ESR1 gene variants affect FSHR-depended risk of fibrocystic mastopathy in infertile women.

BACKGROUND: The infertile women have an increased risk of developing benign and malignant tumors, in particular, breast cancer. Most studies have examined the role of gene variants in the risk of developing breast cancer, but there is little evidence of genetic risk factors for benign tumors. AIM: To assess the combined genetic risk of developing mastopathy in women with FSHR (rs6165, rs6166) and ESR1 (rs9340799, rs2234693) gene variants. MATERIALS AND METHODS: The study included 87 infertile women (45 with concomitant fibrocystic mastopathy and 42 without mastopathy). RESULTS: For rs9340799 and rs2234693 variants of the ESR1 gene, we did not find any significant differences in the distribution of genotypes in infertile women with or without mastopathy. In patients with mastopathy, there was a reliable increase in the frequency of 307Ala/Ala and 680Ser/Ser genotypes of FSHR gene (χ2 = 6.39, p = 0.012, OR = 4.49 (1.48-13.65)) as compared to patients without mastopathy. In the presence of 307Thr/Thr and 680Asn/Asn genotypes of the FSHR gene, a 4.88-fold reduction of mastopathy risk (χ2 = 8.06, p = 0.005, OR = 0.21(0.07-0.59)) was observed. The frequency of the FSHR and the ESR1 genotypes combinations - 307Thr/Thr+680Asn/Asn+351AG+397TC was significantly decreased in patients with mastopathy. CONCLUSIONS: Our study did not find an association of ESR1 gene variants with the risk of developing of mastopathy in infertile women although heterozygous variants of the ESR1 gene enhanced the "protective" effect of FSHR gene variants and reduced the risk of mastopathy.

[Microglandular adenosis of the breast in a patient with a history of mediastinal radiotherapy]. / Adenosis microglandular mamaria en paciente con antecedente de radioterapia mediastínica.

The risk of secondary tumors in patients who have received mediastinal radiation therapy is well-known. Microglandular adenosis of the breast is a rare lesion that is considered benign, although its possible role as a precursor of invasive breast carcinoma has been considered. We present a case of microglandular adenosis in a patient who received mediastinal radiation therapy in childhood for Hodgkin's lymphoma. To our knowledge, this is the first reported case of microglandular adenosis in a patient with mediastinal radiotherapy which may shed light on its pathogenesis.

Is contrast-enhanced spectral mammography (CESM) helpful in differentiating diabetic mastopathy from breast carcinoma?

Diabetic mastopathy (DM) is a rare benign inflammatory disease of the breast, which nevertheless gives suspicious image of malignancy by breast ultrasound and mammography. MRI studies of this disease have indicated both nonspecific enhancement and non-enhancement of the lesion, depending on its degree of lymphocytic infiltration. This is the first case report discussing the appearances of DM on CESM, a novel mammographic technique.

First results of the preoperative accelerated partial breast irradiation (PAPBI) trial.

BACKGROUND AND PURPOSE: The aim of this study is to assess the toxicity and cosmetic outcome of preoperative accelerated partial breast irradiation (PAPBI) for breast cancer patients with low risk on local recurrence. MATERIAL AND METHODS: Women aged ⩾60years with an invasive, unifocal ⩽3cm on MRI, (non-lobular) adenocarcinoma of the breast and a negative sentinel node received PAPBI (40Gray in 10 fractions over 2 weeks). Six weeks after radiotherapy a wide local excision was performed. RESULTS: 70 patients with a median follow-up of 23 months (3-44 months) were evaluated. The overall postoperative infection rate was 11%. At 1, 2 and 3 years of follow-up respectively 89%, 98% and 100% of patients had no or mild induration-fibrosis. Fibrosis was only found in a small volume of the breast. The global cosmetic outcome was good to excellent in 77% at 6 months to 100% at 3 years. Two patients developed a local recurrence. CONCLUSION: Our first results show limited fibrosis in a small volume and good to excellent cosmetic outcome. In selected patients, preoperative radiotherapy appears to be a good option for breast conserving therapy.

Radiation-induced CD8 T-lymphocyte Apoptosis as a Predictor of Breast Fibrosis After Radiotherapy: Results of the Prospective Multicenter French Trial.

BACKGROUND: Monocentric cohorts suggested that radiation-induced CD8 T-lymphocyte apoptosis (RILA) can predict late toxicity after curative intent radiotherapy (RT). We assessed the role of RILA as a predictor of breast fibrosis (bf +) after adjuvant breast RT in a prospective multicenter trial. METHODS: A total of 502 breast-cancer patients (pts) treated by conservative surgery and adjuvant RT were recruited at ten centers. RILA was assessed before RT by flow cytometry. Impact of RILA on bf + (primary endpoint) or relapse was assessed using a competing risk method. Receiver-operator characteristic (ROC) curve analyses were also performed in intention to treat. This study is registered with ClinicalTrials.gov, number NCT00893035 and final analyses are presented here. FINDINGS: Four hundred and fifty-six pts (90.8%) were included in the final analysis. One hundred and eight pts (23.7%) received whole breast and node irradiation. A boost dose of 10-16 Gy was delivered in 449 pts (98.5%). Adjuvant hormonotherapy was administered to 349 pts (76.5%). With a median follow-up of 38.6 months, grade ≥ 2 bf + was observed in 64 pts (14%). A decreased incidence of grade ≥ 2 bf + was observed for increasing values of RILA (p = 0.012). No grade 3 bf + was observed for patients with RILA ≥ 12%. The area under the ROC curve was 0.62. For cut-off values of RILA ≥ 20% and < 12%, sensitivity and specificity were 80% and 34%, 56% and 67%, respectively. Negative predictive value for grade ≥ 2 bf + was equal to 91% for RILA ≥ 20% and positive predictive value was equal to 22% for RILA < 12% where the overall prevalence of grade ≥ 2 bf + was estimated at 14%. A significant decrease in the risk of grade ≥ 2 bf + was found if patients had no adjuvant hormonotherapy (sHR = 0.31, p = 0.007) and presented a RILA ≥ 12% (sHR = 0.45, p = 0.002). INTERPRETATION: RILA significantly predicts the risk of breast fibrosis. This study validates the use of RILA as a rapid screening test before RT delivery and will change definitely our daily clinical practice in radiation oncology. FUNDING: The French National Cancer Institute (INCa) through the "Program Hospitalier de Recherche Clinique (PHRC)".

Diabetic mastopathy: case report and summary of literature.

Diabetic mastopathy is an uncommon, benign breast condition seen in type 1 and less frequently type 2 diabetic patients. It is characterized by a dense fibrous stromal proliferation of breast tissue, clinically mimicking cancerous masses, thus leading to worrisome investigations. Clinicians and pathologists must distinguish this benign condition from malignant causes because surgery may worsen the case as these lesions tend to recur more extensively at the site of resection. We present the case of a young woman with type 1 diabetes with typical diabetic mastopathy and summarize the literature to increase awareness of this troublesome but benign disorder.

Leptin induces a proliferative response in breast cancer cells but not in normal breast cells.

Obesity is a risk factor for breast cancer in postmenopausal women. Leptin, a hormone excessively produced during obesity, is suggested to be involved in breast cancer. The aim of the study was to investigate procarcinogenic potential of leptin by evaluating influence of leptin on cell proliferation, cell cycle, apoptosis, and signaling on numerous breast cells lines, including 184B5 normal cells, MCF10A fibrocystic cells and MCF-7, MDA-MB-231, and T47D cancer cells. Expressions of leptin and Ob-R were analyzed using qRT-PCR and immunohistochemistry, proliferation using fluorimetric resazurin reduction test and xCELLigence system, apoptosis and cell cycle by flow cytometry, and effect of leptin on different signalling pathways using qRT-PCR and Western blot. Cells were exposed to increasing concentrations of leptin. All cell lines expressed mRNA and protein of leptin and Ob-R. Leptin stimulated proliferation of all cell lines except for 184B5 and MDA-MB-231 cells. Leptin inhibited apoptosis but didn't alter proportion of cells within cell cycle in MCF7 cells. Leptin induced overexpression of leptin, Ob-R, estrogen receptor, and aromatase mRNA in MCF-7 and T47D cells. Autoregulation induced by leptin, relationship with estrogen pathway, and proliferative and antiapoptic activity in breast cancer cells may explain that obesity-associated hyperleptinemia may be a breast cancer risk factor.

Mastopatia Diabética: una entidad infrecuente a diferenciar / Diabetic mastitis: an uncommon entity differentiate

Introducción: La Diabetes mellitus produce microvasculitis y alteración histoarquitectural de la mama. Se encuentra en el 1% de la mastopatía benigna. Sin embargo, la distorsión delparénquima produce sintomatología inflamatoria clínicamente similar a las mastopatías inflamatorias infecciosas. Su diagnóstico imagenológico, es a su vez, de gran dificultad interpretativa. Estos parámetros inespecíficos, desembocan a tratamientos que no logran eficacia en la enfermedad, más aún si se ignora el contexto de la enfermedad de origen, la cual essistémica. Objetivos: destacar la importancia del diagnóstico diferencial de esta infrecuente entidad patológica. Material y Métodos: se revisaron historias clínicas de un servicio de mastología por el término de seis meses, a efectos de recabar información estadística. Resultados: histológicamente, estas pacientes presentaron rasgos microscópicos que consisten en una lobulitis linfocitaria que afecta al epitelio y gran vasculitis edematosa. El diagnóstico histológico es crucial para llegar al tratamiento. Conclusiones: la mastopatía de las pacientes diabéticas insulinodependientes es la manifestación crónica de eventos sistémicos, producido en un porcentaje muy bajo de pacientes con la enfermedad. La correcta interpretación clínica y mamográfica, además de la sospecha semiológica desembocanen el adecuado tratamiento de esta enfermedad, inserta en un contexto sistémico.

Introduction: Diabetes mellitus occurs histoarquitectural microvasculitis and alteration of the breast. It is found in 1% of benign breast disease . However, distortion occurs parenchymal inflammatory symptoms clinically similar to infectious inflammatory breast disease. Its diagnostic imaging , is in turn highly interpretive difficulty. These non specific parameters lead to effective treatments that fail in the disease , especially if the context of disease origin is unknown, which is systemic. Objectives: To highlight the importance of the differential diagnosis of this rare disease entity. Material and Methods : Clinical histories mastology service for a period of six months for the purpose of collecting statistical data were reviewed.Results: Histologically , these patients had microscopic features consisting lobulitis lymphocytic affecting large edematous epithelium and vasculitis. Histological diagnosis is crucial to get the treatment. Conclusions: Diabetic mastopathy in insulin dependent patients is chronic manifestation of systemic events , produced in a very low percentage of patients with the disease. The correct clinical and mammographic interpretation, in addition to lead to suspicion semiológica proper treatment of this disease, inserted in a systemic context.

Alcohol intake between menarche and first pregnancy: a prospective study of breast cancer risk.

BACKGROUND: Adult alcohol consumption during the previous year is related to breast cancer risk. Breast tissue is particularly susceptible to carcinogens between menarche and first full-term pregnancy. No study has characterized the contribution of alcohol consumption during this interval to risks of proliferative benign breast disease (BBD) and breast cancer. METHODS: We used data from 91,005 parous women in the Nurses' Health Study II who had no cancer history, completed questions on early alcohol consumption in 1989, and were followed through June 30, 2009, to analyze breast cancer risk. A subset of 60,093 women who had no history of BBD or cancer in 1991 and were followed through June 30, 2001, were included in the analysis of proliferative BBD. Relative risks (RRs) were estimated using Cox proportional hazard regression. RESULTS: We identified 1609 breast cancer cases and 970 proliferative BBD cases confirmed by central histology review. Alcohol consumption between menarche and first pregnancy, adjusted for drinking after first pregnancy, was associated with risks of breast cancer (RR = 1.11 per 10 g/day intake; 95% confidence interval [CI] = 1.00 to 1.23) and proliferative BBD (RR = 1.16 per 10 g/day intake; 95% CI = 1.02 to 1.32). Drinking after first pregnancy had a similar risk for breast cancer (RR = 1.09 per 10 g/day intake; 95% CI = 0.96 to 1.23) but not for BBD. The association between drinking before first pregnancy and breast neoplasia appeared to be stronger with longer menarche to first pregnancy intervals. CONCLUSIONS: Alcohol consumption before first pregnancy was consistently associated with increased risks of proliferative BBD and breast cancer.

Dairy intakes in older girls and risk of benign breast disease in young women.

Previous investigations found high dairy intakes in girls associated with rapid height growth and excess weight gain, which had opposite relationships with benign breast disease (BBD) in young women. We use data from the longitudinal Growing Up Today Study (GUTS) to investigate whether dairy intakes, in older children/adolescents, are associated with BBD risk in young women. GUTS includes 9,039 females, ages 9-15 years in 1996, who completed questionnaires annually through 2001, then in 2003, 2005, 2007, and 2010. Dietary food frequencies (1996-2001) obtained milk, yogurt, and cheese intakes. On 2005-2010 surveys, 7,011 females (18-29 years) reported whether a health care provider ever diagnosed them with BBD (n = 250) and if confirmed by breast biopsy (n = 105). Logistic regression models estimated associations between prevalent biopsy-confirmed BBD and dairy intakes, adjusted for age and energy. Multivariable-adjusted models additionally included menarche age, childhood adiposity, adolescent alcohol consumption, and pregnancy. Further analyses stratified by family history. Age-energy-adjusted models of dairy (milk, yogurt, cheese, total dairy servings, dairy protein, dairy fat) intakes at 14 yr found no significant associations with BBD risk [milk: OR, 0.90/(serving/d); 95% confidence interval (CI), 0.76-1.05; dairy protein: OR, 0.98/(10 g/d); 95% CI, 0.82-1.17). Separate analyses of dairy intakes at 10 yr, intakes before the growth spurt, during the growth spurt, before menses-onset, and after menses-onset provided no significant associations with BBD. Multivariable adjustment, and family history stratification, did not alter the above findings. We conclude that dairy intakes by older girls have no strong relation with BBD risk in young women. Because of small number of cases, it is important to continue follow-up and re-examine later.

[Diabetic mastopathy]. / Diabetische mastopathie.

BACKGROUND: Diabetic mastopathy is a rare condition, which is clinically not easily to differentiate from breast cancer. CASE DESCRIPTION: A 32-year-old woman, with a long-standing history of insulin-dependent diabetes mellitus presented at the breast outpatient clinic with a firm palpable, painless mass in her right breast. Mammography and ultrasound examination showed, respectively, slight asymmetry with dense glandular tissue and a hypoechoic area with posterior shadowing. MR mammography showed no suspicious abnormalities. Histopathological examination revealed fibrous tissue with lymphocytic inflammation. The combination of clinical presentation, history of diabetes mellitus, and histological findings led to a diagnosis of diabetic mastopathy. CONCLUSION: A palpable breast abnormality in a woman with diabetes mellitus can be caused by diabetic mastopathy. Knowledge of this condition by the disciplines involved can prevent over-diagnosis and unnecessary interventions.

Endometrial cancer in a 14-year-old girl with Cowden syndrome: a case report.

The appearance of endometrial cancer in adolescence is uncommon and warrants investigation for an hereditary cancer syndrome. Cowden syndrome is an autosomal dominant cancer syndrome associated with a germline PTEN mutation and increased risk of breast, thyroid, endometrial and colon cancer. In this report we present a case of a 14-year-old nulligravid female diagnosed with grade 1 endometrial adenocarcinoma. She subsequently developed fibrocystic breast disease and colon polyps and was diagnosed with Cowden syndrome at age 20. We therefore recommend formal evaluation for Cowden syndrome to be considered when endometrial cancer is diagnosed in adolescence.

An uncommon case of T1b breast cancer with diabetic mastopathy in type II diabetes mellitus.

A 64-year-old postmenopausal female had been treated with insulin therapy for type 2 diabetes mellitus for 18 years, but her diabetes mellitus was not well controlled and she developed retinopathy. Her screening mammography showed abnormal findings, and thus she consulted a hospital. A physical examination showed her mammary glands to be hard on both sides and no palpable mass was observed. Mammography revealed an amorphous calcification in the middle outer portion of the left breast. Ultrasonography showed an irregular hypoechoic mass measuring about 11 mm in size in the upper outer portion of the left breast. Although a core-needle biopsy specimen of the hypoechoic mass showed hyalinizing fibrosis without any evidence of malignancy, a stereotactic guided vacuum-assisted biopsy was performed because magnetic resonance imaging revealed an enhanced area in the region of the amorphous calcification that could not be distinguished from breast cancer. The histological findings indicated noninvasive ductal carcinoma, and therefore a quardrantectomy with a sentinel lymph node biopsy was performed. The pathological diagnosis was invasive ductal carcinoma (0.7 × 0.3 cm) with a predominant intraductal component accompanying diabetic mastopathy. The sentinel lymph nodes demonstrated no metastasis. The surgical margin was positive for carcinoma and the patient later underwent a mastectomy. No malignant cells were observed in the specimen. The patient has so far experienced no recurrence after surgery.

Diabetic mastopathy: a case report.

Diabetic mastopathy (DMP) is an uncommon collection of clinical, radiological, and histological features, classically described in premenopausal women with long-term insulin-dependent diabetes mellitus. This entity can mimic breast carcinoma, but, in the appropriate clinical and imaging setting, the diagnosis can be made by core biopsy, avoiding unnecessary surgeries. We report the case of a 34-year-old female, with a 12-year history of type 1 diabetes, who presented with bilateral breast lumps. Mammography, ultrasonography, and magnetic resonance imaging could not exclude the suspicion of malignancy, and a core biopsy was performed showing the typical histologic features of DMP. The literature is briefly reviewed.

Extranodal NK/T-cell lymphoma, nasal type, arising in association with saline breast implant: expanding the spectrum of breast implant-associated lymphomas.

Extranodal NK/T-cell lymphoma, nasal type, is a rare type of non-Hodgkin lymphoma that is most common in Asia and is driven by Epstein-Barr virus infection. These tumors usually arise in the nasal region; in rare cases they can involve extranasal sites, most often skin, with involvement of the breast being rare. Lymphomas arising adjacent to breast implants are rare, and most cases reported to date have been anaplastic lymphoma kinase (ALK)-negative anaplastic large cell lymphoma. Here we report a 41-year-old white woman with bilateral saline breast implants placed for cosmetic reasons who almost 9 years later developed painful swelling at the right-breast implant site. Excisional biopsy revealed lymphoma composed of monomorphic large cells associated with necrosis and angioinvasion. Immunohistochemical analysis showed an aberrant, NK/T-cell immunophenotype with the lymphoma cells being CD2+, CD3+, CD56+, partial CD30+, granzyme B, TIA-1+, CD4+, CD5+, CD7+, and CD8+. In situ hybridization analysis showed Epstein-Barr virus-encoded RNA within the neoplastic cells. Polymerase chain reaction analysis showed monoclonal T-cell receptor-γ chain gene rearrangement. These findings support the diagnosis of extranodal NK/T-cell lymphoma, nasal type. On the basis of our review of the literature, this case is unique. In addition, we believe this case is important to report, because it expands the spectrum of T-cell lymphomas that can be associated with breast implants and may be a forerunner of additional cases to follow.

[Association of polymorph variants of CYP1A2 and CYP1A1 genes with reproductive and thyroid diseases in female workers of petrochemical industry].

The article presents results obtained in study of relationship between polymorph variants of CYP1A1 and CYP1A2 genes with reproductive and thyroid diseases risk in female workers of petrochemical industry, when compared with reference group females. Variants TD and DD of CYP1A2 gene appeared to be associated with nodes formation in uterus and breast in female workers and reference group females. Following liability markers are obtained: homozygous in rare allele genotype CC of CYP1A1 gene for reproductive and thyroid diseaes (fibrous cystic mastopathy and nodular goitre), heterozygous genotype AG of CYP1A1 gene in uterine myoma and fibrous cystic mastopathy, homozygous in deleted T genotype of CYP1A2 gene in autoimmune thyroiditis. Occupational hazards and long length of service at hazardous industries increase effects of rare alleles of the genes studied.

Intakes of alcohol and folate during adolescence and risk of proliferative benign breast disease.

OBJECTIVES: To examine the combined effect of alcohol and folate intake during adolescence on the risk of proliferative benign breast disease (BBD). METHODS: We used data from 29 117 women in the Nurses' Health Study II who completed both adolescent alcohol consumption questions in 1989 and an adolescent diet questionnaire in 1998. A total of 659 women with proliferative BBD diagnosed between 1991 and 2001 were confirmed by central pathology review. Cox proportional hazards models were used to estimate hazard ratios and 95% confidence intervals (CIs), adjusted for established risk factors of breast cancer. RESULTS: Adolescent alcohol consumption was dose-dependently associated with an increased risk of proliferative BBD (hazard ratio = 1.15 per 10 g/day consumption; 95% CI, 1.03-1.28). There was no significant association between adolescent folate intake and the risk of proliferative BBD. Stratified analyses showed that each 10-g/day alcohol intake during adolescence was associated with a 21% (95% CI, 1.01-1.45) increase in the risk of proliferative BBD among women with low folate intake during adolescence, which was not significantly different from the alcohol-associated risk among women with moderate and high folate intake during adolescence (P for interaction = 0.18). CONCLUSIONS: Adolescent alcohol consumption is associated with increased risk of proliferative BBD, which may not be reduced by increased folate intake during adolescence.

Six-year analysis of treatment-related toxicities in patients treated with accelerated partial breast irradiation on the American Society of Breast Surgeons MammoSite Breast Brachytherapy registry trial.

BACKGROUND: The American Society of Breast Surgeons (ASBrS) enrolled women in a registry trial to prospectively study patients treated with the MammoSite RTS device. This report presents 6-year data on treatment-related toxicities from the trial. METHODS: A total of 1449 primary early-stage breast cancers were treated with accelerated partial breast irradiation (APBI) using the MammoSite device (34 Gy in 10 fractions) in 1440 women. Of these, 1255 case (87%) had invasive breast cancer (IBC) (median size = 10 mm) and 194 cases (13%) had ductal carcinoma in situ (DCIS) (median size = 8 mm). Median follow-up was 59 months. Fisher exact test was performed to correlate categorical covariates with toxicity. RESULTS: Breast seromas were reported in 28% of cases (35.5% with open cavity and 21.7% with closed cavity placement). Also, 13% of all treated breasts developed symptomatic seromas, and 77% of these seromas developed during the 1st year after treatment. There were 172 cases (11.9%) that required drainage to correct. Use of chemotherapy and balloon fill >50 cc were associated with the development of symptomatic seromas. Also, 2.3% of patients developed fat necrosis (FN). The incidence of FN during years 1 and 2 were 0.9% and 0.8%, respectively. Seroma formation, use of hormonal therapy, breast infection, and A/B cup size were associated with fat necrosis. There were 138 infections (9.5%) recorded; 98% occurred during the 1st year after treatment. Chemotherapy and seroma formation were associated with the development of infections. CONCLUSIONS: Treatment-related toxicities 6 years after treatment with APBI using the MammoSite device are similar to those reported with other forms of APBI with similar follow-up.

Is hyperandrogenemia protective for fibrocystic breast disease in PCOS?

The aim of this study is to evaluate the fibrocystic breast disease rates and its association with different clinical, endocrine and metabolic parameters between main polycystic ovary syndrome (PCOS) phenotypes. One hundred thirty two consecutive women were included in the study. Body mass index, serum follicle-stimulating hormone, luteinizing hormone (LH), progesterone, estradiol, testosterone, dehydroepiandrosterone sulphate, fasting glucose, low density lipoprotein (LDL-C), total cholesterol, high density lipoprotein, insulin, insulin sensitivity and fibrocystic breast disease rates were compared among different phenotypes of PCOS. Group 1: Polycystic ovaries (PCO)-anovulation (n = 32), Group 2: Hyperandrogenemia (HA)-anovulation (n = 28), Group 3: HA-PCO (n = 29), Group 4: HA-PCO-anovulation (n = 43). There were statistically significant differences between the different phenotype groups in terms of waist-hip ratio (p = 0.006), serum LDL-C (p = 0.008), LH (p = 0.002), estradiol (p = 0.022), fasting glucose (p = 0.001), progesterone (p = 0.007), free testosterone levels (p < 0.001) and Ferriman-Gallwey (FG) scores (p < 0.001). Different phenotype groups had significantly different fibrocystic breast disease rates. (p = 0.016). Higher free testosterone >3 pg/dl was protective for fibrocystic disease (RR = 0.316, 95:% CI 0.109-0.912, p = 0.033). Higher FG scores were more protective for fibrocystic disease (RR = 0.005, 95:% CI 0.001-0.042, p < 0.001). Group 3 ovulatory PCOS patients with PCO and hyperandrogenemia phenotype had lower risk to develop fibrocystic disease, while higher rates were observed in group 1 anovulatory-normoandrogenemic PCOS patients. Hyperandrogenemia is protective for fibrocystic diseases in PCOS.