Current medical treatment of estrogen receptor-positive breast cancer

Approximately 80% of breast cancers (BC) are estrogen receptor (ER)-positive and thus endocrine therapy (ET) should be considered complementary to surgery in the majority of patients. The advantages of oophorectomy, adrenalectomy and hypophysectomy in women with advanced BC have been demonstrated many years ago, and currently ET consist of (i) ovarian function suppression (OFS), usually obtained using gonadotropin-releasing hormone agonists (GnRHa), (ii) selective estrogen receptor modulators or down-regulators (SERMs or SERDs), (iii) aromatase inhibitors (AIs), or a combination of two or more drugs. For patients aged less than 50 years and ER+ BC, there is no conclusive evidence that the combination of OFS and SERMs (i.e. tamoxifen) or chemotherapy is superior to OFS alone. Tamoxifen users exhibit a reduced risk of BC, both invasive and in situ, especially during the first 5 years of therapy, and extending the treatment to 10 years further reduced the risk of recurrences. SERDs (i.e. fulvestrant) are especially useful in the neoadjuvant treatment of advanced BC, alone or in combination with either cytotoxic agents or AIs. There are two types of AIs: type I are permanent steroidal inhibitors of aromatase, while type II are reversible nonsteroidal inhibitors. Several studies demonstrated the superiority of the third-generation AIs (i.e. anastrozole and letrozole) compared with tamoxifen, and adjuvant therapy with AIs reduces the recurrence risk especially in patients with advanced BC. Unfortunately, some cancers are or became ET-resistant, and thus other drugs have been suggested in combination with SERMs or AIs, including cyclin-dependent kinase 4/6 inhibitors (palbociclib) and mammalian target of rapamycin (mTOR) inhibitors, such as everolimus. Further studies are required to confirm their real usefulness

Laparoscopic totally extraperitoneal inguinal hernia repair in the elderly: A prospective control study

Inguinal hernia (IH) repair can be obtained with both open and laparoscopic techniques, which are usually performed using a transabdominal preperitoneal (TAPP) or a totally extraperitoneal (TEP) approach. The aim of the study was to evaluate whether the results of laparoscopic TEP IH repair in the elderly ( 6565 years old) are different with respect to results obtained in younger patients. One hundred and four consecutive patients (four women and 100 men, median age of 57 years, range=21-85 years) with unilateral (N=21, 20.2%) or bilateral (N=83, 79.8%) IH were prospectively enrolled in the study. Patients were divided into two groups according to their age: group A (N=68, 65.4%) aged <65 years and group B (N=36, 34.6%) aged 6565 years. The mean operative time was not significantly different between groups (48\ub120 vs. 52\ub120 min, p=0.33). One case of increased PaCO2 was observed in each group (p=0.72) and two and one case of pneumoperitoneum (p=0.57) in groups A and B, respectively. Two (1.9%) patients (one in each group; p=0.55) required TEP conversion. Mild postoperative complications developed in four patients of each group (p=0.44). After one-year follow-up, three (2.9%) recurrences occurred (group 1=1, group 2=2, p=0.55), both in patients who had undergone direct IH repair. The overall postoperative relative risk of complications related to age was 1.08 (95% confidence interval=0.91-1.27, p=0.53). In conclusion, our results suggest that in patients with IH scheduled for TEP repair, age does not represent a contraindication to surgery in terms of complication rate and postoperative results

Prognostic factors of survival in patients treated with nab-paclitaxel plus gemcitabine regimen for advanced or metastatic pancreatic cancer: A single institutional experience.

The objectives of this study were to evaluate the effectiveness of nab-paclitaxel plus gemcitabine (NAB-P/GEM) regimen in an unselected population of patients with advanced inoperable or metastatic pancreatic cancer (PC), and to identify the prognostic factors influencing overall survival (OS). EXPERIMENTAL DESIGN: Patients with age < 85 years, ECOG-performance status (PS) < 3, and adequate renal, hepatic and hematologic function were eligible. NAB-P (125 mg/m2) and GEM (1000 mg/m2) day 1,8,15 every 4 weeks were employed for 3-6 cycles or until highest response. RESULTS: Overall, 147 cycles (median 4, range 1-11 cycles) were administered on thirty-seven consecutive patients (median 66 years old, range 40-82) treated. The median overall progression-free survival and OS were 6.2 and 9.2 months, respectively. The G 3-4 dose-limiting toxicity were neutropenia (20.7%), severe anemia (17.2%), and cardiovascular toxicity (10.3%). PS, number of cycles, baseline CA 19-9 and LDH serum levels, were found to be significantly related to OS. The multivariate analysis showed that both number of cycles (HR = 9.14, 95% CI 1.84-45.50, p = 0.001) and PS (HR = 13.18, 95% CI 2.73-63.71, p = 0.001) were independently associated with OS. CONCLUSION: NAB-P/GEM regimen should be used in all patients with advanced or metastatic PC, with the exception of those with serious contraindications to chemotherapy, such as severe renal or hepatic impairment or major cardiovascular diseases

Unusual Development of Iatrogenic Complex, Mixed Biliary and Duodenal Fistulas Complicating Roux-en-Y Antrectomy for Stenotic Peptic Disease of the Supraampullary Duodenum Requiring Whipple Procedure: An Uncommon Clinical Dilemma

Complex fistulas of the duodenum and biliary tree are severe complications of gastric surgery. The association of duodenal and major biliary fistulas occurs rarely and is a major challenge for treatment. They may occur during virtually any kind of operation, but they are more frequent in cases complicated by the presence of difficult duodenal ulcers or cancer, with a mortality rate of up to 35%. Options for treatment are many and range from simple drainage to extended resections and difficult reconstructions. Conservative treatment is the choice for well-drained fistulas, but some cases require reoperation. Very little is known about reoperation techniques and technical selection of the right patients. We present the case of a complex iatrogenic duodenal and biliary fistula. A 42-year-old Caucasian man with a diagnosis of postoperative peritonitis had been operated on 3 days earlier; an antrectomy with a Roux-en-Y reconstruction for stenotic peptic disease was performed. Conservative treatment was attempted with mixed results. Two more operations were required to achieve a definitive resolution of the fistula and related local complications. The decision was made to perform a pancreatoduodenectomy with subsequent reconstruction on a double jejunal loop. The patient did well and was discharged on postoperative day 17. In our experience pancreaticoduodenectomy may be an effective treatment of refractory and complex iatrogenic fistulas involving both the duodenum and the biliary tree

Editorial: Calcium metabolism and treatment of hypercalcemia

Calcium is essential for many physiologic process, including nerve function, muscle contraction, and blood clotting. It is the main mineral constituent of bones, and regulates several enzymatic activities, and cellular membranes excitability. Calcium-sensing receptors (CASR) are the key mediator of Ca2+ actions on parathyroid glands and kidney, regulating homeostatic responses that restore normal Ca2+ levels. However, the function of other actors, such as fibroblast growth factor-23 (FGF23), Klotho, and the transient receptor potential cation channel, subfamily V (TRPV), which are essential for maintaining calcium-phosphate homeostasis and regulating calcium metabolism, should be considered. FGF23 is involved in the molecular mechanism of renal phosphate reabsorption, increases urinary excrection of phosphorus, and inhibits both renal tubular phosphate transport and renal production of 1,25(OH)2D3, thereby decreasing PTH serum levels and its secretion. Klotho is a transmembrane protein which regulates transepithelial Ca2+ transport, PTH secretion and subsequent serum Ca2+ increase, signal transduction of FGF23, and downregulation of 1,25(OH)2D3 production. Apical Ca2+ entry via TRPV-calcium channels, induced by 1,25(OH)2D3, represents the first step of intestinal and renal epithelial Ca2+ transport mechanisms. 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. Primary hyperparathyroidism (PHPT) and malignancy-associated hypercalcemia (MAH) are responsible for more than 90% of all causes of hypercalcemia, usually presenting with chronic hypercalcemia. PTHrP also stimulates stromal bone cells and osteoblasts production of RANKL, a potent inducer of osteoclast maturation, and acts locally to induce bone lesions. RANK, its ligand RANKL, and osteoprotegerin, the natural decoy receptor for RANKL, represent the three essential molecules that control osteoclast function. There are five keystones of therapy of acute hypercalcemia: (1) restore normovolemia to prevent renal impairment, (2) restore renal function and enhance renal excretion of calcium, (3) dialysis, (4) inhibit osteoclastic bone resorption, and (5) reduce intestinal calcium absorption. Due to their antiresorptive action, bisphosphonates are currently the treatment of choice especially in cancer-related bone diseases. However, their clinical efficacy is usually short-lived and sometimes incomplete. This is due to the increased distal tubular calcium reabsorption mainly driven by paraneoplastic release of PTHrP by the cancer tissue. A monoclonal antibody against human RANKL (denosumab) is currently available, and it seems to be more effective than bisphosphonates to suppress bone resorption. Denosumab prevents the binding between RANKL and RANK receptor on the surface of both osteoclasts and osteoclast precursors, and reduces the differentiation, activation, and survival of osteoclasts, slowing the rate of bone resorption. A humanized monoclonal antibody against human PTHrP has also been generated, and is still under evaluation. Cathepsin K is the most abundant cysteine protease expressed in osteoclasts, and a cathepsin K inhibitor (odanacatib) may suppress bone resorption in patients with bone metastases from breast cancer. In conclusion, advances in the understanding of all actors of calcium metabolism may have several practical consequences in the treatment and prevention of hypercalcemia

Vida escolar

Expone las tres orientaciones filosóficas que hay en Estados Unidos para la solución de los problemas de la educación: educación académica, educación progresiva, educación comunitaria. Se centra en esta última y analiza su función principal de escuela para todos, planeada y construida para satisfacer las necesidades de la comunidad, para pasar a describir la experiencia de la escuela comunitaria de Flint, Michigan.Ministerio Educación CIDEBiblioteca de Educación del Ministerio de Educación, Cultura y Deporte; Calle San Agustín, 5 - 3 Planta; 28014 Madrid; Tel. +34917748000; [email protected]