A role for endothelial nitric oxide synthase in intestinal stem cell proliferation and mesenchymal colorectal cancer

Abstract Background Nitric oxide (NO) has been highlighted as an important agent in cancer-related events. Although the inducible nitric oxide synthase (iNOS) isoform has received most attention, recent studies in the literature indicate that the endothelial isoenzyme (eNOS) can also modulate different tumor processes including resistance, angiogenesis, invasion, and metastasis. However, the role of eNOS in cancer stem cell (CSC) biology and mesenchymal tumors is unknown. Results Here, we show that eNOS was significantly upregulated in VilCre ERT2 Apc fl/+ and VilCre ERT2 Apc fl/fl mouse intestinal tissue, with intense immunostaining in hyperproliferative crypts. Similarly, the more invasive VilCre ERT2 Apc fl/+ Pten fl/+ mouse model showed an overexpression of eNOS in intestinal tumors whereas this isoform was not expressed in normal tissue. However, none of the three models showed iNOS expression. Notably, when 40 human colorectal tumors were classified into different clinically relevant molecular subtypes, high eNOS expression was found in the poor relapse-free and overall survival mesenchymal subtype, whereas iNOS was absent. Furthermore, Apc fl/fl organoids overexpressed eNOS compared with wild-type organoids and NO depletion with the scavenger carboxy-PTIO (c-PTIO) decreased the proliferation and the expression of stem-cell markers, such as Lgr5, Troy, Vav3, and Slc14a1, in these intestinal organoids. Moreover, specific NO depletion also decreased the expression of CSC-related proteins in human colorectal cancer cells such as β-catenin and Bmi1, impairing the CSC phenotype. To rule out the contribution of iNOS in this effect, we established an iNOS-knockdown colorectal cancer cell line. NO-depleted cells showed a decreased capacity to form tumors and c-PTIO treatment in vivo showed an antitumoral effect in a xenograft mouse model. Conclusion Our data support that eNOS upregulation occurs after Apc loss, emerging as an unexpected potential new target in poor-prognosis mesenchymal colorectal tumors, where NO scavenging could represent an interesting therapeutic alternative to targeting the CSC subpopulation

Difficulties in the diagnosis of thyroid paraganglioma: a clinical case

Thyroid Paragangliomas are exceptionally rare tumors and only 35 documented cases have been reported in the literature. We report an additional unusual male case of thyroid Paraganglioma associated to a chronic lymphocytic thyroiditis and a papillary microcarcinoma. A 45-year-old man presented with a solitary thyroid nodule. Physical examination revealed a smooth, well-circumscribed, firm, mobile, painless thyroid nodule in the right lobe measuring 3 cm. Ultrasound examination showed a 40 mm hypoechoic, non-homogeneous nodule with peri- and intra-nodular vascular flow. An ultrasound-guided fine needle aspiration biopsy was performed showing the presence of atypical cells (Thy 3). He underwent a total thyroidectomy associated to VI level lymphectomy. Histology showed a thyroid Paraganglioma associated to a chronic lymphocytic thyroiditis and a papillary microcarcinoma measuring 0.3 cm in the greatest dimension. Thyroid Paraganglioma is an elusive tumor. It is difficult to diagnose and should be included in the differential diagnosis of all neuroendocrine tumors of the thyroid, even those arising in men or behaving in a locally aggressive fashion

Difficulties in the diagnosis of thyroid paraganglioma: a clinical case.

35 documented cases have been reported in the literature. We report an additional unusual male case of thyroid Paraganglioma associated to a chronic lymphocytic thyroiditis and a papillary microcarcinoma. A 45-year-old man presented with a solitary thyroid nodule. Physical examination revealed a smooth, well-circumscribed, firm, mobile, painless thyroid nodule in the right lobe measuring 3 cm. Ultrasound examination showed a 40 mm hypoechoic, non-homogeneous nodule with peri- and intra-nodular vascular flow. An ultrasound-guided fine needle aspiration biopsy was performed showing the presence of atypical cells (Thy 3). He underwent a total thyroidectomy associated to VI level lymphectomy. Histology showed a thyroid Paraganglioma associated to a chronic lymphocytic thyroiditis and a papillary microcarcinoma measuring 0.3 cm in the greatest dimension. Thyroid Paraganglioma is an elusive tumor. It is difficult to diagnose and should be included in the differential diagnosis of all neuroendocrine tumors of the thyroid, even those arising in men or behaving in a locally aggressive fashion

Intraoperative recurrent laryngeal nerve monitoring in thyroid surgery: Is it really useful?

The aim of this study was to evaluate the ability of intraoperative recurrent laryngeal nerve monitoring to predict the postoperative functional outcome and the potential role of this technique in reducing the postoperative nerve palsy rate. Materials and Methods. Between June 2007 and December 2011, 1693 consecutive patients who underwent thyroidectomy by a single surgical team were evaluated. We compared patients who have had a neuromonitoring and patients who have undergone surgery with the only visualization. Patients in which NIM was not utilized (Group A) were 942 against the others 751 (group B). Results. In group A there were 28 recurrent laryngeal nerve injuries (2.97%) of which 21 were transients (2.22%) and 7 were permanents (0.74%). In group B there were 20 recurrent laryngeal nerve injuries (2.66%) of which 14 (1.86%) transients and 6 (0.8%) permanents. Differences between the two groups were not statistically significative. Conclusions. The technique of intraoperative neuromonitoring in thyroid surgery is safe and reliable in excluding postoperative recurrent laryngeal nerve palsy; it has high accuracy, specificity, sensitivity and negative predictive value. Neuromonitoring is useful to identify the recurrent laryngeal nerve and it can be a useful adjunctive technique for reassuring surgeons of the functional integrity of the nerve but it does not decrease the incidence of injuries compared with visualization alone. Its application can be particularly recommended for high-risk thyroidectomies

Bloodless surgery in geriatric surgery.

AbstractIn bloodless surgery a series of measures has to be implemented to reduce the perioperative need for transfusion of whole blood or its components. Jehovah's Witness are the most representative group of patients opting for bloodless surgery as their faith follows strict believes that prohibits receiving blood.Geriatric patients requiring bloodless surgery are even more delicate and represent a challenge for surgeons. The physiological response of the over 65 year population to decreased hemoglobin level is slower and less effective than in young and adult patients.Herby we describe the perioperative protocol implemented in our surgical Department offered to geriatric Jehovah's Witness patients. Preoperative optimization of the patients is the key step in the preparation period. Intraoperative anesthetic and surgical measures are also required along with a strict postoperative follow-up.From our experience, bloodless surgery is feasible in the geriatric population as long as it is performed in specialized centers where a multidisciplinary team is prepared to specifically manage this scenario. Rigorous patients selection and preparation are mandatory

Association between Pituitary Langerhans Cell Histiocytosis and Papillary Thyroid Carcinoma.

Here we report a case of panhypopituitarism caused by pituitary Langerhans cell hystocitosis (LCH) in a 22-year-old woman affected by papillary thyroid carcinoma (PTC). Although several cases of the coexistence of PTC and LCH within thyroid tissue have been described in relative literature, in this case, the patient presented a unique suprasellar retrochiasmatic histocytosis localization which, to the best of our knowledge, had never been described before in association with PTC. Even if this aspect is not addressed in the present case report, it is worth noting that about 50\% of the patients affected either by LCH or PTC are characterized by activating mutations of the proto-oncogene BRAF. This, along with other clinical studies, may warrant further biomolecular large-scale case study investigations in order to evaluate a possible connection between the 2 conditions and shed light on the etiology of these diseases, which are still largely unknown