Metformin in the management of fibrocystic breast disease: a placebo-controlled randomized clinical trial.

BACKGROUND AND PURPOSE: Fibrocystic disease (FCD) of the breast as a very common health problem in women has estrogen-dependent and proliferative features. No effective management strategy has been validated for this disorder, so far. The anti-hyperglycemic agent metformin has both anti-proliferative and estrogen-suppressing effects. Thus, we investigated metformin as a management strategy for FCD. METHODS: The study was a double-blind placebo-controlled randomized clinical trial. Premenopausal women with FCD according to history, physical exam and ultrasound, who had measurable microcyst clusters on ultrasound (US) were entered the study. Oral placebo and metformin tablets (500 mg) were used twice daily by participants in the intervention and control groups. Size and number of microcyst clusters on US and the subjective pain score were recorded before and after the intervention. RESULTS: 154 participants were randomly allocated into two groups of 77 interventions and 77 controls. The decrease in size of the largest microcyst cluster in each patient and the mean decrease in number of microcyst clusters were not statistically significant (P = 0.310 and P = 0.637, respectively). However, those microcyst clusters which were ≥ 14 mm became significantly smaller after metformin use (P = 0.006). Additionally, in the subset of participants with pain at baseline, a larger proportion in the intervention group experienced at least 50% reduction in pain score (63.8% (30/47) in the intervention vs. 44.2% (19/43) in the placebo groups, P = 0.031). CONCLUSION: Our study showed that metformin might be effective in the management of FCD. Further studies are proposed for confirmation of this subject.

A Randomized Multicenter Phase II Study of Docosahexaenoic Acid in Patients with a History of Breast Cancer, Premalignant Lesions, or Benign Breast Disease.

Obesity, a cause of subclinical inflammation, is a risk factor for the development of postmenopausal breast cancer and is associated with poorer cancer outcomes. Docosahexaenoic acid (DHA), an omega-3 fatty acid, possesses anti-inflammatory properties. We hypothesized that treatment with DHA would reduce the expression of proinflammatory genes and aromatase, the rate-limiting enzyme for estrogen biosynthesis, in benign breast tissue of overweight/obese women. A randomized, placebo-controlled, double-blind phase II study of DHA given for 12 weeks to overweight/obese women with a history of stage I-III breast cancer, DCIS/LCIS, Paget's disease, or proliferative benign breast disease was carried out. In this placebo controlled trial, the primary objective was to determine whether DHA (1,000 mg by mouth twice daily) reduced breast tissue levels of TNFα. Secondary objectives included evaluation of the effect of DHA on breast tissue levels of COX-2, IL1ß, aromatase, white adipose tissue inflammation, and gene expression by RNA-seq. Red blood cell fatty acid levels were measured to assess compliance. From July 2013 to November 2015, 64 participants were randomized and treated on trial (32 women per arm). Increased levels of omega-3 fatty acids in red blood cells were detected following treatment with DHA (P < 0.001) but not placebo. Treatment with DHA did not alter levels of TNFα (P = 0.71), or other biomarkers including the transcriptome in breast samples. Treatment with DHA was overall well-tolerated. Although compliance was confirmed, we did not observe changes in the levels of prespecified biomarkers in the breast after treatment with DHA when compared with placebo. Cancer Prev Res; 11(4); 203-14. ©2018 AACRSee related editorial by Fabian and Kimler, p. 187.

Metabolic Response to Omega-3 Fatty Acids and Vitamin E Co-Supplementation in Patients with Fibrocystic Breast Disease: A Randomized, Double-Blind, Placebo-Controlled Trial.

BACKGROUND: There is scarce data on the effects of omega-3 fatty acids and vitamin E co-supplementation on metabolic status in patients with fibrocystic breast disease (FBD). The current study was carried out to determine the effects of omega-3 fatty acids and vitamin E co-supplementation on metabolic status in patients with FBD. METHODS: A randomized clinical trial was conducted on 56 patients with FBD. Participants were randomly divided into two groups to receive either 1000 mg omega-3 fatty acids plus 400 mg vitamin E (n = 28) or placebo (n = 28) for 12 weeks. Fasting blood samples were taken at the beginning of the study and after 12 weeks of intervention to determine inflammatory factors, biomarkers of oxidative stress, and metabolic profiles. RESULTS: After 12 weeks of intervention, changes in serum high-sensitivity C-reactive protein (-2171.4 ± 3189.1 vs. +696.9 ± 2774.8 ng/mL, P = 0.001) and plasma nitric oxide (+1.8 ± 4.0 vs. -0.1 ± 2.4 µmol/L, P = 0.04) in supplemented women were significantly different from those in the placebo group. In addition, compared to the placebo group, subjects who consumed omega-3 fatty acids plus vitamin E supplements had significantly decreased serum insulin concentrations (-3.2 ± 6.5 vs. -0.2 ± 1.7 µIU/mL, P = 0.01), the homeostasis model of assessment-estimated insulin resistance (-0.8 ± 1.7 vs. -0.02 ± 0.4, P = 0.03), serum triglycerides levels (-11.5 ± 47.3 vs. +10.6 ± 24.3 mg/dL, P = 0.03) and VLDL-cholesterol (-2.3 ± 9.5 vs. +2.1 ± 4.9 mg/dL, P = 0.03), as well as increased quantitative insulin sensitivity check index (+0.01 ± 0.01 vs. +0.001 ± 0.007, P = 0.001) and HDL-cholesterol (+3.4 ± 6.0 vs. -1.3 ± 4.3 mg/dL, P = 0.001). CONCLUSION: Overall, omega-3 fatty acids and vitamin E co-supplementation for 12 weeks had beneficial effects on inflammatory markers and metabolic profiles in patients with FBD.

The evaluation of the effect of metformin on breast fibrocystic disease.

BACKGROUND: Fibrocystic changes (FCC) is the most common benign breast disease. The main pathophysiologic mechanism of FCC, excessive cell proliferation in response to monthly estrogen and progesterone changes. Regarding to antiproliferative of metformin, the aim of this study is the evaluation of the effect of metformin on FCC in women who were referred to gynecology clinics of ArakMETHODS:This study is a double blind placebo control randomized clinical trial. At the first among women who were referred to gynecology of Arak, 186 women with FCC between 18-40 years were selected. The women were randomly classified into three groups. The first group took metformin and the second group as placebo group took vitamin E and the third group did not take any drug during six months. All groups were compared in clinical symptoms based on visual analogue scale (VAS) and the sonographic data also were recorded and compared. Data analysis was performed by unilateral variance, student t and Chi-square. RESULTS: The three groups were not different in aspect of mean of the cysts number, cyst size, tenderness and discharge from breast before the intervention, but after the intervention, there was a significant decrease in metformin group (p value < 0.001) based on variance analysis test. There was not a meaningful difference of pain and the location of cysts between the groups after the intervention. CONCLUSIONS: The present study showed that metformin is effective in treatment of FCC and decreasing of clinical symptoms and imaging items.

Danazol alters mitochondria metabolism of fibrocystic breast Mcf10A cells.

Fibrocystic Breast Disease (FBD) or Fibrocystic change (FC) affects about 60% of women at some time during their life. Although usually benign, it is often associated with pain and tenderness (mastalgia). The synthetic steroid danazol has been shown to be effective in reducing the pain associated with FBD, but the cellular and molecular mechanisms for its action have not been elucidated. We investigated the hypothesis that danazol acts by affecting energy metabolism. Effects of danazol on Mcf10A cells homeostasis, including mechanisms of oxidative phosphorylation, cytosolic calcium signaling and oxidative stress, were assessed by high-resolution respirometry and flow cytometry. In addition to fast physiological responses the associated genomic modulations were evaluated by Affimetrix microarray analysis. The alterations of mitochondria membrane potential and respiratory activity, downregulation of energy metabolism transcripts result in suppression of energy homeostasis and arrest of Mcf10A cells growth. The data obtained in this study impacts the recognition of direct control of mitochondria by cellular mechanisms associated with altered energy metabolism genes governing the breast tissue susceptibility and response to medication by danazol.

COMPARISONS BETWEEN THE NON-PROLIFERATIVE AND PROLIFERATIVE THERAPY IN FIBROCYSTIC MASTOSIS.

AIM: Fibrocystic mastosis (FCM) is the most frequent benign breast lesion. Most treatments for fibrocystic mastosis are: hormonl, with beneficial results and non-hormonal, with fluctuating results. MATERIAL AND METHODS: A number of 210 cases were studied, which were divided into 7 groups. The study lasted for 9 months and it was carried out on the basis of a personal examination sheet. The following were monitored: age groups, mastodynia, reducing breast nodules, a significant reduction in the volume of the mastosic cysts, reducion of the fibrous tissue, medication tolerance. RESULTS: Mastodynia has declined by 90% in the cases treated with Tamoxifen and Danazol, by 70% in the case of Lynestrenol and Bromocriptine, by 50% in the 15 patients who were given Utrogestan. Knowing the advantages and disadvantages of drugs (contraindications, side effects), age category, breast pain reduction, antiproliferative activity, tolerability, relapse allow us to assess the benefit-risk. Even in those circumstances that remained incompletely clarified for objective reasons, related to the inaccurate/incorrect reporting by the patients, there is a significant difference (p < 0.05) between the frequency of relapses following the treatment with Tamoxifen and the other categories of drugs who were administered. CONCLUSIONS: Our study shows that in the groups that were administered Logest, Utrogestan and Bromocriptine, only antalgic effects were achieved (disappearance or only decrease of mastodynia) and no anti-proliferative effects were obtained. Basically, hormone treatment should be made based on a histopathological examination.

IgG4-related sclerosing disease of the breast successfully treated by steroid therapy.

IgG4-related sclerosing disease was first identified and defined in the twenty-first century. In this pathology, the serum IgG4 level increases and IgG4-positive plasma cells and lymphocytes infiltrate organs such as the pancreas, salivary glands, lacrimal glands, kidneys, and the retroperitoneum. Presented in this report is a case of IgG4-related sclerosing disease that occurred in the breast and was treated successfully with steroid therapy. A 51-year-old woman presented with bilaterally swollen eyelids and an elevated serum IgG4 concentration. Screening CT revealed a lesion in her right breast but no other lesions. Mammography, ultrasonography, and MRI could not rule out malignancy, so a core needle biopsy was performed. Histologically, the lesion was composed of papilloma with fibrosis, adenosis, and severe lymphoplasmacytic infiltration. No malignant features were observed. Many plasma cells within the lesion were immunohistochemically positive for IgG4. IgG4-related sclerosing disease of the breast was diagnosed, and steroid therapy was initiated. During 4 weeks of steroid treatment the lesion became smaller in size, and at 7-months follow-up the lesion showed no new growth. Since steroid therapy is effective for this disease, IgG4-related sclerosing disease should be considered in the differential diagnosis of breast lesions in order to avoid unnecessary surgery.

[Clinical comparision of alpha dihydroergocryptine against cabergoline in the treatment of the fibrocystic mastopathy]. / Comparación clínica de alfa dihidroergocriptina contra cabergolina en el tratamiento de la mastopatía fibroquística.

BACKGROUND: Fibrocystic breast disease is one of the most frequent conditions of the breast among women from 30 to 49 years, with a frequency of about 60%, hence the interest in studying and treating it with the most advanced and effective resources. OBJECTIVE: To compare the efficacy and adverse events of alpha dihydroergocryptine with cabergoline in patients with fibrocystic breast disease. MATERIAL AND METHODS: A prospective, longitudinal, open, comparative study between alpha-dihydroergocryptine and cabergoline, made in the service of Gynecology and Obstetrics at the Dr. Miguel Silva General Hospital in Morelia, Michoacán. 171 patients diagnosed with fibrocystic breast disease were randomly assigned to the alpha-dihydroergocryptine or the cabergoline group. Assessments were made at baseline and every month subsequently. The following symptoms were evaluated: breast tenderness, breast pain, lumps and nipple discharge. The concentrations of prolactin were determined and an ultrasound was performed at baseline and at 3 and 6 months, patients were questioned about adverse events. RESULTS: 171 patients were included (81treated with alpha-dihydroergocryptine and 90 with cabergoline); 156 completed the study. The age limits were 18 and 51 years. The evolution time prior to study entry was 17.71 +/- 18.3 months for the alpha-dihydroergocryptine group and 18.57 +/- 20.35 for the cabergoline group. 15 patients discontinued treatment due to adverse events (8 of the alpha-dihydroergocryptine group and 7 of the cabergoline group). The most common adverse event was headache. CONCLUSIONS: In this study alpha-dihydroergocryptine was better tolerated and had better clinical response compared with cabergoline; breast pain and breast tenderness disappeared within the first month of treatment. Adverse events were similar for both treatments.

[Invasive carcinoma arising in breast microglandular adenosis: a clinicopathologic study of three cases and review of the literature].

OBJECTIVE: To study the clinicopathologic features, immunophenotypes and differential diagnoses of invasive carcinoma arising in breast microglandular adenosis (MGACA). METHODS: Clinical and pathologic findings of 3 cases of MGACA were analyzed by histomorphology and immunohistochemical staining of CK7, S-100 protein, ER, PR, HER2, SMA, MSA, p63 and PAS. Literatures were reviewed. RESULTS: (1) Histologically, 3 tumors all showed a spectrum of glandular proliferations ranging from microglandular adenosis (MGA) to atypical microglandular adenosis (AMGA) to in situ carcinoma (DCIS) to invasive carcinoma. The invasive carcinoma component was ductal in case 1, and matrix-producing in case 2 and case 3. (2) All epithelial cells in MGA, AMGA, DCIS and MGACA were positive for CK7 and S-100 protein, but were negative for ER and HER2. PR was negative in case 1 and case 2 but was low positive in case 3. Myoepithelial cell differentiation was not demonstrated in MGA, AMGA, DCIS and MGACA by immunohistochemical staining for SMA, MSA or p63. PAS staining showed the presence of basement membrane in MGA, AMGA and DCIS, except MGACA. CONCLUSIONS: MGACA is an extremely rare tumor of the breast and has distinct morphological and immunohistochemical features. Further studies are needed to evaluate the clinical behavior of this rare neoplasm.

Dienogest and the breast.

In a clinical pilot study, 21 women with endometriosis have been primarely treated with dienogest 2 x 10 mg daily p.o. for 24 weeks. Besides the effect on endometriosis the action of such high-dose progestogen treatment on the breast was evaluated by breast ultrasound prior to medication and at 24 weeks of medical treatment. In all women, a significant size reduction of the mammary gland (p < 0.023) and regression of mastopathic changes were observed. There was a non-significant reduction (p = 0.089) of the maximum diameter of the ducts. The portion of the fatty tissue increased slightly, but not significantly (p = 0.348).

Tratamiento de la displasia mamaria atípica con tamoxifeno como profilaxis del cáncer de mama en Santiago de Cuba / Treatment of the atypical mammary dysplasia with tamoxifeno as prophylaxis of breast cancer in Santiago de Cuba

Se realizó un estudio retrospectivo de 7 años (2001 – 2007) en la consulta especializada de mastología del Hospital Provincial Docente Saturnino Lora Torres de Santiago de Cuba, radicada en el Policlínico de Especialidades perteneciente a dicha institución. Se obtuvieron los datos clínicos de 164 pacientes con displasia mamaria de diferentes grados y alta predisposición a padecer cáncer, las cuales eran tratadas y consultadas bimensualmente por cirujanos, quienes concluyeron que el control hormonal y el examen periódico de las mujeres afectadas, mejoraron el pronóstico e incrementaron los índices de curación.

A 7 year-old retrospective study (2001 - 2007) was carried out in the breast specialized department from Saturnino Lora Torres Teaching Provincial Hospital from Santiago de Cuba, sited in the Specialties Polyclinic belonging to this institution. The clinical data of 164 patients with mammary dysplasia of different grades and high predisposition to suffer from cancer, who were treated and examined every two months by surgeons were obtained. They concluded that the hormonal control and the periodic examination of the affected women, improved the prognosis and increased the cure rates.

Tratamiento de la displasia mamaria atípica con tamoxifeno como profilaxis del cáncer de mama en Santiago de Cuba / Treatment of the atypical mammary dysplasia with tamoxifeno as prophylaxis of breast cancer in Santiago de Cuba

Se realizó un estudio retrospectivo de 7 años (2001 2007) en la consulta especializada de mastología del Hospital Provincial Docente Saturnino Lora Torres de Santiago de Cuba, radicada en el Policlínico de Especialidades perteneciente a dicha institución. Se obtuvieron los datos clínicos de 164 pacientes con displasia mamaria de diferentes grados y alta predisposición a padecer cáncer, las cuales eran tratadas y consultadas bimensualmente por cirujanos, quienes concluyeron que el control hormonal y el examen periódico de las mujeres afectadas, mejoraron el pronóstico e incrementaron los índices de curación(AU)

A 7 year-old retrospective study (2001 - 2007) was carried out in the breast specialized department from Saturnino Lora Torres Teaching Provincial Hospital from Santiago de Cuba, sited in the Specialties Polyclinic belonging to this institution. The clinical data of 164 patients with mammary dysplasia of different grades and high predisposition to suffer from cancer, who were treated and examined every two months by surgeons were obtained. They concluded that the hormonal control and the periodic examination of the affected women, improved the prognosis and increased the cure rates(AU)

Importancia de la información en el control de los síntomas de la displasia mamaria / Importance of information in the control of the symptoms of breast dysplasia

La displasia mamaria es un problema de salud de gran repercusión social, por el estrés y la ansiedad que suelen acompañarla. El presente trabajo tuvo el objetivo de valorar diferentes variantes de conducta ante esta afección.. La información médica es una opción que puede utilizarse en más del 70 por ciento de las mujeres que presentan displasia mamaria (enfermedad fibroquística). Tiene la ventaja de que los resultados son más duraderos que los del tratamiento médico, y de que disminuye el consumo innecesario de medicamentos. El tratamiento quirúrgico de la enfermedad fibroquística está solo justificado ante la duda de cáncer y en lesiones que no se modifican ni duelen durante el ciclo menstrual, sobre todo en el caso de mujeres mayores de 35 años(AU)

Breast dysplasia is a health problem of great social impact due to the stress and anxiety accompanying it. The present paper was aimed at assessing different variants of behavior before this affection.Medical information is an option that may be used in more than 70 per cent of females with breast dysplasia (fibrocystic disease). Some of its advantages are that the results last more than those of medical treatment and that it reduces the unnecessary administration of drugs. The surgical treatment of the fibrocystic disease is only justified when cancer is suspected and in lesions that neither modify nor hurt during the menstrual cycle, mainly in females over 35(AU)

Suppressive therapy after surgical treatment of thyroid gland cancer in patients with mastopathy.

State of lactation system during oncological disorders of thyroid gland is one of the poorly studied topics of modern medicine. Controversy in clinical and experimental data creates the need of performing studies in this direction. The goal of this study is to investigate determining pathogenic mechanisms of thyroid and lactation systems. Realization of the study results will enable development of guidelines for prophylaxis, diagnosis and treatment of mammary gland cancer in patients with thyroid gland malignancy. For this purpose we investigated patients with different types of malignant cancer of thyroid gland (after surgery), who had diffuse fibrocystic mastopathy as a concomitant disorder. Patients underwent conservative therapy only with thyroid agents. We observed patients for 6 months since the beginning of the treatment. During this period patients' condition was evaluated several times using examinations involved in the study. Summarization of study results demonstrated that suppressive therapy might prevent precancerous diseases of mammary gland.

Terapia neural como tratamiento contra el dolor en la displasia mamaria cíclica de grado II / Neural therapy as pain-relief treatment in grade III cyclic breast dysplasia

De enero a diciembre de 2004 se realizó un estudio experimental del tipo ensayo clínico de fase II, controlado y monocéntrico, cuyo objetivo fue evaluar la eficacia de la terapia neural en el tratamiento del dolor como manifestación de la displasia mamaria cíclica de grado II en comparación con la terapéutica convencional. Se estudiaron 240 pacientes, que fueron divididos en 4 grupos según el tipo de tratamiento: con terapia neural (grupo I), con vitamina E (grupo II), con progesterona (grupo III) y con antiinflamatorios no esteroideos (grupo IV). Se observó mejoría del dolor en más de 60 por ciento del grupo I y fue similar con el uso de la progesterona. Con los antiinflamatorios no esteroideos y la vitamina E hubo diferencias significativas. Se obtuvieron resultados satisfactorios con el empleo de la terapia neural con procaína al 1 por ciento, por lo que pudimos considerarla eficaz en la terapéutica de esta manifestación(AU)

A controlled monocentered experimental study of phase II clinical assay type was carried out from January to December, 2004 to evaluate the effectiveness of neural therapy in treating pain as manifestation of grade II cyclic breast dysplasia in comparison to the conventional therapy. Two hundred and forty patients were studied. They were divided into 4 groups according to the type of treatment: neural therapy (group I); vitamin E (group II); progesterone (group III); and non-steroidal anti-inflammatory drugs (group IV). Pain relief was observed in over 60 per cent of patients in group I, a result similar to that of group III (progesterone). There were significant differences in groups treated with non-steroidal anti-inflammatory drugs and Vitamin E. The use of neural therapy based on 1per cent procaine yielded satisfactory results, so we considered it as an effective therapy for pain relief in grade II breast dysplasia(AU)

Terapia neural como tratamiento contra el dolor en la displasia mamaria cíclica de grado II / Neural therapy as pain-relief treatment in grade III cyclic breast dysplasia

De enero a diciembre de 2004 se realizó un estudio experimental del tipo ensayo clínico de fase II, controlado y monocéntrico, cuyo objetivo fue evaluar la eficacia de la terapia neural en el tratamiento del dolor como manifestación de la displasia mamaria cíclica de grado II en comparación con la terapéutica convencional. Se estudiaron 240 pacientes, que fueron divididos en 4 grupos según el tipo de tratamiento: con terapia neural (grupo I), con vitamina E (grupo II), con progesterona (grupo III) y con antiinflamatorios no esteroideos (grupo IV). Se observó mejoría del dolor en más de 60 por ciento del grupo I y fue similar con el uso de la progesterona. Con los antiinflamatorios no esteroideos y la vitamina E hubo diferencias significativas. Se obtuvieron resultados satisfactorios con el empleo de la terapia neural con procaína al 1 por ciento, por lo que pudimos considerarla eficaz en la terapéutica de esta manifestación(AU)

A controlled monocentered experimental study of phase II clinical assay type was carried out from January to December, 2004 to evaluate the effectiveness of neural therapy in treating pain as manifestation of grade II cyclic breast dysplasia in comparison to the conventional therapy. Two hundred and forty patients were studied. They were divided into 4 groups according to the type of treatment: neural therapy (group I); vitamin E (group II); progesterone (group III); and non-steroidal anti-inflammatory drugs (group IV). Pain relief was observed in over 60 per cent of patients in group I, a result similar to that of group III (progesterone). There were significant differences in groups treated with non-steroidal anti-inflammatory drugs and Vitamin E. The use of neural therapy based on 1per cent procaine yielded satisfactory results, so we considered it as an effective therapy for pain relief in grade II breast dysplasia(AU)