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ESMO Open Aug 2023Human epidermal growth factor receptor 2 (HER2)-low expression in breast cancer has been recently identified as a new therapeutic target. However, it is unclear if... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Human epidermal growth factor receptor 2 (HER2)-low expression in breast cancer has been recently identified as a new therapeutic target. However, it is unclear if HER2-low status has an independent impact on prognosis.
MATERIALS AND METHODS
A systematic literature research was carried out to identify studies comparing survival outcomes of patients affected by HER2-low versus HER2-zero breast cancer. Using random-effects models, pooled hazard ratios (HRs) and odds ratios (ORs) with 95% confidence intervals (CIs) were calculated for progression-free survival (PFS) and overall survival (OS) in the metastatic setting as well as disease-free survival (DFS), OS and pathological complete response (pCR) in the early setting. Subgroup analyses by hormone receptor (HoR) status were carried out. The study protocol is registered on PROSPERO (n.CRD42023390777).
RESULTS
Among 1916 identified records, 42 studies including 1 797 175 patients were eligible. In the early setting, HER2-low status was associated with significant improved DFS (HR 0.86, 95% CI 0.79-0.92, P < 0.001) and OS (HR 0.90, 95% CI 0.85-0.95, P < 0.001) when compared to HER2-zero status. Improved OS was observed for both HoR-positive and HoR-negative HER2-low populations, while DFS improvement was observed only in the HoR-positive subgroup. HER2-low status was significantly associated with a lower rate of pCR as compared to HER2-zero status both in the overall population (OR 0.74, 95% CI 0.62-0.88, P = 0.001) and in the HoR-positive subgroup (OR 0.77, 95% CI 0.65-0.90, P = 0.001). In the metastatic setting, patients with HER2-low breast cancers showed better OS when compared with those with HER2-zero tumours in the overall population (HR 0.94, 95% CI 0.89-0.98, P = 0.008), regardless of HoR status. No significant PFS differences were found.
CONCLUSIONS
Compared with HER2-zero status, HER2-low status appears to be associated with a slightly increased OS both in the advanced and early settings, regardless of HoR expression. In the early setting, HER2-low tumours seem to be associated to lower pCR rates, especially if HoR-positive.
Topics: Humans; Female; Breast Neoplasms; Prognosis; Disease-Free Survival; Progression-Free Survival; Proportional Hazards Models
PubMed: 37413762
DOI: 10.1016/j.esmoop.2023.101592 -
Endocrine-related Cancer Aug 2023Cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors have shown advantages in hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-)... (Meta-Analysis)
Meta-Analysis
Adjuvant and neoadjuvant therapy with cyclin-dependent kinase 4 and 6 inhibitors in hormone receptor-positive, human epidermal growth factor receptor 2-negative early breast cancer: a systematic review and meta-analysis.
Cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors have shown advantages in hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) advanced breast cancer. This study aimed to evaluate the efficacy and safety of CDK4/6 inhibitors combined with endocrine therapy (ET) in patients with HR+, HER2- early breast cancer. The PubMed, Embase, Cochrane Library, and Web of Science databases were searched for randomized controlled trials (RCTs) related to CDK4/6 inhibitors combined with ET. Literature conforming to the research content was identified according to the inclusion and exclusion criteria. The efficacy endpoints included invasive disease-free survival (IDFS), distant relapse-free survival (DRFS), and overall survival (OS) with adjuvant therapy. The efficacy endpoint of neoadjuvant therapy was complete cell cycle arrest (CCCA). The safety outcomes included the incidence of adverse events (AEs) and grade 3-4 hematological and non-hematological AEs. Data analysis was performed using Review Manager software (version 5.3). A statistical model (fixed-effects model or random-effects model) was selected based on the level of heterogeneity, and a sensitivity analysis was performed if strong heterogeneity existed. Subgroup analyses were performed based on the baseline patient characteristics. Nine articles (including six RCTs) were included in the study. In adjuvant therapy, compared with the control group, CDK4/6 inhibitors combined with ET showed no statistically significant difference in IDFS (hazard ratio = 0.83, 95% confidence interval (CI) = 0.64-1.08, P = 0.17) and DRFS (hazard ratio = 0.83, 95% CI = 0.52-1.31, P = 0.42). In neoadjuvant therapy, CDK4/6 inhibitors combined with ET significantly improved CCCA compared with the control group (odds ratio = 9.00, 95% CI = 5.42-14.96, P < 0.00001). In terms of safety, the combination treatment group had a significantly increased incidence of grade 3-4 hematological AEs in patients, especially grade 3-4 neutropenia (risk ratio (RR) = 63.90, 95% CI = 15.44-264.41, P < 0.00001) and grade 3-4 leukopenia (RR = 85.89, 95% CI = 19.12-385.77, P < 0.00001), with statistically significant differences. In patients with HR+, HER2- early breast cancer, the addition of CDK4/6 inhibitors may prolong IDFS and DRFS in adjuvant therapy, especially in high-risk patients. Further follow-up is needed to establish whether OS can be improved with CDK4/6 inhibitors plus ET. CDK4/6 inhibitors also showed effective anti-tumor proliferation activity in neoadjuvant therapy. Regular monitoring of routine blood tests in patients using CDK4/6 inhibitors is essential.
Topics: Female; Humans; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Cyclin-Dependent Kinase 4; Neoadjuvant Therapy; Neoplasm Recurrence, Local; Receptor, ErbB-2; Protein Kinase Inhibitors
PubMed: 37283514
DOI: 10.1530/ERC-22-0365 -
Biochimica Et Biophysica Acta. Reviews... Nov 2023This study aimed to explore the efficacy and safety of trastuzumab plus tyrosine kinase inhibitors (TKIs) compared with those of trastuzumab monotherapy in patients with... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
This study aimed to explore the efficacy and safety of trastuzumab plus tyrosine kinase inhibitors (TKIs) compared with those of trastuzumab monotherapy in patients with human epidermal growth factor receptor (HER2)-positive breast cancer.
METHODS
The PubMed, Embase, Cochrane, and Web of Science databases were systematically searched for relevant articles from inception until September 2022. The primary outcomes were overall survival (OS) and progression-free survival (PFS). Subgroup analyses were performed based on disease status, TKI type, and hormone receptor status.
RESULTS
Sixteen studies were included in the current analysis. Trastuzumab plus TKI significantly improved OS and PFS compared to trastuzumab monotherapy. In the neoadjuvant setting, trastuzumab plus TKI significantly increased the pathologic complete response (pCR) rate compared to trastuzumab monotherapy. Moreover, a higher objective response rate (ORR) was observed with trastuzumab plus TKI. Patients who received the combination therapy had a higher incidence of discontinuation, all-grade diarrhea, and grade ≥ 3 diarrhea.
CONCLUSIONS
Trastuzumab plus TKI was better than trastuzumab monotherapy for treating different stages of HER2-positive breast cancer. The safety of trastuzumab plus TKI anti-HER2 therapy was controllable. The different efficacies of TKIs combined with trastuzumab may be related to the mechanism of action of the different TKIs, needing further investigations.
Topics: Humans; Female; Trastuzumab; Breast Neoplasms; Tyrosine Kinase Inhibitors; Receptor, ErbB-2; Protein Kinase Inhibitors; Diarrhea
PubMed: 37640146
DOI: 10.1016/j.bbcan.2023.188969 -
Frontiers in Endocrinology 2023To appraise the current randomized clinical trials (RCTs) for evidence of the association of growth hormone (GH) with improved outcomes in infertile women with... (Meta-Analysis)
Meta-Analysis
OBJECTIVE
To appraise the current randomized clinical trials (RCTs) for evidence of the association of growth hormone (GH) with improved outcomes in infertile women with diminished ovarian reserve (DOR) undergoing fertilization (IVF).
METHODS
Relevant RCTs published in Chinese or English were identified through a comprehensive search of nine databases from the period of database inception to April 20, 2023. We included trials investigating adjuvant GH during ovarian stimulation and reported the subsequent outcomes. The group with adjuvant GH treatment and the group without adjuvant GH treatment were set up as the trial and control groups, respectively. The quality of RCTs was measured according to the Cochrane Collaboration Handbook.
RESULTS
Of the 579 studies initially identified, 10 RCTs comprising 852 infertile women with DOR were included. The GH dose of individual trials ranged between 3 and 5 IU/day. Overall, we judged the trials to be at high risk of bias in the blinding domain. Pooled results showed that GH was associated with an increased clinical pregnancy rate (RR = 1.63, 95%CI [1.31, 2.03], < 0.0001) and a greater number of oocytes retrieved (MD = 0.91, 95%CI [0.47, 1.35], < 0.0001). Favorable associations were also observed when ovarian stimulation was combined with GH therapy for improving the optimal embryos rate (RR = 1.84, 95%CI [1.30, 2.59], = 0.0005) and the number of optimal embryos (MD = 0.28, 95%CI [0.08, 0.48], = 0.005) along with reducing the cycle cancellation rate (RR = 0.46, 95%CI [0.24, 0.89], = 0.02). Moreover, GH resulted in an increase in the fertilization rate (RR = 1.33, 95%CI [1.18, 1.50], < 0.00001) and the embryo implantation rate (RR = 1.56, 95%CI [1.21, 2.01], = 0.0006). In addition, there was a significant enhancement in estradiol levels (SMD = 1.18, 95%CI [0.46, 1.91], = 0.001) and endometrial thickness (MD = 0.75, 95%CI [0.41, 1.09], < 0.0001) on the day of hCG. With regard to the total number of days and total dose of gonadotrophins used, GH treatment was correlated with shorter days (MD = -0.26, 95%CI [-0.46, -0.06], = 0.01) and lower dose (MD = -460.97, 95%CI [-617.20, -304.73], < 0.00001) of gonadotrophins applied during ovarian stimulation. Furthermore, GH in conjunction with the GnRH antagonist protocol was more conducive to improving the number of oocytes retrieved when compared with the GnRH agonist protocol ( < 0.0001). Moreover, a notable association was also seen in IVF combined with GH more than or equal to 4.5 IU/day to increase the number of optimal embryos and estradiol levels on the day of hCG ( < 0.05).
CONCLUSION
For infertile women with DOR undergoing IVF, adjuvant treatment with GH during ovarian stimulation protocols showed better clinical outcomes, shorter days and lower dosages of gonadotrophin required. Furthermore, well-designed RCTs are needed to verify our results in the future.
SYSTEMATIC REVIEW REGISTRATION
https://www.crd.york.ac.uk PROSPERO (CRD42023421739).
Topics: Pregnancy; Female; Humans; Growth Hormone; Gonadotropin-Releasing Hormone; Ovarian Reserve; Gonadotropins; Fertilization in Vitro; Infertility, Female; Human Growth Hormone; Ovarian Diseases; Estradiol
PubMed: 38027219
DOI: 10.3389/fendo.2023.1215755 -
Endocrine Journal Oct 2023An association exists between nonalcoholic fatty liver disease (NAFLD) and growth hormone (GH). Patients with growth hormone deficiency (GHD) may be more susceptible to... (Meta-Analysis)
Meta-Analysis
An association exists between nonalcoholic fatty liver disease (NAFLD) and growth hormone (GH). Patients with growth hormone deficiency (GHD) may be more susceptible to NAFLD. The prevalence of NAFLD and nonalcoholic steatohepatitis (NASH) in GHD patients is currently unknown. Multiple databases were searched for experiments related to NAFLD (or NASH) and GHD. Screening, quality evaluation and data extraction were carried out independently by two authors. Analyses used random or fixed effects models, including NAFLD prevalence, NASH prevalence, odds ratio (OR) and 95% confidence interval (CI). We included 10 studies with a total of 782 participants. The results showed that the prevalence of NAFLD in GHD patients was 51% (95% CI: 39-63). The risk of NAFLD in GHD patients was significantly higher than that in controls (age-, sex- or body mass index-matched, without GHD) (pooled OR = 4.27, 95% CI: 1.33-13.68%, p = 0.015). The prevalence of NASH in GHD patients was 18% (95% CI: 5-31). The prevalence of NAFLD in GHD patients is significantly higher than that in the general population, especially NASH. There is a need to develop targeted strategies for the early identification, prevention, or control of NAFLD/NASH in patients with GHD.
Topics: Humans; Non-alcoholic Fatty Liver Disease; Hypopituitarism; Risk Assessment; Growth Hormone; Liver
PubMed: 37468264
DOI: 10.1507/endocrj.EJ23-0157 -
Biomolecules Sep 2023Cyclin-dependent kinase 4 and 6 inhibitors (CDK4/6is) have transformed the treatment of hormone receptor-positive (HR+) and human epidermal growth factor receptor... (Review)
Review
Cyclin-dependent kinase 4 and 6 inhibitors (CDK4/6is) have transformed the treatment of hormone receptor-positive (HR+) and human epidermal growth factor receptor 2-negative (HER2-) breast cancer over the last decade. These inhibitors are currently established as first- and second-line systemic treatment choices for both endocrine-sensitive and -resistant breast cancer populations alongside endocrine therapy (ET) or monotherapy. Data on targeted therapy continue to mature, and the number of publications has been constantly rising. Although these drugs have been demonstrated to prolong overall survival (as well as progression-free survival (PFS) in breast cancer patients), changing the paradigm of all current knowledge, they also cause important adverse events (AEs). This review provides the latest summary and update on the safety profile of the three CDK4/6 inhibitors, as it appears from all major phase II and III randomized clinical trials regarding palbociclib, ribociclib, and abemaciclib, including the most relevant 15 clinical trials.
Topics: Humans; Female; Breast Neoplasms; Progression-Free Survival; Cyclin-Dependent Kinase 4; Clinical Trials, Phase II as Topic
PubMed: 37759823
DOI: 10.3390/biom13091422 -
European Journal of Endocrinology Jan 2024Hypogonadotropic hypogonadism is characterized by inadequate secretion of pituitary gonadotropins, leading to absent, partial, or arrested puberty. In males, classical... (Meta-Analysis)
Meta-Analysis
OBJECTIVE
Hypogonadotropic hypogonadism is characterized by inadequate secretion of pituitary gonadotropins, leading to absent, partial, or arrested puberty. In males, classical treatment with testosterone promotes virilization but not testicular growth or spermatogenesis. To quantify treatment practices and efficacy, we systematically reviewed all studies investigating gonadotropins for the achievement of pubertal outcomes in males with hypogonadotropic hypogonadism.
DESIGN
Systematic review and meta-analysis.
METHODS
A systematic review of Medline, Embase, Global Health, and PsycINFO databases in December 2022. Risk of Bias 2.0/Risk Of Bias In Non-randomized Studies of Interventions/National Heart, Lung, and Blood Institute tools for quality appraisal. Protocol registered on PROSPERO (CRD42022381713).
RESULTS
After screening 3925 abstracts, 103 studies were identified including 5328 patients from 21 countries. The average age of participants was <25 years in 45.6% (n = 47) of studies. Studies utilized human chorionic gonadotropin (hCG) (n = 93, 90.3% of studies), human menopausal gonadotropin (n = 42, 40.8%), follicle-stimulating hormone (FSH) (n = 37, 35.9%), and gonadotropin-releasing hormone (28.2% n = 29). The median reported duration of treatment/follow-up was 18 months (interquartile range 10.5-24 months). Gonadotropins induced significant increases in testicular volume, penile size, and testosterone in over 98% of analyses. Spermatogenesis rates were higher with hCG + FSH (86%, 95% confidence interval [CI] 82%-91%) as compared with hCG alone (40%, 95% CI 25%-56%). However, study heterogeneity and treatment variability were high.
CONCLUSIONS
This systematic review provides convincing evidence of the efficacy of gonadotropins for pubertal induction. However, there remains substantial heterogeneity in treatment choice, dose, duration, and outcomes assessed. Formal guidelines and randomized studies are needed.
Topics: Humans; Male; Chorionic Gonadotropin; Follicle Stimulating Hormone; Gonadotropin-Releasing Hormone; Gonadotropins; Hypogonadism; Klinefelter Syndrome; Spermatogenesis; Testis; Testosterone; Young Adult
PubMed: 38128110
DOI: 10.1093/ejendo/lvad166 -
Pharmaceuticals (Basel, Switzerland) Sep 2023Osteoporosis is a serious implication of Turner syndrome (TS). Common methods for the treatment of TS are growth hormone (GHT) and estrogen replacement therapy (ERT). We... (Review)
Review
Osteoporosis is a serious implication of Turner syndrome (TS). Common methods for the treatment of TS are growth hormone (GHT) and estrogen replacement therapy (ERT). We examined the relationship between the treatment of TS and bone mineral density (BMD) of the lumbar spine. The purpose of our study was to show the currency of BMD states among patients with TS for treatment with GHT and ERT. We searched databases for studies published from inception to April 2023. The articles were related to TS, osteoporosis, ERT, GHT, BMD and treatment patients with TS. We applied the selection criteria: lumbar spine values at L1-L4; dual-energy X-ray absorptiometry (DXA); treatment which was applied: one group of articles: ERT and two group of articles: GHT; results performed as means ± SD. In total, 79 articles were analyzed, of which 20 studies were included and 5 were considered for meta-analysis. The total number of women in the articles selected was 71. Based on the results of the meta-analysis, the effect of ERT on BMD demonstrated a significant increase in BMD (the standardized mean difference in the random model was 0.593 g/cm, 95% CI: 0.0705 to 1.116; = 0.026), which showed that treatment with estrogen particularly increases bone mass during treatment, which contributes to reducing the risk of fractures. The effect of GHT on BMD demonstrated a non-significant decrease in BMD in patients with TS. The results for growth hormone show that this therapy does not improve bone density. However, our review emphasizes the beneficial effect of supplementing growth hormone (GH) on the clinical presentation of TS.
PubMed: 37765128
DOI: 10.3390/ph16091320 -
Human Reproduction Update May 2024The establishment and maintenance of pregnancy depend on endometrial competence. Asherman syndrome (AS) and intrauterine adhesions (IUA), or endometrial atrophy (EA) and...
BACKGROUND
The establishment and maintenance of pregnancy depend on endometrial competence. Asherman syndrome (AS) and intrauterine adhesions (IUA), or endometrial atrophy (EA) and thin endometrium (TE), can either originate autonomously or arise as a result from conditions (i.e. endometritis or congenital hypoplasia), or medical interventions (e.g. surgeries, hormonal therapies, uterine curettage or radiotherapy). Affected patients may present an altered or inadequate endometrial lining that hinders embryo implantation and increases the risk of poor pregnancy outcomes and miscarriage. In humans, AS/IUA and EA/TE are mainly treated with surgeries or pharmacotherapy, however the reported efficacy of these therapeutic approaches remains unclear. Thus, novel regenerative techniques utilizing stem cells, growth factors, or tissue engineering have emerged to improve reproductive outcomes.
OBJECTIVE AND RATIONALE
This review comprehensively summarizes the methodologies and outcomes of emerging biotechnologies (cellular, acellular, and bioengineering approaches) to treat human endometrial pathologies. Regenerative therapies derived from human tissues or blood which were studied in preclinical models (in vitro and in vivo) and clinical trials are discussed.
SEARCH METHODS
A systematic search of full-text articles available in PubMed and Embase was conducted to identify original peer-reviewed studies published in English between January 2000 and September 2023. The search terms included: human, uterus, endometrium, Asherman syndrome, intrauterine adhesions, endometrial atrophy, thin endometrium, endometritis, congenital hypoplasia, curettage, radiotherapy, regenerative therapy, bioengineering, stem cells, vesicles, platelet-rich plasma, biomaterials, microfluidic, bioprinting, organoids, hydrogel, scaffold, sheet, miRNA, sildenafil, nitroglycerine, aspirin, growth hormone, progesterone, and estrogen. Preclinical and clinical studies on cellular, acellular, and bioengineering strategies to repair or regenerate the human endometrium were included. Additional studies were identified through manual searches.
OUTCOMES
From a total of 4366 records identified, 164 studies (3.8%) were included for systematic review. Due to heterogeneity in the study design and measured outcome parameters in both preclinical and clinical studies, the findings were evaluated qualitatively and quantitatively without meta-analysis. Groups using stem cell-based treatments for endometrial pathologies commonly employed mesenchymal stem cells (MSCs) derived from the human bone marrow or umbilical cord. Alternatively, acellular therapies based on platelet-rich plasma (PRP) or extracellular vesicles are gaining popularity. These are accompanied by the emergence of bioengineering strategies based on extracellular matrix (ECM)-derived hydrogels or synthetic biosimilars that sustain local delivery of cells and growth factors, reporting promising results. Combined therapies that target multiple aspects of tissue repair and regeneration remain in preclinical testing but have shown translational value. This review highlights the myriad of therapeutic material sources, administration methods, and carriers that have been tested.
WIDER IMPLICATIONS
Therapies that promote endometrial proliferation, vascular development, and tissue repair may help restore endometrial function and, ultimately, fertility. Based on the existing evidence, cost, accessibility, and availability of the therapies, we propose the development of triple-hit regenerative strategies, potentially combining high-yield MSCs (e.g. from bone marrow or umbilical cord) with acellular treatments (PRP), possibly integrated in ECM hydrogels. Advances in biotechnologies together with insights from preclinical models will pave the way for developing personalized treatment regimens for patients with infertility-causing endometrial disorders such as AS/IUA, EA/TE, and endometritis.
REGISTRATION NUMBER
https://osf.io/th8yf/.
PubMed: 38796750
DOI: 10.1093/humupd/dmae013 -
Endocrine Mar 2024Growth hormone deficiency (GHD) is the most common pituitary hormone deficiency and is one of the main causes of short stature in children and adolescents. The aim of... (Review)
Review
OBJECTIVE
Growth hormone deficiency (GHD) is the most common pituitary hormone deficiency and is one of the main causes of short stature in children and adolescents. The aim of this study is to evaluate the epidemiology of pediatric GHD worldwide, since no other systematic review has been published so far.
METHODS
We searched PubMed, Embase, and Web of Science up to July 2023 to find epidemiological studies involving children with GHD. Two review authors independently screened articles, extracted data and performed the quality assessment.
RESULTS
We selected 9 epidemiological studies published from 1974 to 2022. The range of prevalence was 1/1107-1/8,646. A study based on a registry of GH users in the Piedmont region (Italy) reported the highest mean prevalence. In the included studies, the mean incidence ranged from 1/28,800 to 1/46,700 cases per year. One study reported a 20-year cumulative incidence of 127/100,000 for boys and 93/100,000 for girls. Studies were heterogeneous in terms of population (age and GHD etiology) and diagnostic criteria. As for the methodological quality of included studies, all but one study satisfied the majority of the checklist items.
CONCLUSIONS
The included studies are mostly European, so the provided estimates cannot be considered global. International multicentre studies are needed to compare epidemiological estimates of GHD among different ethnical groups. Considering the considerable cost of human recombinant GH, the only available therapy to treat GHD, understanding accurate epidemiological estimates of GHD in each country is fundamental for resource allocation.
PubMed: 38498128
DOI: 10.1007/s12020-024-03778-4