Transcervical extended mediastinal lymphadenectomy for mediastinal restaging after induction therapy.

BACKGROUND: The aim of this study was to retrospectively evaluate long-term survival of stage IIIA-N2 non-small cell lung cancer patients operated after induction chemotherapy or chemoradiotherapy and negative mediastinal restaging with transcervical extended mediastinal lymphadenectomy (TEMLA). METHODS: From January 2007 to December 2013, 48 stage IIIA-N2 non-small cell lung cancer (NSCLC) patients (36 men, 12 women) underwent anatomic pulmonary resection after induction therapy and negative result of mediastinal restaging with TEMLA. Mean age was 58.3 years (range, 46-75 years). There were 28 squamous cell carcinomas, 13 adenocarcinomas, 1 mixed carcinoma and 6 non-small cell lung cancers. Neoadjuvant chemotherapy was given in 24 patients, chemoradiotherapy in 23 and chemotherapy with bradytherapy in 1 patient. All patients were followed-up until death or 60 months since pulmonary resection. RESULTS: There were 29 pneumonectomies, 2 lower bilobectomies and 17 lobectomies. 2 patients had R1 resection. After negative TEMLA, persistent metastatic N2 nodes were discovered in 5 patients (10.4%). The only complication after TEMLA was bilateral vocal cord paralysis observed in 1 patient (2.1%); 2 patients died in early postoperative period due to bronchial fistula (4.2%). Overall 5-year survival of patients operated after negative TEMLA was 39.5%. 5-year survival was not statistically different in patients who underwent lobectomy/bilobectomy and in patients who underwent pneumonectomy (47.4% vs. 34.5%). Five-year survival was lower in patients after chemoradiotherapy than in patients after chemotherapy alone (21.7% vs. 56.0%, P=0.022). 5-year survival was not statistically different in patients with true mediastinal downstaging and in patients with false negative TEMLA (41.9% vs. 20%, P=0.19). CONCLUSIONS: Stage IIIA-N2 non-small cell lung cancer patients who underwent pulmonary resection after induction treatment and negative mediastinal restaging with TEMLA showed good long-term survival. In these patients aggressive surgery, including pneumonectomy, lead to satisfactory outcomes. However, prognosis of patients after induction chemoradiotherapy was worse.

Non-intercostal access for video-assisted thoracic surgery-analysis of technical advantages and disadvantages.

BACKGROUND: Video-assisted thoracoscopic surgery (VATS) lobectomy has become an accepted method for the treatment of early-stage non-small-cell lung cancer (NSCLC). The standard VATS approach is an intercostal one which is often followed by postoperative pain due to injury of the intercostal nerve. The non-intercostal techniques of VATS include the subxiphoid, transcervical, transdiaphragmatic and transoral procedures. METHODS: The technical difficulty of operative management of the anatomical structures during VATS anatomical resection are compared for the intercostal, subxiphoid and transcervical approaches. RESULTS: Some operative steps have different range of difficulty, which are analyzed in detail. CONCLUSIONS: The clearest advantages of the non-intercostal approaches include less postoperative pain and superradial bilateral mediastinal lymphadenectomy in case of the transcervical approach. However, the non-intercostal approaches are more technically demanding procedures, which therapeutic role has to be clarified in the future.

Prognosis of Patients With Stages I and II Non-Small Cell Lung Cancer With Nodal Micrometastases.

BACKGROUND: This retrospective study aimed to determine the prognostic significance of immunohistochemically detected occult micrometastases (OM) in mediastinal lymph nodes (LNs) obtained during transcervical extended mediastinal lymphadenectomy of stages I and II non-small cell small cancer (NSCLC) patients before complete surgical resection. METHODS: From January 2007 to June 2011, 75 patients with pathologic stage I NSCLC and 73 patients with pathologic stage II NSCLC underwent transcervical extended mediastinal lymphadenectomy and subsequent radical pulmonary resection. During transcervical extended mediastinal lymphadenectomy, 4,810 mediastinal LNs resected and determined as metastases-free by hematoxylin and eosin staining were immunohistochemically labelled with anticytokeratin and BerEp4 antibodies to detect OM. RESULTS: OM were detected in 9 mediastinal LNs of 7 stage I (9.3%) and in 10 mediastinal LNs of 7 stage II (9.6%) NSCLC patients. Patients with mediastinal LN OM had reduced 5-year disease-free and overall survival (21.4%) compared with stage I (61.8%, p < 0.001) and stage II (47.0%, p < 0.05) patients. Multivariable analysis showed the presence of OM was a significant negative prognostic factor for 5-year overall and disease-free survival rates. CONCLUSIONS: The presence of OM in the mediastinal LNs was associated with decreased total and disease-free survival rates in stages I and II NSCLC patients. Immunohistochemical staining of mediastinal LNs obtained preoperatively improved the accuracy of staging and allowed for the identification of patients with a poorer prognosis.

Resection of thymomas with use of the new minimally-invasive technique of extended thymectomy performed through the subxiphoid-right video-thoracoscopic approach with double elevation of the sternum.

OBJECTIVES: To present the new technique of minimally invasive extended thymectomy performed through the subxiphoid-right video-thoracoscopic (VATS) approach with double elevation of the sternum and the early results of resection of thymomas with the use of this technique. OPERATIVE TECHNIQUE: whole dissection was performed through a 4- to 7-cm transverse subxiphoid incision, and a single 5-mm port was inserted into the right chest cavity for the video thoracoscope and subsequently for the chest tube. The sternum was elevated with two hooks connected to the sternal frame (Rochard bar, Aesculap-Chifa, Nowy Tomysl, Poland). The lower hook was inserted through the subxiphoid incision, and the superior hook was inserted percutaneously after the mediastinal tissue including the major mediastinal vessels was dissected from the inner surface of the sternum. The fatty tissue of the anterior mediastinum and the aorta-pulmonary window was completely removed. RESULTS: There were 24 patients operated on for the Masaoka Stage I-III thymoma in the period from 1 January 2009 to 30 March 2012. There was no mortality and complications occurred in 1 patient necessitating revision for bleeding (morbidity rate 4.2%). The median operative time was 105.0 (range 70-195) min. In 2 patients it was possible to completely resect Masaoka Stage III tumour infiltrating the right lung, which was resected with the use of an endostapler. The dimensions of the thymomas ranged from 1.8 × 1.5 × 1.5 to 12 × 9 × 5 cm. CONCLUSIONS: In our opinion, the presented technique is probably the least invasive and the most complete technique of VATS thymectomy with excellent cosmetic results and is a valid alternative to sternotomy approach for the Masaoka Stage I-III thymomas.

Functional alterations in endothelial NO, PGI2 and EDHF pathways in aorta in ApoE/LDLR-/- mice.

Adequate endothelial production of nitric oxide (NO), endothelium-derived hyperpolarizing factor (EDHF), and prostacyclin (PGI2) is critical to the maintenance of vascular homeostasis. However, it is not clear whether alterations in each of these vasodilatory pathways contribute to the impaired endothelial function in murine atherosclerosis. In the present study, we analyze the alterations in NO-, EDHF- and PGI2-dependent endothelial function in the thoracic aorta in relation to the development of atherosclerotic plaques in apoE/LDLR⁻/⁻ mice. We found that in the aorta of 2-month-old apoE/LDLR⁻/⁻ mice there was no lipid deposition, subendothelial macrophage accumulation; and matrix metalloproteinase (MMP) activity was low, consistent with the absence of atherosclerotic plaques. Interestingly, at this stage the endothelium was already activated and hypertrophic as evidenced by electron microscopy, while acetylcholine-induced NO-dependent relaxation in the thoracic aorta was impaired, with concomitant upregulation of cyclooxygenase-2 (COX-2)/PGI2 and EDHF (epoxyeicosatrienoic acids, EETs) pathways. In the aorta of 3-6-month-old apoE/LDLR⁻/⁻ mice, lipid deposition, macrophage accumulation and MMP activity in the intima were gradually increased, while impairment of NO-dependent function and compensatory upregulation of COX-2/PGI2 and EDHF pathways were more accentuated. These results suggest that impairment of NO-dependent relaxation precedes the development of atherosclerosis in the aorta and early upregulation of COX-2/PGI2 and EDHF pathways may compensate for the loss of the biological activity of NO.

Activation of nicotinamide N-methyltrasferase and increased formation of 1-methylnicotinamide (MNA) in atherosclerosis.

Nicotinamide N-methyltrasferase (NMMT) catalyzes the conversion of nicotinamide (NA) to 1-methylnicotinamide (MNA). Recent studies have reported that exogenous MNA exerts anti-thrombotic and anti-inflammatory activity, suggesting that endogenous NMMT-derived MNA may play a biological role in the cardiovascular system. In the present study, we assayed changes in hepatic NNMT activity and MNA plasma levels along the progression of atherosclerosis in apoE/LDLR(-/-) mice, as compared to age-matched wild-type mice. Atherosclerosis progression in apoE/LDLR(-/-) mice was quantified in aortic root, while hepatic NNMT activity and MNA plasma concentrations were concomitantly measured in 2-, 3-, 4-, and 6-month-old mice. In apoE/LDLR(-/-) mice, atherosclerotic plaques developed in the aortic roots beginning at the age of 3 months and gradually increased in size, macrophage content, and inflammation intensity over time, as detected by Oil-Red O staining, CD68 immunostaining, and in situ zymography (MMP2/MMP9 activity). Hepatic NNMT activity was upregulated approximately two-fold in apoE/LDLR(-/-) mice by the age of 2 months, as compared to wild-type mice (1.03 +/- 0.14 vs. 0.64 +/- 0.23 pmol/min/mg, respectively). MNA plasma concentrations were also elevated approximately two-fold (0.30 +/- 0.13 vs. 0.17 +/- 0.04 micromol/l, respectively). As atherosclerosis progressed, hepatic NMMTactivity and MNA plasma concentrations increased five-fold in 6-month-old apoE/LDLR(-/-) mice at the stage of advanced atherosclerotic plaques (NMMT activity: 2.29 +/- 0.34 pmol/min/mg, MNA concentration: 1.083 +/- 0.33 micromol/l). In summary, the present study demonstrated that the progression of vascular inflammation and atherosclerosis was associated with the upregulation of hepatic NNMT activity and subsequent increase in endogenous MNA plasma levels. Given the anti-thrombotic and anti-inflammatory properties of exogenous MNA, robust activation of an endogenous NA-MNA pathway in atherosclerosis may play an important compensatory role.

Large-conductance K+ channel opener CGS7184 as a regulator of endothelial cell function.

Large-conductance Ca(2+)-activated potassium (BK(Ca)) channels are present in endothelium, but their regulatory role remains uncharacterized. The aim of the present study was to investigate the pharmacological effects of the BK(Ca) channel opener ethyl-1-[[(4-chlorophenyl)amino]oxo]-2-hydroxy-6-trifluoromethyl-1H-indole-3-carboxylate (CGS7184) on endothelium in the aorta and coronary circulation, particularly with regard to nitric oxide (NO)-dependent regulation of vascular tone, as well as effects of CGS7184 on NO production, calcium homeostasis, and mitochondrial function in cultured endothelial cells. The vasorelaxant action of CGS7184 was studied in coronary circulation and in the aorta using isolated perfused guinea pig heart and rat aortic rings, respectively. The effects of CGS7184 on calcium homeostasis, mitochondrial membrane potential, NO production, and mitochondrial respiration were tested in cultures of EA.hy 926 endothelial cells. The BK(Ca) channel opener CGS7184 caused a concentration-dependent (0.03-3 microM) relaxation of the rat aorta and coronary vasodilatation in the isolated guinea pig heart. Both responses were profoundly inhibited by the nitric oxide (NO) synthase (NOS) inhibitor N(G)-nitro-L-arginine methyl ester (L-NAME) (100 microM). CGS7184 (5 microM) also increased basal NO production in EA.hy 926 cells by approximately two-fold. Moreover, CGS7184 induced a concentration-dependent (0.1-10 microM) elevation in intracellular calcium concentration. Interestingly, CGS7184 affected mitochondrial function by causing mitochondrial potential depolarization and an increase in oxygen consumption in EA.hy 926 endothelial cells. The BK(Ca) channel opener CGS7184 activates NOS pathways and modulates mitochondrial function in the endothelium. Both effects may be triggered by the CGS7184-induced modulation of intracellular Ca(2+) homeostasis in EA.hy 926 endothelial cells.

Prostacyclin, but not nitric oxide, is the major mediator of acetylcholine-induced vasodilatation in the isolated mouse heart.

In many species, acetylcholine (Ach) induces coronary vasodilatation via endothelium-derived nitric oxide (NO). The aim of the present study was to examine if this rule pertains also to the coronary circulation of the mouse. We examined the involvement of NO and prostacyclin (PGI2) in the coronary flow response to Ach as compared to response to bradykinin (Bk) in hearts isolated from FVB or C57Bl/6 mice and perfused according to the Langendorff technique. In the isolated mouse heart, response to Ach consisted of two distinct phases: immediate, transient vasodilatation/vasoconstriction (less than 1 min) that differed between FVB and C57Bl/6 mice; and delayed sustained vasodilatation (up to 8 min) that was similar in FVB and C57Bl/6 mice. In FVB mice, the immediate phase of the Ach response consisted of a short-lasting vasodilatation followed by a vasoconstriction. In contrast, in C57Bl/6 mice, the immediate phase of the Ach response consisted exclusively of a short-lasting vasoconstriction. However, both in FVB and C57Bl/6 mice, the delayed vasodilatation was a major part of the coronary flow response to Ach and it was associated with an increase in 6-keto-PGF(1 alpha) concentration in the effluent. L-NAME (5 x 10(-4) M) displayed a minor effect on the delayed phase of the Ach response in either mice strain. In turn, indomethacin (10(-6) M), but not rofecoxib (5 x 10(-6)M), completely inhibited the delayed phase of the Ach response and the concomitant PGI2 release. On the other hand, vasodilatation induced by Bk was markedly inhibited by L-NAME, while it was unaffected by indomethacin in FVB as well as in C57Bl/6 mice. In summary, in the isolated mouse heart, Ach-induced coronary flow response displays an unusual biphasic nature and is mediated in major part by PGI2, but not by NO. Thus, in the isolated mouse heart, in parallel to Bk or other agents that are suited for the functional assessment of NO-dependent endothelial function, Ach should be used to assess PGI2-dependent endothelial function.