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

Cost-effectiveness of indwelling pleural catheter compared with talc in malignant pleural effusion

Background and objective: Malignant pleural effusion is associated with morbidity and mortality. A randomized controlled trial previously compared clinical outcomes and resource use with indwelling pleural catheter (IPC) and talc pleurodesis in this population. Using unpublished quality of life data, we estimate the cost-effectiveness of IPC compared with talc pleurodesis. Methods: Healthcare utilization and costs were captured during the trial. Utility weights produced by the EuroQol Group five-dimensional three-level questionnaire and survival were used to determine quality-adjusted life-years (QALYs) gained. The incremental cost-effectiveness ratio (ICER) was calculated over the 1-year trial period. Sensitivity analysis used patient survival data and modelled additional nursing time required per week for catheter drainage. Results: Utility scores, cost and QALYs gained did not differ significantly between groups. The ICER for IPC compared with talc was favorable at $US10 870 per QALY gained. IPC was less costly with a probability exceeding 95% of being cost-effective when survival was <14 weeks, and was more costly when 2-h nursing time per week was assumed for catheter drainage. Conclusion: IPC is cost-effective when compared with talc, although substantial uncertainty exists around this estimate. IPC appears most cost-effective in patients with limited survival. If significant nursing time is required for catheter drainage, IPC becomes less likely to be cost-effective. Either therapy may be considered as a first-line option in treating malignant pleural effusion in patients without history of prior pleurodesis, with consideration for patient survival, support and preferences

Deciphering the Molecular Basis of Melatonin Protective E ects on Breast Cells Treated with Doxorubicin: TWIST1 a Transcription Factor Involved in EMT and Metastasis, a Novel Target of Melatonin

Melatonin mitigates cancer initiation, progression and metastasis through inhibition of both the synthesis of estrogens and the transcriptional activity of the estradiol-ER (Estrogen receptor) complex in the estrogen-dependent breast cancer cell line MCF-7. Moreover, melatonin improves the sensitivity of MCF-7 to chemotherapeutic agents and protects against their side e ects. It has been described that melatonin potentiates the anti-proliferative e ects of doxorubicin; however, the molecular changes involving gene expression and the activation/inhibition of intracellular signaling pathways remain largely unknown. Here we found that melatonin enhanced the anti-proliferative e ect of doxorubicin in MCF-7 but not in MDA-MB-231 cells. Strikingly, doxorubicin treatment induced cell migration and invasion, and melatonin e ectively counteracted these e ects in MCF-7 but not in estrogen-independent MDA-MB-231 cells. Importantly, we describe for the first time the ability of melatonin to downregulate TWIST1 (Twist-related protein 1) in estrogen-dependent but not in estrogen-independent breast cancer cells. Combined with doxorubicin, melatonin inhibited the activation of p70S6K and modulated the expression of breast cancer, angiogenesis and clock genes. Moreover, melatonin regulates the levels of TWIST1-related microRNAs, such as miR-10a, miR-10b and miR-34a. Since TWIST1 plays a pivotal role in the epithelial to mesenchymal transition, acquisition of metastatic phenotype and angiogenesis, our results suggest that inhibition of TWIST1 by melatonin might be a crucial mechanism of overcoming resistance and improving the oncostatic potential of doxorubicin in estrogen-dependent breast cancer cells.Funding: The present study was funded by grants from the Spanish Economy and Competitiveness Ministry (SAF2016-77103-P) and from Instituto de Investigación Sanitaria Valdecilla (NVAL 16/01)