Alessandro Sanguinetti

Nuclear receptors agonists exert opposing effects on the inflammation dependent survival of breast cancer stem cells.

Recent literature highlights the importance of pro-inflammatory cytokines in the biology of breast cancer stem cells (CSCs), unraveling differences with respect to their normal counterparts. Expansion of mammospheres (MS) is a valuable tool for the in vitro study of normal and cancer mammary gland stem cells. Here, we expanded MSs from human breast cancer and normal mammary gland tissues, as well from tumorigenic (MCF7) and non-tumorigenic (MCF10) breast cell lines. We observed that agonists for the retinoid X receptor (6-OH-11-O-hydroxyphenanthrene), retinoic acid receptor (all-trans retinoic acid (RA)) and peroxisome proliferator-activated receptor (PPAR)-γ (pioglitazone (PGZ)), reduce the survival of MS generated from breast cancer tissues and MCF7 cells, but not from normal mammary gland or MCF10 cells. This phenomenon is paralleled by the hampering of pro-inflammatory Nuclear Factor-κB (NF-κB)/Interleukin-6 (IL6) axis that is hyperactive in breast cancer-derived MS. The hindrance of such pathway associates with the downregulation of MS regulatory genes (SLUG, Notch3, Jagged1) and with the upregulation of the differentiation markers estrogen receptor-α and keratin18. At variance, the PPARα agonist Wy14643 promotes MS formation, upregulating NF-κB/IL6 axis and MS regulatory genes. These data reveal that nuclear receptors agonists (6-OH-11-O-hydroxyphenanthrene, RA, PGZ) reduce the inflammation dependent survival of breast CSCs and that PPARα agonist Wy14643 exerts opposite effects on this phenotype.

Total thyroidectomy with ultrasonic dissector for cancer: multicentric experience

BackgroundWe conducted an observational multicentric clinical study on a cohort of patients undergoing thyroidectomy for thyroid carcinoma. The aim of this study was to evaluate the benefits of the use of ultrasonic dissector (UAS) vs. the use of a conventional technique (vessel clamp and tie) in patients undergoing thyroid surgery for cancer.MethodsFrom June 2009 to May 2010 we evaluated 321 consecutive patients electively admitted to undergo total thyroidectomy for thyroid carcinoma. The first 201 patients (89 males, 112 females) presenting to our Department underwent thyroidectomy with the use of UAS while the following 120 patients (54 males, 66 females) underwent thyroidectomy performed with a conventional technique (CT): vessel clamp and tie.ResultsThe operative time (mean: 75 min in UAS vs. 113 min in CT, range: 54 to 120 min in UAS vs. 68 to 173 min in CT) was much shorter in the group of thyroidectomies performed with UAS. The incidence of transient laryngeal nerve palsy (UAS 3/201 patients (1.49%); CT 1/120 patients (0.83%)) was higher in the group of UAS; the incidence of permanent laryngeal nerve palsy was similar in the two groups (UAS 2/201 patients (0.99%) vs. CT 2/120 patients (1.66%)). The incidence of transient hypocalcaemia (UAS 17/201 patients (8.4%) vs. CT 9/120 patients (7.5%)) was higher in the UAS group; no relevant differences were reported in the incidence of permanent hypocalcaemia in the two groups (UAS 5/201 patients (2.48%) vs. 2/120 patients (1.66%)). Also the average postoperative length of stay was similar in two groups (2 days).ConclusionThe only significant advantage proved by this study is represented by the cost-effectiveness (reduction of the usage of operating room) for patients treated with UAS, secondary to the significant reduction of the operative time. The analysis failed to show any advantages in terms of postoperative transient complications in the group of patients treated with ultrasonic dissector: transient laryngeal nerve palsy (1.49% in UAS vs. 0.83% in CT) and transient hypocalcaemia (8.4% in UAS vs. 7.5%in CT). No significant differences in the incidence of permanent laryngeal nerve palsy (0.8% in UAS vs. 1.04% in CT) and permanent hypocalcaemia (2.6% in UAS vs. 2.04% in CT) were demonstrated. The level of surgeons’ expertise is a central factor, which can influence the complications rate; the use of UAS can only help surgical action but cannot replace the experience of the operator.

Antibiotic prophylaxis in thyroid surgery: a preliminary multicentric italian experience

Post-operatory wound infections are a very uncommon finding after thyroidectomy. For these reasons international guidelines do not routinely recommend systemic antibiotic prophylaxis.The benefits of this antibiotic prophylaxis is not supported by clinical evidence in the literature. We have conducted a multicentric randomized double-blind trial on 500 patients who had undergone thyroidectomy for goitre or thyroid carcinoma. The 500 patients enrolled in the study (mean age 47 years) were randomized in two subgroups of 250 patients. 250 patients were treated with standard antibiotic prophylaxis with sulbactam/ampicillin 1 fl (3 gr.) 30 min before surgery. No antibiotic prophylaxis was instituted in the remainder 250 patients. Our RCT showed that prophylactic antibiotic treatment is not beneficial in patients younger than eighty years old, with no concomitant metabolic, infective and hematologic disease, with no cardiac valvulopathies, not under steroidal or immunosuppressive treatment, and not severely obese. Our study should be regarded only as a preliminary RCT, and should be followed by a study in which a larger number of patients should be enrolled so that statistically significant data can be obtained.

Peroxisome Proliferator Activated Receptor-α/Hypoxia Inducible Factor-1α Interplay Sustains Carbonic Anhydrase IX and Apoliprotein E Expression in Breast Cancer Stem Cells

Aims Cancer stem cell biology is tightly connected to the regulation of the pro-inflammatory cytokine network. The concept of cancer stem cells “inflammatory addiction” leads to envisage the potential role of anti-inflammatory molecules as new anti-cancer targets. Here we report on the relationship between nuclear receptors activity and the modulation of the pro-inflammatory phenotype in breast cancer stem cells. Methods Breast cancer stem cells were expanded as mammospheres from normal and tumor human breast tissues and from tumorigenic (MCF7) and non tumorigenic (MCF10) human breast cell lines. Mammospheres were exposed to the supernatant of breast tumor and normal mammary gland tissue fibroblasts. Results In mammospheres exposed to the breast tumor fibroblasts supernatant, autocrine tumor necrosis factor-α signalling engenders the functional interplay between peroxisome proliferator activated receptor-α and hypoxia inducible factor-1α (PPARα/HIF1α). The two proteins promote mammospheres formation and enhance each other expression via miRNA130b/miRNA17-5p-dependent mechanism which is antagonized by PPARγ. Further, the PPARα/HIF1α interplay regulates the expression of the pro-inflammatory cytokine interleukin-6, the hypoxia survival factor carbonic anhydrase IX and the plasma lipid carrier apolipoprotein E. Conclusion Our data demonstrate the importance of exploring the role of nuclear receptors (PPARα/PPARγ) in the regulation of pro-inflammatory pathways, with the aim to thwart breast cancer stem cells functioning.

Interleukin-6 and pro inflammatory status in the breast tumor microenvironment

BackgroundGreater than 50,000 new cases of breast cancer cases were diagnosed in Italy during 2013, with nearly 15,000 women succumbing to the disease. These epidemiological statistics highlight the overwhelming clinical dilemma of breast cancer and emphasize the need for novel therapeutic targets and prevention strategies. Countless studies in the fields of mammary gland development and breast cancer have led to an appreciation of a breast tumor microenvironment that actively contributes to the heterogeneous nature of breast cancer.MethodsThe current review will focus on the impact of IL-6 and in the breast tumor microenvironment. Excessive IL-6 has been demonstrated in primary breast tumors and breast cancer patient sera and is associated with poor clinical outcomes in breast cancer. These clinical associations are corroborated by emerging preclinical data revealing that IL-6 is a potent growth factor and promotes an epithelial-mesenchyme (EMT) phenotype in breast cancer cells to indicate that IL-6 in the breast tumor microenvironment is clinically relevant.ResultsHigh serum levels of interleukin-6 correlate with poor outcome in breast cancer patients. However, few data are yet available on the relationship between IL-6 and stem/progenitor cells, which may fuel the genesis of breast cancer in vivo. Mammospheres (MS) from node invasive breast carcinoma tissues express IL-6 mRNA at higher levels than MS from matched non-neoplastic mammary glands. IL-6 mRNA is detectable only in basal-like breast carcinoma tissues; our results reveal that IL-6 triggers a Notch-3-dependent upregulation of the Notch ligand Jagged-1, whose interaction with Notch-3 promotes the growth of MS and Michigan Cancer Foundation-7 (MCF-7)-derived spheroids. IL-6 induces a Notch-3-dependent upregulation of the carbonic anhydrase IX gene and promotes a hypoxia-resistant/invasive phenotype in MCF-7 cells and MS.ConclusionsIn conclusion, our data support the hypothesis that IL-6 induces malignant features in Notch-3-expressing, stem/progenitor cells from human ductal breast carcinoma and normal mammary gland.

Surgical morbidity of cervical lymphadenectomy for thyroid cancer: A retrospective cohort study over 25 years.

INTRODUCTION Prognosis of thyroid cancer is strictly related to loco-regional metastases. Cervical lymphadenectomy has a specific oncologic role but may lead to significant increase of morbidity. Aim of the study is the analysis of surgical morbidity in cervical lymphadenectomy for thyroid cancer. METHODS We retrospectively analyzed 1.765 thyroid cancers operated over a period of 25 years at S. Maria University Hospital, Terni, University of Perugia, Italy. Type of lymphadenectomy, histology and complications were analysed. RESULTS A prevalence of differentiated and medullary cancers was observed (respectively 88% and 7.2%). Central lymphadenectomy was carried out in 425 patients, lateral modified and radical lymphadenectomy respectively in 651 and 17 cases. Following central neck dissection we observed: bilateral and unilateral temporary recurrent nerves palsy respectively of 0.7% and 3.5%, unilateral permanent palsy in 1.6% of cases, temporary and permanent hypoparathyroidism respectively in 17.6% and 4.4%. After lateral neck dissection we observed: intra and post-operative haemorrhage respectively in 2% and 0.29%, respiratory distress in 0.29%, lesions of facial nerve in 0.44%, of vagus in 0.14%, of phrenic nerve in 0.14%, of hypoglossal nerve in 0.29%, of the accessory nerve, transient in 1.34% and permanent in 0.29%, permanent lesion of cervical plexus in 0.29%, salivary fistula in 0.14% and chylous fistula in 1.04% of patients. Students t test was used to compare groups when appliable. CONCLUSION Central and lateral cervical lymph node dissection are associated to severe morbidity. Correct indication, surgical expertise, high volume of patients and early multidisciplinary management of complications is the key of an acceptable balance between oncologic benefits and surgical morbidity.

Intra-abdominal drainage after pancreatic resection: Is it really necessary? A meta-analysis of short-term outcomes

INTRODUCTION Pancreatic fistula (PF) is the most dreadful complication of patients after pancreatic resection. The use of operative site drains is considered routine all along in pancreatic surgery in order to remove any collections and to act as a warning of hemorrhage or anastomotic leakage. To date few studies investigated the potential benefit and safety of routine drainage compared with no drainage after pancreatic resection and the evidence by literature is not clear. METHODS A systematic review of the literature was carried out performing an unrestricted search in MEDLINE, EMBASE and Cochrane Library up to 28th February 2014. Reference lists of retrieved articles and review articles were manually searched for other relevant studies. The currently available data regarding the incidence of post-operative short-term outcomes after pancreatic resection were meta-analyzed according to the presence or absence of the intra-abdominal drainage. RESULTS Overall 7 studies were included in the meta-analysis, that is 2 randomized controlled trials (RCTs) and 5 non-RCTs resulting in 2704 patients totally. Intra-abdominal drainage showed to increase the PF (OR 2.31, 95% CI 1.52-3.51), the total post-operative complications (OR 1.52, 95% CI 1.30-1.78) and the re-admission (OR 1.30, 95% CI 1.06-1.61) rates. A non-significant correlation was found with the presence/absence of the drainage about biliary and enteric fistula, post-operative hemorrhage, intra-abdominal infected collection, wound infection and overall mortality rates. CONCLUSION The meta-analysis shows that the presence of an intra-abdominal drainage does not improve the post-operative outcome after pancreatic resection.

Robot-assisted or conventional laparoscoic rectopexy for rectal prolapse? Systematic review and meta-analysis

AIM The use of robotic technology has proved to be safe and effective, arising as a helpful alternative to standard laparoscopy in a variety of surgical procedures. However the role of robotic assistance in laparoscopic rectopexy is still not demonstrated. METHODS A systematic review of the literature was carried out performing an unrestricted search in MEDLINE, EMBASE, the Cochrane Library, and Google Scholar up to 30th June 2014. Reference lists of retrieved articles and review articles were manually searched for other relevant studies. We meta-analyzed the data currently available regarding the incidence of recurrence rate of rectal prolapse, conversion rate, operative time, intra-operative blood loss, post-operative complications, re-operation rate and hospital stay in robot-assisted rectopexy (RC) compared to conventional laparoscopic rectopexy (LR). RESULTS Six studies were included resulting in 340 patients. The meta-analysis showed that the RR does not influence the recurrence rate of rectal prolapse, the conversion rate and the re-operation rate, whereas it decreases the intra-operative blood loss, the post-operative complications and the hospital stay. Yet, the RR resulted to be longer than the LR. Post-operative ano-rectal and the sexual functionality and procedural costs could not meta-analyzed because the data from included studies about these issues were heterogeneous and incomplete. CONCLUSION The meta-analysis showed that the RR may ensure limited improvements in post-operative outcomes if compared to the LR. However, RCTs are needed to compare RR to LR in terms of short-term and long-term outcomes, specially investigating the functional outcomes that may confirm the cost-effectiveness of the robotic assisted rectopexy.

Necrotizing pancreatitis: A review of the interventions

Acute pancreatitis may have a wide range of severity, from a clinically self-limiting to a quickly fatal course. Necrotizing pancreatitis (NP) is the most dreadful evolution associated to a poor prognosis: mortality is approximately 15% and up to 30-39% in case of infected necrosis, which is the major cause of death. Intervention is generally required for infected pancreatic necrosis and less commonly in patients with sterile necrosis who are symptomatic (gastric or duodenal outlet or biliary obstruction). Traditionally the most widely used approach to infected necrosis has been open surgical necrosectomy, but it is burdened by high morbidity (34-95%) and mortality (11-39%) rates. In the last two decades the treatment of NP has significantly evolved from open surgery towards minimally invasive techniques (percutaneous catheter drainage, per-oral endoscopic, laparoscopy and rigid retroperitoneal videoscopy). The objective of this review is to summarize the current state of the art of the management of NP and to clarify some aspects about its diagnosis and treatment.

Male breast cancer, clinical presentation, diagnosis and treatment: Twenty years of experience in our Breast Unit

Highlights • Male breast cancer (MBC) is a rare disease representing less than 1% of all malignancies in men andonly 1% of all incident breast cancers.• Management consisted especially of radical mastectomy; followed by adjuvant radiotherapy and hormonal therapy with or without chemotherapy.• Future research for better understanding of this disease at national or international level are needed to improve the management and prognosis of male patients.