether metformin could change the concentration of serum homocysteine (Hcy) with and without simultaneous supplementation of B-group vitamins or folic acid. A literature search was conducted in PubMed, EmBase, and Cochrane Central Register of Controlled Trials (CENTRAL) to identify randomized controlled trials (RCTs) reporting the concentration of serum Hcy in metformin-treated adults. Meta-analysis was applied to assess the association between metformin and the changes of Hcy concentration. Twelve publications were included in this study. In the overall analysis, metformin administration was not statistically associated with the change of Hcy when compared with the control treatment (mean difference (MD), 0.40 μmol/L; 95% confidence interval (CI), -0.07~0.87 μmol/L, = 0.10). In the subgroup analysis, metformin was significantly associated with an increased concentration of Hcy in the absence of exogenous supplementation of folic acid or B-group vitamins (MD, 2.02 μmol/L; 95% CI, 1.37~2.67 μmol/L, < 0.00001), but with a decreased concentration of serum Hcy in the presence of these exogenous supplementations (MD, -0.74 μmol/L; 95% CI, -1.19~-0.30 μmol/L, = 0.001). Therefore, although the overall effect of metformin on the concentration of serum Hcy was neutral, our results suggested that metformin could increase the concentration of Hcy when exogenous B-group vitamins or folic acid supplementation was not given.
Topics: Folic Acid; Homocysteine; Hypoglycemic Agents; Metformin; Vitamin B Complex
PubMed: 27941660
DOI: 10.3390/nu8120798 -
Gynecological Endocrinology : the... Dec 2022Our study aims to compare the effect of metformin, inositol and their combinations on the efficiency in improving outcomes of assisted reproductive technologies in women... (Meta-Analysis)
Meta-Analysis
OBJECTIVE
Our study aims to compare the effect of metformin, inositol and their combinations on the efficiency in improving outcomes of assisted reproductive technologies in women with PCOS.
DATA SOURCES
PubMed, The Cochrane Library, ClinicalTrials.gov, Embase, MEDLINE. The search was performed on studies published before November 14, 2021, to identify articles evaluating the effectiveness of treatment metformin and inositol on ART outcomes.
STUDY SELECTION
The systematic review was conducted according to the PRISMA 2020 checklist and registered in the PROSPERO 2021 CRD42021287887. Randomized controlled trials (RCTs) in English that compared metformin or inositol or metformin + inositol treatment with placebo or no treatment in women with PCOS undergoing assisted reproduction were included. In addition, RCTs with comparison combination and single metformin or inositol treatment were also included.
DATA EXTRACTION AND SYNTHESIS
35 RCTs were included for qualitative analysis reporting on 4668 participants. In group of Metformin treatment were included 1891 patients, in Myo-inositol group - 281, in inositol + metformin group were included 110 participants and in control group (placebo or absence of treatment) - 1865 women with PCOS. 5 meta-analyses were performed. CPR in comparison of metformin and placebo in 1312 patients were higher in metformin group (RR = 1.30, 95% CI: 1.12 to 1.50, = 0.0004). OHSS was less in metformin (RR = 0.34, 95% CI: 0.17 to 0.69, = 0.003). However, LBR were not statistically significant (RR = 1.12, 95% CI: 0.93 to 1.36, = 0.24). In comparison of inositol and no treatment there was also no difference in CPR (RR = 1.37, 95% CI: 0.79 to 2.38, = 0.26). As for metformin and inositol meta-analysis in 220 patients with PCOS, CPR were higher in inositol group (RR = 1.52, 95% CI: 1.05 to 2.18, = 0.03). Combination treatment included only two RCTs and was illegible for meta-analysis.
CONCLUSION
To our knowledge, it is the first meta-analysis that estimates inositol treatment compared to metformin. Based on our systematic review and meta-analysis, metformin seems to be a good option for improving ART outcomes in women with PCOS. However, it is not clear whether inositol usage is adequate. Nevertheless, we need more clinical trials of good quality to answer all questions thoroughly.
Topics: Pregnancy; Female; Humans; Metformin; Hypoglycemic Agents; Inositol; Polycystic Ovary Syndrome; Live Birth
PubMed: 36285403
DOI: 10.1080/09513590.2022.2136160 -
Frontiers in Medicine 2021The coronavirus disease (COVID-19) pandemic is a critical public health issue. Evidence has shown that metformin favorably influences COVID-19 outcomes. This study...
The coronavirus disease (COVID-19) pandemic is a critical public health issue. Evidence has shown that metformin favorably influences COVID-19 outcomes. This study aimed to assess the benefits and risks of metformin in COVID-19 patients. We searched the PubMed, Embase, Cochrane Library, and Chinese Biomedical Literature Database from inception to February 18, 2021. Observational studies assessing the association between metformin use and the outcomes of COVID-19 patients were included. The primary outcome was mortality, and the secondary outcomes included intubation, deterioration, and hospitalization. Random-effects weighted models were used to pool the specific effect sizes. Subgroup analyses were conducted by stratifying the meta-analysis by region, diabetic status, the adoption of multivariate model, age, risk of bias, and timing for adding metformin. We identified 28 studies with 2,910,462 participants. Meta-analysis of 19 studies showed that metformin is associated with 34% lower COVID-19 mortality [odds ratio (OR), 0.66; 95% confidence interval (CI), 0.56-0.78; = 67.9%] and 27% lower hospitalization rate (pooled OR, 0.73; 95% CI, 0.53-1.00; = 16.8%). However, we did not identify any subgroup effects. The meta-analysis did not identify statistically significant association between metformin and intubation and deterioration of COVID-19 (OR, 0.94; 95% CI, 0.77-1.16; = 0.0% for intubation and OR, 2.04; 95% CI, 0.65-6.34; = 79.4% for deterioration of COVID-19), respectively. Metformin use among COVID-19 patients was associated with a reduced risk of mortality and hospitalization. Our findings suggest a relative benefit for metformin use in nursing home and hospitalized COVID-19 patients. However, randomized controlled trials are warranted to confirm the association between metformin use and COVID-19 outcomes. The study was registered on the PROSPERO on Feb 23, 2021 (CRD42021238722).
PubMed: 34490296
DOI: 10.3389/fmed.2021.704666 -
Gynecologic Oncology Oct 2017Endometrial cancer is one of the most common gynecological cancers, which is frequently preceded by atypical endometrial hyperplasia, a premalignant lesion. Metformin,... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Endometrial cancer is one of the most common gynecological cancers, which is frequently preceded by atypical endometrial hyperplasia, a premalignant lesion. Metformin, an antidiabetic drug, has emerged as a new adjunctive strategy for different cancer types, including endometrial cancer. This systematic review and meta-analysis aimed to evaluate the effects of metformin in atypical endometrial hyperplasia and endometrial cancer patients.
METHODS
The search was conducted on January 2017 and the articles were collected in Cochrane, LILACS, PubMed, Scopus and Web of Science. A grey literature search was undertaken using Google SCHOLAR, ProQuest and Open Grey. Nineteen studies were included, which contained information about the following outcomes: reversal of atypical endometrial hyperplasia, cellular proliferation biomarkers expression and overall survival in metformin-users compared to non-users.
RESULTS
Metformin was associated with reversion of atypical endometrial hyperplasia to a normal endometrial, and with decreased cell proliferation biomarkers staining, from 51.94% (CI=36.23% to 67.46%) to 34.47% (CI=18.55% to 52.43%). However, there is a high heterogeneity among studies. Metformin-users endometrial cancer patients had a higher overall survival compared to non-metformin users and non-diabetic patients (HR=0.82; CI: 0.70-0.95; p=0.09, I=40%).
CONCLUSION
Regardless the high heterogeneity of the analyzed studies, the present review suggests that adjunct metformin treatment may assist in the reversal of atypical endometrial hyperplasia to normal endometrial histology, in the reduction of cell proliferation biomarkers implicated in tumor progression, and in the improvement of overall survival in endometrial cancer. Further work on prospective controlled trials designed to address the effects of adjunct metformin on clinical outcomes is necessary for definite conclusions.
Topics: Biomarkers, Tumor; Chemotherapy, Adjuvant; Endometrial Hyperplasia; Endometrial Neoplasms; Endometrium; Female; Humans; Hypoglycemic Agents; Metformin; Prospective Studies
PubMed: 28760367
DOI: 10.1016/j.ygyno.2017.07.120