S.M.M. Basso

Endocrine Therapy of Breast Cancer

Breast cancer remains one of the first leading causes of death in women, and currently endocrine treatment is of major therapeutic value in patients with estrogen-receptor positive tumors. Selective estrogen-receptor modulators (SERMs), such as tamoxifen and raloxifene, aromatase inhibitors, and GnRH agonists are the drugs of choice. Tamoxifen, a partial nonsteroidal estrogen agonist, is a type II competitive inhibitor of estradiol at its receptor, and the prototype of SERMs. Aromatase inhibitors significantly lower serum estradiol concentration in postmenopausal patients, having no detectable effects on adrenocortical steroids formation, while GnRH agonists suppress ovarian function, inducing a menopause-like condition in premenopausal women. Endocrine therapy has generally a relatively low morbidity, leading to a significant reduction of mortality for breast cancer. The aim of chemoprevention is to interfere early with the process of carcinogenesis, reducing the risk of cancer development. As preventive agents, raloxifene and tamoxifene are equivalent, while raloxifene has more potent antiresorptive effects in postmenopausal osteoporosis. Endocrine treatment is usually considered a standard choice for patients with estrogen-receptor positive cancers and non-life-threatening advanced disease, or for older patients unfit for aggressive chemotherapy regimens. Several therapeutic protocols used in patients with breast cancer are associated with bone loss, which may lead to an increased risk of fracture. Bisphosphonates are the drugs of choice to treat such a drug-induced bone disease. The aim of this review is to outline current understanding on endocrine therapy of breast cancer.

Treatment of Estrogen Receptor-Positive Breast Cancer

Estrogen receptor (ER) expression is the main indicator of potential responses to endocrine therapy (ET), and approximately 70% of human breast cancers (BCs) are hormone-dependent and ER-positive. The introduction of adjuvant systemic therapy led to a significant improvement in post-surgical survival and a reduction in disease relapse, especially in women with early BC and those with ER+ tumors, who may receive ET alone or in combination with cytotoxic therapy. Adjuvant ET currently consists of (i) ovarian suppression, (ii) selective estrogen receptor modulators (SERMs) and down-regulators, and (iii) aromatase inhibitors (AIs). In patients with ER+ tumors pharmacologic ovary suppression with gonadotropin-releasing hormone agonists in combination with standard adjuvant therapy is generally more effective than adjuvant chemotherapy alone. Tamoxifen is the best established SERM, has favorable effects on BC control and bone metabolism, but also has adverse effects due to its estrogenic activity in other tissues. For these reasons, other SERMs have been developed. Fulvestrant is an ER down-regulator with several potential advantages over SERMs, including a 100-fold increase in its affinity for ER compared with tamoxifen and no estrogen-like activity in the uterus. The inhibition of the aromatase system with third-generation AIs is associated with improved survival in patients with advanced BC compared with SERMs. In postmenopausal patients with ER+ BC adjuvant treatment with AIs should be performed, either as sequential treatment after tamoxifen or as upfront therapy. Studies evaluating the role of AIs as first-line therapy are ongoing and the results are encouraging.

CT-scan, MRI and image-guided FNA cytology of incidental adrenal masses.

AIM The aim of this study was to compare the usefulness of computed tomography (CT)-scan, magnetic resonance imaging (MRI), and fine-needle aspiration (FNA) cytology in patients with incidentally discovered adrenal masses. PATIENTS AND METHODS Thirty-four consecutive patients (six men and 28 women, median age of 47 years, range 26-80) with non-functioning adrenal masses of 2 cm or more (median 3.5 cm, range 2-9) were studied. All patients underwent CT-scan, MRI, and image-guided FNA cytology using spinal-type narrow-gauge needles prior to further procedures. Nineteen patients underwent adrenalectomy. RESULTS Final pathology showed 13 benign adrenal lesions, four adrenocortical carcinomas, and two unsuspected adrenal metastases. Fifteen patients who did not have surgery were considered definitively as having benign adrenal lesions since the mass was unchanged on CT-scans performed during follow-up. The sensitivity, specificity, and positive predictive value were 66.7, 85.7, and 50.0%, for CT-scan, 83.3, 92.9, and 71.4% for MRI, and 83.3, 100, and 100% (p<0.05) for FNA cytology, respectively. CONCLUSIONS Image-guided FNA cytology is a safe and sensitive procedure that may reveal unsuspected adrenal malignancies, and should be performed in all patients with incidentally discovered adrenal masses of more than 2 cm in size.

Breast complaints and risk of breast cancer. Population-based study of 2,879 self-selected women and long-term follow-up.

The aim of this study was to provide information about risk of breast cancer (BC) in women with breast complaints undergoing spontaneously clinical examination. The records of 2,879 self-selected symptomatic new patients observed consecutively were reviewed, and the chief breast complaint such as pain, lump and nipple discharge had been recorded. Patients were divided in three groups: Group A, 1,186 (41.2%) patients aged < 41 years; Group B, 809 (28.1%) patients aged 41-55 years; and Group C, 884 (30.7%) patients aged > 55 years. Pain was most common (P < 0.01) in Group A (60.8%), and lump in Groups B (53.3%) and C (89.7%). A total of 318 (11.0%) women had histologically confirmed BC (Group A = 3.5%, Group B = 30.5%, Group C = 66.0%), accounting for 3.2, 16.4 and 12.0% of patients with pain, lump and nipple discharge, respectively. Breast complaints were equally (P= NS) distributed between patients with and without BC. The relative risk (RR) of BC developing ranged between 0.5-1.4, 0.5-1.9, and 0.6-3.0 in Groups A, B, and C, respectively. It ranged between 0.3 and 0.7 in patients with breast pain, and was significantly higher (RR = 1.9-3.0) only in patients with breast lump aged > 40 years. In conclusion, in symptomatic patients BC risk is strictly related to age, and independent of the referred symptoms. Therefore, further investigations have to be warranted only when risk factors different from breast complaints are present.

Breast cancer risk in healthy and symptomatic women: results of a multivariate analysis. A case-control study.

Several risk factors for breast cancer (BC) have been investigated in different reports, but none has been really useful in preventing BC development. The aim of this study was to evaluate the risk of BC in self-selected symptomatic women in comparison with the healthy population residing in an urban area of Italy. A group of 404 women (median age 59 years, range 26-89 years) with confirmed BC (cases) were age-matched with 389 healthy women (Group A), and 391 (Group B) symptomatic non-screened patients without BC, who were referred to our Breast unit. The results of univariate analysis showed a significant (P < 0.01) difference between cases and controls in (1) age at menarche, (2) number of birth and age at first births, (3) lactation and months of lactation, and (4) estrogen replacement therapy (ERT) and duration of ERT. Multivariate analysis using a logistic regression model adjusted for age showed that five independent parameters (no pregnancy, age at first birth > 30 years, no lactation, use of ERT, ERT > 40 months) significantly (P < 0.01) correlated with BC onset. The relative odds ratios (ORs) at 95% confidence interval (95% CI) were 5.25, 2.47, 2.82, 2.80, and 5.56, respectively. The cumulative OR (95% CI) calculated from the observed vs. predicted values was 7.15. No differences (P = NS) were found between groups A and B. In conclusion, in our study population, the prolonged use (> 40 months) of ETR in menopausal women resulted in an increased risk of BC, and represented the only risk factor that could be removed.

Short- and Long-Term Changes in Bone Mineral Density of the Lumbar Spine After Parathyroidectomy in Patients with Primary Hyperparathyroidism

The aims of this study were (1) to analyze whether correlations exist between lumbar spine (LS) bone mineral density (BMD) and the main preoperative biochemical parameters in a large population of patients with primary hyperparathyroidism (HPT); and (2) to evaluate the LS-BMD changes after parathyroidectomy (PTx) at long-term follow-up. Sixty-two patients (median age 57 years, range 23–82 years) with confirmed primary HPT underwent LS osteodensitometry by dual-energy X-ray absorptiometry with BMD measurements at the L2–L4 region before surgery and at 1 year and 2 years after successful PTx. Three groups of patients were considered: Group A (men, n = 14, 22.6%), Group B (premenopausal women, n = 12, 19.3%), and Group C (postmenopausal women, n = 36, 58.1%). There were no linear correlations (P = NS) among the main biochemical parameters, the age of the patients, and their baseline LS-BMD values that were significantly (P < 0.01) lower in Group C patients. At 2-year follow-up the LS-BMD improved by 13.0%, 11.5%, and 11.7% in Groups A, B, and C, respectively (P = NS). In order to compare groups with the same linear relationship between age and LS-BMD, a subgroup of postmenopausal patients aged ≤60 years (Group C2) was considered. ANOVA showed that the improvement of the LS-BMD at l- and 2-year follow-up was higher (P = 0.002) in Group B than in Group C2 patients. The result was confirmed by using the Mann-Whitney U-test (P = 0.0078). Improvement of LS-BMD after successful PTx was significantly (P < 0.01) higher in premenopausal women, suggesting a possible role of estrogen hormone in complete bone remodeling.

Imaging Studies in Hypercalcemia

Hypercalcemia is a relatively common clinical problem, mainly (>90%) related to primary hyperparathyroidism (HPT) and malignancies. The anatomical and functional imaging techniques available for locating enlarged parathyroid glands include ultrasound (US), computed tomography (CT), magnetic resonance imaging (MRI), and nuclear medicine imaging techniques. The most commonly employed are US and parathyroid scintigraphy, while CT, MRI, positron emission tomography (PET)/CT, and selective venous sampling are generally used in patients with persistent or recurrent HPT, or when findings of non-invasive studies are negative or conflicting. The reported accuracy is 57-93%, 54-93%, and up to 95% for US, (99m)Tc-sestamibi scintigraphy, and the two modalities combined, respectively. A multimodality approach (x-ray, whole-body scintigraphy, CT, MRI, and PET) is usually recommended for whole body assessment in cases of cancer-induced hypercalcemia (CIH). Imaging studies should evaluate each organ (i.e. breast, kidney, prostate, parathyroid) potentially involved in the pathogenesis of hypercalcemia in patients with CIH. In cases of skeletal metastases, when findings on plain x-ray or bone scans are uncertain, any unexplained region of abnormal uptake should be examined by MRI and/or ¹⁸F-fluoro-2- deoxyglucose (FDG)-PET/CT, which has proved more accurate than classical bone scintigraphy, especially for dealing with hematologic malignancies. A number of radionuclide tracers, other than ¹⁸F-FDG, are available for use in selected cases to locate specific tumors (i.e. ⁶⁸Ga for neuroendocrine tumors). This is a review of recently published information on the imaging techniques currently available for patients with hypercalcemia.

Calcium Metabolism & Hypercalcemia in Adults

Calcium is essential for many metabolic process, including nerve function, muscle contraction, and blood clotting. The metabolic pathways that contribute to maintain serum calcium levels are bone remodeling processes, intestinal absorption and secretion, and renal handling, but hypercalcemia occurs when at least 2 of these 3 metabolic pathways are altered. Calcium metabolism mainly depends on the activity of parathyroid hormone (PTH). Its secretion is strictly controlled by the ionized serum calcium levels through a negative feed-back, which is achieved by the activation of calcium-sensing receptors (CaSRs) mainly expressed on the surface of the parathyroid cells. The PTH receptor in bone and kidney is now referred as PTHR1. The balance of PTH, calcitonin, and vitamin D has long been considered the main regulator of calcium metabolism, but the function of other actors, such as fibroblast growth factor-23 (FGF-23), Klotho, and TPRV5 should be considered. Primary hyperparathyroidism and malignancy are the most common causes of hypercalcemia, accounting for more than 90% of cases. Uncontrolled hypercalcemia may cause renal impairment, both temporary (alteration of renal tubular function) and progressive (relapsing nephrolithiasis), leading to a progressive loss of renal function, as well as severe bone diseases, and heart damages. Advances in the understanding of all actors of calcium homeostasis will be crucial, having several practical consequences in the treatment and prevention of hypercalcemia. This would allow to move from a support therapy, sometimes ineffective, to a specific and addressed therapy, especially in patients with chronic hypercalcemic conditions unsuitable for surgery.

50P Accuracy of serum/pleural fluid lactate dehydrogenase ratio measurement in patients with malignant pleural effusion.

anger and ways of expressing anger in patients with lung cancer. Methods: A total of 132 patients who were getting inpatient treatment in a hospital between the dates 08.06.2014 and 18.12.2015 were included in the study. The data was collected by using a questionnaire form which consisted of 29 questions to find out the socio-demographic and clinical features of patients and Continuous Anger and Anger Expression Style Scale and Beck Hopelessness Scale. Continuous Anger and Anger Expression Style Scale consists of 34 items and quadruplet rating was used in its responding. Total point cannot be obtained from the scale but grading can be made according to sub dimensions (controlled anger, externalized anger, suppressed anger). Beck Hopelessness Scale is a self-assessment scale consisting of 20 items and 3 sub dimensions (feelings and expectations about the future, motivation loss and hope). One can get a score of between 0 and 20 and high scores show that the individual has high levels of hopelessness. Results: 12.9% of the patients were women, while 87.1% were men and the average age of the patients was 62.29±8.85. It was found that 30.3% of the patients were stage IV, 80.3% were receiving chemotherapy; based on the treatment and prognosis of the disease, 79.7% were found to experience exhaustion and 57.8% were found to experience dyspnea. The patients’ Continuous Anger level point average was detected as 22.97±7.97, controlled anger sub dimension average of anger style scale was detected as 22.65±6.20, externalized anger sub dimension point average was detected as 16.41±6.03, suppressed anger sub dimension point average was detected as 16.24±4.75. Total score averages of Beck Hopelessness Scale was 8.42±6.86, average scores were 1.88±2.03 for feelings and expectations about the future sub dimension, 4.12±2.93 for motivation loss sub dimension and 2.42±2.32 for hope sub dimension. Conclusions: It was found that the higher hopeless level people had, the higher anger levels they had and the more they expressed or repressed their anger and the lower hopelessness level they had, the more they could control themselves. Legal entity responsible for the study: Associate Professor Zeliha Koç, Ondokuz Mayıs University Funding: Foundation or academic group WITHOUT funding from a pharmaceutical, biotech, or other commercial company Disclosure: All authors have declared no conflicts of interest.

49P Accuracy of pleural fluid cytology in patients with malignant pleural effusion from non-small-cell lung cancer, pulmonary metastases and pleural mesothelioma. A case-control study.

anger and ways of expressing anger in patients with lung cancer. Methods: A total of 132 patients who were getting inpatient treatment in a hospital between the dates 08.06.2014 and 18.12.2015 were included in the study. The data was collected by using a questionnaire form which consisted of 29 questions to find out the socio-demographic and clinical features of patients and Continuous Anger and Anger Expression Style Scale and Beck Hopelessness Scale. Continuous Anger and Anger Expression Style Scale consists of 34 items and quadruplet rating was used in its responding. Total point cannot be obtained from the scale but grading can be made according to sub dimensions (controlled anger, externalized anger, suppressed anger). Beck Hopelessness Scale is a self-assessment scale consisting of 20 items and 3 sub dimensions (feelings and expectations about the future, motivation loss and hope). One can get a score of between 0 and 20 and high scores show that the individual has high levels of hopelessness. Results: 12.9% of the patients were women, while 87.1% were men and the average age of the patients was 62.29±8.85. It was found that 30.3% of the patients were stage IV, 80.3% were receiving chemotherapy; based on the treatment and prognosis of the disease, 79.7% were found to experience exhaustion and 57.8% were found to experience dyspnea. The patients’ Continuous Anger level point average was detected as 22.97±7.97, controlled anger sub dimension average of anger style scale was detected as 22.65±6.20, externalized anger sub dimension point average was detected as 16.41±6.03, suppressed anger sub dimension point average was detected as 16.24±4.75. Total score averages of Beck Hopelessness Scale was 8.42±6.86, average scores were 1.88±2.03 for feelings and expectations about the future sub dimension, 4.12±2.93 for motivation loss sub dimension and 2.42±2.32 for hope sub dimension. Conclusions: It was found that the higher hopeless level people had, the higher anger levels they had and the more they expressed or repressed their anger and the lower hopelessness level they had, the more they could control themselves. Legal entity responsible for the study: Associate Professor Zeliha Koç, Ondokuz Mayıs University Funding: Foundation or academic group WITHOUT funding from a pharmaceutical, biotech, or other commercial company Disclosure: All authors have declared no conflicts of interest.